Replimune Group, Inc. presented primary analysis data from the IGNYTE clinical trial at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2024), showcasing the potential of RP1 in combination with nivolumab for treating melanoma patients who have progressed on anti-PD-1 therapy. The data demonstrated significant anti-tumor activity and durable responses, offering a promising new treatment option for this challenging patient population.
IGNYTE Trial Results
The IGNYTE trial included 140 patients with anti-PD-1 failed melanoma who received RP1 plus nivolumab after confirmed progression on anti-PD-1 based therapy, with or without anti-CTLA-4. 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, the trial's primary endpoint. An additional analysis requested by the FDA showed a 32.9% ORR by RECIST v1.1 criteria. The complete response (CR) rate by mRECIST v1.1 was 15%.
Notably, in patients who had prior anti-PD1 and anti-CTLA-4 treatment, the ORR was 27.7%, while those with primary resistance to anti-PD1 showed an ORR of 35.9% by mRECIST v1.1. These results suggest that RP1 plus nivolumab can overcome resistance mechanisms in a subset of patients.
Durability and Systemic Activity
The median duration of response from response initiation was 21.6 months, indicating a sustained benefit from the treatment. Furthermore, the therapy induced deep responses in both injected and non-injected lesions, with 85% of lesions in responders experiencing a 30% or greater reduction in size. RP1 plus nivolumab also demonstrated systemic activity by inducing responses in visceral organs 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 presented at SITC 2024 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 further demonstrated that RP1 plus nivolumab may stimulate tumors to a more immune-inflamed state, highlighting the potential of the combination to reverse 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, and pyrexia. Grade 3-4 events occurred in 12.8% of patients, with no Grade 5 events reported.
Ongoing Confirmatory Trial
The IGNYTE-3 confirmatory phase 3 trial, evaluating RP1 plus nivolumab versus physician's choice in patients with advanced melanoma who have progressed on anti-PD1 and anti-CTLA-4 or who are not candidates for anti-CTLA-4 therapy, is currently recruiting.
