ONCOS-102 showed encouraging Phase I efficacy data in a challenging patient population. In its Phase I clinical trial in heavily-pretreated patients with multiple types of solid tumors, ONCOS-102 demonstrated a stable disease (SD) rate of 40% in 10 evaluable patients.
- Patient-level data demonstrate multiple immunotherapeutic mechanisms. The Phase I data showed a dramatic increase in tumor-infiltrating cytotoxic CD8+ T-cells, innate immune system activation, and cancer specific CD8+ T-cells in blood indicating systemic activation of the immune system. Both the increase of innate immune cell infiltration and the increase of CD8+ T-cells were correlated with overall survival.
- Clean safety database in over 100 patients. A five-year compassionate use program has demonstrated an encouraging safety profile in 115 ONCOS-102 treated patients. Adverse events were mostly of grade 1 or 2. The ONCOS-102 Phase I study did not identify a dose-limiting toxicity.
- Synergistic potential in combination usage. Preclinical data has shown synergistic effects between ONCOS-102 and chemotherapy (doxorubicin/ifosfamide). There is also compelling mechanistic rationale for combining ONCOS-102 with immune checkpoint inhibitors, which would benefit from ONCOS-102’s innate immune system activation, co-stimulatory effects and T-cell activation, yielding a complete immunotherapeutic arsenal.
Mechanism of action ONCOS-102
ONCOS-102 in checkpoint inhibitor refractory melanoma
The trial is exploring safety, immune activation, and clinical response, of ONCOS-102 and Keytruda® (pembrolizumab), an anti-PD1 checkpoint inhibitor (CPI), in patients with advanced or unresectable melanoma whose tumors have continued to grow following prior CPI therapy. The trial is being conducted at the Memorial Sloan Kettering Cancer Center in New York, USA, Fox Chase Cancer Center in Philadelphia, USA and University of Maryland Comprehensive Cancer Center in Baltimore, USA. The results from the first six patients were presented at a Key Opinion Leader event hosted by Targovax in New York City on 11 October 2018. ClinicalTrials.gov Identifier: NCT03003676
Abscopal effect when combining oncolytic adenovirus and checkpoint inhibitor in a humanized NOG mouse model of melanoma
Targovax has built on the previous immune activation and anti-tumor findings and showed that the combination of ONCOS-102 and Keytruda can generate systemic responses that reduce the size of non-injected lesions, i.e. abscopal anti-tumor effect. This work was performed in a humanized melanoma mouse model with tumors inoculated dorsally on both sides of the animals. After the tumors were established, ONCOS-102 was injected directly into the tumor on one side only, followed by systemic treatment with Keytruda. By Day 40, tumors on the non-injected side of the animals had shrunk by an average of 70%.
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 (ClinicalTrials.gov Identifier: NCT02879669). To date, early data from the 6-patient safety cohort has been released, showing that the combination of ONCOS-102 with Pem-Cis is well-tolerated, and a disease control rate of 50% after six months. Patients are now being recruited into the randomized part of the trial, and the full data set is expected during the first half of 2020.