8003 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 .
e21058 Background: Definitive concurrent chemoradiation (cCRT) and durvalumab is a standard therapy for patients with unresectable stage III non-small cell lung cancers (NSCLC). Data is limited on outcomes with this regimen outside of clinical trials. Local-regional control rates to date remain undefined. Methods: We reviewed patients with stage III unresectable NSCLC treated between November 2017 and February 2019 with cCRT. Patients that received at least one cycle of durvalumab were further assessed for 12-month progression free survival (PFS), overall survival (OS), and the incidence and pattern of local-regional and metastatic failures. Disease-relapse was characterized to determine patients potentially eligible for metastasis-directed ablative therapies. Toxicities leading to durvalumab discontinuation were evaluated using CTCAE v.5.0. Results: Of the 83 patients with stage III NSCLC treated with cCRT (median 60Gy), 62 received durvalumab and were evaluable (median follow-up: 12 months). Patients (n = 21, 25%) did not receive durvalumab largely related to metastatic progression (n = 9) or persistent cCRT toxicity (n = 10). In the 62 durvalumab treated patients the median age was 66 (range: 49 - 86), 73% had stage IIIB (n = 33) or IIIC (n = 12) disease, and 58% (n = 36) had adenocarcinoma. The median time from cCRT end to durvalumab start was 1.5 months. Patients received a median of 8 months of durvalumab; 35% (n = 22) of patients completed 12 months of therapy. Common reasons for discontinuing durvalumab included disease progression (32%, 20/62) and toxicity (24%, 15/62). The estimated 12-month PFS and OS were 65% (95% CI: 51 - 79%) and 85% (95% CI: 75 - 95%), respectively. High TMB (≥ 8.8 mt/Mb) or PD-L1 (≥ 1% or PD-L1 ≥ 50%) did not predict improved PFS. Patients who discontinued durvalumab due to toxicity did not have inferior PFS. The cumulative 12-month incidence of local-regional and distant metastatic failures were 18% (95% CI: 5.9 - 30%) and 30% (95% CI: 16.3 - 44.5%), respectively. Of the 17 patients with distant metastases, 9 had oligometastases and would have been potential candidates for comprehensive ablative therapies. Conclusions: Outcomes and toxicities outcomes with cCRT and durvalumab in clinical practice align with the PACIFIC trial. Analysis of disease-relapse suggests a substantial minority of patients with disease progression may be potential candidates for metastasis-directed therapies. Local regional outcomes appear improved to historical data of cCRT alone.
