A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma

Abstract

Purpose: 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 II 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 antiangiogenic therapy.

Patients and methods: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. 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, 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% confidence interval (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. Because of adverse events, 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.

Trial registration: ClinicalTrials.gov NCT02118337.

Figure 1.

Percentage change from baseline in target lesion sum of diameters (as-treated population).

Figure 2.

Best percent change from baseline in target lesion sum of diameters for MEDI0680 with durvalumab (A), and nivolumab monotherapy (as-treated population; B). *New lesion occurred at the time best change from baseline achieved. CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease.

Figure 3.

Change in ctDNA mean VAF from baseline to week 4 (A) and percent change from baseline in mean VAF by clinical response (B). Subgroup analysis based on changes in ctDNA fraction using a 50% change from baseline cutoff in association with PFS (C), and OS (D) in the MEDI0680 + durvalumab arm. Reduction in ctDNA fraction ≥ 50% at 4 weeks versus baseline is defined as MR and reduction ctDNA fraction < 50% at 4 weeks versus baseline is defined as non-MR. AIC, Akaike Information Criteria; CI, confidence interval; CR, complete response; ctDNA, circulating tumor DNA; MR, molecular response; NA, not applicable; NS, not significant; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VAF, variant allele frequency.