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Background: In metastatic renal clear cell carcinoma (ccRCC), vascular endothelial growth factor receptor (VEGFR) and immune checkpoint are 2 main therapeutic targets. We investigated the impact of duration exposure to antiangiogenic on immunotherapy clinical outcomes in metastatic ccRCC., Methods: Patients from NIVOREN trial who received nivolumab after only 1 prior antiangiogenic therapy were included. Response rate, clinical benefit, progression free survival (PFS) and overall survival (OS) were prospectively analyzed depending on the duration of the first line (< 6 months, ≥6 months) and exploratory in patients with long first line exposure (≥18 months). The circulating levels of 8 plasma proteins and cytokines at baseline were collected and compared according to first line antiangiogenic duration., Results: Among 354 patients, 127 (36%) and 227 (64%) patients had received first line antiangiogenic for < 6months and ≥ 6months respectively. Respective duration of first line therapy was not associated with objective response to nivolumab (20.5% vs. 23.9%, P = .50), or PFS (HR 0.92; P = .421). Median OS was respectively 16.6 and 31.3 months in the <6 and ≥6 months subgroups respectively. Adjusted on international metastatic renal cell carcinoma database consortium risk, age and metastatic site, OS was longer in patients with longer treatment duration in the first line setting (HR 0.73; P = .017). Duration of first line VEGFR TKI was independent from circulating levels of 8 proteins and cytokines at nivolumab baseline., Conclusion: Nivolumab activity in second line is independent from first-line duration of VEGFR TKI. However, first line VEGFR TKI duration ≥ 6 months is associated with longer OS., Competing Interests: Disclosure GGD, CD, BE : no conflict of interest; SN:Honoraria: Bristol-MyersSquibb; Ipsen; MSD Oncology; Novartis; Pfizer.Consulting or advisory role e Bristol-Myers Squibb;Ipsen; MSD Oncology; Novartis; Pfizer. ResearchFunding: IPSEN (Inst); Pfizer (Inst). Travel, accommodations, and expenses :Bristol-Myers Squibb;IPSEN; Novartis; Pfizer. . GG: Speaker bureau: Janssen, Amgen, BMS, IPSEN, AAA, Astra Zeneca, Bayer, Pfizer Merck, Astellas. Recipient: my institution.Board: Janssen, Amgen, BMS, Curium, Bayer, Pfizer Merck. Recipient: my institution.Expert: BMS, Bayer, Pfizer/ merck. Recipient: my institution. BL: personal fees from Pfizer, Ipsen, MSD, Eisai, Astellas Pharma, and Janssen andnonfinancial support from Pfizer, Bristol Myers Squibb, and MSD; CC: advisory board ordata safety monitoring committee for Ipsen, Pfizer, Esaï, and GSK;and has received support for travel or meetings from Pfizer. SO :  fundings: Astellas, Astra Zeneca, Ipsen, Janssen, MSD, Pfizer, Roche, Sanofi, Bayer, BMS and Novartis. PB: Honoraria Astellas Pharma; BMS; IPSEN;Janssen-Cilag; Merck KGaA; MSD; Novartis; Pfizer.Consulting or advisory role e Amgen; AstraZeneca;BMS; Eisai; Ipsen; Janssen-Cilag; Merck KGaA; MSDOncology; Pfizer. Travel, accommodations, and expenses :Astellas Pharma; BMS; IPSEN; Janssen-Cilag;MSD; SL:Honoraria: BMS; Ipsen; Merck serono;Pfizer. Consulting or advisory role: Ipsen; DB:consulting and advisoryfees from Astellas Pharma, AstraZeneca, Bristol-MyersSquibb, Ipsen, Janssen-Cilag, MSD Oncology, Novartis, Pfizer, and Sanofi; research funding from AstellasPharma, AstraZeneca, Bristol-Myers Squibb, Exelixis,Infinity Pharmaceuticals, Janssen, MSD, and Roche;and travel and accommodations expenses from BristolMyers Squibb, Janssen, Pfizer, and Roche. CL: employment for Chugai (immediate family member); honoraria forPfizer, Astellas, Sanofi, Roche, and Ipsen; consulting/advisory role forAstellas; research funding for Pfizer, Roche, Sanofi, BMS, MSD, and Ipsen(paid to institution); expert testimony for Astellas; travel/accommodation/expenses for Ipsen, Astellas, and Pfizer. RF:Honoraria: Bristol-Myers Squibb, Pfizer, Ipsen, Astellas Pharma, MSD Oncology, Consulting or Advisory Role: Ipsen, Janssen Oncology, Research Funding: Bayer ; LA: grants and honoraria from Pfizer, Novartis, BMS, Ipsen, Roche, AstraZeneca, Amgen, Astellas, Exelixis, Corvus Pharmaceuticals, Peloton therapeutics, MSD and Merck, outside the submitted work. MGG: honoraria for consultancy: BMS, MSD, Ipsen, Pfizer, Eisai;, (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Proton pump inhibitors (PPI) may influence the gut microbiome and thus impact the effectiveness of immune checkpoint inhibitors (ICI). The effect of PPIs on the outcomes of ICI has not been fully explored and investigated in metastatic renal cell carcinoma (mRCC)., Methods: This retrospective analysis used prospectively collected data from the GETUG-AFU 26 NIVOREN (NCT03013335) phase II study which enrolled 729 mRCC patients of whom 720 were treated with nivolumab. The main objective of this analysis was to evaluate the impact of PPI on the efficacy and safety outcomes of mRCC patients. PPI use was defined as PPI administration on the day of ICI initiation., Results: Of the 707 patients with mRCC analyzed in this study, 196 (27.7%) were PPI users. The majority of PPI users were males (80.6%), had an ECOG performance status of 0-1 (78.9%) and a nephrectomy (82.1%). Almost two-thirds of the patients had a favorable and intermediate IMDC risk category and 52% received nivolumab in the third line and beyond. PPI use did not correlate with PFS or OS (HR = 0.89, 95% CI 0.74-1.08 and HR = 1.24; 95% CI, 0.98-1.58, respectively). Grade 3-5 nivolumab-related adverse events were more common among PPI users (25.5% vs. 15.3%)., Conclusions: This real-world study suggests that PPI use in patients with mRCC does not impact the efficacy outcomes but may influence the safety of nivolumab which warrants further investigations., (Copyright © 2022. Published by Elsevier Inc.)

Because of the recent approval of several drugs for the treatment of renal cell carcinoma (including sorafenib, sunitinib, temsirolimus, and, in Europe, bevacizumab plus interferon), the use of sequential therapy has become routine practice. There is now evidence that administering these targeted agents sequentially provides clinical benefit by inducing tumor shrinkage and prolonged progression-free survival (PFS) in a large number of patients. However, data regarding overall survival (OS) are still pending. By adding these drugs in an adequate order, one can expect an increase in overall PFS of up to 27 months and a subsequent improvement in the OS of patients with renal cell carcinoma. It has been recently reported that the OS of patients treated with sunitinib in the first-line setting was 26 months. Expecting a survival of 40 months does appear possible based on currently available data, although this assumption will have to be proven in the future., ((c) 2009 American Cancer Society.)