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) is 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. Therefore, there is 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 turn “cold” MPM tumors “hot” (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 has initiated a randomized, 30-patient phase I/II clinical trial combining ONCOS-102 with Pem-Cis in patients with non-operable MPM ( Identifier: NCT02879669).

The trial is an open label, exploratory phase I/II adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and second (or later) line MPM to assess safety, immune activation and clinical efficacy of the combination treatment. In total, 31 patients have been enrolled in the randomized trial design, with 20 patients in the experimental group receiving the ONCOS-102 and SoC combination, and 11 patients in a control group receiving SoC only. All patients have completed the treatment phase (4 months for the control group and 5 months for the experimental group) and the first data have been analyzed. The combination treatment with ONCOS-102 and SoC was well tolerated, with no safety signals beyond what is expected from SoC alone.

Early data show median Progression Free Survival (mPFS) of 8.4 months (95% CI 2.0, NA) in the experimental group vs 6.8 months (95% CI 2.6, NA) in the control group. In first line patients, the mPFS was 8.9 months (n=11; 95% CI 2.1, NA) vs 6.8 months (n=6; 95% CI 2.6, NA), respectively. This compares favorably to historical control, which have reported mPFS of 5.7-7.3 months (Vogelzang 2003, Ceresoli 2006, Zalcman 2016). Although the mPFS is encouraging, many patients are still censored. Therefore, the results should be considered as emerging and will change over time. The patients continue to be followed, and updated PFS figures will be reported later in 1H20.

Overall Response Rate (ORR) and Best Overall Response Rate (BORR) in first line patients have been in the range of 20-40% in previously published studies (Vogelzang 2003, Hazarika 2005, Ceresoli 2006, Zalcman 2016), but proven a poor predictor of survival outcomes. The first line ORR and Disease Control Rate (DCR) in this trial were 30% and 90% in the experimental group (n=10, measured at 5 months), and 33% and 83% in the control group (n=6, measured at 4 months). For second (or later) line patients, ORR / DCR were 11% / 67% in the experimental group (n=9) and 60% / 80% in the control group (n=5). The unexpected control group ORR of 60% is far above previous results and experience in clinical practice. Due to the relatively small sample size none of the above data reach statistical significance.

The first set of immunological analyses show robust immune activation following ONCOS-102 treatment. In tumor biopsy immunohistochemistry (mIHC), 10 of 15 evaluable patients in the experimental group had increased tumor infiltrating CD8+ T-cells. Importantly, 9 of these 15 had increased PD-L1 expression in the tumor, of whom 7 remained progression free at the time of analysis. These results indicate a positive association between immune activation and clinical outcome, and suggests that the patients would be susceptible to combination treatment with a checkpoint inhibitor. Additional biomarker analyses are being performed and will be reported later in 1H20.