A Randomized Ph2 Study of MEDI0680 in Combination With Durvalumab vs. Nivolumab Monotherapy in Patients With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Abstract Background: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase 2 study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy naïve patients with advanced clear cell renal cell carcinoma who received at least one prior line of anti-angiogenic therapy. Methods: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all IV Q2W. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden (TMB), and tumor-infiltrated immune cell profiles. Results: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% (7/42; 95% CI, 7.0-31.4) with combination treatment and 23.8% (5/21; 95% CI, 8.2- 47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Due to AEs, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. Conclusions: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy.