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. 2021 Nov;9(11):e003743.
doi: 10.1136/jitc-2021-003743.

Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067

Meredith M Regan  1   2 , Charlene M Mantia  3   2 , Lillian Werner  3 , Ahmad A Tarhini  4 , James Larkin  5 , F Stephen Hodi  3   2 , Jedd Wolchok  6   7 , Michael A Postow  6   7 , Brian Stwalley  8 , Andriy Moshyk  8 , Corey Ritchings  8 , Sandra Re  8 , Wim van Dijck  9 , David F McDermott  2   10 , Michael B Atkins  11
Affiliations

Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067

Meredith M Regan et al. J Immunother Cancer. 2021 Nov.

Abstract

Background: Treatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067 and CheckMate 069 trials of the ICIs nivolumab and ipilimumab, alone or in combination, in patients with advanced melanoma after minimum follow-up of 36 months. This analysis investigated TFS differences between treatments in CheckMate 067 after a minimum follow-up of 60 months, and their relation to overall survival (OS) differences.

Methods: Data were from 937 patients who initiated treatment (nivolumab plus ipilimumab, nivolumab, or ipilimumab) in CheckMate 067 (NCT01844505). TFS was defined as the area between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic therapy initiation or death, each measured from randomization. TFS was partitioned as time with and without toxicity. Toxicity included persistent and late-onset grade ≥2 select treatment-related adverse events (ie, those of potential immunologic etiology). The area between Kaplan-Meier curves was estimated by the difference in 60-month restricted-mean times of the endpoints. Between-group differences were estimated with bootstrapped 95% CIs.

Results: At 60 months from randomization, 39%, 24%, and 11% of patients assigned to treatment with nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, had survived and were treatment-free. The 60-month mean TFS was approximately twice as long with the combination (19.7 months) than with nivolumab (9.9 months; absolute difference, 9.8 (95% CI 6.7 to 12.8)) or ipilimumab (11.9 months; absolute difference, 7.8 (95% CI 4.6 to 11.0)). In the respective groups, mean TFS represented 33% (8% with and 25% without toxicity), 17% (2% and 14%), and 20% (3% and 17%) of the 60-month period. Compared with 36-month estimates, mean TFS over the 60-month period represented slightly greater percentages of time in the nivolumab-containing regimen groups and a lesser percentage in the ipilimumab group. TFS differences between the combination and either monotherapy increased with longer follow-up.

Conclusions: Along with improved long-term OS with the nivolumab-containing regimens versus ipilimumab, TFS without toxicity was sustained with nivolumab plus ipilimumab versus either monotherapy, demonstrating larger between-group differences with extended follow-up.

Keywords: CTLA-4 antigen; clinical trials; immunotherapy; melanoma; phase III as topic; programmed cell death 1 receptor.

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Conflict of interest statement

Competing interests: MMR reports receiving grants and non-financial support from Bristol Myers Squibb for the work in this publication; grants and non-financial support (to her institution) for clinical trials from AstraZeneca, Ferring, Ipsen, Merck, Novartis, Pfizer, Pierre Fabre, Roche, and TerSera; grants from Bayer and Bristol Myers Squibb; consulting/advisory fees from Ipsen/Debiopharm; personal fees from Bristol Myers Squibb and Tolmar Pharmaceuticals; and non-financial support from Bristol Myers Squibb. CMM reports institutional support for statistical analysis and writing assistance from Bristol Myers Squibb for the work in this publication. LW reports receiving grants from Bristol Myers Squibb for the work in this publication. AAT reports receiving institutional grants from Bristol Myers Squibb, Genentech-Roche, Merck, and OncoSec; personal fees for advisory/consulting roles from Array Biopharma, BioNTech, Bristol Myers Squibb, Clinigen, EMD Serono, Genentech-Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer, and Sanofi-Genzyme/Regeneron. JL reports receiving personal fees from AIM, AstraZeneca, Bioevents, Bristol Myers Squibb, BUG, ESMO, EUSA Pharma, Incyte, KCA, MedConcept, Merck, NCRI, Novartis, Pfizer, Pierre Fabre, Roche, RVMais, and Syneos Health; consultancy fees from Aptitude, Bristol Myers Squibb, Calithera, Ervaxx, Immunocore, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seagen, and Ultimovacs; and research support from Achilles, Aveo, Bristol Myers Squibb, Convance, Immunocore, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Pharmacyclics, and Roche. FSH reports receiving non-financial support from Bristol Myers Squibb for the work in this publication; receiving grants/royalties to his institution from Novartis; personal fees for consultant/advisory roles from Aduro, Apricity, Bicara, Bioentre, Checkpoint Therapeutics, Compass Therapeutics, Eisai, Genentech/Roche, Idera, Immunocore, Iovance, Novartis, Pionyr, Psioxus Therapeutics, Sanofi, Surface, Takeda, and Trillium; receiving equity from Apricity, Bicara, and Pionyr; receiving other fees from Gossamer; having pending patents and receiving royalties for methods for treating MICA-related disorders (#20100111973); having pending patents for angiopoiten-2 biomarkers predictive of anti-immune checkpoint response (#20170248603), compositions and methods for identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms (#20160340407), therapeutic peptides (#20160046716; #20140004112; #20170022275; #20170008962), and anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses (#20170343552); and holding issued patents for tumor antigens and uses thereof (#7250291), therapeutic peptides (#9402905), vaccine compositions and methods for restoring NKG2D pathway function against cancers (#10279021), antibodies that bind to MHC class I polypeptide-related sequence A (#10106611). JDW reports receiving grants and consultancy fees from Bristol Myers Squibb for the work in this publication; consultancy fees from Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, Elucida, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Linneaus, Merck, Polynoma, Psioxus, Recepta, Sellas, Serametrix, Surface Oncology, Syndax, Syntalogic, Takara Bio, Trieza, Trishula, Truvax, and Werewolf Therapeutics; equity from Adaptive Biotech, Apricity, Arsenal IO, Beigene, Georgiamune, Imvaq, Linneaus, Serametrix, and Tizona Pharmaceuticals; patents pending for anti-CD40 agonist monoclonal antibody fused to monophosphoryl lipid A for cancer therapy, CAR+ T cells targeting differentiation antigens as means to treat cancer, engineered vaccinia viruses for cancer immunotherapy, heteroclitic cancer vaccines, identifying and treating subjects at risk for checkpoint blockade therapy associated colitis, immunosuppressive follicular helper-like T cells modulated by immune checkpoint blockade, phosphatidylserine targeting agents and uses thereof for adoptive T-cell therapies, and recombinant poxviruses for cancer immunotherapy; patents issued for alphavirus replicon particles expressing TRP2, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, anti-PD1 antibody, myeloid-derived suppressor cell assay, Newcastle disease viruses for cancer therapy, and xenogeneic DNA vaccines; patents licensed for anti-CTLA-4 antibodies (licensee: Agenus), anti-GITR antibodies and methods of use thereof (licensee: Agenus/Incyte), anti-PD1 antibody (licensee: Agenus), myeloid-derived suppressor cell assay (licensee: Serametrix), and xenogeneic DNA vaccines (licensee: Meriel); patent royalties for myeloid-derived suppressor cell assay and xenogeneic DNA vaccines. MAP reports receiving personal fees from Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Merck, NewLink Genetics, Novartis, and Pfizer; grants from Array BioPharma, AstraZeneca, Bristol Myers Squibb, Infinity, Merck, Novartis, and RGenix. BS, AM, and SR report being an employee of and holding shares in Bristol Myers Squibb. CR and WvD report being an employee of Bristol Myers Squibb. DFM reports receiving honoraria for consulting from Bristol Myers Squibb, Alkermes, Calithera Biosciences, Eisai, Eli Lilly, EMD Serono, Iovance, Merck, Pfizer, and Werewolf Therapeutics; and research support from Alkermes, Bristol Myers Squibb, Exelixis, Genentech, Merck, Pfizer, and X4 Pharma. MBA reports receiving grants from Bristol Myers Squibb and Merck; personal fees for consulting/advisory roles from Adagene, Agenus, Apexigen, Arrowhead, Asher Bio, AstraZeneca, Aveo, Bristol Myers Squibb, Calithera, Eisai, Elpis, Exelixis, Genetech-Roche, Idera, Iovance, Leads Bio, Merck, Neoleukin, Novartis, Pfizer, Pyxis Oncology, Scholar Rock, Surface, and Werewolf; and equity from Pyxis Oncology and Werewolf Therapeutics.

Figures

Figure 1
Figure 1
Characterization of how patients spent OS time: schematic illustration defining endpoints that partition area under the OS curve into TFS and other survival states. Areas equal restricted-mean times. aTime after cessation of protocol therapy without toxicity, before initiation of subsequent systemic anticancer therapy or death. bTime after cessation of protocol therapy with toxicity while treatment-free. cIncludes toxicity persisting from protocol therapy and toxicity newly presenting after protocol therapy cessation. OS, overall survival; TFS, treatment-free survival.
Figure 2
Figure 2
Kaplan-Meier estimates of endpoints, TFS and survival states characterizing how OS time was spent over the 60-month follow-up period since randomization. Toxicity was defined as grade ≥2 select TRAEs (ie, those of potential immunologic etiology). OS, overall survival; TFS, treatment-free survival; TRAE, treatment-related adverse event.
Figure 3
Figure 3
Percentage of mean times in survival states by time point of analysis: 60 vs 36 months of follow-up. Toxicity was defined as select TRAEs. Total mean TFS as a percentage of follow-up is annotated. TFS, treatment-free survival; TRAE, treatment-related adverse event.
Figure 4
Figure 4
Sixty-month mean times in survival states with various definitions of toxicity during TFS and during protocol therapy. IMM, immunomodulatory medication; TFS, treatment-free survival, TRAE, treatment-related adverse event.
Figure 5
Figure 5
Differences in TFS, OS, and survival state mean times by analysis time point at 24, 36, 48, and 60 months of follow-up from randomization. OS, overall survival; TFS, treatment-free survival.
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