Updated efficacy, safety, and correlative analysis of a phase II trial in metastatic renal cell carcinoma with coordinated pembrolizumab and high dose IL-2.
Authors: Johnson Jeffrey S , Fishman Mayer N , Schell Michael J , Yu Xiaoqing , Wang Xuefeng , Roman Souza Gabriel , Miller Justin , Mizelle Sarah Raymond , Gullapalli Keerthi , Fazili Adnan Nazir , Guske Christopher , Mannam Gowtam , Jameel Ghazal , Cen Ling , Yao Jiqiang , Whiting Junmin , Swank Jennifer , Zhang Jingsong , Spiess Philippe E. , Chahoud Jad 
Published: February 2025

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Background:
The CM 214 trial with Nivolumab-ipilimumab recently presented its long term follow up results with regards to efficacy and safety. In this abstract, we similarly present extended 6 year follow up results of efficacy, safety, and correlative data from the phase 2 clinical trial combining IL-2 and short course pembrolizumab (pembro) for patients (pts) with metastatic renal cell carcinoma (mRCC).
Methods:
This phase 2 study included pts with untreated clear cell mRCC and ECOG 0-1 status. Pts were treated with a maximum of four 9-week blocks of pembro/IL-2. Pembro was dosed every 3 weeks throughout all four blocks without subsequent maintenance dosing. High dose IL-2 was administered only during blocks 2 and 3. At fixed time points, proteomic data via Olink and gene expression data via Nanostring were obtained for correlative analysis. The Kaplan-Meier method was utilized to determine updated overall survival (OS), progression-free survival (PFS), and treatment-free survival (TFS). TFS was defined as the time from completion of pembro/IL-2 to initiation of next therapy, date of last follow up if no subsequent line of therapy, or death. TFS was used to subdivide pts into extreme responders ( > 5 years with no further treatment), non-responders ( < 6 months until next line of therapy), and others. Proteomics and gene expression in extreme responders, non-responders, and others were compared via Wilcoxon rank sum test and logarithmic fold change in expression.
Results:
27 pts were enrolled in the study with 26 receiving treatment. The number of pts with IMDC risk of favorable, intermediate, and poor were 6, 19, and 1, respectively. The median time from the on-study date to last known alive or expired was 73 months (range: 13-86). OS probabilities for 1-, 3-, and 5-year intervals were 100% (95% confidence interval [CI]: 100-100%), 76.9% (CI: 55.7-88.9%), and 73.1% (CI: 51.7-86.2%) respectively. PFS at 1-, 3-, and 5-year intervals were 61.5% (CI: 40.3-77.1%), 42.3% (CI: 23.5-60.0%), and 42.3% (CI: 23.5-60.0%) respectively. TFS probabilities for 1-, 3-, and 5-year intervals were 76.9% (CI: 55.7-88.9%), 42.3% (23.5-60.0%), and 42.3% (23.5-60.0%) respectively. Of the 11 pts with durable disease control not requiring any further systemic therapy, none had persistent adverse events at the grade 2 or higher level. In a comparison of extreme responders to non-responders, IL-8 was found to have a 1.43 log fold change in expression with a p-value of 0.019 detected by the Nanostring assay. Additionally, ADA and GZMH showed -0.82 and -1.57 log fold change in expression detected via Olink assay with p-values of 0.002 and 0.039 respectively. Further correlative data will be presented at the meeting.
Conclusions:
Short course pembro in combination with high dose IL-2 allows for durable immune response. At 6 years median follow up, > 40% of pts have extended disease control without persistent toxicity or need for further systemic therapy. Moreover, we highlight select biomarkers that could be associated with this long-term response. Clinical trial information:
NCT02964078
.