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Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies

Published:October 19, 2017DOI:https://doi.org/10.1016/j.ejca.2017.09.018

      Highlights

      • The regression of PFS and OS demonstrated good associations.
      • Different type of disease and mechanism of action of immune checkpoints inhibitors showed a very weak association.
      • Strong association of the RR with the PFS for CTL-4 checkpoints inhibitors.

      Abstract

      Introduction

      To assess the role of the tumour response rate (RR) after immune checkpoint inhibitors–based therapy as a potential surrogate end-point of progression-free survival (PFS) and overall survival (OS) in patients with solid tumours, we performed a trial-based meta-regression of randomised studies comparing different immune checkpoint inhibitors–based treatments.

      Methods

      The systematic literature search included the electronic databases and the proceedings of oncologic meetings. Treatment effects on PFS and OS were expressed as hazard ratios (HRs); treatment effects on RR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome.

      Results

      Twenty-four trials, for a total of 11,894 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for PFS or the log(HR) for OS on the log(OR) for RR demonstrated weak associations (R2 = 0.47; 95% confidence interval [CI], 0.03–0.77; P = 0.001; and R2 = 0.32; 95% CI, 0.02–0.76; P = 0.01, respectively). The pre-planned analyses stratifying trials according to different type of disease and different mechanism of action of immune checkpoint inhibitors showed a very weak association of the RR with the OS for non–small cell lung cancer indicated and a modest association of the RR with the PFS for cytotoxic T lymphocyte–associated antigen 4 checkpoint inhibitors.

      Conclusion

      The results of the trial-based meta-regression analysis indicated a weak correlation between RR and OS, supporting future investigations to assess the surrogacy of RR in the patient treated with immune checkpoint inhibitors.

      Keywords

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      References

        • Wolchok J.D.
        • Kluger H.
        • Callahan M.K.
        • Postow M.A.
        • Rizvi N.A.
        • Lesokhin A.M.
        • et al.
        Nivolumab plus ipilimumab in advanced melanoma.
        N Engl J Med. 2013; 369: 122-133
        • Tarhini A.A.
        • Iqbal F.
        CTLA-4 blockade: therapeutic potential in cancer treatments.
        Onco Targets Ther. 2010; 3: 15-25
        • Guo L.
        • Zhang H.
        • Chen B.
        Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor.
        J Cancer. 2017 Feb 10; 8: 410-416
        • Martin-Liberal J.
        • Ochoa de Olza M.
        • Hierro C.
        • Gros A.
        • Rodon J.
        • Tabernero J.
        The expanding role of immunotherapy.
        Cancer Treat Rev. 2017 Mar; 54: 74-86
        • Zitvogel L.
        • Kroemer G.
        Targeting PD-1/PD-L1 interactions for cancer immunotherapy.
        Oncoimmunology. 2012; 1: 1223-1225
        • Mavilio D.
        • Lugli E.
        Inhibiting the inhibitors: checkpoints blockade in solid tumors.
        Oncoimmunology. 2013; 2e26535
        • Lipson E.J.
        • Sharfman W.H.
        • Drake C.G.
        • Wollner I.
        • Taube J.M.
        • Anders R.A.
        • et-al
        Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody.
        Clin Cancer Res. 2013; 19: 462-468
        • Cooper Z.A.
        • Frederick D.T.
        • Ahmed Z.
        • Wargo J.A.
        Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma.
        Oncoimmunology. 2013; 2e24320
        • Vacchelli E.
        • Prada N.
        • Kepp O.
        • Galluzzi L.
        Current trends of anticancer immunochemotherapy.
        Oncoimmunology. 2013; 2e25396
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Burzykowski T.
        • Molenberghs G.
        • Buyse M.
        The evaluation of surrogate endpoints.
        Springer, New York, NY2005
        • Gail M.H.
        • Pfeiffer R.
        • Van Houwelingen H.C.
        • Carroll R.J.
        On meta-analytic assessment of surrogate outcomes.
        Biostatistics. 2000; 1: 231-246
        • Chambers J.M.
        Linear models.
        in: Chambers J.M. Hastie T.J. Statistical models in S. Wadsworth & Brooks/Cole, Pacific Grove, CA1992
        • Borghaei H.
        • Paz-Ares L.
        • Horn L.
        • Spigel D.R.
        • Steins M.
        • Ready N.E.
        • et al.
        Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 1627-1639
        • Brahmer J.
        • Reckamp K.L.
        • Baas P.
        • Crinò L.
        • Eberhardt W.E.
        • Poddubskaya E.
        • et al.
        Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 123-135
        • Ferris R.L.
        • Blumenschein Jr., G.
        • Fayette J.
        • Guigay J.
        • Colevas A.D.
        • Licitra L.
        • et al.
        Nivolumab for recurrent squamous-cell carcinoma of the head and neck.
        N Engl J Med. 2016; 375: 1856-1867
        • Herbst R.S.
        • Baas P.
        • Kim D.W.
        • Felip E.
        • Pérez-Gracia J.L.
        • Han J.Y.
        • et al.
        Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
        Lancet. 2016; 387: 1540-1550
        • Kwon E.D.
        • Drake C.G.
        • Scher H.I.
        • Fizazi K.
        • Bossi A.
        • van den Eertwegh A.J.
        • et al.
        Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
        Lancet Oncol. 2014; 15: 700-712
        • Langer C.J.
        • Gadgeel S.M.
        • Borghaei H.
        • Papadimitrakopoulou V.A.
        • Patnaik A.
        • Powell S.F.
        • et al.
        Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.
        Lancet Oncol. 2016; 17: 1497-1508
        • Lynch T.J.
        • Bondarenko I.
        • Luft A.
        • Serwatowski P.
        • Barlesi F.
        • Chacko R.
        • et al.
        Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.
        J Clin Oncol. 2012; 30: 2046-2054
        • Motzer R.J.
        • Escudier B.
        • McDermott D.F.
        • George S.
        • Hammers H.J.
        • Srinivas S.
        • et al.
        Nivolumab versus everolimus in advanced renal-cell carcinoma.
        N Engl J Med. 2015; 373: 1803-1813
        • Lynch T.J.
        • Bondarenko I.
        • Luft A.
        • Serwatowski P.
        • Barlesi F.
        • Chacko R.
        • et al.
        Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.
        Ann Oncol. 2013; 24: 75-83
        • Reck M.
        • Luft A.
        • Szczesna A.
        • Havel L.
        • Kim S.W.
        • Akerley W.
        • et al.
        Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer.
        J Clin Oncol. 2016; 34: 3740-3748
        • Reck M.
        • Rodríguez-Abreu D.
        • Robinson A.G.
        • Hui R.
        • Csőszi T.
        • Fülöp A.
        • et al.
        Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
        N Engl J Med. 2016; 375: 1823-1833
        • Ribas A.
        • Kefford R.
        • Marshall M.A.
        • Punt C.J.
        • Haanen J.B.
        • Marmol M.
        • et al.
        Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
        J Clin Oncol. 2013; 31: 616-622
        • Ribas A.
        • Puzanov I.
        • Dummer R.
        • Schadendorf D.
        • Hamid O.
        • Robert C.
        • et al.
        Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
        Lancet Oncol. 2015; 16: 908-918
        • Robert C.
        • Long G.V.
        • Brady B.
        • Dutriaux C.
        • Maio M.
        • Mortier L.
        • et al.
        Nivolumab in previously untreated melanoma without BRAF mutation.
        N Engl J Med. 2015; 372: 320-330
        • Weber J.S.
        • D'Angelo S.P.
        • Minor D.
        • Hodi F.S.
        • Gutzmer R.
        • Neyns B.
        • et al.
        Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
        Lancet Oncol. 2015; 16: 375-384
        • Bellmunt J.
        • de Wit R.
        • Vaughn D.J.
        • Fradet Y.
        • Lee J.L.
        • Fong L.
        • et al.
        Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
        N Engl J Med. 2017 Mar 16; 376 (Epub 2017 Feb 17): 1015-1026https://doi.org/10.1056/NEJMoa1613683
        • Rittmeyer A.
        • Barlesi F.
        • Waterkamp D.
        • Park K.
        • Ciardiello F.
        • von Pawel J.
        • et al.
        Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
        Lancet. 2017; 389: 255-265
        • Prentice R.L.
        Surrogate endpoints in clinical trials: definition and operational criteria.
        Stat Med. 1989; 8: 431-440
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • Wanders J.
        • Kaplan R.S.
        • Rubinstein L.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
        J Natl Cancer Inst. 2000; 92: 205-216
        • Mahoney K.M.
        • Atkins M.B.
        Prognostic and predictive markers for the new immunotherapies.
        Oncology. 2014; 28: 39-48
        • Patel S.P.
        • Kurzrock R.
        PD-L1 expression as a predictive biomarker in cancer immunotherapy.
        Mol Cancer Ther. 2015; 14: 847-856
        • Carbognin L.
        • Pilotto S.
        • Milella M.
        • Vaccaro V.
        • Brunelli M.
        • Caliò A.
        • et al.
        Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers.
        PLoS One. 2015 Jun 18; 10e0130142
        • Ferrucci P.F.
        • Gandini S.
        • Battaglia A.
        • Alfieri S.
        • Di Giacomo A.M.
        • Giannarelli D.
        • et al.
        Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients.
        Br J Cancer. 2015 Jun 9; 112: 1904-1910
        • Wistuba-Hamprecht K.
        • Martens A.
        • Heubach F.
        • Romano E.
        • Geukes Foppen M.
        • Yuan J.
        • et al.
        Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients.
        Eur J Cancer. 2017 Mar; 73: 61-70
        • Fojo A.T.
        • Noonan A.
        Why RECIST works and why it should stay: counterpoint.
        Cancer Res. 2012; 72: 5151-5157
        • Chiou V.L.
        • Burotto M.
        Pseudoprogression and immune-related response in solid tumors.
        J Clin Oncol. 2015 Nov 1; 33: 3541-3543