First report of efficacy and safety results from a phase 2 trial evaluating BNT327/PM8002 plus chemotherapy (chemo) as first-line treatment (1L) in unresectable malignant mesothelioma.

Abstract

8511 Background: Malignant mesothelioma is a rare neoplasm with a high unmet medical need. BNT327 is an investigational bispecific antibody, targeting both PD-L1 and VEGF-A in the tumor and tumor microenvironment (TME). By binding to PD-L1 on tumor cells it is designed to restore effector T-cell function and by binding to VEGF-A within the TME it also reverses the negative impact of VEGF signaling on immune cell infiltration and activation. In addition, via VEGF-A neutralization, it normalizes tumor vasculature. This dual targeting of PD-L1 and VEGF-A aims to deliver better efficacy and safety. BNT327 has shown encouraging preliminary activity in thoracic malignancies incl. SCLC (ESMO 2023) and NSCLC (ASCO & ESMO 2024). Methods: After a safety run-in (n=6), this ongoing, multicenter, single-arm phase 2 clinical trial recruited chemo naive pts (pts) aged ≥18 yrs with unresectable malignant mesothelioma (pleural (MPM) or peritoneal (MPeM)) to evaluate BNT327 30 mg/kg Q3W IV combined with 4-6 cycles pemetrexed and platinum, followed by BNT327 maintenance. Primary endpoints were efficacy (ORR per RECIST 1.1 for MPeM, mRECIST 1.1 for MPM) and safety (CTCAE V5.0). Results: As of 25 Oct 2023, 31 pts, median age 58 yrs (range 43-71), 80.6% ECOG PS 1 and 83.9% with metastatic disease had been enrolled, of which 23 had MPM and 8 MPeM. At the cutoff date of 20 Dec 2024, the median exposure duration was 16.0 mo (95% CI 8.1, 19.5) and median follow-up time 19.3 mo (95% CI 17.3, 20.9). In 23 pts with MPM, 1 pt had a CR and 9 had PRs as BOR, resulting in a confirmed ORR (cORR) of 43.5%. 10 pts had SD and 1 non-CR/non-PD, giving a DCR of 87.0%. Median PFS (mPFS) was 11.8 mo, and median DOR was 11.8 mo. The 12 mo OS rate was 82.6% (95% CI 60.1, 93.1), with median OS not yet reached. Among 13 pts with MPM of epithelioid histology, cORR was 30.8%, DCR was 84.6% and mPFS was 16.6 mo. Among 8 pts with MPeM, 6 had PR as BOR, leading to a cORR of 75.0%. 2 pts had SD, resulting in a DCR of 100%; median DOR was 16.3 mo. Median PFS and OS were not yet reached, with an OS rate of 62.5% (95% CI 22.9, 86.1) at 12 mo. 6 pts with MPeM of epithelioid histology displayed a cORR of 83.3%, DCR of 100% and mPFS of 19.5 mo. All pts experienced TRAEs, 93.5% of pts (29/31) of Grade (G) 3-4. 5 pts (16.1%) had G 3-4 treatment-related SAEs. 5 pts (16.1%) experienced an irAE, 1 (3.2%) of G 3-4. The most common TRAEs were decreased neutrophil count (27 pts, 87.1%), decreased white blood cell count (26 pts, 83.9%), proteinuria (24 pts, 77.4%), anemia (23 pts, 74.2%), decreased platelet count (19 pts, 61.3%), and nausea (16 pts, 51.6%). 6 pts discontinued treatment due to TRAEs; no treatment-related deaths occurred. 9 pts remain on treatment. Conclusions: BNT327 plus chemo as a 1L regimen for mesothelioma showed encouraging efficacy, including in tumors of epithelioid histology. AEs were consistent with those expected for the treatment regimen. Clinical trial information: NCT05918107 .