A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Geoffrey Yuyat Ku ◽  
David H. Ilson ◽  
Michelle S. Boyar ◽  
Marinela Capanu ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Cancer Resistance ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Tumor Biopsy ◽  
Disease Stabilization ◽  
Heavily Pretreated ◽  
Next Generation Sequencing Ngs

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.

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 52-52 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Marinela Capanu ◽  
Tooba Imtiaz ◽  
David Paul Kelsen ◽  
Geoffrey Yuyat Ku ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Tumor Biopsy ◽  
Disease Stabilization ◽  
Erbb Family Blocker

52 Background: Trastuzumab (T) combined with chemotherapy has been the standard of care for pts with HER2+ EG cancer. Resistance to T is now emerging in this population. Afatinib (A), a potent ErbB Family Blocker, induced nearly complete tumor regression in MSKCC HER2+ patient derived xenografts (PDX). We report the initial results of a phase II study of afatinib in patients with T refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma –progressive on trastuzumab -received A 40 mg. Archival pre-T tissue, tumor biopsy after progression on T and after 1 week on A mandated on protocol. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 14 pts treated with A; median duration 5.1 mos (1.7 to 12.1 mos). Median age 62, KPS 80, median 2 (1 to 4) prior T containing regimens, 64% of tumors IHC3+; 36% IHC2+/FISH>2.2. Adverse events included: diarrhea (Grade 1/2:69%), fatigue (Grade 1/2:54%), rash (Grade 1/2:54%), mucositis (Grade 1:23%), paronychia (Grade 1/2:15%). To date, 13 pts evaluable for response, 3 of 13 pts (23%) had disease stabilization (PR or SD); 1 pt with confirmed PR - a durable 75% regression of biopsy proven metastases. Median OS 6.6 mos (1.9 to NR). PDXs established from biopsies of T refractory tumors of 5 pts. Next generation sequencing of matched pre-T and post-T progression tumors from 6 pts was performed and results will be reported. Conclusions: Afatinib shows clinical efficacy in patients with T refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of T resistance including validation of potential drivers of T resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15017-e15017
Author(s):  
Yelena Yuriy Janjigian ◽  
Marinela Capanu ◽  
Christopher M. Gromisch ◽  
David Paul Kelsen ◽  
Geoffrey Y. Ku ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Single Agent ◽  
Cancer Resistance ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Recist 1.1 ◽  
Disease Stabilization

e15017 Background: Trastuzumab, approved by the FDA, has been the standard of care for pts with HER2-positive EG cancer. Resistance to trastuzumab is now emerging in this population. Afatinib, an oral inhibitor of EGFR, HER2, and HER4 has potent single agent activity in HER2-positive EG cancer NCI-N87 and MSKCC patient derived xenografts (Janjigian JNM 2013). We report the initial results of a phase II study of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2 positive (IHC 3+ or FISH>2.0) metastatic EG adenocarcinoma, following failure of at least one trastuzumab/chemotherapy regimen received afatinib 40 mg daily. Archival tissue from pre-trastuzumab biopsy, a new biopsy prior to the start of therapy and after 1 wk of afatinib are mandated. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD), complete response (CR), or partial response (PR) by RECIST 1.1. Results: Nine patients treated with afatinib; median follow up 2.7mos (0.5 to 5.3mos). Median age 62, KPS 80, 6 males, 56% IHC3+; 44% IHC1+/2+/FISH>2.0. Number of prior trastuzumab containing regimens: median 2 (1 to 4). The following treatment emergent adverse events were observed: nausea/vomiting (Grade 1/2: 22%), diarrhea (Grade 1/2:67%), fatigue (Grade1/2: 33%), rash (Grade 1/2:44%), anorexia (Grade 1/2:33%,Grade 3:11%), mucositis (Grade1/2: 11%), paronychia/nail loss (Grade 1/2:11%). To date, 7 pts evaluable for response, 3 of 7 patients (43%) derived clinical benefit; 1 pt (14%) with ongoing RECIST 1.1 confirmed PR - a durable 50% regression of biopsy proven metastases in lung and lymph nodes at 5.3 mo. A second patient had 20% tumor regression in biopsy proven liver metastasis, 3.6 mos disease stabilization. A third patient experienced 4.7 mos disease stabilization and regression of biopsy proven skin metastasis. Conclusions: Single agent afatinib shows clinical efficacy in patients with trastuzumab refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of trastuzumab resistance in EG cancer are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

scholarly journals Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 400 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hisato Kawakami
Keyword(s):  
Gastroesophageal Junction ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Gastroesophageal Junction Cancer ◽  
Development Of Resistance ◽  
Epidermal Growth ◽  
Antibody Drug

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody–drug conjugates that are under development and have shown promising antitumor activity in early studies.

A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4144-TPS4144 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
David Ilson ◽  
David Paul Kelsen ◽  
Mark Schattner ◽  
Adriana Heguy ◽  
...  
Keyword(s):  
Phase Ii ◽  
De Novo ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Single Agent ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Irreversible Inhibitor ◽  
Clinical Issue ◽  
Esophagogastric Cancer

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.

Overall Survival Benefit With Lapatinib in Combination With Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Final Results From the EGF104900 Study

2012 ◽  
Vol 30 (21) ◽  
pp. 2585-2592 ◽  
Author(s):  
Kimberly L. Blackwell ◽  
Harold J. Burstein ◽  
Anna Maria Storniolo ◽  
Hope S. Rugo ◽  
George Sledge ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Epidermal Growth Factor Receptor ◽  
Metastatic Breast Cancer ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Heavily Pretreated ◽  
Epidermal Growth

Purpose Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here. Patients and Methods Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit. Results In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates. Conclusion These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.

scholarly journals A Case Report Demonstrating the Potential Clinical Relevance of Liquid Tumor Biopsies in Lung Cancer

2016 ◽  
Vol 9 (3) ◽  
pp. 714-717
Author(s):  
Revathi Suppiah ◽  
Bruce Gershenhorn ◽  
Maurie Markman
Keyword(s):  
Lung Cancer ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Molecular Testing ◽  
Tumor Biopsy ◽  
Exon 19 Deletion ◽  
Epidermal Growth ◽  
Tumor Biopsies ◽  
Solid Tumor Tissue

A 50-year-old male with advanced non-small-cell lung cancer was unable to have standard-of-care molecular testing performed at diagnosis as a result of inadequacy of the available tissue. A subsequently performed commercial liquid tumor biopsy (Foundation ACT®) revealed an epidermal growth factor receptor exon 19 deletion, but due to the progression of the tumor and rapid deterioration in the patient’s performance status, a meaningful attempt at therapy directed to this recognized therapeutic target was not possible. This case provides important support for the relevance of liquid tumor biopsies in documenting highly clinically relevant molecular targets, particularly in the setting where limited solid tumor tissue is available for analysis.

scholarly journals Current and Future Management of HER2-Positive Metastatic Breast Cancer

2021 ◽  
pp. OP.21.00172
Author(s):  
Olga Martínez-Sáez ◽  
Aleix Prat
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Standard Of Care ◽  
Trastuzumab Emtansine ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Line Setting ◽  
Future Management

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.

scholarly journals The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Zahi Mitri ◽  
Tina Constantine ◽  
Ruth O'Regan
Keyword(s):  
Breast Cancer ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Standard Of Care ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20–30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab is a HER2 receptor blocker that has become the standard of care for the treatment of HER2 positive breast cancer. The effectiveness of Trastuzumab has been well validated in research as well as in clinical practice. The addition of Trastuzumab to standard of care chemotherapy in clinical trials has been shown to improve outcomes for early stage as well as metastatic HER2 positive breast cancer. The most clinically significant side effect of Trastuzumab is the risk of cardiac myocyte injury, leading to the development of congestive heart failure. The emergence of patterns of resistance to Trastuzumab has led to the discovery of new monoclonal antibodies and other targeted agents aimed at overcoming Trastuzumab resistance and improving survival in patients diagnosed with HER2 positive breast cancers.

Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): Results from a phase I study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 164-164
Author(s):  
Funda Meric-Bernstam ◽  
Erika P. Hamilton ◽  
Muralidhar Beeram ◽  
Diana L. Hanna ◽  
Anthony B. El-Khoueiry ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Eligibility Criteria ◽  
Good Tolerability ◽  
Heavily Pretreated ◽  
Anti Tumor Activity

164 Background: For patients with human epidermal growth factor receptor 2 (HER2)-overexpressing GEA, trastuzumab in combination with chemotherapy is the only approved HER2-targeted therapy, and they have limited treatment options after progression. Zanidatamab, a HER2-targeted bispecific antibody, has shown durable anti-tumor activity with good tolerability in a range of HER2-expressing cancers. Methods: In this 3-part Phase 1 study (NCT02892123), zanidatamab (10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W) is administered as a single agent (Parts 1 & 2; QW or Q2W) or in combination with chemotherapy (Part 3; Q2W or Q3W). Eligibility criteria includes GEA with HER2 expression as assessed by immunohistochemistry (IHC) 3+ or IHC 2+, progression after standard of care therapy, and measurable disease per RECIST 1.1 (Part 2 requirement only). Results: In Parts 1 and 2, 36 GEA patients have been treated with zanidatamab (QW [n = 5]; Q2W [n = 31]). In Part 3, 26 GEA patients have been treated (zanidatamab Q2W + (paclitaxel [n = 11] or capecitabine [n = 6]); zanidatamab Q3W + capecitabine [n = 9]). Conclusions: Zanidatamab, both as a single agent and in combination with chemotherapy, is well tolerated with promising and durable anti-tumor activity in heavily pretreated GEA patients (including prior HER2-targeted therapy). These data support further investigation of zanidatamab as a novel therapeutic for patients with HER2-expressing GEA. Clinical trial information: NCT02892123. [Table: see text]

scholarly journals miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jing Guo ◽  
Xuxian Zhong ◽  
Qinglin Tan ◽  
Shengnan Yang ◽  
Jiaqi Liao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Endoplasmic Reticulum ◽  
Growth Factor ◽  
Er Stress ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Non Invasive ◽  
Underlying Mechanisms ◽  
Leucine Rich Repeats

AbstractTrastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.

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