Exposure-response (E/R) relationship of nivolumab (N) and ipilimumab (I) in patients (pts) with metastatic renal cell clear cell carcinoma (mRCC) from the randomised phase II BIONIKK study

BackgroundN-I is one of the first-line treatment in pts with mRCC. We aimed to investigate the (E/R) relationship of N+/-I in a subgroup of mRCC pts included in the phase 2 BIONIKK trial.MethodsThis ancillary study included mRCC pts treated with either N alone (group A, n=39) or N-I (group B, n=81). Trough plasma concentrations (Cmin) of N and I, and anti-drug antibodies against N (ADA-N) were assayed at week 6 (w6) after treatment start. The clinical endpoints included dose-limiting toxicity (DLT) defined as any toxicity leading to treatment discontinuation, progression-free survival (PFS) and overall survival (OS). Cox proportional hazards and logistic regression models were used to study the relationship between Cmin and clinical outcomes, respectively.ResultsNo statistical difference in baseline characteristics between group A and B was observed. The incidence of ADA-N was 8 and 15% in the groups A and B, respectively. Dose-normalized N Cmin was statistically lower in pts with ADA-N compared to those without (p=0.002). After a median (m) follow-up of 39.6 (IQR 30.0-48.6) months, mPFS [CI95%] was 7.8 [4.9-18.5] and 11.1 [9.9-21.8] months in groups A and B, respectively. In both groups A and B, the presence of ADA-N was not associated with shorter PFS (HR 0.87 [0.30-2.56], p=0.80 and HR 0.53 [0.23-1.26], p=0.15, respectively). In the group A, pts with high (above median) N Cmin had longer mPFS (HR 0.35, [0.17-0.74]; p=0.004) and mOS (HR 0.33, [0.13-0.84]; p=0.019) than pts with low Cmin, whereas N Cmin had no impact on both PFS (p=0.8) and OS (p=0.3) in the group B. However, higher I Cmin was associated with higher mPFS (HR 0.56 [0.33-0.96]; p=0.036), but had no impact on mOS (p=0.16). Finally, DLT occurrence (10% group A, 21% group B) was not associated with either N Cmin or I Cmin.ConclusionsIn the group A, the association between low N Cmin and shorter survival probably reflects the deleterious impact of disease state (cachexia) on drug elimination and survival. However, N Cmin at w6 is not a predictor of PFS in N-I patients, which suggests a different pattern of E/R relationship in these patients and requires further investigations.Clinical trial identificationNCT 02960906.Legal entity responsible for the studyARTIC (Association pour la Recherche en Thérapeutiques Innovantes en Cancérologie).FundingCARPEM.DisclosureB. Blanchet: Financial Interests, Personal, Advisory Board: GSK, Pierre Fabre Oncologie; Financial Interests, Personal, Invited Speaker: Pfizer, Eisai, BMS. A.A. Puszkiel: Financial Interests, Personal, Invited Speaker: Eisai, BMS, Pierre Fabre Oncology. D. Borchiellini: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bristol Myer Squibb, Ipsen, Janssen, Merck, Pfizer; Financial Interests, Institutional, Advisory Board: Bayer, MSD; Financial Interests, Personal, Invited Speaker: Accord HealthCare; Financial Interests, Institutional, Local PI, Clinical Research: Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, Exelixis, Infinity, Janssen, MSD, Roche, Taiho Oncology; Financial Interests, Institutional, Local PI: Aveo, Gilead, Seagen. B. Laguerre: Financial Interests, Personal, Other, ASCO GU symposium 2023 (travel and registration): Pfizer; Financial Interests, Personal, Other, honoraria: Astellas, Janssen, Pfizer, Eisai, Bayer; Financial Interests, Personal, Other, registration ASCO virtual meeting 2022: BMS; Financial Interests, Personal, Other, registration ASCO GU symposium 2022 (virtual): MSD; Financial Interests, Personal, Other, registration and travel for ASCO meeting 2023: Astra-Zeneca; Financial Interests, Personal, Other, registration and travel meeting ASCO GU 2024: Ipsen; Financial Interests, Personal, Other, registration virtual meeting EMOS 2023: MSD. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, Amgen, Gilead; Financial Interests, Personal, Invited Speaker: AstraZeneca. C. Tournigand: Non-Financial Interests, Leadership Role: GERCOR; Non-Financial Interests, Advisory Role: Fondation APHP. G. Gravis: Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Ipsen, AstraZeneca, alliance Merck Pfizer, Bayer, Eisai; Financial Interests, Institutional, Advisory Board: Alliance Merck-Pfizer, BMS, Janssen, Pfizer, Ipsen, Bayer, Eisai, Gilead, AstraZeneca, AAA Novartis, MSD; Financial Interests, Personal, Other, Support for attending meetings and/or travel: BMS, AstraZeneca, Bayer, Ipsen, MSD, Pfizer, Janssen, AAA Novartis; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS; Non-Financial Interests, Principal Investigator: Ipsen, BMS, Merck. S. Oudard: Financial Interests, Personal, Advisory Board, consultancy, advisory role: Sanofi; Financial Interests, Personal, Invited Speaker, public speaking and advisory role: Janssen; Financial Interests, Personal, Advisory Board, advisory role and public speaking: AstraZeneca, MSD, Merck, Astellas, Ipsen, Pfizer, Roche, Genentech; Financial Interests, Personal, Advisory Board, Advisory board and public speaking: BMS, Bayer, Novartis. Y. Vano: Financial Interests, Personal, Invited Speaker: Ipsen, BMS, MSD, Pfizer, Eisai; Financial Interests, Personal, Other, Congress and travel funding: Ipsen, MSD, Pfizer; Financial Interests, Institutional, Funding, Funding support for the CABIR study: Ipsen; Financial Interests, Instiotutional, Funding, Funding support for the BIONIKK study: Bristol Myers Squibb; Financial Interests, Personal, Steering Committee Member, Member of the scientific committee of the WITNESS study: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Tesaro. All other authors have declared no conflicts of interest.