Neratinib in HER2-mutant, recurrent/metastatic cervical cancer (R/M CC): Updated findings from the phase 2 SUMMIT basket trial

Somatic HER2 mutations are oncogenic drivers in 3–6% of CC. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated single-agent activity in multiple HER2-mutant cancers [Hyman et al. Nature 2018], including HER2-mutant R/M CC [Oaknin et al. doi.org/10.1016/j.ygyno.2020.07.025]. We describe updated findings from the HER2-mutant R/M CC cohort from SUMMIT (cut-off date: Mar 18, 2022). Patients (pts) with R/M CC and HER2 mutations documented by local testing received oral neratinib 240 mg once daily with up to 2 cycles of mandatory loperamide prophylaxis. Tumor response was assessed by investigators using RECIST 1.1 and/or PET Response Criteria. Endpoints: confirmed objective response rate (ORR); duration of response; clinical benefit rate (CBR); progression-free survival (PFS); safety. Clinicaltrials.gov: NCT01953926. As of Mar 18, 2022, 22 pts with HER2-mutant R/M CC were enrolled (adenocarcinoma, 82%; squamous cell carcinoma, 18%). Single HER2 mutations: S310F/Y (n=10); R678Q (n=2); D769H/N (n=2); other (n=4). Four pts had 2 HER2 mutations, 3 of which included S310F/Y. Prior treatments included platinum-based chemotherapy (100%), bevacizumab (73%), and pembrolizumab (18%). Median duration of neratinib therapy was 3.7 months (range 0.5–64.7 months). Efficacy results (efficacy evaluable population) are shown in the Table. ORR was 18% (95% CI 5–40%) and CBR was 46% (95% CI 24–68%). Median PFS was 5.1 months (95% CI 1.7–7.2 months). Prior treatment with bevacizumab did not appear to influence outcomes. Diarrhea was the most commonly reported adverse event (all grade, 90.9%; grade 1, 31.8%; grade 2, 36.4%, grade 3, 23%; grade 4, 0%). No patients discontinued treatment due to diarrhea.Table: 559PEndpointPrior bevacizumabTotal (N=22)Yes (n=16)No (n=6)Confirmed objective response, n (%)3 (19)1 (17)4 (18)CR1 (6)01 (5)PR2 (13)1 (17)3 (14)ORR, % (95% CI)19 (4–46)17 (0–64)18 (5–40)Median DoR, months (95% CI)5.9 (5.6–9.3)12.3 (NE)7.6 (5.6–12.3)Clinical benefit, n (%)7 (44)3 (50)10 (46)CR1 (6)01 (5)PR2 (13)1 (17)3 (14)SD (≥16 weeks)4 (25)2 (33)6 (27)Clinical benefit rate, % (95% CI)44 (20–70)50 (12–88)46 (24–68)Median PFS, months (95% CI)4.4 (1.7–7.2)5.5 (1.7–20.1)5.1 (1.7–7.2)CBR, CR + PR + SD ≥16 weeks; CR, complete response; DoR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease Open table in a new tab CBR, CR + PR + SD ≥16 weeks; CR, complete response; DoR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease These encouraging results support the clinical benefit of neratinib in this patient population and warrant further investigation following platinum failure.