EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

Abstract

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplifi cation or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplifi cation of EGFR and ERBB2. Heterogeneous 89 Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplifi cation or with acquisition of MET amplifi cation, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplifi ed patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplifi ed EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2-amplifi ed, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR / ERBB2 coamplifi cation and MET amplifi cation, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.

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

“…Afatinib is an oral TKI that irreversibly blocks EGFR, HER2, HER3, and HER4, and it has shown promising preclinical activity against HER2-positive gastrointestinal tumors that are resistant to trastuzumab [52]. A phase II study that evaluated afatinib monotherapy in 20 patients with esophagogastric cancer previously treated with trastuzumab found that afatinib provided moderate therapeutic benefit with an ORR of 10%, and the data suggested that co-amplification of EGFR and HER2 predicted treatment response [53].…”

Drug-adapted cancer cell lines as preclinical models of acquired resistance

“…Resistance can occur by selection of pre-existing drug-resistant subpopulations or by adaptation of originally drug-sensitive cells to anti-cancer therapies. Both mechanisms have been shown to be represented in drug-adapted cancer cell lines [52,[66][67][68][69][70][90][91][92][93][94][95][96][97][98][99][100][101] .…”

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

“…Although acquired RTK coamplification is known as a resistance mechanism to targeted therapies in GEA, the probability that a significant portion of our samples had received prior FGFR2‐directed therapies is minimal owing to the lack of approved agents and real‐world sample set . Similarly, FGFR2 amplification has been observed as an infrequent mechanism of trastuzumab resistance, and “contamination” from post‐trastuzumab samples is not expected to play a major role in our findings . Furthermore, we did not observe prior mechanisms of FGFR2 inhibitor resistance among our samples, adding further indirect support that we are representing an FGFR2‐directed‐therapy‐naive population .…”

“…Thus, NGS‐based evaluation may underestimate the true frequency of FGFR2‐amplified GEA. Although acquired RTK coamplification is known as a resistance mechanism to targeted therapies in GEA, the probability that a significant portion of our samples had received prior FGFR2‐directed therapies is minimal owing to the lack of approved agents and real‐world sample set . Similarly, FGFR2 amplification has been observed as an infrequent mechanism of trastuzumab resistance, and “contamination” from post‐trastuzumab samples is not expected to play a major role in our findings .…”

“…Several series have now clearly demonstrated intertumoral and intratumoral heterogeneity of the actionable RTKs human epidermal growth receptor 2 (HER2), epidermal growth factor receptor (EGFR), and MET. Molecular heterogeneity exists at baseline and evolves over time, as demonstrated by HER2 loss and acquired receptor coamplifications in GEA . Prior small series have demonstrated that pathogenic alterations in fibroblast growth factor receptor 2 ( FGFR2 ) including short variant mutations (SV), amplifications (amp), and rearrangements (re) exist recurrently in GEA .…”