LUGANO-MADRID – Ramucirumab plus docetaxel improves progression-free survival in patients with advanced or metastatic urothelial cancer who have progressed on platinum-based chemotherapy, according to late-breaking results from the phase III RANGE trial presented today at the ESMO 2017 Congress in Madrid (1) to be published in The Lancet (2).
Checkpoint inhibitors are effective in about 25% of patients with platinum-refractory advanced or metastatic urothelial cancer, but there are few options for those who progress or are ineligible. A phase II study found that adding the vascular endothelial growth factor receptor 2 (VEGFR-2) antibody ramucirumab to docetaxel nearly doubled progression-free survival compared to docetaxel alone in patients with platinum-refractory advanced or metastatic urothelial cancer (3).
The findings provided the rationale for the phase III RANGE trial presented today. The trial included 530 patients with advanced or metastatic urothelial cancer who had progressed on first line platinum-based chemotherapy within the previous 14 months. Patients were randomised 1:1 to ramucirumab plus docetaxel (263 patients) versus placebo plus docetaxel (267 patients).
The primary endpoint of investigator-assessed progression-free survival was significantly prolonged with ramucirumab plus docetaxel compared to placebo plus docetaxel (4.07 months versus 2.76 months; hazard ratio, 0.757). Results were slightly more favourable in a blinded central analysis, with a progression-free survival of 4.04 months with ramucirumab/docetaxel compared to 2.46 months with placebo/docetaxel (hazard ratio, 0.672).
The objective response rate was 24.5% in the ramucirumab/docetaxel arm compared to 14.0% in the placebo/docetaxel arm. Overall survival data is still maturing.
Toxicities were similar between groups, with slightly less anaemia with ramucirumab/docetaxel compared to placebo/docetaxel. Treatment was discontinued, primarily due to progressive disease, in 209 patients on ramucirumab/docetaxel and 229 patients on placebo/docetaxel. Quality of life did not change during the study, and there were no differences between treatment arms.
“Ramucirumab reduced the risk of disease progression by 24% and this was consistent across patient subgroups,” said lead author Professor Daniel P. Petrylak, professor of medicine and urology, Yale School of Medicine and Yale Cancer Center, New Haven, CT, US. “The objective response rate nearly doubled with ramucirumab and there were no significant differences in toxicities between treatments.”
He concluded: “Ramucirumab plus docetaxel could become a standard of care in patients with platinum-refractory advanced or metastatic urothelial cancer who have either progressed on checkpoint inhibitors or are not eligible to receive them.”
Commenting on the results, Dr Richard Cathomas, deputy chief physician of oncology and haematology, Kantonsspital Graubünden, Chur, Switzerland, said: “This is the first trial to show a progression-free survival benefit compared to chemotherapy alone in patients with platinum-refractory urothelial cancer. However, the magnitude of benefit was 1.3 months and, while statistically significant, it raises the question of whether it is clinically relevant.”
“We need to know if the improvement in progression-free survival translates into an overall survival benefit,” continued Cathomas. “We have seen from other trials combining chemotherapy with angiogenesis inhibitors in different cancers that such a small progression-free survival benefit often does not translate into overall survival.”
He concluded: “It is too early for these results alone to change the standard of care second line treatment, which is immune checkpoint inhibition. But the improvement in response rate shows that ramucirumab does have an impact on the disease, so in future, angiogenesis inhibition may become part of the treatment armamentarium for urothelial cancer.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
- Abstract LBA4_PR ‘RANGE: a randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory advanced or metastatic urothelial carcinoma’ will be presented by Dr Daniel Petrylak during Presidential Symposium II, on Sunday, 10 September, 16:30 to 18:20 (CEST), in Madrid Auditorium.
- Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Dr Daniel P Petrylak et al. The Lancet. Published Online September, 12 2017. doi:10.1016/S0140-6736(17)32365-6 The full paper will be available online from 12 September 00:30 CEST, here: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext?elsca1=tlxpr
- Petrylak DP, et al. Docetaxel As Monotherapy or Combined With Ramucirumab or Icrucumab in Second-Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma: An Open-Label, Three-Arm, Randomized Controlled Phase II Trial. J Clin Oncol. 2016;34(13):1500–1509. doi: 10.1200/JCO.2015.65.0218.
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RANGE: a randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory advanced or metastatic urothelial carcinoma
D.P. Petrylak1, K.N. Chi2, A. Drakaki3, C.N. Sternberg4, R. de Wit5, H. Nishiyama6, E.Y. Yu7, D. Castellano8, S. Hussain9, I.J. Percent10, A. Fléchon11, A. Bamias12, M.S. van der Heijden13, N. Matsubara14, B. Alekseev15, R.A. Walgren16, O. Hamid16, A.H. Zimmermann16, K.M. Bell-Mcguinn16, T. Powles17
1Medical Oncology, Yale University School of Medicine, New Haven, CT, USA, 2Medicine, BC Cancer Agency, Vancouver, Canada, 3Medicine and Urology, UCLA Medical Center, Los Angeles, USA, 4Department of Oncology, San Camillo and Forlanini Hospitals, Rome, Italy, 5Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands, 6Oncology, University of Tsukuba, Tsukuba, Japan, 7Medicine, University of Washington, Seattle, USA, 8Medical Oncology, University Hospital 12 De Octubre, Madrid, Spain, 9Oncology, University of Liverpool, Liverpool, UK, 10Oncology, Florida Cancer Specialists, Port Charlotte, USA, 11Oncology, Centre Léon Bérard, Lyon, France, 12Therapeutics Oncology, National and Kapodistrian University of Athens, Athens, Greece, 13Molecular Carcinogenesis, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 14Oncology, National Cancer Center Hospital East, Chiba, Japan, 15Oncology, P.A. Herzen Moscow Oncological Research Institute, Moscow, Russian Federation, 16Oncology, Eli Lilly and Company, Indianapolis, USA, 17Medical Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
Background: Limited treatment options are available for patients (pts) with platinum-refractory advanced or metastatic urothelial carcinoma (UC). In a previous randomized phase 2 study (NCT01282463) of platinum-refractory metastatic UC, RAM plus DOC significantly improved median progression-free survival (PFS) over DOC (5.4 vs 2.8 months; HR, 0.389; 95% CI, 0.235-0.643; P=0.0002) with no unexpected toxicities. To confirm these results, we conducted a randomized phase 3 trial in a similar pt population.
Methods: In this randomized, double-blind, phase 3 trial, pts with progressive advanced or metastatic UC during or after platinum-based chemotherapy were enrolled. Additional prior treatment with 1 immune checkpoint inhibitor was permitted. Pts were randomized (1:1) to receive DOC 75 mg/m2 with RAM 10 mg/kg or placebo (PL) on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint was investigator-assessed PFS, analyzed in the first 437 randomized (intention-to-treat, ITT) pts. Secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and quality of life as assessed with the EORTC QLQ-C30. Radiographic assessment occurred every 6 weeks.
Results: 530 pts were randomized to RAM plus DOC (n=263) or PL plus DOC (n=267). PFS was significantly prolonged in pts treated with RAM plus DOC versus PL plus DOC (median, 4.1 vs 2.8 months; HR, 0.757; 95% CI, 0.607-0.943; p=0.0118). A blinded central analysis demonstrated consistent PFS results (HR, 0.672; 95% CI, 0.536-0.842; p=0.0005). ORR in the first 437 ITT population was 24.5% (95% CI, 18.8-30.3) in the RAM arm and 14.0% (95% CI, 9.4-18.6) in the PL arm. OS data are immature. Grade ≥3 adverse events (AEs) were reported at a similar frequency in both arms with no unexpected toxicities; neutropenia was the most common grade ≥3 AE (15% RAM arm vs 14% PL arm). Mean scores for global quality of life were relatively unchanged over time, with no differences between arms.
Conclusions: RAM plus DOC is the first regimen in a phase 3 study to show superior PFS over chemotherapy in pts with platinum-refractory advanced UC.
Clinical trial identification: NCT02426125
Legal entity responsible for the study: Eli Lilly and Company
Funding: Eli Lilly and Company
Disclosure: K.N. Chi: Reports clinical trial costs from Eli Lilly and Company, during the conduct of the study.
C.N. Sternberg: Reports personal fees for participating in an advisory board and institutional research funding from Eli Lilly and Company, during the conduct of the study.
R. de Wit: Reports grant support or personal fees from Lilly, Merck, Roche and Sanofi.
E.Y. Yu: Reports honorarium and institutional research funding from Eli Lilly and Company
A. Fléchon: Reports personal fees and non-financial support from JANSSEN, NOVARTIS, ASTELLAS, SANOFI, ROCHE, MSD, PFIZER, IPSEN, BAYER, ASTRA ZENECA, outside the submitted work; .
M.S. van der Heijden: Reports personal fees from Roche/Genentech, AstraZeneca, Astellas, BMS, and grants from Astellas, outside the submitted work.
N. Matsubara: Reports honoraria from MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi Taiho, Takeda, Chugai, Novartis, Bayer Yakuhin, Pfizer Japan, Merck Serono Co., Janssen; research funding from Shionogi, Bayer Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD
R.A. Walgren, O. Hamid, A.H. Zimmermann, K.M. Bell-Mcguinn: Employee and shareholder of Eli Lilly and Company
T. Powles: Reports honoraria from Roche, Merck, AstraZeneca, BMS, Lilly, Pfizer; and research funding from Roche and AstraZeneca.
All other authors have declared no conflicts of interest.
Keywords: VEGFR-2, ramucirumab, urothelial bladder carcinoma