Memorial Sloan Kettering Cancer Center, New York, NY
Komal L. Jhaveri , Jonathan W. Goldman , Sara A. Hurvitz , Angel Guerrero-Zotano , Nisha Unni , Adam Brufsky , Haeseong Park , James Ross Waisman , Eddy Shih-Hsin Yang , Iben Spanggaard , Sonya A. Reid , Mark E. Burkard , Aleix Prat , Sherene Loi , John Crown , Ariella Hanker , Cynthia X. Ma , Ron Bose , Lisa DeFazio Eli , Hans Wildiers
Background: N is an oral, irreversible pan-HER TKI with activity against HER2 mutations. Genomic analyses from the SUMMIT MBC cohort following N±F suggest that resistance to N may occur via mutant allele amplification or secondary HER2 mutations. Adding T to N+F in SUMMIT showed encouraging durable responses in patients (pts) with HR+, HER2-mutant MBC and prior CDK4/6 inhibitors (CDK4/6i). Methods: SUMMIT (NCT01953926) enrolled pts with HR+, HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6i. Pts received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1&15 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w). During the small, randomized portion of the trial, pts received N+F+T, F+T or F (1:1:1 ratio). Pts randomized to F+T or F could crossover to N+F+T at progression. Efficacy endpoints: investigator-assessed ORR and CBR (RECIST v1.1); DOR; best overall response. Pre-treatment tumor tissue was centrally assessed retrospectively by next-generation sequencing. ctDNA from patient samples was assessed by NGS. Results: SUMMIT has completed enrolment; we report efficacy from 45 pts in the N+F+T cohort, plus 10 pts who progressed on F (n=6) or F+T (n=4) and crossed over to N+F+T (Table). HER2 allelic variants in the 45 N+F+T pts and ORR (%) (pts may have >1 mutation) were: V777L (n=6, 50%), L755S/P (n=15, 40%), S310F (n=4, 50%), exon 20 insertion (n=11, 36%), other KD missense (n=6, 33%), TMD missense (n=2, 0%), exon 19 deletion (n=1, 0%). Conclusions: N+F+T is a promising combination for HR+, HER2-mutated MBC with prior exposure to CDK4/6i, across a range of activating HER2 mutations. Results from the upcoming Apr 2022 data cut, including biomarkers, safety, mechanisms of acquired resistance, and preclinical mechanism of N+T, will be presented. Clinical trial information: NCT01953926.
All HR+ prior CDK4/6i (N+F+T) (n=45) | Randomized HR+ (F+T) (n=7) | F+T crossover to N+F+T (n=4) | Randomized HR+ (F) (n=7) | F crossover to N+F+T (n=6) | |
---|---|---|---|---|---|
Objective response,a n (%) (95% CI) | 17 (38) (24–54) | 0 (0–41) | 1 (25) (0.6–81) | 0 (0–41) | 2 (33) (4–78) |
CR PR | 1 (2)16 (36) | 00 | 01 (25) | 00 | 02 (33) |
Medianb DOR, months (95% CI) | 14.4 (6.4–NE) | NE | NE | NE | 6.3 (6.2–6.4) |
Clinical benefit,c n (%) (95% CI) | 21 (47) (32–62) | 0 (0–41) | 1 (25) (0.6–81) | 0 (0–41) | 5 (83) (36–100) |
CR PR SD ≥ 24 weeks | 1 (2)16 (36) 4 (9) | 00 0 | 01 (25) 0 | 00 0 | 02 (33) 3 (50) |
Median PFS, months (95% CI) | 8.2 (4.2–15.1) | 3.9 (1.9–4.1) | NE | 4.1 (1.6–4.1) | 8.3 (3.9–10.3) |
aCR or PR confirmed ≥ 4 weeks after response criteria met.bKaplan-Meier analysis.cConfirmed CR or PR or SD for ≥ 24 weeks. Tumor response based on investigator assessment (RECIST v1.1).CI, confidence interval; CR, complete response; DOR, duration of response; F, fulvestrant; HR+, hormone receptor-positive; N, neratinib; NE, not evaluable; PR, partial response; SD, stable disease; T, trastuzumab.
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