Addition of ramucirumab to docetaxel extends PFS in advanced urothelial cancer
MADRID — The addition of ramucirumab to docetaxel conferred a small but statistically significant PFS benefit for patients with advanced or metastatic urothelial cancer whose disease progressed on platinum-based chemotherapy, according to results of a randomized phase 3 study presented at the European Society for Medical Oncology Annual Meeting.
The numerical improvement in PFS equated to less than 2 months. However, a higher objective response rate in the experimental treatment group helps demonstrate the benefit ramucirumab (Cyramza, Eli Lilly) can have for this patient population, Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and Yale Cancer Center, told HemOnc Today.
“We’re seeing a doubling of the objective response rate,” Petrylak, a HemOnc Today Editorial Board Member, said in an interview. “I think that observation — along with the PFS data — makes this clinically meaningful.”
Checkpoint inhibitors are effective for about one-quarter of patients with platinum-refractory advanced or metastatic urothelial cancer. However, treatment options are limited for patients who progress on these agents or are ineligible to receive those agents.
A prior randomized phase 2 study showed the addition of ramucirumab — a VEGFR-2 antibody — to docetaxel nearly doubled median PFS among patients with platinum-refractory advanced or metastatic disease (5.4 months vs. 2.8 months; HR = 0.38; 95% CI, 0.23-0.64).
Petrylak and colleagues conducted the double-blind, randomized phase 3 RANGE trial to confirm those results.
The analysis included 530 patients with advanced or metastatic urothelial carcinoma during or after platinum-based chemotherapy. Eligible patients had prior treatment with no more than one checkpoint inhibitor.
Researchers randomly assigned 263 patients to docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg on day one of each 21-day cycle. The other 267 patients received docetaxel plus placebo.
Treatment continued until disease progression or other discontinuation criteria. Patients underwent radiographic assessment every 6 weeks.
Investigator-assessed PFS in the intention-to-treat population, which included the first 437 patients randomly assigned to treatment, served as the primary endpoint. Secondary endpoints included OS, ORR, safety and quality of life.
Researchers reported a statistically significant improvement in median PFS among patients assigned ramucirumab (4.1 months vs. 2.8 months; HR = 0.75; 95% CI, 0.6-0.94). A blinded central analysis suggested a greater median PFS benefit for ramucirumab (4.04 months vs. 2.46 months; HR = 0.67; 95% CI, 0.53-0.84).
The PFS benefit appeared consistent across patient subgroups, Petrylak said.
Intention-to-treat analysis showed a higher ORR for the ramucirumab-docetaxel combination (24.5% vs. 14%).
OS data are not yet mature.
“They are very eagerly awaited,” Petrylak told HemOnc Today. “Hopefully we’ll see them some time next year.”
Grade 3 or higher adverse events occurred at similar frequencies in both treatment groups. The most common was neutropenia (15% for ramucirumab-docetaxel vs. 14% for placebo-docetaxel). Researchers observed no unexpected toxicities and no differences in quality of life between treatment groups.
The results — published simultaneously in The Lancet — suggest the combination of ramucirumab and docetaxel could become a standard of care for patients with platinum-refractory advanced or metastatic urothelial cancer who progressed during treatment with checkpoint inhibitors or are not eligible to receive those agents, Petrylak said.
Although the RANGE trial is the first to show a PFS benefit compared to chemotherapy alone in patients with platinum-refractory urothelial cancer, the question remains whether that benefit is clinically relevant, according to Richard Cathomas, MD, deputy chief physician of oncology and hematology at Kantonsspital Graubunden in Switzerland.
“We need to know if the improvement in progression-free survival translates into an overall survival benefit,” Cathomas said in an ESMO-issued press release. “We have seen from other trials combining chemotherapy with angiogenesis inhibitors into different cancers that such a small progression-free survival benefit often does not translate into overall survival.
It is too early for these results alone to change the standard-of-care second-line treatment, which is immune checkpoint inhibition,” Cathomas added. “But the improvement in response rate shows that ramucirumab does have an impact on the disease so, in the future, angiogenesis inhibition may become part of the treatment armamentarium for urothelial cancer.”– by Mark Leiser
Petrylak DP, et al. Abstract LBA4_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.
Disclosures: Eli Lilly funded this study. Petrylak reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.