The KEYNOTE-826 study investigators show that the significant improvements in overall survival (OS) and progression-free survival (PFS) with addition of pembrolizumab to chemotherapy reported in the efficacy analysis were not accompanied by deterioration in Health-Related Quality-of-Life (HRQoL) compared with placebo in the intention-to-treat (ITT) population and in patients with PD-L1 combined positive score (CPS) of at least 1. Overall, findings from patient reported outcomes (PRO) analysis provide further support for the use of pembrolizumab plus chemotherapy with or without bevacizumab as a new standard-of-care for persistent, recurrent, or metastatic cervical cancer.
Diversity of patients enroled in KEYNOTE-826 is unprecedented in such a pivotal, practice-changing study, with more than a third of enroled patients being non-White. Findings from the HRQoL analysis are published by Prof. Bradley J Monk of the Division of Gynecologic Oncology, University of Arizona College of Medicine, Creighton University School of Medicine, HonorHealth Research Institute in Phoenix, AZ, US, and colleagues on 3 March 2023 in The Lancet Oncology.
Cervical cancer is commonly associated with bleeding, fatigue, pain, bladder and bowel dysfunction, leg swelling, and sexual dysfunction. Symptom severity is worse in patients with advanced or recurrent disease. Disease-related symptoms in patients with advanced cervical cancer have been associated with decreased HRQoL, including reduced social wellbeing and social functioning, anxiety, and depression. Additionally, side effects associated with treatment might also negatively affect HRQoL. The goal of treatment in patients with advanced or recurrent cervical cancer is to prolong life while preserving or improving HRQoL.
At the protocol-specified first interim analysis of the KEYNOTE-826 study, the addition of pembrolizumab to platinum-based chemotherapy with or without bevacizumab as a first-line treatment significantly improved the study primary endpoints of OS and PFS in patients with persistent, recurrent, or metastatic cervical cancer with a PD-L1 CPS of at least 1 with hazard ratio (HR) for OS of 0.64 (95% confidence interval [CI] 0.50–0.81; p < 0.001) and HR for PFS 0.62 (95% CI 0.50–0.77; p < 0.001). HR for OS in ITT population was 0.67 (95% CI 0.54–0.84; p < 0.001) and HR for PFS was 0.65 (95% CI 0.53–0.79; p < 0.001). HR for OS in patients with PD-L1 CPS of at least 10 was 0.61 (95% CI 0.44–0.84; p = 0.001) and HR for PFS was 0.58 (95% CI 0.44–0.77; p < 0.001). Side effects were manageable.
To evaluate whether these OS and PFS improvements were accompanied by changes in HRQoL, PROs were evaluated as prespecified secondary and exploratory endpoints in KEYNOTE-826. In the latest article published in The Lancet Oncology, the study team reported outcomes from PRO analyses using validated instruments. PRO instruments were the EORTC QLQ-C30, the EORTC cervical cancer module (QLQ-CX24), and the EuroQol-5 dimension-5 level visual analogue scale, each collected before treatment at cycles 1–14 and every other cycle thereafter.
Primary endpoints were OS and PFS per RECIST v1.1 by investigator review. Change from baseline in QLQ-C30 global health status (GHS)–QoL was a prespecified secondary endpoint and was assessed in the PRO full analysis population (all patients who received at least one dose of study treatment and completed at least one post-baseline PRO assessment). Other PRO analyses were protocol-specified exploratory endpoints.
Between 20 November 2018 and 31 January 2020, of 883 patients screened, 617 were randomly assigned, 308 to pembrolizumab group and 309 to placebo group. A total, 587 of 617 patients (95%) received at least one dose of study treatment and completed at least one post-baseline PRO assessment and were therefore included in the PRO analyses (290 in the pembrolizumab group and 297 in the placebo group). Median follow-up was 22.0 months. At week 30, QLQ-C30 completion was 199 of 290 patients (69%) in the pembrolizumab group and 168 of 297 patients (57%) in the placebo group; compliance was 199 of 211 (94%) and 168 of 186 (90%), respectively.
The least squares mean change in QLQ-C30 GHS–QoL score from baseline to week 30 was −0.3 points (95% CI −3.1 to 2.6) in the pembrolizumab group and −1.3 points (−4.2 to 1.7) in the placebo group, with a between-group difference in least squares mean change of 1.0 point (95% CI −2.7 to 4.7). Median time to true deterioration in GHS–QoL was not reached (NR; 95% CI 13.4 months–NR) in the pembrolizumab group and 12.9 months (6.6–NR) in the placebo group (HR 0.84, 95% CI 0.65–1.09). A total, 122 of 290 patients (42%) in the pembrolizumab group versus 85 of 297 (29%) in the placebo group had improved GHS–QoL at any time during the study (p = 0.0003).
The authors commented that PRO findings provide important context for the assessment of safety data from the KEYNOTE-826 study and inform the patient experience. Although the incidence of side effects, particularly immune-mediated, was higher in the pembrolizumab group than in the placebo group in the primary analysis, findings from the current analysis indicate this did not appear to have a meaningful effect on HRQoL. The longer time to disease progression in the pembrolizumab group versus the placebo group might have contributed to the reported HRQoL outcomes despite increased toxicity.
These HRQoL data support the efficacy and safety findings from KEYNOTE-826 and provide further support for the use of pembrolizumab plus chemotherapy with or without bevacizumab as a new standard of care for patients with advanced cervical cancer.
Funding for this research was provided by Merck Sharp & Dohme, a subsidiary of Merck Rahway, NJ, US.
Monk BJ, Tewari KS, Dubot C, et al. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology; Published online 3 March 2023. DOI: https://doi.org/10.1016/S1470-2045(23)00052-9