In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.
Contributed by Lauren Hitchings
ABSTRACT: Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials.gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.
