The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma

Abstract

Purpose: High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2.

Experimental design: Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with "good" predictive pathologic features based on an "integrated selection" model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression.

Results: One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%-33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification ("good-risk" 23% vs. "poor-risk" 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC.

Conclusions: In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both "good" and "poor-risk" patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation.

Fig. 1. Maximum change in summary target lesion measurements compared with baseline (WHO criteria)

Characteristics of tumor regression in patients with mRCC receiving HD IL-2 therapy by investigator assessment. Maximum reduction or minimum increase in sum of target lesion measurements compared with baseline in all treated patients with on-treatment tumor measurements. Graph shows best individual change up to first progression according to WHO criteria. Tumors were assessed after each cycle per WHO guidelines. Baseline tumor measurements were standardized to zero, tumor burden was measured as sum of the longest diameters of target lesions. Horizontal line at −50% indicates threshold for defining objective response (partial tumor regression) in the absence of new lesions or non-target disease progression according to WHO. By independent review, some degree of tumor regression was seen in 49 patients (42%). Red bars indicate patients with a PFS less than 3 years, blue bars indicate patients with a PFS greater than 3 years.

Fig. 2

Efficacy outcomes in patients with mRCC receiving HD IL-2. Kaplan-Meier curves of response duration in 30 objective responders (A), and overall survival and progression-free survival in 120 HD IL-2 treated patients with mRCC (B). The median duration of response in 30 responding patients was 20.6 months (A). Patients with mRCC had a median overall survival of 42.8 months (B). Progression-free survival rate was 11% at 3 years, and the median 4.2 months (B). Tick marks indicate censored events, defined for overall survival as the time to last known alive date before the date of data analysis for patients without a death and for progression-free survival as the time to the last tumor assessment before the date of data analysis for patients without disease progression or death.