ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment

Abstract

BackgroundONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.MethodsIn this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×1011virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.ResultsIn total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.ConclusionsONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.

Exploring treatment options in cancer: tumor treatment strategies

“…One is the treatment-related adverse events including some severe reactions such as lymphopenia, and thrombocytopenia, 20 , 329 , and combination with other therapy may increase the risk. 330 It is currently uncertain how OVs caused those adverse events, perhaps related to virus load and tumor necrosis. 331 Several measures have been taken to reduce the virulence and risks of adverse events.…”

Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy

“…Following these promising results, the phase III INFINITE trial was launched, which is evaluating the efficacy of intrapleural Ad-IFN in combination with celecoxib and gemcitabine in the second-or third-line context, and the results are expected in 2024. ONCOS-102 is a GM-CSF oncolytic adenovirus that demonstrated activity in a phase 1-2 study in combination with cisplatin and pemetrexed [67]. Phase 1 included 15 patients, and it was shown that the administration of the virus was safe and induced immune activation.…”