Abstract CT139: NCI Molecular Analysis for Therapy Choice (NCI-MATCH EAY131) arm B: Phase II study of afatinib in patients (pts) with HER2 (ERBB2) activating mutations
Authors: Bedard Philippe L. , Li Shuli , Wisinski Kari B. , Yang Eddy S. , Limaye Sewanti A. , Mitchell Edith P. , Zwiebel James A. , Moscow Jeffrey , Gray Robert J. , McShane Lisa M. , Rubenstein Larry V. , Patton David R. , Williams P Mickey , Hamilton Stanley R. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay N. , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith T. 
Published: August 2019

Abstract
BACKGROUND: NCI-MATCH is a multi-cohort, signal finding trial that assigns pts with advanced cancers to targeted therapies based on central tumor genomic testing. Arm B evaluated afatinib, an ErbB family blocker, in pts with ERBB2 activating mutations.
METHODS: Eligible pts had advanced refractory solid tumors, lymphoma, or multiple myeloma, tumor biopsies with selected ERBB2 single nucleotide variants or insertions/deletions, but no ERBB2 amplification detected by the NCI-MATCH next generation sequencing assay. Pts had performance status (PS) ≤1, left ventricular ejection fraction &gt;50%, grade ≤1 diarrhea, and no prior HER2 therapy. Non-small cell lung cancers were excluded. Pts received afatinib 40 mg daily in 28 day cycles. Concomitant endocrine therapy was not allowed. Tumor assessments were every two cycles. The primary objective was overall response rate (ORR). Secondary objectives were: 6-month progression-free survival (PFS6), overall survival, toxicity and molecular correlates. Initial planned enrollment was 35 pts, but a subsequent amendment permitted accrual of up to 70 pts to provide additional information in rarer histologies.
RESULTS: 59 pts were assigned and 40 enrolled (37 evaluable) to Arm B. Median age was 62 (range 29-83), 78% female, 32% PS0, and 58% had received &gt;3 prior therapies. Tumor histologies: breast (n=12; 5 lobular/7 ductal, all ER+), colorectal (n=5), urothelial (n=4), biliary (n=3), cervix (n=2), small bowel (n=2) and other (n=9). The qualifying ERBB2 variants were L755S (n=6), V777L (n=6), V842I (n=6), S310F (n=6), D769Y (n=5), S310Y (n=4), V777_G778insGSP (n=2), and other (n=7). The ORR was 2.7% (n=1/37; 90% CI 0.14%-12.2%) and PFS6 was 11% (90% CI 5.0%-23.5%). A confirmed partial response (PR) occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed PRs were observed (low grade serous gynecological tract and ER+/HER2- IHC breast ductal carcinoma). Of 12 evaluable breast cancer pts, there was 1 additional pt with lobular carcinoma (ER+/HER2-FISH) who had 51% reduction in target lesions but progressed due to a new lesion at cycle 6. The most common (&gt;20%) treatment-related AEs were: diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%) dehydration (27%), vomiting (27%), nausea (27%), anemia (27%) and anorexia (22%). Most AEs were grade ≤2. Four pts (11%) discontinued due to AEs.
CONCLUSION: Although afatinib did not meet the pre-specified threshold for anti-tumor activity, the response in a rare tumor type is notable. The results in breast/gynecologic malignancies, along with the SUMMIT trial (Hyman Nature 2018), suggest differential activity of HER2 inhibitors in ERBB2 mutant cancers by tumor histology. The safety profile of afatinib was consistent with prior studies.
Citation Format: Philippe L. Bedard, Shuli Li, Kari B. Wisinski, Eddy S. Yang, Sewanti A. Limaye, Edith P. Mitchell, James A. Zwiebel, Jeffrey Moscow, Robert J. Gray, Lisa M. McShane, Larry V. Rubenstein, David R. Patton, P Mickey Williams, Stanley R. Hamilton, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty. NCI Molecular Analysis for Therapy Choice (NCI-MATCH EAY131) arm B: Phase II study of afatinib in patients (pts) with HER2 (ERBB2) activating mutations [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 CT139.