ONCOS-102 in malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is a rare cancer of the lining of the lung, which is believed to be mainly caused by exposure to asbestos or industrial pollution. It is a very aggressive form of cancer, and the expected survival for MPM patients is less than one year from diagnosis. Currently, there are no curative treatment options available for MPM, however, standard treatments such as surgery, chemotherapy and radiotherapy can help improve prognosis and prolong life expectancy. Treatment with the chemotherapy combination of pemetrexed and cisplatin (Pem-Cis) has been the only widely recognized standard of care (SoC) for unresectable MPM, but the median progression-free survival (PFS) is only 6 months and median overall survival (mOS) 12 months from the initiation of treatment. The U.S. Food and Drug Administration (FDA) approved the combination of ipilimumab and nivolumab (Yervoy and Opdivo) for the first-line treatment of MPM based on mOS of 18.1 months (Baas 2020), and this is expected to serve as a benchmark for further approvals. This confirms that immunotherapy may benefit this patient group, although there is uncertainty related to how this combination will be implemented in clinical use (standard of care), i.e. for which patient groups. There is however still a high unmet medical need for patients suffering from this difficult-to-treat cancer.
Two end-stage MPM patients were included in Targovax’s Phase I basket trial testing ONCOS-102 as a single agent, with promising results. Both of these patients showed immune activation, both systemically and at the lesional level, indicating that ONCOS-102 can activate the immune system and increase tumor infiltrating T-cells into MPM tumors (Ranki et al. 2016). Strikingly, one of the patients had a 47% reduction in tumor volume 6 weeks after completing the trial and went on to live for 18 months, far longer than expected. As a next step, the effect of combining ONCOS-102 and Pem-Cis was assessed in an MPM mouse model, demonstrating synergistic anti-tumor activity of the combination (Kuryk et al. 2016). Following up on this work, it was shown that ONCOS-102 induces the activation of mesothelin-specific T-cells in mice with mesothelin-positive tumors, indicating that ONCOS-102 is capable of driving an MPM tumor-specific immune response.
Based on these findings Targovax initiated a randomized, phase I/II clinical trial combining ONCOS-102 with Pem-Cis in 31 patients with non-operable MPM.
Targovax demonstrates encouraging survival data for ONCOS-102 in mesothelioma
This study was a randomized phase 1/2 trial adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and later line malignant pleural mesothelioma (MPM) to assess safety, immune activation and clinical efficacy in 31 patients.
At the 30-month follow-up, 34% of ONCOS-102-treated patients (n=20) were still alive vs only 18% in the control group (n=11). Median overall survival (mOS) was 25.0 months for first-line ONCOS-102-treated patients (n=8) vs 13.5 months in the first-line SoC-only control group (n=6). The first line mOS of 25.0 months also compares favorably to historical control of 12-16 months for patients receiving the same SoC chemotherapy treatment, as well as the combination of nivolumab / ipilimumab double CPI which was recently approved as a first-line treatment option for MPM based on a phase 3 trial showing 18.1 months mOS.
Immune activation was assessed in tumor biopsies pre- and post-ONCOS-102 treatment and showed broad and powerful ONCOS-102-induced remodeling of the tumor microenvironment. In particular, this remodeling was hallmarked by increased T-cell infiltration and a shift towards pro-inflammatory immune cells, far beyond what was observed for the SoC-only control group. The level of immune activation was associated with both tumor responses and survival outcomes, indicating that the
immune activating capacity of ONCOS-102 is driving the clinical benefit for patients.
ONCOS-102 is still in development in mesothelioma. We are not supplying the product outside trials such as expanded or compassionate uses basis until further data have been generated.