Genomic alterations (GAs) associated with durability of benefit from trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1) and sacituzumab govitecan (SG) in metastatic breast cancer (MBC).

Abstract

1048 Background: Predictive biomarkers are needed to guide use of T-DXd, T-DM1 and SG in MBC. We used real-world comprehensive genomic profiling (CGP) of tumor tissue and circulating tumor DNA (ctDNA) to describe pre- and post-treatment somatic GAs in patients receiving these antibody-drug conjugates (ADCs) and evaluated the predictive value of ERBB2 amplification ( ERBB2 amp) in MBC treated with T-DXd and T-DM1. Methods: MBC patients with FoundationOne CDx or FoundationOne Liquid CDx who received T-DXd, T-DM1 or SG monotherapy were included. Clinical data originated from 280 cancer clinics (~800 sites of care) between 1/2011-4/2024 included in the US-wide de-identified Flatiron Health-Foundation Medicine MBC clinicogenomic database. For each ADC and MBC subtype, we characterized the GA profile of pre-ADC samples. Pre- and post-treatment GAs were then compared by chi-square, adjusted for multiple comparisons. For patients who received T-DXd or T-DM1, time to next treatment (TTNT) was compared between patients with or without ERBB2 amp by tissue CGP by Cox models, adjusted for age, ECOG status, HR status, and line of therapy. Results: We identified 1,177 pre-ADC samples (n = 972 tissue, n = 205 liquid biopsy; T-DXd n = 492, T-DM1 n = 167, SG n = 518). TP53 (59.7%), PIK3CA (34.4%), and ERBB2 (20.6%) were most commonly altered across all samples. Median TTNT for T-DXd in HER2+ MBC (n = 106) was 16.6 mo; ERBB2 alterations were present in 84.6% of cases above the median vs 47.5% below. Median TTNT for cases with somatic BRCA1/2 mutations (n = 6) was 8.48 mo vs 18 mo for BRCA1/2 wildtype. Formal statistical analyses of baseline GAs and associations with TTNT on each ADC will be presented at the conference. GAs in ATM (24% vs 3.7%, p < 0.0001), GNAS (6% vs 2%, p < 0.0001), EGFR (4% vs 0.2%, p < 0.01) and ERCC4 (2% vs 0, p = 0.02) were more prevalent in samples post-T-DXd (n = 50, 15 tissue/35 liquid) vs pre-T-DXd (n = 492, 378 tissue/114 liquid). GAs in ERCC4 (3.3% vs. 0, p = 0.001) were more prevalent in samples post-SG (n = 60, 31 tissue/29 liquid) vs pre-SG (n = 518, 439 tissue/79 liquid). HER2+ MBC with ERBB2 amp by CGP (n = 54) had more favorable TTNT on T-DXd vs non-amplified HER2+ (n = 30; 22.5 vs 6.4 mo, HR 0.10, 95% CI 0.04-0.24, p < 0.0001). HER2-low MBC with ERBB2 amp by CGP (n = 6) had more favorable TTNT on T-DXd vs non-amplified HER2-low (n = 263; NR vs 7.4 mo, HR 0.22, 95% CI 0.05-0.90, p = 0.035). HER2+ MBC with ERBB2 amp by CGP (n = 102) had more favorable TTNT on T-DM1 vs non-amplified HER2+ (n = 45; 8.3 vs 2.6 mo, HR 0.50, 95% CI 0.33-0.75, p < 0.001). Conclusions: This real-world analysis provides insight into baseline GAs and associations with TTNT on T-DXd, T-DM1 and SG in MBC as well as GAs that emerge on treatment. ERBB2 amp by CGP carried additional predictive value to IHC/FISH HER2 status in both HER2+ and HER2-low MBC treated with T-DXd and HER2+ MBC treated with T-DM1.