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. Recently, 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

The trial is an open label, randomized, exploratory phase I/II adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and second (or later) line malignant pleural mesothelioma (MPM) to assess safety, immune activation and clinical efficacy of the combination treatment. In total, 31 patients were randomized in the trial, 20 patients in the ONCOS-102 in combination with SoC (8 patients were randomized in first line), and 11 patients in the control group receiving SoC only (6 in first line). The combination treatment with ONCOS-102 and SoC was well tolerated, with no safety signals beyond what is expected from SoC alone.

At the 30-month follow-up, mOS was 25.0 months for the subgroup of randomized, first-line ONCOS-102-treated patients (n=8). This is a clear improvement over the mOS of 13.5 months observed in the first-line SoC-only control group (n=6). Previous phase 3 clinical trials in MPM have reported mOS in the range of 12-16 months for patients receiving the same SoC chemotherapy treatment in the first-line setting.

Earlier, it was reported that ONCOS-102 treatment induces broad and powerful immune activation in MPM, far beyond what is achieved with SoC alone. Importantly, this immune activation is associated with better survival outcomes at the 21-month analysis, indicating that the immunological activity of ONCOS-102 drives the observed clinical benefit.

Based on the encouraging efficacy and the associated broad immune activation, the US FDA granted ONCOS-102 Fast Track designation for malignant pleural mesothelioma in February 2021.

The powerful immune activation generated by ONCOS-102 in mesothelioma, together with the emerging survival data (already exceeding that seen in the recent FDA approved combination of ipilimumab and nivolumab), builds a compelling rationale for combining ONCOS-102 with a checkpoint inhibitor in MPM and suggests we could reasonably expect a combination of ONCOS-102 with checkpoint inhibition to add incremental clinical benefit to patients with mesothelioma.

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.