Trastuzumab (T) + chemo is standard 1st line therapy (tx) for HER2+ GEA patients (pts). Pts typically progress in 6-8 months, with loss of HER2 positivity in 40% of treated pts. No anti-HER2 agents are approved in the post-T setting. We report the results of M, an anti-HER2 monoclonal antibody Fc-optimized for antibody-dependent cellular cytotoxicity, + P in HER2+ GEA pts and describe potential strategies for biomarker-guided response enrichment based on ERBB2 amplification and/or PD-L1 expression.
HER2+, PD-L1-unselected, 2nd line GEA pts post T progression received M (15 mg/kg Q3) + P (200 mg Q3). Safety, objective response rate (ORR), median overall and progression-free survival (mOS, mPFS), disease control rate (DCR), circulating-tumor DNA (ctDNA), and tumor PD-L1 expression were assessed.
At data cutoff, 60 GEA pts were dosed in cohort expansion; 16.7% had treatment-related adverse events ≥ Grade 3. Overall, 21.6% had objective response (OR), 10 confirmed and 3 unconfirmed. DCR was 55% and mOS was 15.6 mos (95% CI: 7.26, NR). In GC pts, OR occurred in 10 of 34 (29.4%), mPFS was 4.24 mos (95% CI: 1.68, 5.62), and mOS not reached. Notably, only 31 of 51 (61%) of pts with baseline ctDNA testing showed ERBB2-amplification; 21 of 30 (70%) of pts with fresh tumor biopsy were HER2 3+ by IHC (80% concordance). Tumors were PD-L1+ positive in 13 of 28 (46%) pts tested, with higher rates in pts with GC. The presence of ERBB2 amplification by ctDNA and tumor PD-L1 expression by IHC were both associated with increased probability of OR: 33.3% v. 10.5% (p = 0.0948) and 43.8% v. 16.7% (p = 0.0769), respectively. ORR was 5 of 8 (62.5%) in ERBB2 amplified/PD-L1+ pts. In pts with activating HER2 mutations DCR was 11/15 (73%), indicating ADCC.
Consistent with prior tissue-based reports, many GEA pts progressing on T have lost ERBB2 amp. ERBB2 status by ctDNA NGS post-T could help identify patients more likely to respond to M+P, particularly in PD-L1+ pts. Our results suggest that M+P is well tolerated and has encouraging preliminary activity in 2nd line HER2+ GEA. Biomarker selection may further enrich for responding pts, advancing a potential chemo-free regimen in this population.
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D.V.T. Catenacci: Honoraria: Merck, BMS, Lilly, Genentech/Roche, Amgen, Taiho, Guardant Health, Foundation Medicine; Research funding: Genentech/Roche. H.E. Uronis: Consulting, Advisory role: Bristol-Myers Squibb; Research funding: Genentech/Roche, Bristol-Myers Squibb, Advaxis, MacroGenics, Merck. Y-K. Kang: Consulting, Advisory role: Lily/ImClone, Taiho Pharmaceutical, Ono Pharmaceutical, Roche/Genentech, Novartis; Research funding: LSK Biopharma. M. Ng: Consulting, Advisory role: MSD Oncology, Bristol-Myers Squibb; Honoraria: Taiho Pharmaceutical; Research funding: ASLAN Pharmaceuticals. J. Lacy: Advisory board: Celgene. P.C. Enzinger: Consultant: Astellis, Celgene, FivePrime, Lilly, Loxo, Merck, Taiho. K-W. Lee: Research funding: AstraZeneca/Medimmune, Green Cross Corp, MSD, Ono Pharmaceutical, Merck KGaA, Five Prime Therapeutics, MacroGenics, ASLAN Pharmaceuticals, LSK BioPharma, Array BioPharma, Pharmacyclics, Pfizer. J. Yen, A. Franovic: Employee: Guardant Health. J. Odegaard: Employee, Stock holder: Guardant Health. J. Baughman: Employee: MacroGenics, Inc. J. Muth, T. Wu, A. Wynter-Horton: Employee, Stock ownership: MacroGenics, Inc. J. Wigginton, J.K. Davidson-Moncada: Employee, Leadership, Stock and other ownership interests: MacroGenics. Y-J. Bang: Consulting, Advisory role: Samyang; Research funding: AstraZeneca/Medimmune, Novartis, Genentech/Roche, MSD, Merck/Serano, Bayer, GlaxoxSmithKline, Bristol-Myers Squibb, Pfizer, Lilly, Boehringer Ingelheim, MacroGenics, Boston Miomedical, kFive Prime Therapeutics, Chong Kun Dang Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, BeiGene, Curis, Green Cross Corp. All other authors have declared no conflicts of interest.