Carol Aghajanian

Purpose:The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes. Experimental Design:We analyzed 68,920 tumor–normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. We curated oncogenic or likely oncogenic SMARCA4 alterations using OncoKB and classified them based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade. Results:SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non–small cell lung cancer (7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including 1 who attained a complete response. Conclusions:SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.

Purpose: The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes. Experimental Design: We analyzed 68,920 tumor–normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. We curated oncogenic or likely oncogenic SMARCA4 alterations using OncoKB and classified them based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade. Results: SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non–small cell lung cancer (7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including 1 who attained a complete response. Conclusions: SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.

Clinical characteristics and prior treatments of study participants.

Exploratory analysis of the three components of the HRD score.

Comparison of HRD scores in primary vs. recurrent disease and untreated vs. previously treated disease.

Representativeness of study participants.

Purpose: Copy number–high (CN-H)/p53-abnormal endometrial cancers are high-grade uterine malignancies characterized by TP53 mutations, copy-number alterations, mismatch repair proficiency (MMRp), and absence of POLE mutations. A subset may be homologous recombination deficient (HRD), potentially conferring sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. We aimed to test the combination of PARP and immune checkpoint inhibitors in this subgroup, leveraging possible synergy from immune priming. Patients and Methods: We conducted a single-arm, open-label, phase II trial evaluating the efficacy and safety of olaparib (300 mg orally twice daily) plus pembrolizumab (200 mg intravenously every 3 weeks) in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Eligible patients had p53-abnormal, MMRp, and POLE-negative disease and up to 3 prior lines of therapy. The primary endpoint was the best overall response rate (ORR) at 24 weeks. Results: Of the 25 patients evaluable for efficacy, 2 patients achieved a complete response, and 6 achieved a partial response, resulting in an ORR of 32% [90% one-sided confidence interval (CI), 19.6%–100%]. The median duration of response was 11.2 months (80% two-sided CI, 6.4–11.9). The median progression-free survival was 3.9 months (80% two-sided CI, 2.1–5.8), and the median overall survival was 16.5 months (80% two-sided CI, 9.6–23.6). No new safety signals were identified. Genomic analyses suggested that responders had a numerically higher frequency of HRD tumors than nonresponders (50% vs. 17%). Conclusions: The combination of olaparib plus pembrolizumab has promising activity with durable responses in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Molecular biomarkers may be helpful for patient selection in future studies of this combination.