Abstract PD17-01: Genomic analysis of circulating tumor DNA (ctDNA) from patients with HR+, HER2-mutant metastatic breast cancer (MBC) enrolled in SUMMIT: mechanisms of acquired resistance to neratinib + fulvestrant + trastuzumab (N+F+T)

Abstract Background: In the SUMMIT trial, original cohorts of patients with HR+, HER2-negative (locally assessed), HER2-mutant MBC received N alone or N+F, with promising clinical response rates but abbreviated duration. Clinical progression coincided with emergence of additional HER2 mutations and/or amplification of the mutant allele [Smyth et al. Cancer Discov 2020;10:198–213]. Addition of T to the combination was postulated to prolong response; the combination of N+F+T in heavily pretreated patients with HR+, HER2-mutant MBC who had received CDK4/6 inhibitors (n=51) yielded a confirmed overall response rate (ORR) of 35.3%, median duration of response (DOR) of 14.3 months, clinical benefit rate (CBR) of 47.1%, and median progression-free survival (PFS) of 8.2 months [Jhaveri et al. J Clin Oncol 2022;40:1028]. Seven of these 51 patients were part of a randomized (1:1:1) cohort who received N+F+T, F+T, or F alone. Patients randomized to F+T or F could crossover to N+F+T upon progression. No patients responded to F or F+T; however, one of four patients who crossed over to N+F+T upon progression on F+T responded to the triplet, as did two of six who crossed over upon progression on F. We undertook ctDNA sequencing in patients who responded to N+F+T upfront and after crossover. Methods: Patients with HR+, HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6i received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1, d15, and d29 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w) or F+T or F alone. Efficacy endpoints included investigator-assessed ORR and CBR (RECIST v1.1), DOR, and best overall response. ctDNA was collected at baseline, every third cycle during treatment, and at the end of treatment and analyzed by next-generation sequencing. Samples were analyzed using the TEMPUS xF assay. Results: Sequencing results from ctDNA analysis are pending at the time of this abstract submission. Baseline HER2 mutations and co-alterations will be reported and compared with those found in tissue samples. Genomic spectrum and variant allele frequencies in samples taken at baseline, on treatment, and at the end of treatment from patients who experienced complete or partial response to N+F+T and then progressed (n=25) will be sequenced and mechanisms of acquired resistance will be posited. ctDNA genomic profiles of serial time points from patients randomized to F or F+T before and after crossover to N+F+T (n=10) will also be evaluated. Conclusions: Similarities and differences between the mechanisms of acquired resistance to N+F+T, and those previously reported to be associated with progression on N or N+F, will be discussed. Citation Format: Cynthia Ma, James Waisman, Adam M. Brufsky, Eddy S. Yang, Hans Wildiers, John P. Crown, Sarina A. Piha-Paul, Jennifer M. Suga, José Ángel García-Sáenz, Valentina Gambardella, Angel Guerrero, Salomon Stemmer, Ron Bose, Tonya Novara-Demgen, Daniel DiPrimeo, Lisa D. Eli, Komal Jhaveri. Genomic analysis of circulating tumor DNA (ctDNA) from patients with HR+, HER2-mutant metastatic breast cancer (MBC) enrolled in SUMMIT: mechanisms of acquired resistance to neratinib + fulvestrant + trastuzumab (N+F+T) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-01.