Taken together with the primary clinical results, a secondary analysis of the phase III SWOG S1404 randomized clinical trial demonstrated that pembrolizumab provides superior clinical and patient-reported quality-of-life outcomes compared to standard of care with adjuvant ipilimumab or high-dose interferon alfa-2b for high-risk resected melanoma. The findings were published by Joseph M. Unger, PhD, and colleagues in JAMA Oncology.
Joseph M. Unger, PhD
Study Background
The authors emphasized in the study background that an important issue in the adjuvant treatment of patients with high-risk melanoma is how patients weigh the benefits of recurrence-free survival, overall survival, and quality of life.
Adjuvant high-dose interferon alfa-2b improves recurrence-free survival in this patient population, but it is associated with major grade 3 to 4 side effects and impaired quality of life. The benefit of immune checkpoint blockade as adjuvant treatment for high-risk melanoma has been demonstrated in multiple randomized clinical studies. Ipilimumab, an anti–CTLA4 antibody, provides longer recurrence-free survival in resectable high-risk melanoma—but with potentially dose-limiting side effects and treatment discontinuation in half of patients in a clinical trial setting. Anti–PD-1 agents as monotherapy have a more favorable side effect profile and are more efficacious compared with ipilimumab in the advanced and adjuvant settings. However, they can also result in acute and occasionally irreversible immune-related side effects.
The authors advocated that in a setting with potentially complex trade-offs that consider efficacy, risk reduction, and quality of life, a comprehensive evaluation of patient-reported outcomes (PROs) is vital for aiding in decision-making. Physicians may underreport symptomatic side effects and overall quality of life is not reflected in standard physician side effects reporting. PROs represent an important component of the patient experience, particularly in the resected setting, in which many patients are already cured with local treatment.
SWOG S1404
Clinical findings of SWOG S1404, an intergroup, randomized phase III study in patients with high-risk melanoma that examined whether adjuvant pembrolizumab improved clinical outcomes compared with standard care of adjuvant ipilimumab or high-dose interferon alfa-2b, previously showed that patients treated with pembrolizumab had statistically significantly longer recurrence-free survival, with a 23% reduction in risk of relapse. In the latest article published in the JAMA Oncology, the study team reports quality-of-life outcomes.
The study was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the United States, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this quality-of-life substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary quality-of-life endpoint.
Quality of life was assessed at baseline and cycles 1, 3, 5, 7, and 9 after random assignment using the Functional Assessment of Cancer Therapy (FACT) Biological Response Modifiers (FACT-BRM), FACT-General, Functional Assessment of Chronic Illness Therapy–Diarrhea, and European QoL 5-Dimension 3-Level scales. The primary endpoint was the comparison by arm of cycle 3 FACT-BRM trial outcome index (TOI) scores using linear regression. Linear-mixed models were used to evaluate quality-of-life scores over time. Regression analyses included adjustments for the baseline score, disease stage, and PD-L1 status. A clinically meaningful difference of five points was targeted.
Among 1,303 eligible patients, the median age was 56.7 years (range = 18.3–86.0 years); 524 were women (40.2%) and 779 were men (59.8%); 10 were Asian (0.8%), 7 were Black (0.5%), 44 were Hispanic (3.4%), and 1,243 were White (95.4%); 1,188 (91.1%) had baseline FACT-BRM TOI scores, and 832 were evaluable at cycle 3, of whom 267 were treated with ipilimumab or high-dose interferon alfa-2b (32.1%) and 565 with pembrolizumab (67.9%). Evaluable patients were predominantly younger than 65 years (74.9%) and male (58.9%).
FACT-BRM TOI
Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm: 96.0% in the ipilimumab or high-dose interferon arm vs 98.3% in the pembrolizumab arm (P = .25). The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% confidence interval [CI] = 7.9–11.3, P < .001) higher, indicating better quality of life with pembrolizumab compared to ipilimumab or high-dose interferon alfa-2b and exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded five points in favor of pembrolizumab through cycle 7.
In post hoc analyses, FACT-BRM TOI scores favored the pembrolizumab arm compared with the subset of patients receiving ipilimumab, with a difference of 6.0 points (95% CI = 4.1–7.8, P < .001) or high-dose interferon alfa-2b, with a difference of 17.0 points (95% CI = 14.6–19.4, P < .001).
The authors encouraged physicians to incorporate and discuss treatment-related quality-of-life issues with patients when making shared decisions regarding the risks and benefits of adjuvant treatment in resected melanoma.
Disclosure: This work was supported by the National Institutes of Health and National Cancer Institute grant awards, and in part by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit jamanetwork.com.
