1269P - Results from a randomised phase I/II trial evaluating the safety and antitumour activity of anti-PD-1 (MEDI0680)/anti-PD-L1 (durvalumab) vs anti-PD-1 (nivolumab) alone in metastatic clear cell renal cell carcinoma (ccRCC)

Abstract

BackgroundMEDI0680 is a humanised IgG4κ anti-programmed cell death-1 (PD-1) mAb. We hypothesised that simultaneous blockade of PD-1:PD-L1/PD-L2 with MEDI0680 (M) and PD-1:PD-L1/CD80 with anti-PD-L1 mAb durvalumab (D) would improve efficacy vs blockade of the PD-1:PD-L1/PD-L2 pathway (with nivolumab; N) alone. M+D was well tolerated in the dose-escalation phase of a Phase I/II study in pts with advanced solid tumours, with an ORR of 33% (10/30; including 3/4 RCC pts). In the Phase II portion of the study, we compared M+D to N in a dose-expansion cohort of pretreated, immunotherapy (IO)-naïve pts with metastatic ccRCC. MethodsEligible pts had received 1–3 prior therapy lines, no prior IO exposure and ≥1 measurable lesion. They were randomised 2:1 (stratified by MSKCC risk group and PD-L1 expression) to M 20mg/kg IV + D 750mg Q2W or N 240mg IV Q2W until unacceptable toxicity or disease progression, for ≤2 years. Endpoints included investigator-assessed ORR by RECIST v1.1 (primary endpoint), PFS and safety (secondary). Sample size was ∼60 to detect a difference of 26.0% (ie, ORR = 47.5%, assuming ORR of 21.5% for N) with 76% power at a 1-sided significance level of 0.10. ResultsBy Feb 24, 2019, 63 pts were randomised. Baseline pt/disease characteristics were generally well balanced, but more pts on N had favourable MSKCC risk (7/21; 33.3%) vs M+D (10/42; 23.8%). ORR was 14.3% (6/42; 2 CR, 4 PR; plus 2 unconfirmed PR) vs 19.0% (4/21; 4 PR, 0 unconfirmed) for M+D and N, respectively. There was no difference between arms in ORR by PD-L1 expression (<1% vs≥1%). All responses are ongoing. Median PFS was 3.6 months in both arms. Grade 3/4 treatment-related AEs (TRAEs) occurred in 26% on M+D (including 1 case of autoimmune encephalitis) and 19% on N. On M+D, 12% had TRAEs leading to treatment discontinuation, including colitis or diarrhoea (n=3) and increased ALT/transaminases (n=2), vs 5% on N (pancreatitis and increased lipase and amylase in 1pt). There were no Grade 5 TRAEs. ConclusionsEfficacy was similar with combined M+D and N monotherapy in pts with TKI-pretreated, IO-naïve, metastatic ccRCC, but more pts discontinued M+D due to TRAEs. Clinical trial identificationNCT02118337. Editorial acknowledgementAaron Korpal, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureM.H. Voss: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Honoraria (self): Eisai; Honoraria (self): Exelixis; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Calithera; Honoraria (self): Corvus. A.A. Azad: Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Research grant / Funding (institution), Non-remunerated activity/ies: Merck Serono; Honoraria (self), Advisory / Consultancy: Tolmar; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy: Telix Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Sanofi. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Triptych Health Partners; Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Epic Sciences; Research grant / Funding (institution): BMS; Research grant / Funding (institution): BI; Research grant / Funding (institution): Trovagene; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Novartis. I. Achour: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H. Hu: Full / Part-time employment: AstraZeneca. L. Lewis: Travel / Accommodation / Expenses, Full / Part-time employment: AstraZeneca. F.L. Walcott: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.F. Oosting: Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.