Dutcher, Janice P.

PURPOSE Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

4521 Background: Expression of PDL1 by RCC has been associated with aggressive histology and poor survival. Tissue obtained from the patients enrolled in the IL-2 Select Trial, a prospective, single arm, multicenter CWG study, was analyzed by IHC to determine if PDL1or PDL3 expression predicted for response to initial or subsequent therapy. Methods: Paraffin embedded tumor tissue was stained for PDL1 and PDL3 expression, and results were correlated with RECIST defined response to IL2 treatment. Tumor tissue was considered positive for PDL1 if >5% of the tumor membranes stained for the marker. A cutoff of 10% was used for PDL3. Duration of subsequent VEGFR/mTOR inhibitor therapy was also correlated with tissue PDL1/3 expression. Results: 120 eligible pts were enrolled; 115 had clear cell histology. The overall response rate (ORR) to IL2 was 25% (30/120) with a median OS of 40.6 months. 113 tumors were stained. 18 (16%) were PDL1+. ORR was 19% and 50% in the patients PDL1- and PDL1+ tumors, respectively (p=0.012). 85 (75%) tumors were PDL3+. ORR was 10.7% and 29.4% in the PDL3- and PDL3+ tumors, respectively (p=0.075). In the 17 patients who were positive for both PDL1 and PDL3, ORR was 52.9%. In the 27 pts who were negative for both PDL1 and PDL3, ORR was 11.1%. 69 patients received at least 1 dose of a VEGFR TKI as next therapy following IL2 treatment. 66 tumors were stained. Pts who were PDL1+/PDL3+ had a shorter duration on VEGFR TKI therapy compared to pts who were PDL1-/PDL3- (see Table). Conclusions: This small, retrospective analysis suggests that PDL1 and PDL3 tissue expression may predict for better response to IL2. PDL1 expression has been suggested as a possible predictor of response to anti-PD1 therapy. The current data suggests that its expression may predict for benefit to other immune therapies. PDL3 (+/- PDL1) expression appears to correlate to less benefit from subsequent VEGFR TKI therapy. Funded by NCI SPORE Grant # 5 P50 CA101942-08. [Table: see text]

4502 Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. > 1 site of resected disease, and by disease-free interval ≤ vs. > 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.

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. Clin Cancer Res; 21(3); 561–8. ©2014 AACR.