Статті в журналах з теми "EGFR / ErbB-1 / HER1"
Щоб переглянути інші типи публікацій з цієї теми, перейдіть за посиланням: EGFR / ErbB-1 / HER1.
Оформте джерело за APA, MLA, Chicago, Harvard та іншими стилями
Ознайомтеся з топ-50 статей у журналах для дослідження на тему "EGFR / ErbB-1 / HER1".
Біля кожної праці в переліку літератури доступна кнопка «Додати до бібліографії». Скористайтеся нею – і ми автоматично оформимо бібліографічне посилання на обрану працю в потрібному вам стилі цитування: APA, MLA, «Гарвард», «Чикаго», «Ванкувер» тощо.
Також ви можете завантажити повний текст наукової публікації у форматі «.pdf» та прочитати онлайн анотацію до роботи, якщо відповідні параметри наявні в метаданих.
Переглядайте статті в журналах для різних дисциплін та оформлюйте правильно вашу бібліографію.
1
Elster, Naomi, Sinead Toomey, Yue Fan, Mattia Cremona, Clare Morgan, Karolina Weiner Gorzel, Una Bhreathnach, et al. "Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer." Therapeutic Advances in Medical Oncology 10 (January 1, 2018): 175883591877829. http://dx.doi.org/10.1177/1758835918778297.
Анотація:
Background: Somatic mutations in the ERBB genes (epidermal growth factor receptor: EGFR, ERBB2, ERBB3, ERBB4) promote oncogenesis and lapatinib resistance in metastatic HER2+ (human epidermal growth factor-like receptor 2) breast cancer in vitro. Our study aimed to determine the frequency of mutations in four genes: EGFR, ERBB2, ERBB3 and ERBB4 and to investigate whether these mutations affect cellular behaviour and therapy response in vitro and outcomes after adjuvant trastuzumab-based therapy in clinical samples. Methods: We performed Agena MassArray analysis of 227 HER2+ breast cancer samples to identify the type and frequency of ERBB family mutations. Of these, two mutations, the somatic mutations ERBB4-V721I and ERBB4-S303F, were stably transfected into HCC1954 (PIK3CA mutant), HCC1569 (PIK3CA wildtype) and BT474 (PIK3CA mutant, ER positive) HER2+ breast cancer cell lines for functional in vitro experiments. Results: A total of 12 somatic, likely deleterious mutations in the kinase and furin-like domains of the ERBB genes (3 EGFR, 1 ERBB2, 3 ERBB3, 5 ERBB4) were identified in 7% of HER2+ breast cancers, with ERBB4 the most frequently mutated gene. The ERBB4-V721I kinase domain mutation significantly increased 3D-colony formation in 3/3 cell lines, whereas ERBB4-S303F did not increase growth rate or 3D colony formation in vitro. ERBB4-V721I sensitized HCC1569 cells (PIK3CA wildtype) to the pan class I PI3K inhibitor copanlisib but increased resistance to the pan-HER family inhibitor afatinib. The combinations of copanlisib with trastuzumab, lapatinib, or afatinib remained synergistic regardless of ERBB4-V721I or ERBB4-S303F mutation status. Conclusions: ERBB gene family mutations, which are present in 7% of our HER2+ breast cancer cohort, may have the potential to alter cellular behaviour and the efficacy of HER- and PI3K-inhibition.
2
Erben, Philipp, Felix Wezel, Ralph Wirtz, Thomas Martini, Doron Stein, Cleo-Aaron Weis, Arndt Hartmann, and Christian Bolenz. "Bedeutung der ERBB-Rezeptorfamilie beim Urothelkarzinom der Harnblase: mRNA-Expression und prognostische Relevanz." Aktuelle Urologie 48, no. 04 (July 27, 2017): 356–62. http://dx.doi.org/10.1055/s-0043-110403.
Анотація:
Zusammenfassung Hintergrund Es sind widersprüchliche Ergebnisse zur (Über)-Expression der Epidermalen Wachstumsfaktoren (ERBB1 – 4) Rezeptoren beim Urothelkarzinom der Harnblase (UCB) beschrieben. EGFR (ERBB1) und HER2 (ERBB2) stellen interessante und bereits bei anderen Entitäten etablierte therapeutische Zielstrukturen dar. Wir untersuchten die Expression von ERBB 1 – 4 auf mRNA-Ebene. Material und Methoden 94 Patienten (w = 22; m = 72; medianes Alter: 66,5 (39 – 88) wurden retrospektiv analysiert. In Zystektomiepräparaten wurde die Expression der ERBB-Familie (ERBB1 – 4) auf RNA-Ebene nach Extraktion aus Formalin-fixiertem und Paraffin-eingebettetem Gewebe bestimmt. Die Genexpression wurde mittels Partitionstest, univariable und multivariable Regressionsanalysen in Assoziation mit histopathologischen Parametern, dem rezidivfreien (RFS) und krebsspezifischen Überleben (CSS) untersucht. Das mediane Follow up betrug 28,2 Monate (0,6 – 139). Ergebnisse Unter Verwendung des für das CSS etablierten Cut off Levels wurde eine Überexpression bei 18 % (ERBB3), 39 % (EGFR), 34 % (HER2, ERBB2), und 30 % (ERBB4) der Patienten beobachtet. In der univariablen Analyse zeigten eine hohe HER2 – (ERBB2-) Expression (p = 0,014), ein höheres pT-Stadium (p = 0,012), ein positiver pN-Status (p = 0,0002) und eine hohe ERBB4-Expression (p = 0,012) eine signifikante Assoziation mit dem RFS. Eine niedrige HER2 – (ERBB2-) Expression (p = 0,042) und ein pN0-Status (p = 0,0003) waren signifikant mit einem längeren CSS assoziiert. Ein positiver pN-Status (p = 0,0011) und eine hohe ERBB4-Expression (p = 0,0073) waren unabhängige Prognosefaktoren für ein reduziertes RFS. Ein positiver pN-Status (p = 0,0016) war ein unabhängiger Prognosefaktor für ein reduziertes CSS. Schlussfolgerungen Eine hohe HER2-Expression ist mit einem reduzierten krankheitsspezifischen Überleben bei Patienten mit UCB nach radikaler Zystektomie assoziiert, zeigte jedoch keinen unabhängigen Prognosewert. Weitere Studien müssen klären, welche Patienten von einer zielgerichteten Therapie gegen HER2 (ERBB2) profitieren könnten.
3
Hullmann, Grace, and Michael A. Azfer. "Immunogenic properties of outer membrane protein of Acinetobacter baumannii that loaded on chitosan nanoparticles." American Journal of BioMedicine 5, no. 1 (February 11, 2017): 32–44. http://dx.doi.org/10.18081/2333-5106/017-32-44.
Анотація:
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR. The most common adverse effect of EGFR inhibitors, found in more than 90% of patients, is a papulopustular rash and in 10% to 15% of patients the effects can be serious and require treatment. While the risk of neutropenic fever toxicity has only recently been recognized. A total of 279 patients were enrolled in the present study. Progression-free survival (PFS) and overall survival (OS) of patients with a lowh grade of neutropnic fever were significantly longer than those with a high grade of neutropnic fever (median PFS: 3.6 months vs 8.4 months, P<0.001; median OS: 7.6 months vs 17.1 months, P=0.006, respectively).
4
Shen, Wang, Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, ZhenZhong Wang, Harry Pedersen, et al. "THER-01. PRECLINICAL DEVELOPMENT OF EO1001, A NOVEL IRREVERSIBLE BRAIN PENETRATING PAN-ErbB INHIBITOR." Neuro-Oncology Advances 1, Supplement_1 (August 2019): i10—i11. http://dx.doi.org/10.1093/noajnl/vdz014.044.
Анотація:
Abstract Dysregulation of ErbB-mediated signaling is observed in up to 90% of solid tumors. ErbB family cross-talk is implicated in the development of resistance and metastasis, including CNS metastases. Inhibition of multiple ErbB receptors may result in improved patient outcomes. EO1001 is a novel, patented, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). METHODS: (1) In vitro testing. EO1001 demonstrates high specificity for the ErbB family of receptors with excellent, balanced equipotent activity against EGFR, HER2 and HER4 (0.4 to 7.4 nM). EO1001 inhibits signaling downstream of wild type EGFR, mutant EGFR (T790M, L858R and d746-750) and HER2. (2) PK and toxicity. In rodent studies in vivo, EO1001 exhibited a half-life of 16–20 hours. EO1001 rapidly enters the CNS and penetrates tumor tissue at higher concentrations relative to plasma. Safety of EO1001 was evaluated by repeat-dosing studies in SD rats and beagle dogs. Toxicities typical of the ErbB inhibitor class, including gastro-intestinal effects, weight loss and decreased activity were observed at higher dose groups in both species. Mortality was observed in SD rats at higher dose groups. (3) In vivo efficacy studies. EO1001 was studied following oral administration in several erbB-positive mouse xenograft models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). Following oral administration, treatment with EO1001 resulted in a statistically significant improvement in outcomes compared to positive and negative controls in both CNS and systemic tumor models. EO1001 was well-tolerated with no gastrointestinal side effects observed at efficacious doses in these models. CONCLUSION: Based on research to date, EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor with a safety and pharmacokinetic profile amenable for use as a single agent and in combination with other agents. EO1001 is poised to enter phase 1-2a clinical testing in the second-half of 2019.
5
Ma, Fei, Qiao Li, Xiuwen Guan, Shanshan Chen, Zongbi Yi, Bo Lan, Puyuan Xing, et al. "Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: A phase I clinical trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1035. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1035.
Анотація:
1035 Background: Cross-signaling in the ErbB family is an important mechanism in Trastuzumab resistance. Pyrotinib is an irreversible pan-ErbB inhibitor targeting EGFR/HER1, HER2 and HER4, which may offer the potential for improved efficacy to block HER2 signaling in trastuzumab-resistant breast cancer. This phase I study assessed the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected predose on day 1 and day 14 of treatment. Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) to probe for predictive biomarkers of this combination. Results: A total of 28 patients were enrolled. All 28 (100%) patients experienced at least one treatment-related Adverse Events (AE), which were predominantly grade 1 or 2. Grade 3 treatment-related AE occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. Three (10.7%) patients discontinued capecitabine administration due to AEs. The overall response rate (ORR) was 78.6% (95% CI: 59.0% to 91.7%), and the disease control rate (complete response+ partial response+ stable disease) was 96.4% (95% CI: 81.7% to 99.9%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0 to 26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naive patients. NGS analysis of all genetic alterations of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway and TP53 in baseline blood samples suggested that concomitant (two or more) genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 15.8 vs. 26.2 months, p = 0.006). Conclusions: Pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients. Clinical trial information: NCT02361112.
6
Choudhury, Noura, Alexa Campanile, Tatjana Antic, James Lloyd Wade, Walter Michael Stadler, Yusuke Nakamura, and Peter H. O'Donnell. "Afatinib activity in platinum-refractory metastatic urothelial carcinoma (UC) patients with ErbB alterations: Results of a phase II trial." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 459. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.459.
Анотація:
459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p < 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.
7
Choudhury, Noura, Alexa Campanile, James Lloyd Wade, Tatjana Antic, Walter Michael Stadler, Yusuke Nakamura, and Peter H. O'Donnell. "Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 312. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.312.
Анотація:
312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.
8
Janjigian, Yelena Yuriy, David Ilson, David Paul Kelsen, Mark Schattner, Adriana Heguy, and Efsevia Vakiani. "A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS4144. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps4144.
Анотація:
TPS4144 Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in >90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.
9
Schuler, Martin H., David Planchard, James Chih-Hsin Yang, Joo-Hang Kim, Filippo De Marinis, Yuh-Min Chen, Caicun Zhou, et al. "Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 7557. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7557.
Анотація:
7557 Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p<0.0001). The most common grade 3/4 adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 patients remain on treatment. Conclusions: Afatinib monotherapy provided a clinically meaningful benefit in this large, treatment-refractory NSCLC trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs achieved prolonged disease control upon continued ErbB blockade.
10
Choudhury, Noura J., Alexa Campanile, Tatjana Antic, Kai Lee Yap, Carrie A. Fitzpatrick, James L. Wade, Theodore Karrison, Walter M. Stadler, Yusuke Nakamura, and Peter H. O’Donnell. "Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations." Journal of Clinical Oncology 34, no. 18 (June 20, 2016): 2165–71. http://dx.doi.org/10.1200/jco.2015.66.3047.
Анотація:
Purpose Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response. Patients and Methods In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted. Results The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations ( P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations ( P < .001). Conclusion Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.
11
Chen, Bo, Ning Liao, Guo-Chun Zhang, Yulei Wang, Xiaoqing Chen, Liping Guo, Li Cao, et al. "Distinct mutational landscape between HR+ and HR- HER2+ early-stage breast cancer patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 543. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.543.
Анотація:
543 Background: HER2 targeted therapy has revolutionized the survival outcomes of early and advanced HER2+ breast cancer (BC). However, among HER2+ patients, the therapeutic response to HER2 inhibitors vary. To understand the molecular mechanism of the variability in therapeutic efficacies, the mutational landscape of HER2+ tumors need to be elucidated. Methods: 107 HER2+ Chinese stage I-III BC patients were included in the study, including 64 HR+ and 43 HR- patients. A majority of the patients were diagnosed with infiltrating ductal carcinoma (99/107). Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes spanning 1.64 MB of the human genome. Results: 1,119 alterations were detected, including 478 single nucleotide variants (SNVs), 14 insertions or deletions, 29 fusions, 593 copy number amplifications (CNA), 2 large genomic rearrangements and 3 CN deletions in 267 genes. Alterations in 99 genes were shared between HR+/HER2+ and HR-/HER2+ tumors; while 123 and 45 genes were only detected in either HR+/HER2+ or HR-/HER2+ tumors, respectively. CNA, splice site and frameshift mutations were significantly more in HR+/HER2+ patients ( p= 0.017). Specifically, CNA in SPOP, CCND1, FGF19, FGF3, FGF4, RNF43, RAD51C, ADGRA4 and MDM4 and various alterations in GATA3 were significantly more among HR+/HER2+ tumors ( p< 0.05). In addition to HER2 amplifications, concurrent fusions in ERBB2 (67%, 4/6), SNVs in ERBB3 (100%, 3/3) and ERBB4 (100%, 1/1) were more likely to be detected in HR+/HER2+ tumors, while concurrent EGFR amplifications were exclusively detected in HR-/HER2+ tumors. The trend of concurrent mutations was consistent with mutation types detected in HER2- tumors based on HR status, wherein EGFR amplifications were more frequent in HR-/HER2- tumors, while SNVs in EGFR, ERBB2, ERBB3 and ERBB4 were more predominant in HR+/HER2- tumors. Based on KEGG pathway analysis, HR+/HER2+ tumors had more frequent alterations in TGFb ( p= 0.007), WNT ( p= 0.002) and homologous recombination ( p= 0.004) pathways than HR-/HER2+ tumors. Furthermore, our data revealed that HR+/HER2+ and HR-/HER2+ patients had comparable TMB ( p= 0.24), with a median TMB of 4.0 mutations/Mb for both. Conclusions: Our study revealed genetic heterogeneity between HR+ and HR- HER2+ tumors. The distinct genetic alterations are potentially relevant in the development of optimal treatment strategies for such patients.
12
LI, Hongbing, Juan SÁNCHEZ-TORRES, Alan del CARPIO, Valentina SALAS, and Antonio VILLALOBO. "The ErbB2/Neu/HER2 receptor is a new calmodulin-binding protein." Biochemical Journal 381, no. 1 (June 22, 2004): 257–66. http://dx.doi.org/10.1042/bj20040515.
Анотація:
We have demonstrated previously that the EGFR (epidermal growth factor receptor) is a calmodulin (CaM)-binding protein. To establish whether or not the related receptor ErbB2/Neu/HER2 also binds CaM, we used human breast adenocarcinoma SK-BR-3 cells, because these cells overexpress this receptor thus facilitating the detection of this interaction. In the present paper, we show that ErbB2 could be pulled-down using CaM–agarose beads in a Ca2+-dependent manner, as detected by Western blot analysis using an anti-ErbB2 antibody. ErbB2 was also isolated by Ca2+-dependent CaM-affinity chromatography. We also demonstrate using an overlay technique with biotinylated CaM that CaM binds directly to the immunoprecipitated ErbB2. The binding of biotinylated CaM to ErbB2 depends strictly on the presence of Ca2+, since it was prevented by the presence of EGTA. Moreover, the addition of an excess of free CaM prevents the binding of its biotinylated form, demonstrating that this was a specific process. We excluded any interference with the EGFR, as SK-BR-3 cells express considerably lower levels of this receptor, and no detectable EGFR signal was observed by Western blot analysis in the immunoprecipitated ErbB2 preparations used to perform the overlay assays with biotinylated CaM. We also demonstrate that treating living cells with W7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide], a cell-permeant CaM antagonist, down-regulates ErbB2 phosphorylation, and show that W7 does not interfere non-specifically with the activity of ErbB tyrosine kinases. We also show that W7 inhibits the phosphorylation (activation) of both ERK1/2 (extracellular-signal-regulated kinases 1 and 2) and Akt/PKB (protein kinase B), in accordance with the inhibition observed in ErbB2 phosphorylation. In contrast, W7 treatment increased the phosphorylation (activation) of CREB (cAMP-response-element-binding protein) and ATF1 (activating transcription factor-1), two Ca2+-sensitive transcription factors that operate downstream of these ErbB2 signalling pathways, most likely because of the absence of calcineurin activity. We conclude that ErbB2 is a new CaM-binding protein, and that CaM plays a role in the regulation of this receptor and its downstream signalling pathways in vivo.
13
Yang, James Chih-Hsin, Martin H. Schuler, Nobuyuki Yamamoto, Kenneth John O'Byrne, Vera Hirsh, Tony Mok, Sarayut Lucien Geater, et al. "LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations." Journal of Clinical Oncology 30, no. 18_suppl (June 20, 2012): LBA7500. http://dx.doi.org/10.1200/jco.2012.30.18_suppl.lba7500.
Анотація:
LBA7500 Background: Afatinib (A) is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. This global study investigated the efficacy and safety of A compared with pemetrexed/cisplatin (PC) in pts with EGFR mutation positive advanced lung adenocarcinoma. Methods: Following central testing for EGFR mutations (companion diagnostic TheraScreen EGFR RGQ PCR kit), 345 pts (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1 (A: 230; PC: 115) to daily A 40 mg or iv PC (500 mg/m2 + 75 mg/m2 q21 days up to 6 cycles). Primary endpoint was progression-free survival (PFS) by central independent review. Results: Baseline characteristics were balanced in both arms: median age, 61 y; female, 65%; Asian, 72%; never-smoker, 68%; Del19, 49%; L858R, 40%; other mutations, 11%. Treatment with A led to a significantly prolonged PFS vs PC (median 11.1 vs 6.9 mos; HR 0.58 [0.43–0.78]; p=0.0004). In 308 pts with common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 mos, respectively (HR=0.47 [0.34–0.65]; p<0.0001). Objective response rate was significantly higher with A (56% vs 23%; p<0.0001). Significant delay in time to deterioration of cancer-related symptoms of cough (HR=0.60, p=0.0072) and dyspnea (HR=0.68, p=0.0145) was seen with A vs PC. Most common drug-related adverse events (AEs) were diarrhea (95%), rash (62%) and paronychia (57%) with A, and nausea (66%), decreased appetite (53%) and vomiting (42%) with PC. Drug-related AEs led to discontinuation in 8% (A; 1% due to diarrhea) and 12% of pts (PC). Conclusions: LUX-Lung 3 is the largest prospective trial in EGFR mutation positive lung cancer and the first study using pemetrexed/cisplatin as a comparator. Treatment with afatinib significantly prolonged PFS compared to PC, with significant improvements in secondary endpoints. AEs with afatinib were manageable, with a low discontinuation rate. With 4.2 mos PFS improvement in the overall population and 6.7 mos in pts with common mutations, afatinib is a clinically relevant first-line treatment option.
14
Harbeck, Nadia, Seock-Ah Im, Chiun-Sheng Huang, Young-Hyuck Im, Binghe Xu, Sara A. Hurvitz, Keun-Seok Lee, et al. "LUX-breast 1: Randomized, phase III trial of afatinib and vinorelbine versus trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS649. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps649.
Анотація:
TPS649 Background: Afatinib is an ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (NSCLC/HNSCC) and HER2 (ErbB2)-driven (breast) malignancies. In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib and increased by addition of IV vinorelbine. Afatinib monotherapy also demonstrated clinical activity (progression-free survival [PFS] = 15.1 wk; objective response [OR] = 10%) in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab. Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/d oral) + vinorelbine (IV 25 mg/m2/wk) or trastuzumab (IV 2 mg/kg/wk after 4 mg/kg loading dose) + vinorelbine (IV 25 mg/m2/wk). Patients receive continuous treatment in the absence of disease progression or adverse events. Key eligibility criteria include histologically-confirmed HER2-positive BC, stage IV disease; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or <12 months after trastuzumab completion) or first-line (or <6 months after trastuzumab completion) setting; prior anthracycline and/or taxane chemotherapy; ECOG score 0 or 1. The primary endpoint is PFS and secondary endpoints include OR, overall survival and safety. Serum and tissue biomarkers will be assessed on archival tissue. HER-receptor and HER-ligand reprogramming, putative resistance markers and EGFR response signature will be explored in fresh tissue biopsies. Enrollment began in June 2010 and is ongoing, targeting >240 sites with a recruitment target of 780 patients.
15
Kim, Joo-Hang, Francesco Grossi, Filippo De Marinis, Manuel Cobo, James Chih-Hsin Yang, Yury Ragulin, Igor N. Bondarenko, et al. "Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: Interim subset analysis from a phase III trial." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 7558. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7558.
Анотація:
7558 Background: Patients with squamous NSCLC have limited treatment options. For those deriving benefit from EGFR TKIs, it is unclear whether sustained ErbB family blockade offers benefit upon progression. We evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC who had failed chemotherapy and E/G. Here we describe a pre-specified analysis of those with squamous histology in Part A. Methods: This randomized Phase III, open-label, multi-center trial enrolled patients with pathologically confirmed metastatic NSCLC after failing ≥1 line of cytotoxic chemotherapy and E/G. In Part A, patients received oral afatinib 50 mg until disease progression. Those with clinical benefit (≥12 wks) who progressed were eligible to receive afatinib plus paclitaxel or investigator’s choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). Following an amendment, an interim analysis of Part A was performed to assess afatinib monotherapy. Results: Patient enrolment into Part A was from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, respectively (by investigator). Median age was 63 yrs, 71% were male, 76% were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the squamous histology subset. Of 91 patients, 42 had PFS ≥3 mths; 13 had PFS of ≥6 mths. In evaluable patients (n=77), 1 CR and 3 PRs were confirmed; 51 and 22 patients had best overall response of SD and PD, respectively. Of the 31 patients with PD on prior E/G with no intervening chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A were diarrhea (13%) and rash/acne (12%). The safety profile in the squamous histology subset was similar to that observed for the whole trial. Conclusions: Afatinib monotherapy demonstrated encouraging activity in treatment-refractory NSCLC patients with squamous histology that merits further evaluation.
16
Jena, Bipulendu, Natalya Belousova, George T. McNamara, David Rushworth, Tiejuan Mi, Helen Huls, Richard E. Champlin, and Laurence JN Cooper. "Specifically Targeting the Interface Between HER1-HER3 Heterodimer on Breast Cancer to Limit Off-Target Effects Using Chimeric Antigen Receptor Designs with Improved T-Cell Energy Balance." Blood 124, no. 21 (December 6, 2014): 2151. http://dx.doi.org/10.1182/blood.v124.21.2151.2151.
Анотація:
Abstract Human epidermal growth factor receptor (EGFR) family consists of four members i.e. EGFR (HER1), HER2 (ErbB2), HER3 (ErbB3,) and HER4 (ErbB4). Overexpression, mutation, or catalytic activation of these proteins can lead to malignancies in breast, ovarian, colorectal, pancreatic and lung. Therapies targeting EGFR-associated proteins to disrupt signaling may fail because of crosstalk within the EGFR family or among downstream pathways. One mechanism of escape is HER3 activation and concomitant heterodimer formation with HER1 causing disease relapse and treatment failure. A bi-specific monoclonal antibody (mAb, MEHD7945A) can specifically bind an epitope shared between HER1-HER3 heterodimer thereby blocking EGFR-HER3 mediated signaling (Schaefer et al., Cancer Cell, 2011). We now report that the specificity of this mAb can be used to redirect the specificity of T cells through enforced expression of a chimeric antigen receptor (CAR) targeting the HER1-HER3 heterodimer, such as expressed on breast cancer cells. A 2nd generation CAR targeting the HER1-HER3 heterodimer was expressed from DNA plasmid constituting scFv (designated DL11f, derived from mAb MEHD7945A) coupled to CD3-zeta fused in frame with chimeric CD28 or CD137 T-cell signaling domains on a clinical-grade Sleeping Beauty (SB) backbone. T cells were electroporated with SB system and numerically expanded on irradiated “universal” activating and propagating cells (uAaPC) (Rushworth et al., J Immunotherapy, 2014). These feeder cells are derived from K-562 cells engineered to co-express a CAR activating ligand (CAR-L, a scFV specific to CAR stalk) to sustain proliferation of genetically modified T cells. We validated CAR expression on genetically modified T cells by flow cytometry and western blot. The specificity of HER1-HER3 specific CAR T cells was confirmed in situ by a proximity ligation-based assay using breast cancer cells. The redirected killing by CAR+ T cells to HER1+HER3+ breast cancer cells was confirmed in vitro and its efficacy evaluated in vivo in NSG mice bearing a breast tumor xenograft. HER1-HER3 specific CAR+ T cells activated via CD137 signaling exhibited superior proliferation compared with T cells expressing CAR with CD28 signaling domain. This is consistent with the ability of CD3-zeta/CD137 endodmain to alter mitochondrial metabolism and to suppress apoptosis leading to proliferation after initial activation. In summary, we report a new CAR design that can interrogate the conformation between two tumor-associated antigens (TAAs). This will likely improve specificity and limit on-target off-tissue side effects compared to CARs targeting only HER-1 or HER-3. Thus, targeting an epitope derived from two TAAs may help distinguish normal cells versus malignant cells and treat HER1+HER3+ malignancies that are resistant to therapies targeting single EGFR family members. These data have immediate translation appeal for targeting solid tumors as we use the SB and AaPC platforms to manufacture CAR+ T cells in our clinical trials. Disclosures Cooper: InCellerate: Equity Ownership; Sangamo: Patents & Royalties; Targazyme: Consultancy; GE Healthcare: Consultancy; Ferring Pharmaceuticals: Consultancy; Fate Therapeutics: Consultancy; Janssen Pharma: Consultancy; BMS: Consultancy; Miltenyi: Honoraria.
17
Wu, Yi Long, Caicun Zhou, Cheng-Ping Hu, Ji Feng Feng, Shun Lu, Yunchao Huang, Wei Li, et al. "LUX-Lung 6: A randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8016. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8016.
Анотація:
8016 Background: A is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), HER2 (ErbB2) and ErbB4. A was superior to first-line pemetrexed/cisplatin in a global phase III trial (LUX-Lung 3) in EGFR M+ NSCLC. This study compared the safety and efficacy of first-line A with GC in EGFR M+ Asian pts. Methods: The trial was conducted in Asian countries. Following central testing for EGFR mutations (TheraScreen EGFR RGQ PCR kit), 364 pts (stage IIIB/IV, PS 0–1, chemo-naïve) were randomized 2:1 (A: 242; GC: 122) to daily A 40 mg or IV GC (1,000 mg/m2 D1, 8 + 75 mg/m2q21 days up to 6 cycles). Primary endpoint was PFS by central independent review. Results: Baseline characteristics were balanced in both arms: Female (64.0 vs 68.0%), non-smoker (74.8 vs 81.1%), exon 19 deletion (51.2 vs 50.8%), L858R (38.0 vs 37.7%) in A and GC arms, respectively. PFS was significantly prolonged with A compared with GC by independent review (median PFS 11.0 vs 5.6 months, HR=0.28, p<0.0001); this finding was consistent across all subgroups. Results from the investigator review were similar: HR=0.26, p<0.0001, median 13.7 (A) vs 5.6 months (GC). Objective response (66.9% vs 23.0%, p<0.0001) and disease control (92.6% vs 76.2%, p<0.0001) rates (ORR/DCR) were significantly higher with A. OS, based on 43% of events shows HR=0.95, p=0.7593. Drug-related AEs of ≥G3 were reported in 36.0% (A) and 60.2% (GC) of pts, the most common of which were rash/acne (14.6%), diarrhea (5.4%) and stomatitis/mucositis (5.4%) with A and neutropenia (17.7%), vomiting (15.9%) and leukopenia (13.3%) with GC. Related AEs led to discontinuation in 5.9% (A) and 39.8% (GC) of pts. Patient reported-outcomes (PROs) showed significantly better control of cancer-related dyspnea, cough and pain with A. Conclusions: In EGFR M+ Asian pts, A significantly prolonged PFS with significant improvements in ORR, DCR, PROs. AEs in both arms were as expected, with a more favorable safety profile with A. LUX-Lung 6 is the largest prospective trial in EGFR M+ lung cancer, providing further evidence of superiority of A over standard chemotherapy in this setting. Clinical trial information: NCT01121393.
18
Burtness, Barbara, Jean Bourhis, Jan Baptist Vermorken, Luyan Dai, Charlotte Lind, Eva Ehrnrooth, and Ezra E. W. Cohen. "LUX head and neck 2: A randomized, double-blind, placebo-controlled, phase III study of afatinib as adjuvant therapy after chemoradiation in primarily unresected, clinically high-risk, head and neck cancer patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS5599. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps5599.
Анотація:
TPS5599 Background: Locally advanced squamous cell cancer of the head and neck (SCCHN) is treated with curative intent, but recurrence and death are common. SCCHN frequently over-expresses EGFR (ErbB1). Co-expression of other HER family members such as HER2 (ErbB2) may contribute to resistance to EGFR inhibition, which is the only validated targeted therapy in SCCHN. Methods: The trial investigates if adjuvant afatanib, an irreversible ErbB family blocker, which has shown preclinical activity against all ErbB dimers including EGFR and HER2, reduces the risk of recurrence in high-risk patients who have no evidence of disease following platinum-based chemoradiation with or without neck dissection. Patients are eligible who have received definitive chemoradiation to a minimum of 66 Gy, with concurrent cisplatin (≥200 mg/m2) or carboplatin (≥AUC 9), for SCC of the oral cavity, oropharynx, or hypopharynx or larynx. Patients with base of tongue or tonsil cancer and ≤10 pack years of tobacco use, as well as those with nasopharynx, sinus or salivary gland cancer, are excluded. Adequate bone marrow, liver and kidney function is required. Prior therapy with investigational agents or EGFR inhibitors is not permitted. Randomization must take place within 16 weeks of the completion of chemoradiation with or without subsequent neck dissection. Patients are randomized 2:1 to afatinib 40 mg po qd or placebo, and treatment continues for 18 months in the absence of disease recurrence, second primary tumors, or intolerance to the study medication. Dose escalation to 50 mg qd is undertaken in patients with no side effects, and stepwise dose reduction to 30 or 20 mg po qd for diarrhea, skin toxicity or other adverse events is permitted. The primary endpoint is disease-free survival (DFS). The study is planned to accrue approximately 669 patients worldwide, with a 90% power to detect a hazard ratio of 0.72. Secondary endpoints are DFS at 2 years, overall survival, health-related quality of life, and safety.
19
Hamilton, Erika Paige, Manish R. Patel, Jordi Rodon, David S. Hong, Alison M. Schram, Pasi A. Janne, Patricia LoRusso, et al. "Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS3665. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3665.
Анотація:
TPS3665 Background: A significant unmet need exists for drugs targeting allosteric ErbB mutations (non-canonical mutations outside the ATP binding site). Current EGFR and HER2 tyrosine kinase inhibitors or mAbs have limited antitumor activity against allosteric mutations, resulting in toxicity before adequate drug exposure (Connell and Doherty, 2017). BDTX-189 is a potent and selective orally available irreversible inhibitor targeting unique oncogenic driver mutations of ErbB kinases in EGFR and HER2, while sparing WT EGFR. Preclinical studies demonstrated antitumor activity across a range of allosteric ErbB mutants, including extracellular domain allosteric mutations of HER2 as well as EGFR and HER2 kinase domain exon 20 insertions (Buck, 2019). This first-in-human trial (NCT04209465) is aimed to determine the recommended phase 2 dose (RP2) and schedule (Phase 1, P1), and evaluate the efficacy (Phase 2, P2) of BDTX-189. P1 primary objective is to determine the RP2 dose and schedule of monotherapy BDTX-189. Secondary objectives include assessment of safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects in tumor, and preliminary efficacy. The P2 primary objective is to assess antitumor activity of monotherapy BDTX-189. Methods: The study will enroll patients (pts) ≥18 yrs with histologically or cytologically confirmed locally advanced or metastatic solid tumors with no standard therapy available or for whom standard therapy is unsuitable or intolerable. P1 dose-escalation will use a BOIN design (Yuan, 2016) and will enroll ≤ 88 pts with allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplified or overexpressing tumor; or EGFR exon 19 deletion or L858R mutation. BDTX-189 will be dosed orally (PO) initially QD in 3 wk cycles. Regimen optimization will use PK, PD and safety data and may explore a BID schedule. An expansion cohort of ≤12 pts will further evaluate safety and preliminary efficacy of BDTX-189 prior to P2. P2, utilizing a Simon 2-stage design, will enroll ≤100 pts with NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1); breast cancer with an allosteric ErbB mutation (cohort 2); tumors (except breast) with S310F/Y mutation (cohort 3); and other allosteric ErbB mutations not defined in cohorts 1-3 (cohort 4). Assessments include safety, tolerability, DLTs, evaluation of MTD, PK, PD, and preliminary antitumor activity. Enrollment began 1/2020. Clinical trial information: NCT04209465 .
20
Geater, Sarayut Lucien, Caicun Zhou, Cheng-Ping Hu, Ji Feng Feng, Shun Lu, Yunchao Huang, Wei Li, et al. "LUX-Lung 6: Patient-reported outcomes (PROs) from a randomized open-label, phase III study in first-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8061. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8061.
Анотація:
8061 Background: Afatinib (A) is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2; ErbB2) and ErbB4. In LUX-Lung 6, A was significantly better than gemcitabine/cisplatin (GC) in terms of progression free survival (PFS) and tumor response, with a more favorable safety profile. Here, we report the PRO results. Methods: 364 pts were randomized (2:1) to receive A or GC. PROs were measured using EORTC questionnaires QLQ-C30/LC13 at baseline and q3w until progression. Changes of ≥10 points (scale 0–100) were considered clinically significant. Analyses of cough, dyspnea and pain were prespecified. Time to deterioration (1st 10-point worsening from baseline) was analyzed using a stratified log-rank test. Percentage improved/worsened by ≥10 points or stable was determined. Mean scores over time were estimated using longitudinal (mixed-effects growth curve) models. Results: Compliance on treatment with questionnaires was >90%. Baseline symptom burden was low (cough: 35; dyspnea: 25; pain: 24). Compared with GC, therapy with A significantly delayed time to deterioration for cough (HR=0.45; p=0.0001), dyspnea (HR=0.54; p<0.0001) and pain (HR=0.70; p=0.03). A higher proportion of A-treated pts had ≥10-point improvements in cough (76% vs 55%; p=0.0003), dyspnea (71% vs 48%; p<0.0001) and pain (64% vs 47%; p=0.003) compared with GC, particularly among pts with baseline symptoms. Mean scores over time for cough, dyspnea and pain also significantly favored A. Consistent with their safety profiles, a significantly higher proportion of A-treated pts had worsening of diarrhea, sore mouth and dysphagia, while fatigue, nausea, and vomiting were significantly worse with GC. Overall, therapy with A significantly improved global health-related quality of life (HRQoL; p<0.0001), physical (p<0.0001), role (p=0.01) and social (p<0.001) functioning compared with GC. Conclusions: In LUX-Lung 6, prolongation of PFS with A was associated with significantly better HRQoL and significantly longer control of lung cancer-related symptoms compared with GC. Clinical trial information: NCT01121393.
21
Jones, H. E., J. M. W. Gee, I. R. Hutcheson, and R. I. Nicholson. "Growth factor pathway switching: implications for the use of gefitinib and trastuzumab." Breast Cancer Online 9, no. 7 (June 26, 2006): 1–5. http://dx.doi.org/10.1017/s1470903106005451.
Анотація:
Over-expression or aberrant signalling of the erbB family members epidermal growth factor receptor (EGFR) and HER2 (erbB2/neu) have been associated with the pathogenesis of the malignant phenotype. In addition, high levels of EGFR and HER2 expression have been shown to correlate with poor prognosis and also implicated in disease progression. Signal transduction inhibitors (STIs) have been developed with specifically target these receptors and include the small molecule tyrosine kinase inhibitor gefitinib (IressaTM) which targets the EGFR and the humanised monoclonal antibody trastuzumab (HerceptinTM), which has anti-tumour activity against HER2. Studies however, have indicated that de novo or acquired resistance to these agents is a major clinical problem. Cancer cells are highly adaptive and can readily switch from one receptor signalling pathway to another in order to maintain growth or cell survival, a process paradoxically, that in many instances is induced by the anti-tumour agents themselves, ultimately limiting their activity and promoting resistance. Evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR/HER2 and the insulin-like growth factor -1 receptor (IGF-1R) and the article will focus on the growth factor pathway switching that occurs between these receptors which can influence the effectiveness gefitinib and trastuzumab.
22
Paliga, Aleksandra, Horia Marginean, Bibianna Maria Purgina, Basile Tessier, Derek J. Jonker, and E. Celia Marginean. "The prognostic significance of ErbB-1 (EGFR), ErbB-2 (HER2), and c-MET overexpression in resectable gastric carcinoma (GC)." Journal of Clinical Oncology 32, no. 15_suppl (May 20, 2014): 3109. http://dx.doi.org/10.1200/jco.2014.32.15_suppl.3109.
23
Gandhi, Leena, Jean-Charles Soria, Richard Bryce, and Benjamin Besse. "Randomized phase II study of neratinib with or without temsirolimus in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2-activating mutations." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS8124. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps8124.
Анотація:
TPS8124 Background: Recent advances in NSCLC have highlighted the importance of identifying mutations in driver oncogenes (eg EGFR, ALK) and the use of targeted agents to treat genetically-defined pt populations. HER2 (ERBB2) is a member of the ERBB receptor tyrosine kinase (TK) family which, once activated, stimulates several downstream effector pathways including PI3K, MAPK and JAK/STAT. Activating HER2 mutations are documented in approx 2–4% of pts with NSCLC and occur independently of EGFR, KRAS, NRAS and BRAF mutations. The efficacy of single-agent neratinib in HER2-mutated NSCLC is currently unknown; however, in vivo studies suggest that dual inhibition with an irreversible TK inhibitor (TKI) and an mTOR inhibitor is a promising therapeutic approach for HER2-mutated NSCLC [Perera et al. PNAS 2009]. This concept has been supported recently by a phase I study of neratinib, an irreversible pan-ERBB TKI, plus temsirolimus, which showed tumor regression in 5/6 evaluable pts with HER2-mutated NSCLC [Gandhi et al. WCLC, Amsterdam, Netherlands, 2011]. Methods: This international, randomized, open-label phase II study includes pts with previously treated stage IIIB/IV NSCLC and HER2-activating mutations. Pts are randomized 1:1 to oral neratinib 240mg od continuously ± IV temsirolimus 8mg/w (dose escalation to 15mg/w after one 4w cycle if tolerated). The addition of temsirolimus is permitted in pts assigned to neratinib monotherapy after progression. Tumor evaluations will be conducted every 8w. The primary endpoint is overall response rate (RECIST 1.1). Secondary endpoints are: clinical benefit rate; response duration; progression-free and overall survival; safety; health outcomes. Exploratory analyses include: correlative studies between tumor and plasma biomarkers and outcomes; pharmacokinetics. The trial has an optimal 2-stage design. Sample size (13–52 pts/arm) is based on a null response rate of 0.09, an alternative response rate of 0.25, power of 80% and 0.05 type I error rate. Both arms will be compared independently against historical controls. Enrollment is scheduled to open in March 2013. EudraCT identifier: 2012-004743-68. Clinical trial information: 2012-004743-68.
24
Zimmermann, Michael T., Surendra Dasari, Rebecca L. Boddicker, Yu Zeng, Bruce Eckloff, Julie M. Cunningham, Yanhong Wu, et al. "Mutations Targeting the ErbB Pathway and MSC in Peripheral T-Cell Lymphoma." Blood 126, no. 23 (December 3, 2015): 2681. http://dx.doi.org/10.1182/blood.v126.23.2681.2681.
Анотація:
Abstract Background: Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of relatively uncommon and generally aggressive non-Hodgkin lymphomas. Recent studies have begun to reveal their mutational landscape, such as the recurrent mutations affecting RHOA, IDH2, and TET2 in angioimmunoblastic T-cell lymphomas (AITLs) and related PTCLs. Here, we studied the exomes of 63 PTCLs to address several unanswered questions: (1) How frequently do PTCLs have mutations with a strong rationale for being actionable using clinically available targeted therapies? (2) What pathways are enriched in PTCLs that could point to additional targeted therapies? (3) What additional recurrent mutations exist that may provide insight into PTCL pathogenesis and classification? Methods: We performed exome capture and sequencing in 63 frozen PTCL samples (with matched germline controls from 22), including 13 PTCLs, not otherwise specified; 6 AITLs; 37 anaplastic large cell lymphomas (ALCLs: 12 ALK+, 19 ALK-, and 6 cutaneous); 4 extranodal NK/T-cell lymphomas; 2 cutaneous T-cell lymphomas, and 1 enteropathy associated T-cell lymphoma. Following primary variant calling, data were filtered by removing variants that were: outside the capture region, polymorphic (0.1% in ExAC), seen in paired germline or 50 healthy controls, within repetitive elements, or synonymous. Potentially actionable variants required published evidence for altering protein function and demonstrated in vivo or in vitro sensitivity to an available targeted agent (including open clinical trials). Mutated cancer genes (COSMIC) were examined for enrichment of KEGG canonical signaling pathways. A recurrent mutation encoding MSC E116K was validated in tumor DNA and MSC protein was examined by immunohistochemistry. Results: Of 25 unique variants with published evidence suggesting actionability (including ErbB, JAK/STAT, and RAS genes), at least one variant was present in 16/63 patients (25%). Variants in any COSMIC gene were seen in 55/63 samples (87%). Top genes were STAT3, RHOA, ARID1A, MLL2 (KMT2D), PTPRB, TP53, and TET2. The KEGG ErbB pathway was most significantly enriched for mutated genes in our dataset (EGFR, ERBB2, ERBB3, ERBB4, and others; q=3.88x10-3), followed by neurotrophin and mitogen-activated protein kinase signaling pathways. Among 25 recurrent non-synonymous variants, we identified MSC E116K with predicted gain-of-function exclusively in 3 ALK-ALCLs and 1 cutaneous ALCL. All mutated cases strongly expressed MSC protein. Among 96 cases, 13/18 ALK-ALCLs (72%) were positive for MSC, compared to 9/78 (12%) from other PTCL subtypes. Conclusions: Mutations that were potentially actionable based on published variant-specific data were identified in 25% of PTCLs, indicating promise for the role of sequencing in individualizing therapy. Additionally, remaining variants were enriched for several targetable pathways, most significantly ErbB. A novel recurrent mutation, MSC E116K, was seen exclusively in ALK-ALCLs (systemic and cutaneous). MSC protein, a repressor of E2A-mediated transcription of targets such as MYC, was expressed in most ALK- ALCLs and generally was absent in other PTCL subtypes. This finding extends evidence for a genetic relationship between systemic and cutaneous ALCLs and suggests MSC may help distinguish ALK- ALCLs from other PTCLs. Disclosures Link: Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.
25
Collins, Denis M., Neil T. Conlon, Srinivasaraghavan Kannan, Chandra S. Verma, Lisa D. Eli, Alshad S. Lalani, and John Crown. "Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer." Cancers 11, no. 6 (May 28, 2019): 737. http://dx.doi.org/10.3390/cancers11060737.
Анотація:
An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management.
26
Yap, Timothy A., Laura Vidal, Jan Adam, Peter Stephens, James Spicer, Heather Shaw, Jooern Ang, et al. "Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors." Journal of Clinical Oncology 28, no. 25 (September 1, 2010): 3965–72. http://dx.doi.org/10.1200/jco.2009.26.7278.
Анотація:
Purpose Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. Patients and Methods Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. Results Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non–small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting ≥ 6 months. Conclusion Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.
27
Khalid, Zeena Ayad, Sazan Abdulwahab Mirza, and Azza Nazar Dhannoon. "Immunohistochemical Expression of EGFR and ErbB2/ HER2 in Human Meningioma. A Clinicopathological Study." NeuroQuantology 19, no. 8 (September 4, 2021): 20–26. http://dx.doi.org/10.14704/nq.2021.19.8.nq21108.
Анотація:
Background: meningioma is considered a common benign tumor and more frequent happen, they are slow growing primary tumors that originate from meningothelial cells of the arachnoid and spinal cord. The histological grade of the WHO and the extension of the initial surgical resection are determining prognostic factors in these tumors. Aim of the study: To investigate the expression of EGFR and ErbB2 / HER2 in human meningiomas, to correlate this expression with various clinic pathological parameters (age, gender, tumor type, tumor grade), and to study the correlation between these two markers. Methods: this is a retrospective study including 30 cases of human meningiomas. Clinical data collected from patient's files. Immunohistochemical study of EGFR and ErbB2/HER2 performed along with scoring. Results: this study included 30 cases of meningioma. There was a significant statistical correlation between tumor grade and tumor histological type, as 100% of grade II were atypical meningiomas, and 77.8% of grade I were meningiothelial meningiomas, with a P value 0.0001. 25/30 cases showed positive immunohistochemical expression of EGFR, 24/25 (96%) cases were grade I, 1/25 (4%), 16/25(72%) cases were meningiothelial, 1/25 (4%) case angiomatous, 1/25 (4%) case atypical, 5/25 (20%) cases were fibroblastic. only 4/30 cases showed expression of HER 2/ neu, 3/4(75%) cases were female, all cases were above 30 years of age, all cases were grade I, 2/4 (50%) cases were fibroblastic and the other two cases were meningiothelial type. Conclusions: EGFR is frequently over expressed in meningiomas, there was a significant difference between mean of EGFR and HER 2, EGFR have more positive results than HER 2.
28
Smylie, M., G. R. Blumenschein, A. Dowlati, J. Garst, F. A. Shepherd, J. R. Rigas, H. Hassani, M. S. Berger, T. Zaks, and H. J. Ross. "A phase II multicenter trial comparing two schedules of lapatinib (LAP) as first or second line monotherapy in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) with either bronchioloalveolar carcinoma (BAC) or no smoking history." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7611. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7611.
Анотація:
7611 Background: LAP (GW572016) is an oral reversible, dual tyrosine kinase inhibitor of EGFR (ERBB1) and HER2/neu (ERBB2). This study was designed to test the activity of 2 dose schedules of LAP in chemotherapy naïve pts with NSCLC; it was amended to target patients with either BAC or no smoking history in the first or second line and to evaluate the relationship of mutations in target genes to responses. Methods: LAP was given orally 1,500 mg once (QD) or 500 mg twice daily (BID) until progression or intolerance. Safety and efficacy (RECIST) were assessed every 4 & 8 weeks. The primary endpoint was response. The target (BAC/no smoking) and non- target populations were assessed for efficacy, and tumor tissue was analyzed for ERBB1 and ERBB2 mutations and/or amplifications. Results: The study was stopped for futility after 131 pts were randomized (65 QD, 66 BID). Median age 66 (range 32–86); female 56%; BAC 20%, No BAC 71%; previously untreated 98.5%; current/former smokers 70%, never smoker 30%. There were no complete responses. Of 56 pts in the target population, 1 (2%) achieved partial response (PR), 11 (20%) had stable disease (SD) of ≥24 wks; in the non-target population, 1 pt had a PR (1.3%) and 12 (16%) had SD of ≥24 wks. 3 pts had ERBB1 mutations (G719S, S768I, KRAS G12S; L858R and T790M; L858R) but none of them responded. There were no ERBB2 mutations. Three of 77 pts evaluated had ERBB1 gene copy increase (none of whom responded) and 2 had ERBB2 gene copy increase (one had a 51% decrease in tumor size). The most common adverse events were grade 1/2 diarrhea, nausea, rash, vomiting and fatigue, and were similar in both groups. Conclusions: LAP was well-tolerated, with no notable difference in toxicity between the QD and BID groups. Very few responses were seen, stable disease was sometimes prolonged. The prevalence of mutations was low even in the target population. Given the preclinical synergy between LAP and other agents, further studies will be necessary to determine whether LAP is active in combination with other agents for the treatment of NSCLC. [Table: see text]
29
Merrick, D. T., J. Kittelson, R. Winterhalder, G. Kotantoulas, S. Ingeberg, R. L. Keith, T. C. Kennedy, Y. E. Miller, W. A. Franklin, and F. R. Hirsch. "Analysis of c-erb-1 (EGFR) and c-erb-2 (HER2) expression in bronchial dysplasia: Evaluation of potential targets for chemoprevention of lung cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7070. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7070.
Анотація:
7070 Background: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasia (BD) will provide markers of premalignant change and identify targets for chemoprevention. Methods: Immunohistochemical (IHC) analysis of EGFR, HER2, Ki67 and MCM2 expression in BD was undertaken in 268 bronchoscopically obtained biopsies from 134 consecutive subjects recruited to University of Colorado protocols as study subjects with prior sputum atypia and >20 pack years tobacco use or FEV1 < 75% predicted or as never- or healthy-smoker controls. IHC on the worst and best histologic biopsies from each subject were scored and linear regression tests were used to determine significance of correlation between marker expression and histology or proliferation. Results: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (p < 0.001), Ki67 (p < 0.001) and MCM2 (p = 0.001) but not HER2 (p = 0.102). Increased expression of either EGFR or HER2 was associated with increased expression of proliferation markers Ki67and MCM2, and combined overexpression of these receptors was associated with the highest levels of proliferation. Finally, in a comparison of subjects that were grouped according to the degree of difference between their best and worst biopsy histology, the absence of an associated trend toward increased EGFR expression with increased difference in histology suggested a field effect in the induction of EGFR expression. Conclusions: Our results 1) demonstrate a direct correlation between levels of EGFR expression and degree of BD, 2) suggest a field effect in the induction of EGFR expression in the airways of subjects with BD and 3) indicate a potential synergistic effect on epithelial proliferation in lesions with increased expression of both EGFR and HER2. These findings suggest that EGFR plays a prominent role in the development and progression of BD and could provide a promising target for chemoprevention of lung cancer. [Table: see text]
30
Vanderwalde, Ari M., Matthew K. Stein, Lindsay Kaye Morris, Srishti Sareen, Saradasri Karri, Kruti Patel, Jennifer Sullivan, Lee Steven Schwartzberg, and Michael Gary Martin. "Distribution and pathogenicity of nsSNPs in receptor tyrosine kinases (RTKs) in non-small cell lung cancer (NSCLC) patients (pts)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20618-e20618. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20618.
Анотація:
e20618 Background: Non-synonymous SNPs (nsSNPs) in RTKs can alter kinase activity and are not exclusive to the tyrosine kinase domain (TKD). In NSCLC, EGFR lesions were previously identified using TKD-limited tests; however, next-generation sequencing (NGS) enables the entire protein sequence of many RTKs to be interrogated. Methods: We analyzed all nsSNPs in 28 RTKs in lung cancer pts who received tumor profiling with Caris NGS from 2013-2015. Mutations were classified by location including the TKD, extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM), and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to predict pathogenicity. Results: 167 pts (156 NSCLC, 11 SC) were identified with a median age 65 (range 26-85); 51% male; 65% white, 31% black; 77% ≥20 pack-years (py), 11% non-smokers; 52% samples tested were metastases. NSCLC pts were 63% adenocarcinoma, 22%, squamous, 8% large-cell; 81% stage IV, 14% III; 17 were EGFR+, 6 BRAF+, 3 HER2+, 3 ROS1 rearranged and 1 MET exon 14. A total 300 nsSNPs (286 NSCLC, 14 SC) were found in 28 RTKs, excluding EGFR. 123/156 NSCLC pts (79%) and 9/11 SC (82%) had ≥1 RTK lesion with median 2 (range 0-8); 143/300 (48%) nsSNPs were predicted-damaging (pnsSNP) by in silico and 89 pts (53%) had ≥1 pnsSNP (median 1; range 0-5). 28/28 RTKs had ≥3 mutations, with median 11 (range 3-23), and 26/28 contained ≥1 pnsSNP (median 5; range 0-14). RTKs in NSCLC with the most frequent nsSNPs were EPHA3 (14/23 variants were pnsSNP), EPHA5 (11/17), EPHB1 (10/11), RET (9/11), ERBB4 (8/12), ALK (7/16), NTRK3 (7/15), ROS1 (6/22) and FLT1 (6/15). 6/14 lesions in SC pts were pnsSNPs in ERBB3, ERBB4, FGFR1, FLT1, RET and ROS1. nsSNPs were found along RTKs: 57% were ECD (72/172 pnsSNP), 26% TKD (47/77), 10% CT (14/29), 6% JM (8/18) and 1% TM (2/4). 6/6 SC pnsSNPs were ECD. 67% BRAF+ and ROS1-rearranged, 59% EGFR+, 33% HER2+ and 0/1 MET exon 14 pts had ≥1 pnsSNP. Conclusions: Nearly 80% NSCLC and SC pts had ≥1 nsSNP in 28 RTKs, excluding EGFR, with 48% pnsSNPs by in silico analysis. As > 70% nsSNPs were extra-TKD lesions, further characterization is needed to identify kinase-effecting variants and their potential clinical significance.
31
Hameed, M. R., L. Sharer, E. Cho, S. Aisner, L. Cao, Y. Tan, A. Mukherjee, A. Chenna, S. Singh, and C. Petropoulos. "The ERB family receptor dimerization in glioblastoma—An eTag assay analysis of 23 cases." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 1582. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.1582.
Анотація:
1582 Background: Glioblastoma is the most malignant astrocytic tumor and accounts for about 50–60% of all astrocytic neoplasms. Despite intensive radiation and chemotherapy, less than 2% of patients survive more than 3 years. The Erb family of signaling molecules are transmembrane receptors with intrinsic kinase activity (except ErbB3) capable of modifying tyrosine residues on the receptor itself as well as on downstream signaling molecules. Under physiological conditions a variety of ligands interact and act as driving forces in the formation of homo and heterodimeric complexes between the four receptors leading to signal amplification and downstream activities. More than one third of glioblastoma cases show gene amplification of epidermal growth factor receptor (EGFR) which can be in truncated or rearranged form. The eTag assay system (Monogram) is an antibody based fluorescent assay that has the potential to assess the activation state of the EGFR signaling pathway. Methods: Twenty three cases of glioblastoma were selected for eTag analysis. There were twelve males and eleven females with ages ranging from 20–84 years. After reviewing the histology, 10 micron sections were cut from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Specific monoclonal antibodies of the Erb family bound to a fluorescent reporter (eTag) were applied to tissue sections. After binding of specific analyte, a second monoclonal antibody is added which acts as molecular scissors resulting in cleavage of “eTags”. The released eTag molecules are separated by capillary electrophoresis and measured as relative fluorescent units. Various FFPE tumor cell lines were used as controls. Results: Nineteen out of twenty three tumors (82%) showed the presence of dimers of the Erb family signaling pathway. High levels of intra and /or extracellular EGFR homodimers (HER-1-HER-1) were detected in eight samples (35%). EGFR-HER-3 dimers and EGFR-HER-2 dimers were seen at high levels in four and six samples (17% and 26% respectively). High levels of HER-2-HER3 dimers were detected in six samples (26%). Conclusion: The EGFR signaling pathway plays a substantial role in tumorigenesis of glioblastoma. Identification of receptor homo and heterodimers may be of value during treatment planning of individual patients. No significant financial relationships to disclose.
32
Laing, Lance G., Stefano Rossetti, Catherine Kuzmicki, Aaron Broege, Joanna Sabat, Salmaan Khan, Ian A. MacNeil, and Brian Sullivan. "Test identifies ovarian cancer patients with hyperactive c-Met and ErbB signaling tumors who may benefit from c-Met and pan-HER combination therapy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e18038-e18038. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18038.
Анотація:
e18038 Background: No sub-groups of ovarian cancer patients with clinically actionable ErbB genetic variants have yet been found. Measurement of ErbB signaling activity rather than genetic variants may identify ovarian cancer patients likely to benefit from ErbB targeted therapies. We have previously reported studies detecting dysregulated ErbB and c-Met signaling activity in 20%-25% of HER2-negative breast cancer patient tumors using the CELx Signaling Function Test. To determine whether ErbB or c-Met signaling dysregulation is involved in ovarian cancer, the CELx Test was adapted to analyze ovarian tumor cells. The current study set out to: 1) characterize c-Met and ErbB family signaling activity in ovarian patient tumor cells and tumor cell lines; 2) evaluate in vivo response to pan-HER and c-Met inhibitors in an ovarian tumor xenograft model. Methods: For the ex vivo studies, a set of fresh tumor specimens from 15 ovarian cancer patients and a set of 12 ovarian cancer cell lines was obtained. Cell samples were cultured from each. Live cell response to ErbB and c-Met agonists (NRG1b, EGF, or HGF) with or without an antagonist (2C4, a HER2 dimerization inhibitor or tepotinib, a c-Met kinase inhibitor) was measured using an xCELLigence impedance biosensor (Agilent Technologies). Signaling activity above a previously established cut-off value was used to identify abnormal levels of EGFR, HER2 and c-Met signaling activity. For the xenograft study, OVCAR-4, an ovarian cancer cell line, determined to have abnormal HER2, EGFR, and c-Met signaling with the CELx Test, was studied. 40 female NSG mice were each injected with two million cells. Mice were randomly assigned to either a control group or a treatment group that received neratinib, tepotinib, or neratinib and tepotinib for 16 days. Results: Of the patient cell and cell lines samples tested ex vivo with the CELx Test, 4 of 27 (15%; 95% CI = 6%-32%) had hyperactive HER2 and c-Met signaling pathways. In the xenograft study, tumor volume change was 40% less in the tepotinib + neratinib treated group than in the control arm change. There was no significant difference in tumor volume between the control and tepotinib or neratinib groups. Conclusions: These findings suggest that a significant sub-group of ovarian cancer patients have abnormal ErbB and c-Met signaling activity that may respond to treatment with a combination of ErbB and c-Met inhibitors. A clinical trial to evaluate treatment response of this patient sub-set to combined c-Met and pan-HER inhibitors is warranted.
33
De Greve, Jacques, Teresa Moran, Marie-Pascale Graas, Daniella Galdermans, Peter Vuylsteke, Jean-Luc Canon, Vikram K. Chand, Yali Fu, Dan Massey, and Johan Vansteenkiste. "Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8063. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8063.
Анотація:
8063 Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.
34
Ross, Jeffrey S., Siraj Mahamed Ali, Julia Andrea Elvin, Alexa Betzig Schrock, James Suh, Jo-Anne Vergilio, Shakti Ramkissoon, et al. "Targeted therapy for HER2 driven colorectal cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 3583. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.3583.
Анотація:
3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.
35
Janjigian, Yelena Yuriy, Geoffrey Yuyat Ku, David H. Ilson, Michelle S. Boyar, Marinela Capanu, Joanne F. Chou, David Paul Kelsen, Tooba Imtiaz, Michael F. Berger, and Efsevia Vakiani. "A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 59. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.59.
Анотація:
59 Background: Trastuzumab combined with chemotherapy is the standard of care for pts with HER2+ EG cancer. Resistance to trastuzumab clearly emerges in this population. Afatinib, a potent ErbB Family Blocker, induced tumor regression in MSKCC HER2+ patient derived xenografts (PDX). This study assesses safety and preliminary efficacy of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma, after progression on trastuzumab, received oral afatinib 40 mg daily. Archival pre-trastuzumab tissue, tumor biopsy after progression on trastuzumab and after 1 week on afatinib is mandated on protocol for next generation sequencing (NGS), proteomics and establishment of PDX. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 20 pts treated with afatinib; median age 61, KPS 80; median 2 (1 to 4) prior trastuzumab regimens, 67% of tumors IHC3+; 33% IHC2+/FISH>2.0. Common adverse events included: rash or dry skin (Grade 1/2:80%), diarrhea (Grade 1/2:60%), nausea/vomiting (grade 1/2:40%) fatigue (grade1/2: 25%). To date, 19 pts evaluable for response, 2 PRs and 6 SD, 42% disease stabilization rate (PR+SD) at 4months (4 to 13 mos). PDXs established from biopsies of 7 pts. EGFR amplification was detected in the tumor of 2 pts with PRs and 1 of 6 pts with SD. Recurrent PIK3CA, ERBB3 and MTORmutations were observed. Conclusions: Afatinib shows clinical efficacy and is well tolerated in patients with trastuzumab refractory, heavily pretreated EG cancer. Enrollment has now begun in an afatinib + trastuzumab cohort. Efforts to elucidate the mechanisms of trastuzumab resistance including validation of potential drivers of trastuzumab resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.
36
Floros, Konstantinos V., Timothy L. Lochmann, Bin Hu, Carles Monterrubio, Mark T. Hughes, Jason D. Wells, Cristina Bernadó Morales, et al. "Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy." Proceedings of the National Academy of Sciences 115, no. 11 (February 23, 2018): E2594—E2603. http://dx.doi.org/10.1073/pnas.1717820115.
Анотація:
HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.
37
Peng, Xintong, Yanling Zhou, Yongguang Tao, and Shuang Liu. "Nasopharyngeal Carcinoma: The Role of the EGFR in Epstein–Barr Virus Infection." Pathogens 10, no. 9 (August 31, 2021): 1113. http://dx.doi.org/10.3390/pathogens10091113.
Анотація:
Epstein–Barr virus (EBV), a type 4 γ herpes virus, is recognized as a causative agent in nasopharyngeal carcinoma (NPC). Incidence of EBV-positive NPC have grown in recent decades along with worse outcomes compared with their EBV-negative counterparts. Latent membrane protein 1 (LMP1), encoded by EBV, induces NPC progression. The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases (RTK), is a driver of tumorigenesis, including for NPC. Little data exist on the relationship between EGFR and EBV-induced NPC. In our initial review, we found that LMP1 promoted the expression of EGFR in NPC in two main ways: the NF-κB pathway and STAT3 activation. On the other hand, EGFR also enhances EBV infection in NPC cells. Moreover, activation of EGFR signalling affects NPC cell proliferation, cell cycle progression, angiogenesis, invasion, and metastasis. Since EGFR promotes tumorigenesis and progression by downstream signalling pathways, causing poor outcomes in NPC patients, EGFR-targeted drugs could be considered a newly developed anti-tumor drug. Here, we summarize the major studies on EBV, EGFR, and LMP1-regulatory EGFR expression and nucleus location in NPC and discuss the clinical efficacy of EGFR-targeted agents in locally advanced NPC (LA NPC) and recurrent or metastatic NPC (R/M NPC) patients.
38
Massip-Copiz, María Macarena, Ángel G. Valdivieso, Mariángeles Clauzure, Consuelo Mori, Cristian J. A. Asensio, María Á. Aguilar, and Tomás A. Santa-Coloma. "Epidermal growth factor receptor activity upregulates lactate dehydrogenase A expression, lactate dehydrogenase activity, and lactate secretion in cultured IB3-1 cystic fibrosis lung epithelial cells." Biochemistry and Cell Biology 99, no. 4 (August 2021): 476–87. http://dx.doi.org/10.1139/bcb-2020-0522.
Анотація:
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It has been postulated that reduced HCO3− transport through CFTR may lead to a decreased airway surface liquid pH. In contrast, others have reported no changes in the extracellular pH (pHe). We have recently reported that in carcinoma Caco-2/pRS26 cells (transfected with short hairpin RNA for CFTR) or CF lung epithelial IB3-1 cells, the mutation in CFTR decreased mitochondrial complex I activity and increased lactic acid production, owing to an autocrine IL-1β loop. The secreted lactate accounted for the reduced pHe, because oxamate fully restored the pHe. These effects were attributed to the IL-1β autocrine loop and the downstream signaling kinases c-Src and JNK. Here we show that the pHe of IB3-1 cells can be restored to normal values (∼7.4) by incubation with the epidermal growth factor receptor (EGFR, HER1, ErbB1) inhibitors AG1478 and PD168393. PD168393 fully restored the pHe values of IB3-1 cells, suggesting that the reduced pHe is mainly due to increased EGFR activity and lactate. Also, in IB3-1 cells, lactate dehydrogenase A mRNA, protein expression, and activity are downregulated when EGFR is inhibited. Thus, a constitutive EGFR activation seems to be responsible for the reduced pHe in IB3-1 cells.
39
Luan, Haitao, Tameka A. Bailey, Robert J. Clubb, Bhopal C. Mohapatra, Aaqib M. Bhat, Sukanya Chakraborty, Namista Islam, et al. "CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation." Cancers 13, no. 16 (August 4, 2021): 3936. http://dx.doi.org/10.3390/cancers13163936.
Анотація:
Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.
40
Arora, P., B. D. Cuevas, A. Russo, G. L. Johnson, and J. Trejo. "Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion." Oncogene 27, no. 32 (March 31, 2008): 4434–45. http://dx.doi.org/10.1038/onc.2008.84.
41
Schram, Alison M., Jordi Rodon Ahnert, Manish R. Patel, Shekeab Jauhari, Jasgit C. Sachdev, Viola Weijia Zhu, Patricia LoRusso, et al. "Safety and preliminary efficacy from the phase 1 portion of MasterKey-01: A First-in-human dose-escalation study to determine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients (pts) with advanced solid malignancies." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3086. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3086.
Анотація:
3086 Background: BDTX-189 is an orally available, ATP-competitive and irreversible inhibitor directed against families of allosteric HER2 and EGFR oncogenic mutations. In preclinical studies BDTX-189 achieved potent inhibition of 48 allosteric HER2 and EGFR/HER2 exon 20 insertion mutant variants with selectivity versus EGFR wild-type (WT) and demonstrated tumor growth inhibition and regression in vivo. The primary objective of the Ph 1 portion of this trial (NCT04209465) is to determine the RP2D and schedule of monotherapy BDTX-189 in pts with advanced solid tumors. Methods: Eligibility includes pts with relapsed or refractory locally advanced or metastatic solid tumors with no standard therapy available whose tumor harbors an allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplification or overexpression; or EGFR exon 19 deletion or L858R mutation. BDTX-189 is dosed continuously orally in 3-wk cycles QD and BID in separate dose escalation cohorts. A separate cohort is also evaluating the high- and low-fat food-effect (FE) on BDTX-189 PK. Results: As of 1/11/21, 46 pts have been dosed, with 36 in the QD (fasting) schedule (25-1200 mg), including pts from the FE cohort who received 800 mg QD fasting after FE evaluation: 58% female; 67% white; median age 63.5 yrs; 53% received ≥ 3 prior tx lines. Cancer types: 12 NSCLC, 5 breast, 4 ovary, 3 biliary, and 12 other. Genomic alterations: 23 HER2 amplification and the following mutations: 11 allosteric HER2, 5 EGFR exon 20 insertion, 5 HER2 exon 20 insertion, 3 EGFR exon 19 del./L858R, and 2 HER3. At ≥ 800 mg QD, 3 and 2 pts had EGFR or HER2 exon 20 mutations, respectively. The maximum tolerated dose (MTD) for QD (fasting) was 800 mg, with 2/6 pts with DLTs at 1200 mg. DLTs: gastrointestinal (G3 diarrhea; G1/2 nausea/vomiting). The most frequent (≥20%) related adverse events were diarrhea (36%, 8% G3), nausea (28%, 0% G3), and vomiting (25%, 3% G3). The rate of skin disorders was 11% with the highest severity of G2 in 1 pt. Dose-dependent exposure increases were observed, with the exposure at 800 mg QD fasting within the projected efficacious range. Pilot FE data suggest possible increased exposure with food. 27 pts were evaluable for efficacy, 15 at ≥ 800 mg QD, with 2 partial responses observed: 1 PR confirmed and ongoing (800 mg QD, CUP, HER2 amp, 3 prior lines of chemo) and 1 PR unconfirmed (NSCLC with brain mets, 1200 mg QD, HER2 amp + exon 19 del., 2 prior EGFR TKIs). 3 pts had a best response of SD and 10 with progressive disease. Conclusions: BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity. Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification. Clinical trial information: NCT04209465.
42
Collins, Denis, Norma O'Donovan, Naomi Walsh, Kathy Gately, Connla Edwards, Anthony Davies, Kenneth John O'Byrne, and John Crown. "The effects of lapatinib and neratinib on HER2 protein levels in breast cancer cell lines." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 637. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.637.
Анотація:
637 Background: HER2, a member of the c-erbB receptor tyrosine kinase family, is over-expressed (HER2 gene amplification/IHC 3+, >30% cells) in approx. 25% of breast cancers. Pre-clinical studies have shown that the HER2-targeted small molecule tyrosine kinase inhibitor (TKI) lapatinib (LAP) can increase HER2 levels in cell line models and can potentiate trastuzumab-mediated antibody dependent cell-mediated cytotoxicity. To assess the potential effects of the next generation TKI neratinib (NER) on expression of HER2 in breast cancer, this study compares the effects of LAP and NER on HER2 protein levels in the HER2-amplified SKBR3 and HER2-non-amplified T47D cell lines in vitro. Methods: SKBR3 and T47D were treated with LAP or NER (0.2, 1 and 2 µM) for 12, 24 and 48 hours.HER2 protein levels were determined by ELISA, immunoblotting and high content analysis (HCA). HER2 protein was examined using two antibodies targeting the extracellular domain (ECD) and the intracellular domain (ICD) of HER2. pHER2, EGFR/pEGFR, MAPK/pMAPK and AKT/pAKT levels were determined by immunoblotting. Proliferation studies utilized an acid phosphatase-based assay. Results: ELISA analysis confirmedsignificantly lower HER2 expression in T47D (44 +/- 17 pg/µg) compared to SKBR3 (748 +/- 296 pg/µg), p = 0.015. NER proved a more potent inhibitor of pHER2 and pEGFR as analyzed by immunoblotting and in proliferation studies (NER IC50 - SKBR3 0.03 +/- 0.01 nM, T47D 199 +/- 70 nM, LAP IC50 - SKBR3 20 +/- 1 nM, T47D 1.2 +/- 0.2 µM). LAP induced an increase in both ECD and ICD-containing HER2 protein levels in SKBR3 and T47D cells. No increase in HER-2 levels was observed with NER treatment, as determined by HCA and immunoblotting. EGFR protein levels increased in response to lapatinib in both cell lines. Conclusions: Our results suggest that LAP and NER have differing effects on HER2 protein levels in the models examined. NER provides greater inhibition of HER2 signaling activity but does not increase HER2 protein levels as was observed with LAP. Further pre-clinical assessment of combinations of LAP and NER with HER2 and EGFR monoclonal antibody therapies is warranted in HER2-amplified, HER2-non-amplified and EGFR-expressing breast cancer models.
43
Agrawal, A., E. Gutteridge, J. M. W. Gee, R. I. Nicholson, and J. F. R. Robertson. "Overview of tyrosine kinase inhibitors in clinical breast cancer." Endocrine-Related Cancer 12, Supplement_1 (July 2005): S135—S144. http://dx.doi.org/10.1677/erc.1.01059.
Анотація:
Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.
44
Pohl, Michael, and Wolff Schmiegel. "Therapeutic Strategies in Diseases of the Digestive Tract - 2015 and Beyond Targeted Therapies in Colon Cancer Today and Tomorrow." Digestive Diseases 34, no. 5 (2016): 574–79. http://dx.doi.org/10.1159/000445267.
Анотація:
Background: Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state. After the introduction of the anti-VEGF MAB bevacizumab, the FDA approved with ramucirumab the second antiangiogenic MAB for the mCRC treatment. Further new drugs are on the horizon and new diagnostic tools will be introduced soon. Key Messages: Molecular heterogeneity of mCRC has been recognized as pivotal in the evolution of clonal populations during anti-EGFR therapies. Mutations in RAS genes predict a lack of response to anti-EGFR MABs. Mutations in the mitogen-activated protein kinase-phosphoinositide 3-kinase pathways like BRAF or PIK3CA mutations or HER2/ERBB2 or MET amplifications bypass EGFR signaling and also may confer resistance to anti-EGFR MABs. HER2/ERBB2 amplification is a further driver of resistance to anti-EGFR MABs in mCRC. The phase II study of HER2 Amplification for Colo-Rectal Cancer Enhanced Stratification (HERACLES) discovers that a dual HER2-targeted therapy may be an option for HER2-amplified mCRC. The mismatch repair deficiency predicts responsiveness to an immune checkpoint blockade with the anti-PD-1 immune checkpoint inhibitor pembrolizumab. Conclusions: The understanding of primary (de novo) and secondary (acquired) resistance to anti-EGFR therapies, new targeted therapies, immuno-oncology and about predictive biomarkers in mCRC is guiding the development of rational therapeutic strategies. Combinations of targeted therapies are necessary to effectively treat drug-resistant cancers. Liquid biopsy is an upcoming new tool in the primary diagnosis and follow-up analysis of mutations in circulating tumor DNA.
45
Sousa, Vítor, Joana Espírito Santo, Maria Silva, Teresa Cabral, Ana Maria Alarcão, Ana Gomes, Patrícia Couceiro, and Lina Carvalho. "EGFR/erB-1, HER2/erB-2, CK7, LP34, Ki67 and P53 expression in preneoplastic lesions of bronchial epithelium: an immunohistochemical and genetic study." Virchows Archiv 458, no. 5 (March 22, 2011): 571–81. http://dx.doi.org/10.1007/s00428-011-1062-5.
46
Wakelee, H. A., J. R. Molina, J. M. Fehling, J. L. Lensing, and B. I. Sikic. "A phase I study with exploratory pharmacodynamic endpoints of XL647, a novel spectrum selective kinase inhibitor, administered orally daily to patients (pts) with advanced solid malignancies." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14044. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14044.
Анотація:
14044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis, angiogenesis, and metastasis, including EGFR/ErbB1, ErbB2/HER2, VEGFR2/KDR, and EphB4. In a previous Phase I study, the MTD was 350 mg when XL647 was dosed orally for 5 consecutive days every 14 days. Of 41 pts treated, one pt with NSCLC achieved a PR and 14 pts had prolonged stable disease (3.5–14+ months). The purpose of the present study is to determine the MTD of XL647 administered orally on a continuous daily schedule. Methods: Pts are enrolled in successive cohorts to receive XL647 daily for repeated 28 day cycles. PK sampling is performed to determine Cmax, and AUC at each dose level. Plasma samples are analyzed by ELISA for mechanism-of-action related molecules. Eyebrow hair bulbs are being evaluated by IHC to monitor effects of XL647 on signal transduction pathways downstream of EGFR. Tumor response is assessed every 8 weeks by RECIST. Pts remain on study until PD or unacceptable AEs. Results: Twelve pts have been enrolled. The starting dose was 75 mg (n=3) and has been escalated to150 mg (n=3), 200 mg (n=3) and 300 mg (n=3). To date, dose escalation continues as no DLTs have occurred and the MTD has not been determined. Ten pts remain on study, including 4 with stable disease for at least 3 months. In cohort 2, eyebrow samples from 3 pts were analyzed. XL647 caused a significant reduction in the phosphorylation of the EGFR downstream signaling kinases AKT (up to 73%) and ERK (up to 78%) in 2/3 and 3/3 pts, respectively. Preliminary analysis of potential plasma protein biomarkers from pts in cohorts 1 and 2 showed a trend towards upregulation of PlGF plasma levels in 4/6 pts during XL647 treatment. Conclusions: XL647 is well-tolerated when administered daily at doses tested to date. Dose escalation will continue until the MTD is defined. Analysis of eyebrow samples demonstrated its feasibility as a potential surrogate epidermal tissue for assessing inhibition of EGFR downstream targets by XL647. Updated safety, PK and pharmacodynamic results will be presented. [Table: see text]
47
Giaccone, Giuseppe, Ariel Lopez-Chavez, Anish Thomas, Arun Rajan, Mark Raffeld, Regan M. Duffy, Betsy Morrow, et al. "Custom (Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies) trial." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 7513. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7513.
Анотація:
7513 Background: CUSTOM is the first completed prospective clinical trial using molecular selection for treatment assignments into multiple targeted therapy arms and in multiple cancer histological subtypes concurrently. Methods: All patients with advanced NSCLC, SCLC or TM were eligible to participate in the study. Oncogenic mutations, amplifications or translocations in 12 genes detected in CLIA-certified laboratories were used to assign patients to 1 of 5 biomarker/treatment groups per histological subtype: EGFR mutations/erlotinib; KRAS, NRAS, HRAS or BRAF mutations/AZD6244; PIK3CA, AKT or PTEN mutations/MK2206; ERBB2 mutations or amplifications/lapatinib; and KIT or PDGFRA mutations/sunitinib; or to standard-of-care therapy. For each arm, the study was conducted as an optimal two-stage phase II trial in favor of a response rate of 40% or more. Results: 668 patients were enrolled at two academic institutions. The most frequent genetic alterations in NSCLC were KRAS and EGFR mutations (25.2 and 19.7% respectively), ALK rearrangements 7.8%, HER2 amplifications 2.7% and mutations in PIK3CA 2.5%, BRAF 1.9%, HRAS 1.5%, ERBB2 1.7%, AKT1 0.4%, and NRAS 0.7%. PTEN mutation analysis was only feasible in 13 patients with NSCLC of which 3 were positive (23%). The most frequent genetic alterations in SCLC were mutations in PIK3CA 6.5%, ERBB2 amplifications 5.3% and mutations in HRAS 3.4%, AKT1 2.2%, BRAF 2% and KRAS 2%. The most frequent genetic alterations in TMs were HER2 amplifications 7.7% and mutations in HRAS 4.7%, PIK3CA 1.4% and EGFR 1.4%. Only 6.2% (n=42) of patients met criteria for enrollment into the treatment arms of the study. Efficacy analyses including response rates will be presented. Conclusions: CUSTOM is the first completed prospective clinical trial demonstrating the feasibility of conducting efficacy analyses of multiple biomarker-matched therapies in multiple cancer histological subtypes concurrently. CUSTOM is also the largest prospective molecular profiling study of patients with SCLC and TMs. Clinical trial information: NCT01306045.
48
Iqbal, S., B. Goldman, H. J. Lenz, C. M. Fenoglio-Preiser, and C. D. Blanke. "S0413: A phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4621. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4621.
Анотація:
4621 Background: GW572016 is a dual tyrosine kinase inhibitor of EGFR and HER2/ErbB2. Overexpression of EGFR and ErbB2 has been described in 15 to 45% of gastric cancer, making this a potential target in advanced/metastatic tumors. Methods: The primary objective of this study was to assess the response rate (confirmed complete (CR) and partial responses (PR)). Secondary objectives included time to treatment failure (TTF), overall survival (OS), toxicities and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome in patients treated with GW572016. A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one response occurred after the first 20 pts, another 20 were to be accrued. GW572016 was administered to chemonaiive metastatic gastric cancer patients at a dose of 1,500 mg orally daily. A cycle was defined as 28 days of therapy, and patients were staged after 2 cycles of treatment. Results: The study met its first stage goal, and continued until full accrual. The study accrued 47 pts from February 2005 until May 2006. Two patients lacked required tissue/blood submission but are included in this clinical analysis. One patient did not receive treatment and is not analyzable. Pt characteristics: male/female30/16 (65%/35%); median age 68.7 years (range 38.9 - 90). Significant toxicities: 1 grade 4 cardiac ischemia/infarction, 2 grade 4 fatigue, 1 grade 4 vomiting. There was one treatment related death due to CNS ischemia. Three pts (7%) had a confirmed PR and 2 (5%) unconfirmed PR, and 9 (20%) had stable disease. Median TTF was 2 months, and OS was 5 months. Molecular correlative data was available on 42 pts. Conclusions: GW572016 is a well tolerated regimen with modest single-agent activity in pts with advanced/metastatic gastric cancer. Although, GW572016 did not meet the primary endpoint, this targeted agent may warrant further investigation in combination regimens. Molecular correlatives will be reported in a separate abstract. No significant financial relationships to disclose.
49
Ang, J., C. Mikropoulos, F. Stavridi, S. Rudman, M. Uttenreuther-Fisher, M. Shahidi, K. Pemberton, S. Wind, J. de Bono, and J. F. Spicer. "A phase I study of daily BIBW 2992, an irreversible EGFR/HER-2 dual kinase inhibitor, in combination with weekly paclitaxel." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14541-e14541. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14541.
Анотація:
e14541 Background: BIBW 2992 is an oral, potent and irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases. The efficacy of cytotoxic agents can be enhanced by erbB inhibition. The primary objective of this Phase I open- label dose-escalation trial was to determine the maximum tolerated dose (MTD) of BIBW 2992 in combination with weekly paclitaxel. Methods: This study evaluated safety, pharmacokinetics (PK), and anti-tumor efficacy of daily BIBW 2992 combined with paclitaxel administered on Days 1, 8 and 15 of a 4-weekly cycle. The dose of paclitaxel was 80 mg/m2, and the BIBW 2992 starting dose was 20 mg, escalated in successive cohorts to 40 then 50 mg. After 6 cycles of combination therapy, patients benefiting and tolerating treatment were eligible to continue single agent BIBW 2992. Results: Sixteen patients with advanced solid tumors expressing erbB receptors and suitable for treatment with a taxane have been enrolled (6 male/10 female; median age: 59 [range: 39–72]; ECOG PS 0/1: 5/11). Two dose-limiting toxicities of fatigue and mucositis occurred at a BIBW 2992 dose of 50 mg. The most frequent adverse events were fatigue, rash, mucositis and diarrhea. Partial responses were seen in patients with non-small cell lung cancer (3), prostate cancer (1), oesophageal cancer (1) and cholangiocarcinoma (1). Eight patients have remained on treatment beyond 4 cycles. The PK data of paclitaxel (with and without BIBW 2992 administration) as well as of BIBW 2992 at steady state (in combination with paclitaxel) will be described. Conclusions: A BIBW 2992 dose of 40 mg daily in combination with weekly paclitaxel 80 mg/m2 is the likely recommended dose for Phase II study. Promising anti-tumor activity was seen with this combination. The addition of bevacizumab to BIBW 2992 with 80 mg/m2 weekly paclitaxel is now being evaluated. Adverse events of BIBW 2992 combined with paclitaxel were generally mild to moderate and manageable. [Table: see text]
50
O'Neill, Fiona, Stephen F. Madden, Martin Clynes, Padraig Doolan, John Crown, Sinead Aherne, and Robert O'Connor. "A gene expression profile indicative of early stage HER2 tyrosine kinase inhibitor response." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e11536-e11536. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e11536.
Анотація:
e11536 Background: Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth receptors. A panel of breast cancer cell lines was treated with these agents and gefintib (EGFR inhibitor) and the expression pattern of a specific panel of genes investigated as a potential marker of early drug response. Methods: RNA was extracted from breast cancer cell lines (BT474, SKBR3 and MDAMB453) with differing HER2 expression patterns and sensitivity to lapatinib before and 12hrs after treatment with 1 µM of lapatinib, 150nM of afatinib, 150nM of neratinib or 1µM of gefitinib. Gene expression changes were measured by Taqman RT-PCR and RQ values were determined using the comparative cycle threshold (Ct) method. Results: The expression of RB1CC1, ERBB3, FOXO3a, NR3C1 was directly correlated with the degree of sensitivity of the cell line to lapatinib and was observed to “switch” from up-regulated to down-regulated in the HER2 expressing lapatinib insensitive cell line (MDAMD453). The CCND1 gene (functionally linked to the other four genes) demonstrated an inversely proportional response to drug exposure; showing a trend of strong down-regulation in lapatinib-sensitive lines. A similar expression pattern was observed following the treatment with both neratinib and afatinib. In contrast, gefitinib treatment, resulted in a completely different expression pattern change. Conclusions: In these HER2-expressing cell models, lapatinib, neratinib and afatinib treatment generated a common, characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor. Characterisation of changes in these genes shortly after drug treatment may therefore give a valuable predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.