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In the latest of our series of expert oncologist interviews, Dr Michael Wong, Physician in Chief at Roswell Park Comprehensive Cancer Center, discussed his paper, “RP1 Combined With Nivolumab in Advanced Anti–PD-1–Failed Melanoma (IGNYTE),” which was recently published in Journal of Clinical Oncology.
The past decades of innovation have changed advanced melanoma from a disease that proves lethal in less than a year to one in which patients can often achieve long-term remission of their cancers. However, benefits have been mostly limited to patients who have targetable mutations or tumors that can drive immune responses after circumvention of an immune checkpoint using monoclonal antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), both of which are generally well tolerated. Outside of these subsets, patients must often undergo more-toxic therapy approaches, often with limited benefit, and there is an urgent medical need for additional therapy options.
In this area of unmet need, the capability of viruses to infect and kill cells in an immunogenic manner has been leveraged to develop viral oncolytic therapies for localized delivery into melanoma lesions. Although there has been some success with initial agents developed from the herpes simplex virus type 1 (HSV-1) backbone, they have shown limited activity to date beyond that of immune checkpoint inhibition alone for metastatic melanoma that has progressed during treatment with an immune checkpoint inhibitor. The latest generation of viral oncolytics includes RP1, now referred to as vusolimogene oderparepvec. This agent was generated using an HSV-1 strain with increased oncolytic activity in preclinical model systems. In addition to transgenes incorporated in the backbone of prior generation viral oncolytics, RP1 expresses an additional transgene (GALV-GP R-) that is designed to promote tumor cell fusion and immunogenic cell death. (as described previously by Dr Omid Hamid).
In this interview, Michael Wong, MD, PhD, FRCPC, discusses the recently published primary analysis of the IGNYTE trial, which investigated the activity of RP1 in combination with nivolumab in patients with melanoma that had progressed on an anti–PD-1—based therapy (N = 140). In this challenging patient population, the RP1 combination achieved responses in 32.9% of treated patients (95% CI, 25.2% to 41.3%; with 15.0% achieving complete response), and responses were durable (median, 33.7 months; 95% CI,14.1 to not reached). Notably, responses were similar for injected and noninjected lesions, including visceral lesions. In commenting on how a systemic antitumor immune response could be achieved in lesions refractory to anti–PD-1 therapy, Dr Wong explained, “The job is to overcome this refractoriness . . . by creating the proper environment. Exposing the body’s immune cells to tumor material in that proper environment, is the key factor here.”
In terms of toxicity, the RP1 + nivolumab regimen was generally well tolerated. Grade 1 or 2 treatment-related adverse events occurred in 77.1% of patients (mostly flu-like reactions), but grade 3 and 4 events occurred in only 9.3% and 3.6% of patients, respectively. There were no treatment-related deaths.
