A Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) Analysis of Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma (aRCC)

Ruchitbhai Shah, Marc Botteman, Caitlyn T Solem, Linlin Luo, Justin Doan, David Cella, Robert J Motzer, Ruchitbhai Shah, Marc Botteman, Caitlyn T Solem, Linlin Luo, Justin Doan, David Cella, Robert J Motzer

Abstract

Background: This analysis compared quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between nivolumab and everolimus among previously treated patients with advanced renal cell carcinoma enrolled in the phase III CheckMate 025 trial (NCT01668784).

Materials and methods: At 45-month follow-up, overall survival (OS) was partitioned into 3 health states: TWiST, time with grade ≥ 3 toxicity (TOX), and time after progression (REL). Mean Q-TWiST was determined by multiplying each state's duration with its utility (TWiST, 1.0; TOX, 0.5; REL, 0.5). Relative Q-TWiST gains (calculated as Q-TWiST difference divided by everolimus OS) of ≥ 10% were predefined as clinically important. Immuno-oncology-specific sensitivity analyses considered 4 alternative progression definitions: Tumor size increase ≥ 25% from nadir; treatment discontinuation; ≥ 2-point reduction from baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms scores; and a composite definition. A scenario incorporating grade ≥ 2 toxicities was tested.

Results: Compared with everolimus, nivolumab was associated with a significant Q-TWiST improvement of 3.3 months (P < .001). In all sensitivity analyses, nivolumab was associated with Q-TWiST gains (relative gain %) ranging from 3.3 months (14.4%) to 4.8 months (20.9%).

Conclusions: Nivolumab is associated with a statistically significant and clinically meaningful gain in quality-adjusted OS versus everolimus among previously treated patients with advanced renal cell carcinoma.

Keywords: CheckMate 025; Immunotherapy; Kidney cancer; Quality-adjusted survival; Risk-benefit.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Alternative Progression Measures Considered for…
Figure 1. Alternative Progression Measures Considered for REL
Abbreviations: FSKI-DRS = Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; REL = time after progression.
Figure 2. Subgroup Analyses of Q-TWiST Difference
Figure 2. Subgroup Analyses of Q-TWiST Difference
Abbreviations: CI = confidence interval; MSKCC = Memorial Sloan Kettering Cancer Center; Q-TWiST = quality-adjusted time without symptoms of disease progression or toxicity; US = United States.
Figure 3. Kaplan-Meier Curve of PFS Based…
Figure 3. Kaplan-Meier Curve of PFS Based on Different Relapse Definitions
Abbreviations: CI = confidence interval; FKSI-DRS = Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors.

References

    1. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010; 7:245–57.
    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10–29.
    1. Fisher R, Gore M, Larkin J. Current and future systemic treatments for renal cell carcinoma. Semin Cancer Biol 2013; 23:38–45.
    1. Motzer RJ, Agarwal N, Beard C, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw 2009; 7:618–30.
    1. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017; 15: 804–34.
    1. Nurieva RI, Liu X, Dong C. Molecular mechanisms of T-cell tolerance. Immunol Rev 2011; 241:133–44.
    1. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8þ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007; 104:3360–5.
    1. Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006; 66:3381–5.
    1. Motzer RJ, Escudier B, McDermott DF, et al.; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373:1803–13.
    1. Salvatore L. Management of metastatic colorectal cancer patients: guidelines of the Italian Medical Oncology Association (AIOM). ESMO Open 2017; 2:e000147.
    1. Postmus D, Richard S, Bere N, et al. Individual trade-offs between possible benefits and risks of cancer treatments: results from a stated preference study with patients with multiple myeloma. Oncologist 2018; 23:44–51.
    1. Postmus D, Mavris M, Hillege HL, et al. Incorporating patient preferences into drug development and regulatory decision making: results from a quantitative pilot study with cancer patients, carers, and regulators. Clin Pharmacol Ther 2016; 99: 548–54.
    1. U.S. Food and Drug Administration. Plan for issuance of patient-focused drug development guidance under 21st Century Cures Act Title III Section 3002 2017. Available at: . Accessed: September 5, 2017.
    1. Schnipper LE, Davidson NE, Wollins DS, et al.; American Society of Clinical Oncology. American Society of Clinical Oncology Statement: a conceptual framework to assess the value of cancer treatment options. J Clin Oncol 2015; 33: 2563–77.
    1. Goldhirsch A, Gelber RD, Simes RJ, Glasziou P, Coates AS. Costs and benefits of adjuvant therapy in breast cancer: a quality-adjusted survival analysis. J Clin Oncol 1989; 7:36–44.
    1. Gelber RD, Goldhirsch A. A new endpoint for the assessment of adjuvant therapy in postmenopausal women with operable breast cancer. J Clin Oncol 1986; 4:1772–9.
    1. Husson O, Jones RL. Q-TWiST: what really matters to the cancer patient? Cancer 2017; 123:2200–2.
    1. Zbrozek AS, Hudes G, Levy D, et al. Q-TWiST analysis of patients receiving temsirolimus or interferon alpha for treatment of advanced renal cell carcinoma. Pharmacoeconomics 2010; 28:577–84.
    1. Solem CT, Kwon Y, Shah RM, Aly A, Botteman MF. Systematic review and benchmarking of quality-adjusted time without symptoms or toxicity (Q-TWiST) in oncology. Expert Rev Pharmacoecon Outcomes Res 2018; 18:245–53.
    1. Patil S, Figlin RA, Hutson TE, et al. Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-alpha. Br J Cancer 2012; 106:1587–90.
    1. Beaumont JL, Salsman JM, Diaz J, et al. Quality-adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma. Cancer 2016; 122:1108–15.
    1. Escudier B, Sharma P, McDermott DF, et al.; CheckMate 025 Investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol 2017; 72:962–71.
    1. Hoos A, Eggermont AMM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 2010; 102:1388–97.
    1. Revicki DA, Feeny D, Hunt TL, et al. Analyzing oncology clinical trial data using the Q-TWiST method: clinical importance and sources for health state preference data. Qual Life Res 2006; 15:411–23.
    1. Gelber RD, Cole BF, Gelber S, Goldhirsch A. Comparing treatments using quality-adjusted survival: the Q-TWiST method. Am Statist 1995; 49:161–9.
    1. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004; 22:454–63.
    1. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016; 34:1510–7.
    1. Chen TT. Statistical issues and challenges in immuno-oncology. J Immunother Cancer 2013; 1:18.
    1. Quinn DI, Shore ND, Egawa S, Gerritsen WR, Fizazi K. Immunotherapy for castration-resistant prostate cancer: progress and new paradigms. Urol Oncol 2015; 33:245–60.
    1. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412–20.
    1. Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. Am Soc Clin Oncol Educ Book 2013.
    1. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol 2012; 23(Suppl 8): viii15–21.
    1. Cella D, Yount S, Brucker PS, et al. Development and validation of a scale to measure disease-related symptoms of kidney cancer. Value Health 2007; 10:285–93.
    1. Haanen J, Carbonnel F, Robert C, et al.; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28:iv119-i142.
    1. Mazza C, Escudier B, Albiges L. Nivolumab in renal cell carcinoma: latest evidence and clinical potential. Ther Adv Med Oncol 2017; 9:171–81.
    1. Chen RC, Feuilly M, Meng J, et al. Quality-adjusted time without symptoms or toxicity (Q-TWiST): analysis of cabozantinib (Cabo) vs sunitinib (Sun) in patients with advanced renal cell carcinoma (aRCC) of intermediate or poor risk (Alliance A031203). J Clin Oncol 2018; 36(15 Suppl):4556.
    1. Rini BI. Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol 2009; 27:3225–34.
    1. Sundar R, Cho BC, Brahmer JR, Soo RA. Nivolumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol 2015; 7:85–96.
    1. Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol 2015; 33:3541–3.
    1. Wallace T, Torre T, Grob M, et al. Current approaches, challenges and future directions for monitoring treatment response in prostate cancer. J Cancer 2014; 5:3–24.
    1. Johal S, Santi I, Doan J, George S. Is RECIST-defined progression free-survival a meaningful endpoint in the era of immunotherapy? J Clin Oncol 2017; 35(6 Suppl):488.
    1. George S, Motzer RJ, Hammers HJ, et al. Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol 2016; 2:1179–86.
    1. Secord AA, Coleman RL, Havrilesky LJ, Abernethy AP, Samsa GP, Cella D. Patient-reported outcomes as end points and outcome indicators in solid tumours. Nat Rev Clin Oncol 2015; 12:358–70.
    1. Cella D, Bushmakin AG, Cappelleri JC, Charbonneau C, Michaelson MD, Motzer RJ. Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma. Br J Cancer 2012; 106: 646–50.
    1. Seymour L, Bogaerts J, Perrone A, et al.; RECIST Working Group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017; 18:e143–52.
    1. Berry V, Basson L, Bogart E, et al. REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma: a quality-adjusted time without symptoms of progression or toxicity analysis. Cancer 2017; 123: 2294–302.</References>

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