PURPOSE
To evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) among patients with advanced/metastatic HER2-amplified solid tumors.
PATIENTS AND METHODS
This was a single-center, non-randomized phase 2 basket trial conducted at Memorial Sloan Kettering Cancer Center. All 95 patients had HER2-amplified metastatic/advanced disease and were enrolled in 1 of 5 cohorts. HER2 amplification was diagnosed either with next-generation sequencing or in-situ hybridization. All patients received intravenous T-DM1 3.6 mg/kg every 21 days. The primary endpoint was overall response rate (ORR). Overall survival (OS), progression-free survival (PFS), duration of response (DOR), and safety were secondary endpoints.
RESULTS
We treated 95 patients, and 22 (23% [95% CI, 16-33%]) had a confirmed response by investigator assessment. The investigator-assessed confirmed ORRs by cohort were: salivary 11/19 (58% [95% CI, 36-77%]); lung 4/23 (17% [95% CI, 7-37%]); colorectal 0/7 (0% [95% CI, 0-35%]); endometrial 5/23 (22% [95% CI, 10-42%]); "other" 2/23 (9% [95% CI, 2-27%]). Median PFS was 3.6 months (95% CI, 2.6-5.4) and ranged from 1.4 months in the "other" cohort to 10.2 months in the salivary cohort. Median OS was 11.9 months (95% CI, 8.4-17.2) and ranged from 7.8 months in the "other" cohort to 29.2 months in the salivary cohort. Median DOR was 13.1 months (95% CI, 7.3-30.5), ranging from 6.4 months in the lung cohort to 18.4 months in the "other" cohort.
CONCLUSIONS
T-DM1 demonstrated heterogenous efficacy among HER2-amplified tumor types, with promising response and outcomes among patients with salivary gland cancer.
J. Ross, W. Wong, Lauren Schoech et al.· Clinical Cancer Research· 0 citations
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.
PATIENTS AND METHODS
We analyzed 68,920 tumor-normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. Oncogenic or likely oncogenic SMARCA4 alterations were curated using OncoKB and classified 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 (NSCLC; 7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and class 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 one 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.
M. Repetto, M. Gormally, Jason Chang et al.· Clinical Cancer Research· 0 citations
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