Adjuvant Pembrolizumab Improves QoL in Patients with High-Risk Resected Melanoma

Taken together with the primary clinical results, the secondary analysis of the SWOG S1404 phase III randomised clinical study demonstrated that pembrolizumab provides superior clinical and patient-reported quality-of-life (QoL) outcomes compared to standard of care with adjuvant ipilimumab or high-dose interferon-α2b for high-risk resected melanoma. S1404 is the largest published adjuvant anti-PD1 monotherapy study in melanoma that included 1303 eligible patients and those randomised to adjuvant treatment with pembrolizumab compared with ipilimumab or high-dose interferon-α2b had statistically significantly improved QoL outcomes according to multiple validated measures. The findings are published by Joseph M. Unger, PhD of the SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Center in Seattle, WA, US and colleagues on 23 November 2022 in the JAMA Oncology.

The authors emphasized in the 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 (RFS), overall survival, and QoL.

Adjuvant high-dose interferon improves RFS in this patient population, but it is associated with major grade 3 to 4 side effects and impaired QoL. The benefit of immune checkpoint blockade as adjuvant treatment for high-risk melanoma has been demonstrated in multiple randomised clinical studies. Ipilimumab, anti-CTLA4 antibody provides longer RFS 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-PD1 agents as monotherapy have a more favourable side effects 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 QoL, a comprehensive evaluation of patient-reported outcomes (PROs) is vital for aiding in decision-making. Physicians may underreport symptomatic side effects and overall QoL 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.

Clinical findings of SWOG S1404, an intergroup, randomised 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-α2b previously showed that patients treated with pembrolizumab had statistically significantly longer RFS, with a 23% reduction in risk of relapse. In the latest article published in the JAMA Oncology, the study team reports QoL outcomes.

The study was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this QoL substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary QoL endpoint.

QoL was assessed at baseline and cycles 1, 3, 5, 7, and 9 after randomisation 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 QoL scores over time. Regression analyses included adjustments for the baseline score, disease stage, and PD-L1 status. A clinically meaningful difference of 5 points was targeted.

Among 1303 eligible patients, median age was 56.7 years (range, 18.3-86.0), 524 were women (40.2%), 779 men (59.8%), 10 Asian (0.8%), 7 Black (0.5%), 44 Hispanic (3.4%), and 1243 White (95.4%); 1188 (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-α2b (32.1%) and 565 with pembrolizumab (67.9%). Evaluable patients were predominantly younger than 65 years (74.9%) and male (58.9%).

Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm, 96.0% in ipilimumab or high-dose interferon-α2b versus 98.3% in pembrolizumab arm (p = 0.25).

The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% confidence interval [CI] 7.9-11.3; p < 0.001) higher, indicating better QoL for pembrolizumab compared with ipilimumab or high-dose interferon-α2b, exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded 5 points in favour of pembrolizumab through cycle 7.

In post hoc analyses, FACT-BRM TOI scores favoured the pembrolizumab arm compared with the subset of patients receiving ipilimumab with difference of 6.0 points (95% CI 4.1-7.8; p < 0.001) or high-dose interferon-α2b with difference of 17.0 points (95% CI 14.6-19.4; p < 0.001).

The authors encouraged physicians to incorporate and discuss treatment-related QoL issues with patients when making shared decisions regarding the risks and benefits of adjuvant treatment in resected melanoma.

This work was supported by the US National Institutes of Health and National Cancer Institute grant awards, and in part by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

Reference

Unger JM, Darke A, Othus M, et al. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncology; Published online 23 November 2022. doi:10.1001/jamaoncol.2022.5486

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