Clinical impact of TOP1 alterations on outcomes to topoisomerase-I–directed therapies across chemotherapy and antibody-drug conjugates.

e15044 Background: Topoisomerase-I (TOP1)–directed therapies are used broadly in solid tumors, including irinotecan-based chemotherapy and TOP1-payload antibody–drug conjugates (ADCs). While TOP1 alterations have been implicated in resistance to TOP1-payload ADCs, their real-world clinical impact across therapeutic classes remains incompletely defined. Methods: We conducted a retrospective clinico-genomic analysis of the MSK-CHORD 2024 cohort integrating baseline tumor sequencing with longitudinal treatment timelines. Baseline TOP1 alteration status was defined on the earliest available tumor sequencing as (i) nonsynonymous TOP1 mutation and/or (ii) focal TOP1 copy-number alteration (CNA; amplification or deep deletion). We evaluated patients who received, after baseline sequencing, either (1) irinotecan-based chemotherapy (irinotecan or liposomal irinotecan) and/or (2) TOP1-payload ADCs (sacituzumab govitecan or fam-trastuzumab deruxtecan). Real-world effectiveness endpoints were time-to-next-treatment (TTNT) and time-to-treatment discontinuation (TTD) from first exposure to each therapy class. Outcomes were summarized with Kaplan–Meier methods and compared by TOP1 status using the log-rank test. Results: Among 24,950 sequenced patients, 430 (1.7%) had baseline TOP1 alterations (197 mutations, 235 focal CNAs, and 2 overlap). After baseline sequencing, 3,009 patients received irinotecan-based chemotherapy (64 TOP1-altered) and 503 received TOP1-payload ADCs (6 TOP1-altered). For irinotecan-based chemotherapy, median TTNT was 5.5 months (TOP1-altered) vs 4.1 months (TOP1-wild-type); median TTD was 5.4 vs 3.3 months, respectively. For TOP1-payload ADCs, median TTNT was 2.8 months (TOP1-altered) vs 4.5 months (TOP1-wild-type); median TTD was 2.2 vs 4.1 months, respectively (exploratory given small TOP1-altered ADC sample size [n = 6]). Conclusions: In a large real-world clinico-genomic cohort, baseline TOP1 alterations were uncommon but associated with class-dependent differences in effectiveness of TOP1-directed therapies. The directionality of association differed between irinotecan-based chemotherapy and TOP1-payload ADCs, supporting further evaluation of TOP1 genomics along with tumor context and treatment line for therapeutic selection and sequencing, particularly in ADC-treated populations.