FP14.15 Neratinib-Based Combination Therapy in HER2-Mutant Lung Adenocarcinomas: Findings from two International Phase 2 Studies

Somatic HER2 mutations are present in 3–5% of lung cancers, which induce constitutive signaling and oncogenesis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated antitumor activity across a spectrum HER2-mutated solid cancers manageable safety profile [Hyman et al. Nature 2018]. Findings from HER2-mutant cancer model suggest that neratinib is enhanced when given combination with mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) [Ivanova Clin Cancer Res 2020]. We data two international phase 2 studies neratinib-based therapy patients cancer: PUMA-NER-4201 – randomized study ± temsirolimus (NCT01827267); PUMA-NER-5201 (SUMMIT) multi-tumor ‘basket’ trial including treated trastuzumab (NCT01953926). Patients histologically confirmed advanced non-small cell (NSCLC) were oral 240 mg once daily alone (both studies) 8 weekly intravenously optional dose escalation to 15 mg/week if tolerated (PUMA-NER-4201) mg/kg initially then 6 every 3 weeks (SUMMIT). Protocol-defined endpoints common both objective response rate (RECIST v1.1), best overall response, clinical benefit rate, duration progression-free survival, (NCI CTCAE, v4.0). In PUMA-NER-4201, 62 NSCLC enrolled (60 evaluable for efficacy). SUMMIT, as 17 July 2020, 78 received at least one drug (all Baseline characteristics studies: median age range 62–66 years, female 66%, adenocarcinoma 92–100%. Exon 20 insertion accounted 95% tumors 66% SUMMIT. The most mutant allele was Y772_A775dup (53% PUMA-NER-4201; 28% SUMMIT). consistent previous reports, diarrhea being the adverse event (81–86% any grade, 12–40% grade ≥3) monotherapy arms. Efficacy results summarized table. monotherapy, limited NSCLC. Neratinib combined either produced numerically greater efficacy durable responses subset pre-treated patients. Genomic analysis responders forthcoming. Additional novel combinations other HER2-directed therapies considered.