Adjuvant Pembrolizumab Does Not Affect Long-Term HRQOL in Stage III Melanoma

Treatment with pembrolizumab (Keytruda) in the adjuvant setting did not have a significant impact on long-term health-related quality of life (HRQOL) outcomes vs treatment with placebo in patients with resected stage III melanoma, supporting the utility of pembrolizumab in the adjuvant setting, according to data from the phase 3 EORTC 1325-MG/KEYNOTE-054 trial (NCT02362594) published in The Lancet Oncology.¹

At a clinical data cutoff date of January 17, 2022, a total of 514 patients were treated with pembrolizumab, and 505 were treated with placebo; completion of the HRQOL evaluation at baseline was 94% in the pembrolizumab group and 92% in the placebo group. From baseline, the mean change in long-term global health status/quality of life scale (GHQ) was –0.56 (95% CI, –2.33-1.22) and 1.63 (95% CI, –0.12-3.38) in the pembrolizumab and placebo arms, respectively. This led to a difference of –2.19 (95% CI, –4.65-0.27; P = .081) between the 2 groups, though all other scales were not statistically significant.

“When discussing adjuvant immunotherapy with patients, we must balance efficacy with toxicity, particularly long-term toxicity that might affect long-term HRQOL,” Emanuel Bührer, MD, of the European Organization for Research and Treatment of Cancer, and coauthors, wrote. “This balance is important for patients in the adjuvant setting because they have a relatively high chance of cure. Our results aid in the understanding of the effect immune checkpoint inhibitors [ICIs] might have on long-term HRQOL, an area with scarce evidence to date.”

Due to the significant improvement in survival outcomes—particularly in the adjuvant setting—seen with ICI treatment in melanoma, oncologists have widely accepted the adoption of this treatment approach for eligible patients, which has been associated with reduced recurrence risks. One of these inhibitors is pembrolizumab, which yielded increased effectiveness when used in the double-blind, randomized, controlled KEYNOTE-054 trial.

In February 2019, data from the KEYNOTE-054 trial supported the FDA approval of pembrolizumab for the treatment of patients with high-risk stage III melanoma with lymph node involvement following complete resection in the adjuvant setting.² Despite this regulatory decision, HRQOL remained an exploratory end point in the clinical study, leading investigators to report on long-term HRQOL data, which was defined as HRQOL data collected approximately 2 to 4 years from randomization on the study.¹

To be eligible for evaluation, patients must have been 18 years of age or older, have an ECOG performance status of 0 or 1, and have histologically confirmed cutaneous stage IIIA, IIIB, or IIIC melanoma. These participants were recruited from 123 academic centers and community hospitals in 23 countries. Patients were excluded from participation if they had received prior systemic therapy for their disease.

Eligible patients (n = 1019) were randomly assigned 1:1 to receive treatment with either 200 mg of intravenous pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for a total of 18 doses or until disease recurrence, unacceptable toxicity, major protocol violation, or withdrawal of consent. Stratification factors included disease stage and geographical region.

To assess HRQOL, the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30; version 3) was utilized. The questionnaire features 5 functioning scales including physical, role, emotional, cognitive, and social; 8 symptom scales including fatigue, nausea or vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, and diarrhea; and GHQ. These assessments were completed by patients at baseline, every 12 weeks between weeks 12 and 108, and every 6 months between months 30 and 48 regardless of treatment and disease status. Long-term HRQOL assessments took place between and including those given at 108 weeks and 48 months after treatment randomization.

“HRQOL was assessed with the EORTC QLQ-C30 and the EQ-5D-5L questionnaires, revealing no significant difference between pembrolizumab and placebo up to 48 weeks of treatment. These data support our findings that improved efficacy does not necessarily come with reduced HRQOL in patients with melanoma treated with adjuvant pembrolizumab compared with placebo,” he reported.

Of the patients enrolled on the study, 33 treated with pembrolizumab and 38 treated with placebo did not have baseline evaluation. This led to 481 patients in the pembrolizumab arm and 467 patients in the placebo arm having baseline evaluation and being included in the analysis of the mean post-baseline HRQOL.

Notably, all patients who were evaluated at baseline for HRQOL and were alive 108 weeks from randomization were included in the analysis of long-term HRQOL.

The primary end point of the study was recurrence-free survival in the intention-to-treat population and patients with PD–L1-positive tumors, though HRQOL was a prespecified exploratory end point. Secondary end points included distant metastasis–free survival, overall survival (OS), safety, pharmacokinetics, and development of antidrug antibodies. Notably, OS data are immature and will be reported at a later time.

“We chose physical functioning, one of the core HRQOL domains, because it has been consistently recognized as an outcome that can be directly affected by treatments, can be observed, and is of key relevance to patients,” Bührer stated in the research, adding that “we focused on fatigue because it was identified as a key potential symptom associated with immune-related adverse effects [IRAEs].”

Of the patients evaluated at baseline, most were male (pembrolizumab arm, 62%; placebo arm, 61%). The median age of patients was 54 years in both the pembrolizumab arm (interquartile range [IQR], 45-64) and the placebo arm (IQR, 44-65). Additionally, in the pembrolizumab arm, 38%, 39%, and 24% of patients were less than 50 years of age, between 50 and 64 years of age, and 65 years of age or older, respectively; these respective rates were 37%, 38%, and 25% in the placebo group.

Patients’ American Joint Committee on Cancer (AJCC)–7 stages were IIIA (pembrolizumab arm, 15%; placebo arm, 14%), IIIB (47%; 46%), IIIC with 1 to 3 positive lymph nodes (17%; 19%), and stage IIIC with more than 4 positive lymph nodes (21%; 21%). Furthermore, patients’ AJCC-8 stages were IIIA (pembrolizumab arm, 8%; placebo arm, 7%), IIIB (31%; 37%), IIIC (52%; 48%), stage IIID (4%; 4%), and stage III with exact stage unknown (5%; 4%).

Patients were recruited between August 26, 2015, and November 14, 2016. The rates of patients who completed the HRQOL assessment when enrolled were similar between the pembrolizumab and placebo groups and were similar across sex and age. Patients who had disease recurrence had lower completion rates than those who did not.

The mean change in long-term physical functioning from baseline was –0.46 (95% CI, –1.69-0.77) in the pembrolizumab group and 0.10 (–1.14-1.34) in the placebo group; the difference between the groups was –0.56 (–2.31-1.19; P = .53). The mean change from baseline to long-term role functioning was 4.23 (95% CI, 1.72-6.73) in the pembrolizumab arm and 5.62 (95% CI, 3.29-7.95) in the placebo group; the difference between the 2 groups was –1.39 (–4.78-1.99; P = .42). The mean change in long-term emotional functioning from baseline was 1.02 (95% CI, 0.19-3.64) in the pembrolizumab group and 3.87 (95% CI, 2.08-5.65) in the placebo group; the difference between the groups was –1.95 (–4.42-0.52; P = .12). Regarding long-term cognitive functioning, these changes were –2.47 (95% CI, –4.04 to –0.90) and –1.61 (95% CI, –3.15 to –0.07) in the pembrolizumab and placebo groups, respectively; the difference between the 2 groups was –0.86 (–3.06-1.33; P = .44).

Regarding social functioning, the mean change from baseline was 4.19 (95% CI, 2.23-6.16) and 5.94 (95% CI, 3.88-8.00) in the pembrolizumab and placebo groups, respectively; the difference between the 2 groups was –1.75 (–4.58-1.09; P = .23). For fatigue, the mean change from baseline was 1.52 (95% CI, –0.39-3.43) and –0.64 (95% CI, –2.60-1.33) in the pembrolizumab and placebo groups, respectively; the difference between the 2 groups was 2.16 (–0.59-4.91; P = .12).

When considering all post-baseline evaluations, the mean change from baseline to post-baseline GHQ was –2.61 (95% CI, –4.19 to –1.02) in the pembrolizumab arm and 0.30 (95% CI, –1.25-1.85) in the placebo group, with a difference of –2.91 (–5.06 to –0.76; P = .0079); the absolute value did not exceed the threshold of clinical relevance.

“Among 481 patients from the pembrolizumab group with a baseline HRQOL questionnaire available, an IRAE of any grade during the adjuvant treatment was reported for 185 [38%] patients,” investigators stated of the safety findings. “The associations between IRAEs and long-term HRQOL of patients treated with pembrolizumab were neither statistically significant nor clinically relevant.”

The most commonly observed IRAEs in the pembrolizumab arm were hypothyroidism (15%), hyperthyroidism (11%), vitiligo (5%), colitis (4%), and pneumonitis (4%). Common IRAEs without reported recovery were hypothyroidism (11%) and vitiligo (4%). Of the patients from the pembrolizumab group with a baseline HRQOL questionnaire available, 7% had grade 3 or 4 IRAEs during the adjuvant treatment, and complete recovery was reported within 2 years from treatment start in 5% of patients.

“In conclusion, to our knowledge, this study is the first trial presenting long-term HRQOL data in adjuvant melanoma... These findings, along with primary efficacy results and previous HRQOL analyses, support the use of adjuvant pembrolizumab in patients with stage III melanoma after complete resection,” Bührer and colleagues concluded.

References

1. Bührer E, KicinskiM, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): long-term, health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. Published online August 12, 2024. doi:10.1016/S1470-2045(24)00338-3
2. FDA approves pembrolizumab for adjuvant treatment of melanoma. News release. FDA. February 15, 2019. Accessed August 20, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adjuvant-treatment-melanoma