Data from Replimune's IGNYTE clinical trial, presented at the Society for Immunotherapy of Cancer (SITC) 2024, demonstrate promising anti-tumor activity of RP1 in combination with nivolumab in melanoma patients who have progressed on anti-PD-1 therapy. The study highlights the potential of this combination to generate a potent anti-tumor immune response and overcome resistance to prior immunotherapy.
IGNYTE Trial Results
The IGNYTE trial included 140 patients with anti-PD-1 failed melanoma who received RP1 plus nivolumab. The primary analysis, conducted after a median follow-up of 15.4 months, revealed an overall response rate (ORR) of 33.6% by modified RECIST (mRECIST) v1.1 criteria. Notably, the complete response (CR) rate was 15%. In patients who had prior anti-PD1 and anti-CTLA-4, the ORR was 27.7%, and for those with primary resistance to anti-PD1, the ORR was 35.9% by mRECIST v1.1.
The median duration of response from response initiation was 21.6 months, indicating durable anti-tumor activity. An impressive 85% of lesions in responders, both injected and non-injected, experienced a 30% or greater reduction in size. The combination induced deep responses in non-injected lesions in visceral organs, even those distant from the injection site.
Median overall survival for the trial has not been reached, but one-, two-, and three-year survival rates were 75.3%, 63.3%, and 54.8%, respectively. The 12-month progression-free survival (PFS) was 32.8%, and the median PFS was 3.7 months.
Biomarker Analysis
Initial biomarker data from the SITC presentation showed an increase in the expression of genes associated with CD8+ T cells and inflammatory cytokines, as revealed by tumor inflammation signature (TIS) and nano string analysis. Immunohistochemistry (IHC) images suggest that RP1 plus nivolumab may stimulate tumors to a more immune-inflamed state, potentially reversing mechanisms of resistance to anti-PD-1 therapy.
Kostas Xynos, MD, PhD, MBA, Chief Medical Officer of Replimune, stated, "The initial biomarker analyses included in the SITC presentation which demonstrate increases in tumor CD8+ T cell infiltration and PD-L1 expression along with the induction of an immune inflammatory gene signature after treatment, further support the intended mechanism of RP1 in combination with nivolumab, including its ability to induce a systemic response after progression on prior anti-PD1 therapy."
Safety and Tolerability
RP1 combined with nivolumab continues to be well-tolerated. Treatment-related adverse events were predominantly Grade 1-2 constitutional type events, including fatigue, chills, pyrexia, and nausea. The incidence of Grade 3-4 events was low (12.8% of patients), with rare Grade 4 events reported.
Ongoing Confirmatory Trial
The IGNYTE-3 confirmatory phase 3 trial is currently recruiting patients with advanced melanoma who have progressed on anti-PD1 and anti-CTLA-4 or who are not candidates for anti-CTLA-4 therapy. This trial evaluates RP1 plus nivolumab versus physician’s choice and aims to further validate the efficacy and safety of this combination.
