Abstract 929: Paired tumor and cfDNA in patients with HER2-mutant solid tumors treated with neratinib reveals convergence of multiple on-target resistance mechanisms: Results from the SUMMIT "Basket" Trial
Authors: Helen H. Won, S. Duygu Selcuklu, Sarina A. Piha-Paul, Cristina Saura, Jordi Rodon, Ingrid A. Mayer, Sherene Loi, Geoffrey I. Shapiro, Janice Lu, Adam Brufsky, Catherine Zimel, Myra Melcer, Maurizio Scaltriti, Lisa D. Eli, Richard E. Cutler, Alshad S. Lalani, Richard P. Bryce, Carlos Arteaga, Funda Meric-Bernstam, Michael F. Berger, David B. Solit, Alison Schram, David M. Hyman
Journal: Cancer Research (2019)

Abstract Background: Somatic mutations in ERBB2 occur across various tumor types at relatively low frequencies and can lead to constitutive kinase signaling and oncogenic transformation. SUMMIT is an ongoing basket trial of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, in pts with ERBB2 mutant cancers (NCT01953926). Methods: Pts with advanced solid tumors and locally documented ERBB2 mutations received neratinib 240 mg daily (N=8) +/- fulvestrant at the labeled dose for pts with ER+ breast cancer (N=6) as part of the global Phase II SUMMIT basket study. Pre- and post-treatment tumor and cfDNA were subjected to NGS using MSK-IMPACT for tissue (410 genes) and MSK-ACCESS for plasma (129 genes) to identify SNVs, indels, and copy number alterations. Results: In total, 14 pts had successful sequencing of both paired tissue and cfDNA sample (10 breast, 2 gallbaldder, 1 bladder, and 1 unknown primary). All pts achieved clinical benefit on neratinib including 2 CRs, 7 PRs, and 5 SDs. In 1 gallbladder pt, paired tissue sequencing identified loss of the pretreatment clonal ERBB2 mutation but retention of a truncal TP53 mutation, suggesting emergence of a distantly related ERBB2 wildtype clone. In the remaining 13 patients, the pretreatment ERBB2 mutation was retained in tissue at progression. 64% (9/14) pts had at ≥1 acquired alteration in tissue including 3 pts who acquired secondary alterations in ERBB2, both clonal and subclonal ERBB2 mutations as well new focal amplifications. Consistent with this finding, plasma cfDNA sequencing revealed 57% (8/14) of pts acquired ≥1 secondary ERBB2 mutation with the majority occurring at known activating hotspots. Analysis of mutant allele frequencies of these emergent ERBB2 alterations, in comparison to other variants, suggested the majority were subclonal with evidence of multiple independent subclones arising in the same patient. Two pts developed known ERBB2 gatekeeper mutations (T798I and L785F). Conclusion: In pts with ERBB2-mutant solid tumors with clinical benefit on neratinib, a potential on-target resistance mechanism was identified in 71% (10/14, including 7 with acquired gain-of-function ERBB2 mutations, 2 with ERBB2 both gain-of-function and gatekeeper mutations, and 1 with outgrowth of an ERBB2 wildtype clone). Collectively, these data provide additional evidence that ERBB2 mutations lead to oncogene addiction in solid tumors. We also demonstrate that tumor and cfDNA sequencing provides complementary information that can be integrated to more fully elucidate potential resistance mechanisms. Citation Format: Helen H. Won, S. Duygu Selcuklu, Sarina A. Piha-Paul, Cristina Saura, Jordi Rodon, Ingrid A. Mayer, Sherene Loi, Geoffrey I. Shapiro, Janice Lu, Adam Brufsky, Catherine Zimel, Myra Melcer, Maurizio Scaltriti, Lisa D. Eli, Richard E. Cutler Jr., Alshad S. Lalani, Richard P. Bryce, Carlos Arteaga, Funda Meric-Bernstam, Michael F. Berger, David B. Solit, Alison Schram, David M. Hyman. Paired tumor and cfDNA in patients with HER2-mutant solid tumors treated with neratinib reveals convergence of multiple on-target resistance mechanisms: Results from the SUMMIT "Basket" Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 929.