Feasibility and safety of neoadjuvant nivolumab and chemotherapy for resectable diffuse pleural mesotheliomas: Results of a prospective pilot study.
Authors: Offin Michael , Lavin Yonit , Zatzman Matthew , Sauter Jennifer L. , Ceglia Nicholas , Travis William D. , Aly Rania G. , Rimner Andreas , Shepherd Annemarie , Simone Charles B. , Kris Mark G. , Ginsberg Michelle S. , Chow Andrew , Quintanal-Villalonga Alvaro , Shah Sohrab P , Rudin Charles M. , Rusch Valerie W. , Adusumilli Prasad S. , Zauderer Marjorie Glass 
Published: June 2024

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Background: Diffuse pleural mesotheliomas (DPM) are an aggressive malignancy where even patients with potentially resectable disease have poor outcomes. With an evolving understanding of the role of pleurectomy/decortication (P/D) as the standard of care for resectable disease, the need to improve upfront therapies is more urgent. Here we report the results of our single institution prospective pilot study of nivolumab with platinum (cisplatin/carboplatin) and pemetrexed prior to P/D for patients with resectable DPM (NCT04162015). Methods: Patients deemed operable and resectable by a multidisciplinary team received 2 cycles of neoadjuvant nivolumab, pemetrexed, and platinum followed by P/D. Subsequent therapy was at the physician's discretion. Using a minimax Simon two-stage design, the primary objective was defined as attempted P/D within 30 days of the planned surgery date. Secondary objectives included evaluating safety, overall survival (OS) from diagnosis, and progression free survival (PFS). Tumor tissue and plasma were collected for exploratory analyses such as immune cell profiling and pathologic response. Using single cell RNA sequencing (scRNAseq), we explored DPM transcriptional heterogeneity and treatment-associated tumor microenvironment (TME) changes. Results: 22 patients received neoadjuvant chemo-immunotherapy and 19 underwent attempted P/D (2 progressed and 1 declined surgery). 68% were men (13/19), 89% were epithelioid (17/19; remaining 2 were biphasic), and the median age at diagnosis was 72 (range: 33-80). No patient experienced pre-operative toxicity precluding P/D. 95% (18/19) of patients underwent P/D within 30 days of the planned date; 1 patient had biopsy-proven tumor flare after cycle 2 and had surgery at day +37. As of January 2024, median OS for the 19 patients that went for attempted P/D was 41.0 mos (median follow up: 25.3mos). OS for those who underwent R1 resections (n = 12) was not reached and for R2 (n = 7) was 31.4 mos (p = 0.67; HR 1.43, 95% CI 0.28-7.30). 26% of specimens (5/19) had ≤ 10% viable tumor cells on the resection; there was no clear correlation with outcomes. scRNAseq was performed on 15 resection specimens with available material. Comparing patients with PFS greater than or less than 12mos (PFS12), we found significantly increased abundance of CD8 cytotoxic T cells, and ISG+ (interferon stimulated) T cells. Conclusions: Neoadjuvant platinum, pemetrexed, and nivolumab was reliably able to be given to patients with DPM without impacting their ability to undergo P/D. The encouraging OS of this cohort to date, and tolerance of the regimen, highlights the importance of patient selection and preoperative treatments when considering P/D. Ongoing exploratory analyses will profile the cellular and transcriptional landscape of DPM and identify correlates of response to neoadjuvant chemo-immunotherapy. Clinical trial information: NCT04162015 .