Health-Related Quality of Life in the Randomized KEYNOTE-002 Study of Pembrolizumab Versus Chemotherapy in Patients With Ipilimumab-Refractory Melanoma: Beyond the Abstract

The programmed death 1 (PD-1) pathway inhibits tumor-specific T-cell responses, allowing tumors to evade an antitumor immune response (1). The anti–PD-1 monoclonal antibody pembrolizumab, which is designed to block PD-1 from binding to its ligands PD-L1 and PD-L2 (2), has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types and is currently approved in more than 60 countries for one or more advanced malignancies, including unresectable or metastatic melanoma.

In the international, randomized, phase 2 KEYNOTE-002 study (ClinicalTrials.gov, number NCT01704287), pembrolizumab significantly prolonged progression-free survival (hazard ratios of 0.57 [95% confidence interval (CI), 0.45-0.73] for the 2-mg/kg arm and 0.50 [95% CI, 0.39-0.64] for the 10-mg/kg arm) compared with the investigator’s choice of chemotherapy (P < 0.0001 for both) in patients with advanced melanoma whose disease progressed with ipilimumab (3). Additionally, incidence of treatment-related grade 3/4 adverse events was lower with pembrolizumab than with chemotherapy (11% in the pembrolizumab 2-mg/kg arm, 14% in the pembrolizumab 10-mg/kg arm, and 26% in the chemotherapy arm) (3). Because a patient’s perspective on disease management and treatment benefit can be strongly linked to treatment adherence and therefore clinical outcome (4), we evaluated patient-reported outcomes (PROs) as a pre-specified exploratory analysis in KEYNOTE-002. These analyses were recently published in the European Journal of Cancer (5) and are discussed herein.

Patients with unresectable stage III or IV melanoma, disease progression after ≥2 prior ipilimumab doses, and previous BRAF and/or MEK inhibitor therapy (for patients with BRAFV600 mutation only) were randomly assigned 1:1:1 to receive pembrolizumab 2 mg/kg every 3 weeks (Q3W), pembrolizumab 10 mg/kg Q3W, or investigator’s choice of chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). PROs were analyzed in patients who received ≥1 dose of study treatment and who completed ≥1 PRO assessment. Health-related quality of life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 instrument (QLQ-C30) (6) at baseline; weeks 3, 6, 12, 24, and 36; at treatment discontinuation; and during safety follow-up. In addition to reporting their global health status (GHS)/HRQoL, patients self-reported functional scales (physical, role, emotional, cognitive, and social) and symptom scales (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea). To determine whether there were differences between treatment arms, we analyzed GHS/HRQoL scores using a constrained longitudinal data analysis model. We also performed PRO responder analyses using a scale that rated GHS/HRQoL as improved, stable, or deteriorated, with a clinically meaningful difference defined as a change from baseline to week 12 of ≥10 points. 

Across the 3 treatment arms, 520 patients (n = 167 in the chemotherapy arm, n = 176 in the pembrolizumab 2-mg/kg arm, and n = 177 in the pembrolizumab 10-mg/kg arm) were evaluable for this analysis. Patient compliance rates for filling out the EORTC QLQ-C30 survey at baseline were 93.4%, 96.0%, and 96.0% in the chemotherapy, pembrolizumab 2-mg/kg arm, and pembrolizumab 10-mg/kg arms, respectively; at week 12, compliance rates were 76.6%, 82.3%, and 86.4%. Regardless of treatment, patients were less likely to complete the survey as time went on, either because of disease progression, toxicity, death, or administrative error. This difference was more pronounced in the chemotherapy arm than in either pembrolizumab arm beginning at week 3 and continuing through week 12 because of disease progression. 

A comparison of baseline GHS/HRQoL scores revealed similarities across the treatment arms (93.4%, 96.0%, and 96.0% in the chemotherapy, pembrolizumab 2-mg/kg arm, and pembrolizumab 10-mg/kg arms, respectively), suggesting that any changes observed at future time points were attributable to treatment or disease progression. When assessing GHS/HRQoL as the difference in scores from baseline to week 12 using least-squares mean, patients receiving pembrolizumab had significantly smaller decrements from baseline than those receiving chemotherapy (decrease of –2.6 for each pembrolizumab arm vs a decrease of –9.1 for the chemotherapy arm; P = 0.01 for each pembrolizumab arm vs chemotherapy). Similarly, for patients in the 2 pembrolizumab arms, longitudinal score changes from baseline to week 12 were consistently smaller across functional and symptom scales than those in the chemotherapy arm. Additionally, GHS/HRQoL scores were stable (42.6% for the 2 mg/kg arm and 46.3% for the 10 mg/kg arm) in more patients receiving pembrolizumab than in those receiving chemotherapy (32.9%) at week 12. The proportion of patients who experienced deterioration at week 12 was 7%-12% lower for those receiving pembrolizumab (31.8% for the 2-mg/kg arm and 26.6% for the 10-mg/kg arm) than for those receiving chemotherapy (38.3%). The proportion of patients who experienced improvement at week 12 was similar across treatment arms (28.7%, 25.6%, 27.1%, and for the chemotherapy, pembrolizumab 2-mg/kg, and pembrolizumab 10-mg/kg arms, respectively). Overall, results consistently demonstrated that there were no differences in QoL outcomes between the 2 pembrolizumab doses. 

We also summarized the observed mean GHS/HRQoL scores at different time points for each of the treatment groups. In the chemotherapy arm, the GHS/HRQoL score decreased from baseline to week 12, with a sharp decrease at week 3. In contrast, in both pembrolizumab arms, scores were relatively stable at different time points through week 36, suggesting that pembrolizumab may help maintain HRQoL among patients who remain on therapy for a relatively long duration. 

This pre-specified PRO analysis of KEYNOTE-002 suggests that pembrolizumab is well tolerated and either improves or maintains GHS/HRQoL and symptoms compared with chemotherapy in patients with ipilimumab-refractory advanced melanoma. As with other PRO analyses, there were limitations to this study. First, patients in clinical trials may be more motivated to complete PRO instruments and are more likely to tolerate toxicity from study treatment than patients outside of a clinical trial setting. Additionally, HRQoL outcomes in the chemotherapy arm probably reflected tumor progression and chemotherapy-related side effects because more patients in the chemotherapy arm than in the pembrolizumab arms experienced disease progression. Last, assignment to receive pembrolizumab or chemotherapy was open label, which might have introduced bias in estimating the treatment effects. Nevertheless, the combination of the superior progression-free survival of pembrolizumab that was demonstrated previously in KEYNOTE-002 (3) and the clinically meaningful improvement in HRQoL with pembrolizumab compared with chemotherapy in this analysis suggests that PROs may be associated with clinical outcomes. In summary, the smaller proportion of patients experiencing deterioration and the larger proportion of patients experiencing improvement in GHS/HRQoL scores and functional and symptoms scales support the use of pembrolizumab in patients with ipilimumab-refractory advanced melanoma. 

Written by: Dirk Schadendorf1 and Wei Zhou2 

1University Hospital Essen, Essen, Germany; 2Merck & Co., Inc., Kenilworth, NJ, USA 

Corresponding author

Prof. Dr. Dirk Schadendorf, Comprehensive Cancer Center ,University Hospital Essen, Hufelandstr 55, 45122 Essen, Germany

Funding: Study was funded by Merck & Co., Inc., Kenilworth, NJ, USA

Acknowledgments

The authors thank the patients and their families for participating in this study and all investigators and site personnel, as well as Roger Dansey, MD (Merck & Co., Inc., Kenilworth, NJ, USA), for critical review of the manuscript. Medical writing and editorial assistance were provided by Tricia Brown, MS, and Payal Gandhi, PhD, of the ApotheCom oncology team (Yardley, PA, USA). The study and editorial assistance were funded by Merck & Co., Inc., Kenilworth, NJ, USA. 

References:
1. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704. 

2. Keytruda [package insert]. Whitehouse Station, NJ, USA: Merck Sharp & Dohme Corp.; 2016.

3. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015;16:908-18. 

4.   Doyle C, Lennox L, Bell D: A systematic review of evidence on the links between patient experience and clinical safety and effectiveness. BMJ Open 2013;3:e001570.

5. Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, et al. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer 2016;67:46-54. 

6. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76. 

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