Comprehensive molecular analysis of phase II trial of nivolumab in patients with recurrent or metastatic carcinosarcomas.

Abstract

11542 Background: We conducted a single-center, prospective, phase II trial to evaluate the efficacy and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, in patients with recurrent or metastatic carcinosarcoma who progressed after prior chemotherapy. Carcinosarcoma, a malignant neoplasm composed of both epithelial and mesenchymal elements, is a rare and aggressive tumor categorized as high-grade cancer by NCCN guidelines. Given the potential for nivolumab to selectively target PD-L1 overexpressing tumor cells, this study aims to identify patients who would likely benefit and orphan malignancy components. Methods: In this single arm phase 2 trial (NCT05224999), eligible patients had histologically confirmed metastatic and/or recurrent carcinosarcoma, measurable disease, 1-3 prior chemotherapy, and adequate renal/hepatic/hematologic function. Treatment consisted of nivolumab 3 mg/kg every 2 weeks. We compared the genomic and transcriptomic properties in our carcinosarcoma tissue with those in TCGA sarcoma, TCGA carcinoma, and TCGA uterine carcinosarcoma. Results: Between July 2020 and Nov 2023, 28 patients enrolled and received trial treatment. Of the 28 patients evaluable, 4 (14.3%) achieved confirmed partial response, and 11 (39.3%) had stable disease, yielding and disease control rate of 53.6%. The median PFS was 2.6 months. The pre-specified primary endpoint was met with 6-months PFR of 30.8%. NGS analysis revealed that carcinosarcoma shares molecular features with both carcinoma and sarcoma, while also exhibiting unique genetic and transcriptional profiles. While some molecular characteristics were common across all three tumor types, carcinosarcoma also displayed unique genetic alterations and transcriptional patterns, underscoring its distinct molecular identity. When comparing our genomic data to TCGA datasets, we observed overlapping mutations. In carcinosarcoma, frequently altered genes included TP53 (sarcoma), ZFHX3 (carcinoma), CHD4 (sarcoma), IRS1 (sarcoma), ARID1A (both), ABL1 (sarcoma), MED12, and PIK3CA (carcinoma). These findings suggest potential shared molecular mechanisms and emphasize the unique genomic landscape of carcinosarcoma. Conclusions: Carcinosarcoma comprises features shared with carcinoma and sarcoma, along with distinct characteristics unique to this tumour type. These findings highlight the distinct molecular landscape of carcinosarcoma and pave the way for more precise, biomarker-driven therapeutic approaches. Furthermore, patients were stratified based on the degree of molecular similarity to carcinoma or sarcoma, enabling exploratory analyses to assess the potential relationship between these stratifications and drug response. Clinical trial information: NCT05224999 .