Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).

8561 Background: MPM is an aggressive malignancy without curative treatment. ONCOS-102 is an oncolytic adenovirus expressing GM-CSF (Ad5/3-D24-GMCSF) with a clinically documented ability to stimulate local and systemic immune responses and re-modulate the tumor microenvironment, both as a monotherapy and in combination with anti-PD1 blockade. The study objectives included determining safety and tolerability, efficacy and immunological activation in repeat tumor biopsies, and correlations with clinical outcomes. Methods: Following a safety run-in of n = 6 pts, 25 patients were randomized to receive ONCOS-102 intratumorally under CT or US guidance at a dose of 3 x 10 11 Virus Particles on Day 1, 4, 8, 36, 78 and 120, plus six cycles of P/C starting on Day 22, or control comprising six cycles of P/C only. Both treatment-naïve (1L) and previously treated patients (2L) were enrolled. Imaging was done at baseline, Day 43-64 and 127-148 and tumor biopsy were collected at baseline and at Day 36. Final survival analysis (n = 25) was performed after 30 mo follow up. Multiplex immunofluorescence for immune cell subsets, RNASeq and qPCR was performed on repeat tumor samples. Results: The most frequent adverse events were anaemia, neutropenia and asthenia reported by > 50% in both groups with more frequent reports of pyrexia and nausea in the experimental (exp) group. No difference in the rate of severe events (Gr 3/4 acc to NCI CTCAE vs 4.0) were observed. 30-month survival rate (n = 25) was 34.3 % vs 18.2 % (NS) with mOS of 19.3 mo (95% CI: 4.6, NA) vs 18.3 mo (95% CI: 3.1, 28.9) in the exp group vs control. For patients treated in the 1L setting, 30 mo survival was 33.3 % in the exp group (n = 8) and 0% in the control group (n = 6) with mOS of 25.0 months and 13.5 months, respectively (NS). mPFS was unchanged from prior cut-offs; 9.8 months in the exp group and 7.6 in the control (NS). ONCOS-102 + P/C induced a pronounced increase in tumor infiltration by CD4+, CD8+ and granzyme B expressing CD8+ T-cells as well as M1:M2 macrophage polarization in patients with disease control (n = 13) vs progressing patients (n = 3). The data from RNAseq and qPCR analysis will be presented. Conclusions: The addition of ONCOS-102 to P/C was well tolerated by MPM patients and resulted in numerically improved 30-month survival rate in the overall population, and improved mOS in chemotherapy-naïve patients, albeit not statistically significant. Substantial immunological activation in tumor associated with ONCOS-102 was demonstrated, correlating with clinical benefit. Further exploration of ONCOS-102 as a treatment option in MPM is warranted Clinical trial information: NCT02879669.