Impact of <i>MTAP</i> deletion on immunotherapy outcomes in patients with mesothelioma.

Abstract

8081 Background: MTAP ( methylthioadenosine phosphorylase ) is located on chromosome 9p21 and often co-deleted with CDKN2A across a variety of cancers. MTAP deletions (del) are found in about 30% of diffuse pleural mesotheliomas (DPM). MTAP del has been associated with resistance to immunotherapy (IO) treatment (tx) in multiple tumor types. In patients (pts) with DPM, objective response rate (ORR) on ipilimumab/nivolumab is 40%, disease control rate (DCR) 77%, and median progression-free survival (PFS) 6.8 months (mos): the implications of MTAP status on IO outcomes is unclear but represents a potential predictive biomarker. With multiple targeted therapies underway for MTAP del tumors, such as PRMT5 inhibitors, this alteration is also of therapeutic importance. Methods: We prospectively identified pts with pathologically confirmed DPM whose tumors were sequenced with MSK-IMPACT version 7, a 505-gene next generation sequencing panel that includes MTAP and CDKN2A. IO regimens included anti-PD(L)1 monotherapy, dual checkpoint blockade with additional anti-CTLA4 tx, and anti-PD(L)1 + chemotherapy. MTAP del was defined as low read count and confirmed by FACETS copy number when able. Radiologists reviewed imaging to determine best response and PFS on IO using mRECIST or, when not applicable, RECIST. Overall survival (OS) was compared between MTAP del and MTAP wildtype (WT) cohorts using Kaplan-Meier curves and log-rank tests. Baseline demographics were compared using Fisher’s exact test. Results: We examined 156 pts with DPM: 39 had CDKN2A del (25%) and 32 had MTAP del (21%). 18/32 were treated with IO and available for analysis. 79 pts with MTAP WT DPM treated with IO were analyzed as a control. There were more pts treated with dual checkpoint blockade in the MTAP del vs MTAP WT group (83% vs 56%, single-agent IO 6% vs 39%, single-agent IO + chemo 11% vs 5%, p=0.03) and more men (94% vs 70%, p=0.04); there was no statistically significant difference in age (median 72 vs 69, p=0.5), histology (72% epithelioid vs 79%, p=0.5), or smoking status (current/former 61% vs 57%, p=0.9). All tumors with MTAP del also harbored a CDKN2A del: 5/79 tumors in the MTAP WT cohort had a CDKN2A del (p&lt;0.001). Among the MTAP del cohort, 13 patients had (m)RECIST-evaluable disease. ORR on IO was 15% (2/13), DCR 38% (5/13), and median PFS 2.5 mos. OS was similar between the MTAP del and MTAP WT cohorts: median 25.4 vs 27.6 mos (HR 0.84, 95% CI 0.36 – 1.94, p=0.98). Conclusions: MTAP del (co-occurring with CDKN2A del ) was identified in both epithelioid and non-epithelioid DPM and was associated with a low ORR and short PFS on IO, but OS was similar compared to MTAP WT. Larger, multi-institution cohorts are needed to validate this finding. If confirmed, this could have implications for tx selection, particularly among pts with epithelioid DPM, in which the optimal choice between 3 FDA-approved first-line regimens is uncertain.