Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE)

Abstract

Background: To evaluate patient-reported outcomes with ramucirumab plus docetaxel, a regimen which improved progression-free survival in platinum-refractory advanced urothelial carcinoma (aUC).

Methods: RANGE-a randomized, double-blinded, phase 3 trial in patients with platinum-refractory aUC. Ramucirumab (10 mg/kg) plus docetaxel (75 mg/m2) or placebo plus docetaxel were administered every 21 days until disease progression or unacceptable toxicity. Patients received maximum 10 cycles of docetaxel. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EuroQoL five-dimensions (EQ-5D-5L) were administered at baseline, start of each cycle, and 30-day follow-up visit. A ≥ 10-point change in QLQ-C30 scores was considered meaningful. Rates of improved/stable scores were compared between treatment arms using Fisher's exact test. Time to deterioration (TtD) was estimated and compared using Kaplan-Meier estimation and log-rank test.

Results: Of the 530 patients, ~ 97% patients in each arm provided baseline QLQ-C30 data. On-treatment compliance was ≥ 88% for first 8 cycles. Mean baseline QLQ-C30 scores were similar between arms, with global quality of life (QoL), fatigue, pain, and insomnia having greatest impairment. Postbaseline rates of improved/stable QLQ-C30 scores were similar between treatment arms except for greater improvement in pain score with ramucirumab. TtD of QLQ-C30 scales favored ramucirumab arm. Baseline EQ-5D-5L index and visual analogue scale scores were similar between arms, followed by relatively stable on-treatment scores. EQ-5D-5L scores worsened at post-discontinuation follow-up visit.

Conclusions: Ramucirumab plus docetaxel did not negatively impact QoL compared with docetaxel alone in platinum-refractory aUC. Improved TtD and tumor associated rates of pain favored ramucirumab treatment.

Clinical trail registration: NCT02426125. https://ichgcp.net/clinical-trials-registry/NCT02426125 . Date of registration: April 24th 2015.

Keywords: Antiangiogenesis; Bladder cancer; Neoplasm metastatsis; Patient-reported outcomes; Quality of life; Ramucirumab; Urinary bladder neoplasm; Urothelial carcinoma.

Conflict of interest statement

Andrea Necchi is consultant for: Merck, Roche, BMS, Bayer, GSK, Astellas, Janssen. Nobuaki Matsubara received research funding from Eli Lilly, AstraZeneca, Astellas, Bayer, Janssen, MSD and Sanofi. Daniel Petrylak received consulting fee from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, Urogen. Grant support from Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics. Ronald de Wit received consultancy or speaker fees from Sanofi, Merck, Janssen, Roche, Clovis, and Bayer. Institutional grants from Sanofi, and Bayer. Alexandra Drakaki received grants from Eli Lilly, BMS, AstraZeneca, Seattle Genetics/Astellas. Astra M Liepa, Huzhang Mao and Katherine-Bell McGuinn are employees and Shareholders in Eli Lilly and Company. Tom Powles received consultancy fee from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics. Received grant/funding from AstraZeneca and Roche. Strategic Advisory for Pfizer, AstraZeneca, Roche, and BMS.

Figures

Fig. 1

Patient disposition. n = number of patients

Fig. 2

Mean change from baseline in the mean scores of the EORTC QLQ-C30 global QoL scale (a), EQ-5D-5L index (b) and visual analogue scale scores (c). DOC docetaxel, EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, EQ-5D-5L EuroQoL five-dimensions, RAM ramucirumab, SD standard deviation, VAS visual analogue scale

Fig. 3

Time to sustained deterioration of QLQ-C30 scales. CI confidence interval; DOC docetaxel, EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, N number of patients, HR hazard ratio, PL placebo, QoL quality of life; RAM ramucirumab. Forest plot of time to sustained deterioration, HRs (unstratified) for each functional and symptom scale are depicted. HRs were estimated using a Cox regression model. 2-sided p-values were based on normal approximation

Fig. 4

Proportion of patients in ITT population with improved, stable or worsened QoL of the scales with greatest impairment at baseline. QoL quality of life, ITT intention-to-treat. For each scale at each postbaseline assessment, proportion of patients with improved or stable scores was compared using the Fisher’s exact test

Fig. 5

Proportion of patients with improvement in global QoL (a) and pain (b) scales among those patients with BOR of CR/PR or SD. BOR best overall response, CR complete response, DOC docetaxel, n number of patients, PL placebo, PR partial response, QoL quality of life; RAM ramucirumab, SD stable disease. For each scale at each postbaseline assessment, proportion of patients with improved or stable scores between treatment and placebo arms was compared using the Fisher’s exact test. PR/CR as BOR: RAM + DOC (n = 68) and PL + DOC (n = 37). SD as BOR: RAM + DOC (n = 104) and PL + DOC (n = 110)