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Clinical Trial
. 2024 Apr 11;12(4):e008293.
doi: 10.1136/jitc-2023-008293.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A)

Michael B Atkins  1 , Opeyemi A Jegede  2 , Naomi B Haas  3 , David F Mcdermott  4 , Mehmet A Bilen  5 , Mark Stein  6   7 , Jeffrey Sosman  8 , Robert Alter  9 , Elizabeth R Plimack  10 , Moshe C Ornstein  11 , Michael Hurwitz  12 , David J Peace  13 , David Einstein  4 , Paul J Catalano  2 , Hans Hammers  14 , Meredith M Regan  2
Affiliations
Clinical Trial

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A)

Michael B Atkins et al. J Immunother Cancer. .

Abstract

Background: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration.

Methods: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured.

Results: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free.

Conclusions: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

Keywords: Clinical Trials as Topic; Immune Checkpoint Inhibitors; Immunotherapy; Renal Cell Carcinoma.

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Conflict of interest statement

Competing interests: MBA has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Exelixis, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio, Pliant Therapeutics, Atreca, OncoRena, Sanofi and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Agenus, Asher Bio, and AstraZeneca. He reports research support to his institution from Bristol-Myers Squibb and Merck. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. OAJ—none. NBH is a paid consultant to BMS, Eisai, Exelixis, Merck and Roche Genentech. DFM has acted as a paid consultant for and/or as a member of the advisory boards of BMS, Pfizer, Merck, Alkermes, Inc, EMD Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Technologies, Calithera Biosciences, Synthekine, Inc., Johnson served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis. MH has served on Advisory Boards for Bristol Myers Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen and has received research support to his institution from Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, SeaGen, Tmunity, Torque, Unum. He also reports Spouse salary from Gamida Cell, Arvinas. DJP holds stock in Bristol-Myers Squibb and Merck. DE reports research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, Mink Therapeutics, Novartis, Puma Biotechnology, and Sanofi, as well as discounted research sequencing from Foundation Medicine and honorarium from OncLive. PJC—none. HH has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, BMS, Pfizer, Merck, Corvus, Armo Biosciences, Eisai, Eli Lilly, Surface Oncology, Aveo and Novartis and has received grants to his institution from Merck, Bristol-Myers Squibb, Surface Oncology and Aravive for work performed as outside of the current study. MMR reports research funding to institution from AstraZeneca, Bayer, Biotheranostics, Bristol-Myers Squibb, DebioPharm, Ipsen, Novartis, Pfizer, Roche, TerSera Therapeutics, all outside of the current study, and a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, DebioPharm, Ipsen, TerSera Therapeutics, Tolmar Pharmaceuticals.

Figures

Figure 1
Figure 1
Schema for TFS analysis. This figure displays the study design for the treatment-free survival (TFS) component of the HCRN GU16-260 trial. This analysis was restricted to the 128 patients enrolled in Cohort A-clear cell RCC. For purposes of this analysis, starting with Part A (nivolumab monotherapy) and going on to Part B (nivolumab+ipilimumab boost) at either the time of progressive disease or if biopsy confirmed radiographic stable disease at 48 weeks was considered one regimen. In this analysis, TFS (blue brackets) begins when treatment stops for either a treatment-related adverse event (TRAE), progressive disease or treatment completion (Part A: up to 96 weeks, Part A to Part B: usually up to 108 weeks) and ends with the start of subsequent systemic therapy or death. ccRCC, clear cell renal cell carcinoma; CR, complete response; nccRCC, non-clear cell renal cell carcinoma; PD, progressive disease; PR partial response; RCC, renal cell carcinoma; stable disease.
Figure 2
Figure 2
Kaplan-Meier plots of survival states. (A) Displays the Kaplan-Meier curves for time to protocol therapy cessation, time to subsequent therapy initiation or death, and overall survival for all study patients over a restricted 36 months period. The right end of the curves denotes the 36-month landmarks for each of these curves. The 96-week maximum treatment for those on Part A is denoted. (B) Displays the same Kaplan-Meier curves with the areas between the curves colored to denote specific survival states. Time on protocol treatment is in purple, time of treatment-free survival (TFS) is in blue, time after subsequent systemic therapy is in dark gray and time not alive is in light gray. Further, the light purple and light blue areas represent the time on treatment and time treatment-free, respectively, with grade 3–4 toxicity. The mean area (months and percentage of 36 months) for the areas beneath the OS and time on protocol therapy curves and between the various Kaplan-Meier curves are provided in Table 3. (C,D) Represent the same plot restricted to patients with International Metastatic RCC Database Consortium-favorable-risk or intermediate/poor-risk, respectively. OS, overall survival; Rx, treatment; TRAE, treatment-related adverse event.
Figure 3
Figure 3
Modified swimmer’s plots. (A) Displays the treatment course for each of the 128 patients by International Metastatic RCC Database Consortium risk category with time 0 on the x-axis denoting the time at which protocol therapy was stopped. Therefore, the lines to the left of time 0 (shown in purple) represent time on protocol therapy and to the right of time 0 represent time in TFS (blue) and after subsequent protocol therapy initiation (gray). Various trial milestones for each patient are represented by the circles (green=time of disease response, yellow=time of disease progression on Part A, brown=time of disease progression on Part B, red=time of death and blue=time of follow-up censoring for being alive either still subsequent treatment free (in TFS) or after initiating subsequent therapy. The
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References

    1. Regan MM, Mantia CM, Werner L, et al. . Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in checkmate 067. J Immunother Cancer 2021;9:e003743. 10.1136/jitc-2021-003743 - DOI - PMC - PubMed
    1. Regan MM, Jegede OA, Mantia CM, et al. . Treatment-free survival after immune checkpoint inhibitor therapy versus targeted therapy for advanced renal cell carcinoma: 42-month results of the checkmate 214 trial. Clinical Cancer Research 2021;27:6687–95. 10.1158/1078-0432.CCR-21-2283 - DOI - PMC - PubMed
    1. Atkins MB, Jegede OA, Haas NB, et al. . Phase II study of nivolumab and salvage nivolumab/Ipilimumab in treatment-naive patients with advanced clear cell renal cell carcinoma (HCRN Gu16-260-cohort A). J Clin Oncol 2022;40:2913–23. 10.1200/JCO.21.02938 - DOI - PMC - PubMed
    1. Atkins MB, Jegede OA, Haas NB, et al. . Phase II study of nivolumab and salvage nivolumab/Ipilimumab in treatment-naive patients with advanced non-clear cell renal cell carcinoma (HCRN Gu16-260-cohort B). J Immunother Cancer 2023;11:e004780. 10.1136/jitc-2022-004780 - DOI - PMC - PubMed
    1. Regan MM, Werner L, Rao S, et al. . Treatment-free survival: a novel outcome measure of the effects of immune checkpoint inhibition-a pooled analysis of patients with advanced melanoma. J Clin Oncol 2019;37:3350–8. 10.1200/JCO.19.00345 - DOI - PMC - PubMed

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