Hint of Survival Gain With Ramucirumab in Urothelial Cancer

Liam Davenport

September 11, 2017

MADRID, Spain — Patients with advanced or metastatic urothelial cancer who have progressed on platinum-based chemotherapy have a significant increase in disease-free survival with an angiogenesis inhibitor, suggest the results of a phase 3 trial.

The vascular endothelial growth factor receptor 2 antibody ramucirumab (Cyramza, Lilly) significantly increased progression-free survival (PFS) by almost 25% compared with placebo.

However, the absolute benefit seen with the drug was small, and quality of life did not improve, leading experts to question the clinical relevance of the treatment in this traditionally hard-to-treat group of patients.

The new results come from the RANGE study, presented during a presidential symposium here at the European Society for Clinical Oncology (ESMO) 2017 Congress and will be published online by The Lancet on September 12.

Lead author, Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine, New Haven, Connecticut, commented in a release that the reduction in the risk for disease progression "was consistent across patient subgroups."

He added: "The objective response rate nearly doubled with ramucirumab, and there were no significant differences in toxicities between treatments."

When asked during a press conference for the study whether the absolute increase in PFS with ramucirumab vs placebo of just over 1.5 months was clinically meaningful, Dr Petrylak said that "the effectiveness of the drug is seen in the objective response rate…I think it's clinically meaningful."

"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," he suggested.

However, an expert not involved with the study disagreed. Richard Cathomas, MD, deputy chief physician of oncology and haematology, Kantonsspital Graubünden, Chur, Switzerland, questioned the clinical relevance of this magnitude of benefit.

 "We need to know if the improvement in progression-free survival translates into an overall survival benefit," he commented, warning that "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."

Consequently, Dr Cathomas believes that "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," he added, and "so, in future, angiogenesis inhibition may become part of the treatment armamentarium for urothelial cancer."

Few Treatment Options  

Until recently, patients with platinum-refractory advanced or metastatic urothelial carcinoma have had few treatment options, and checkpoint inhibitors have been effective in only 25% of patients.

However, a recent phase 2 study by Dr Petrylak and colleagues showed that adding ramucirumab to docetaxel significantly improved PFS over docetaxel alone, almost doubling disease-free survival.

The team therefore conducted a randomized, double-blind, phase 3 trial in 530 patients with progressive advanced or metastatic urothelial carcinoma during or after platinum-based chemotherapy. Patients previously treated with one immune checkpoint inhibitor could be included.

The patients, who had a performance status of 0 or 1, were randomly assigned in a 1:1 fashion to ramucirumab 10 mg/kg plus docetaxel 75 mg/m2 (n = 263), or placebo plus docetaxel 75 mg/m2 (n = 267).

The primary endpoint was investigator-assessed PFS, and the patients were followed up for a median of 5.0 months.

On investigator assessment, the median PFS was 4.07 months with ramucirumab plus docetaxel vs 2.76 months with placebo plus docetaxel, at a hazard ratio of 0.757 (P = .0118). At 12 months, 11.9% of ramucirumab recipients were disease free vs 4.5% of patients given placebo.

When the data were turned over to independent blinded assessment, the median PFS with ramucirumab became 4.04 months vs 2.46 months with placebo, at a hazard ratio of 0.672 (P = .0005). The disease-free survival rate at 12 months was 8.3% with ramucirumab and 5.1% with placebo.

The overall response rate was 24.5% in 216 ramucirumab recipients available for analysis vs 14.0% in 221 placebo recipients. The complete response rates were 4.2% and 1.4%, respectively.

Patient-reported outcome scores did not differ between the ramucirumab and placebo groups on either the European Organization for Research and Treatment of Cancer QLQ-C30 Global Quality of Life or EQ-5D-5L Index scores.

The researchers also report no overall differences in rates of grade 3 or higher adverse events between the two treatments, with no unexpected toxicities, although grade 3 or higher anemia was less common with ramucirumab than placebo, at 3% vs 11%. The most common grade 3 or higher adverse event was neutropenia, seen in 15% of ramucirumab recipients and in 14% of patients given placebo.

Pembrolizumab a More Attractive Option?

Yohann Loriot, MD, Department of Cancer Medicine, Institut Gustave Roussy and University of Paris Sud, Villejuif, France, discussed the findings after they were presented.

He said that the study has many strengths, including that it met its primary endpoint, but he asked whether the absolute improvement in disease-free survival with ramucirumab is "clinically relevant."

He also highlighted the lack of improvement in quality of life and overall survival data.

Asking how the drug could be used in clinical practice, Dr Loriot pointed to data from KEYNOTE 045 showing an improvement in quality of life with the checkpoint inhibitor pembrolizumab (Keytruda, Merck), saying that this may make it a more attractive option.

He also noted that the inclusion criteria for the current ramucirumab trials have been "restrictive" and so it is hard to say how it performs in important subgroups.

Nevertheless, in some clinical situations, such as basal tumors, ramucirumab may be beneficial, and immunotherapy could sensitize tumors to antiangiogenic drugs, a combination that is already being tested.

The study was sponsored by Eli Lilly and Company. Dr Petrylak has disclosed no relevant financial relationships, but many coauthors have ties with pharmaceutical companies, as listed. K.N. Chi: clinical trial costs from Eli Lilly and Company during the conduct of the study. C.N. Sternberg: 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: grant support or personal fees from Lilly, Merck, Roche, and Sanofi. E.Y. Yu: honorarium and institutional research funding from Eli Lilly and Company. A. Fl é chon: personal fees and nonfinancial support from Janssen, Novartis, Astellas, Sanofi, Roche, MSD, Pfizer, Ipsen, Bayer, and Astra Zeneca outside the submitted work. M.S. van der Heijden: personal fees from Roche/Genentech, AstraZeneca, Astellas, and BMS and grants from Astellas outside the submitted work. N. Matsubara: honoraria from MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi Taiho, Takeda, Chugai, Novartis, Bayer Yakuhin, Pfizer Japan, Merck Serono Co., and Janssen; research funding from Shionogi, Bayer Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD. R.A. Walgren, O. Hamid, A.H. Zimmermann, and K.M. Bell-Mcguinn: employee and shareholder of Eli Lilly and Company. T. Powles: honoraria from Roche, Merck, AstraZeneca, BMS, Lilly, and Pfizer and research funding from Roche and AstraZeneca.

European Society for Medical Oncology (ESMO) 2017 Congress. Presented September 10, 2017. Abstract LBA4_PR.

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