BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors

Abstract

ObjectivesLittle is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM).Materials and MethodsForty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne® CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016–2018) MPM patients selected from the electronic databases of two ICC—of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1st-line platinum/pemetrexed+/−antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed.ResultsThere were no differences in ORR or mPFS with CT between the groups: ORR-50% vs. 47% vs. 50% vs. 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2–16.1) vs. 9.2mo (95% CI, 2.9–13.3) vs. 7.2mo (95% CI, 2.3-NR) vs. 10.9mo (95% CI, 2.9–20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% vs. 27% vs. 33% vs. 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4–3.7) vs. 3.0mo (95% CI, 1.3–10.5) vs. 2.0mo (95% CI, 1.9-NR) vs. 4.5mo (95% CI, 0.3–10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7–98.3) vs. 19.4mo (95% CI, 9.7–47.3) vs. 18.8mo (95% CI, 8.5-NR) vs. 19.5mo (95% CI, 8.3–82.2) in groups A, B, B1, and B2, respectively (p>0.3).ConclusionsBAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study

“…[20][21][22][23][24] Few studies have specifically evaluated the association of BAP1 IHC status with platinum and pemetrexed treatment. 14,25,26 On the basis of the biological function of BAP1 and longer survival in treated patients with BAP1 germline mutation, we postulated that loss of BAP1 in the tumor may predict survival after platinum and pemetrexed treatment in a general PM cohort.…”

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform

“…CDKN2A loss has been correlated with worst outcome 12 or proposed as a diagnostic tool, as observed in more than 75% of mesothelioma 13 . BAP1 is also frequently altered in mesothelioma, however a recent study highlights no difference in response to treatment (chemotherapy, immune checkpoint inhibitors or PARP inhibitors) between BAP1 wild-type or mutant mesothelioma 14 . For thymic malignancies, we were unable to confirm findings from TCGA as GTF2I was not part of any of the panels used in SPECTAlung and the sample size was very small.…”

Microbiomes, Epigenomics, Immune Response, and Splicing Signatures Interplay: Potential Use of Combination of Regulatory Pathways as Targets for Malignant Mesothelioma

“…The Food and Drug Administration (FDA) recently approved a combination of ipilimumab and nivolumab as the primary treatment option for MPM that cannot be treated by surgical intervention [ 78 ]. The clinical outcome of BAP1 mutation in MPM patients treated with immunotherapy was studied by Dudnik et al The study found that treatment response to PD-1/PD-L1 inhibitors was not defined by the presence of BAP1 mutations [ 79 ]. However, a combination of BAP1 mutations, mucin proteins, and immunoregulatory factors may be of value.…”