Addition of ramucirumab to docetaxel extends PFS in advanced urothelial cancer

Issue: October 10, 2017

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.

Perspective from Yohann Loriot, MD

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%).

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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

Reference:

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.

Perspective

Yohann Loriot, MD

When a patient is diagnosed with metastatic urothelial cancer, the standard of care is first-line platinum-based therapy. However, the prognosis is poor, with an estimated OS of around 6 months. If a patient is resistant to cisplatin, the prognosis is even poorer, and there is no standard of care in this population. Vinflunine is approved in Europe, but not in the United States. Taxane is another option, but it results in PFS of about 3 months and an OS of about 6 months.

By using ramucirumab, Petrylak and colleagues met the primary endpoint of PFS, with an HR of 0.75 and an absolute difference of 1.31 months. But is it clinically relevant?

The OS interim analysis was planned but not reported. There were better response rates in the ramucirumab arm but, due to the study design, significance was not fairly tested. There was also no improvement of quality of life, but we have limited data after cycle 3 concluded. The difference for PFS is smaller than the difference reported in the phase 2 trial but, regarding the safety points, better tolerance was observed in phase 3 trial than in the phase 2 trial, with no significant additional toxicities.

The strengths of this trial are that it met its endpoint in the intention-to-treat population; its 24% objective response rate was the best ever reported in a phase 3 trial of its kind; and the safety profile was manageable, making ramucirumab possibly one of best angiogenic inhibitors ever investigated in urothelial cancer.

There are some weaknesses, however. PFS is not a surrogate for OS in metastatic disease; the benefit on PFS is quite small; an interim analysis for OS was not reported; there was no improvement in quality of life in these patients, who often complained of grade 2 symptoms; and there was no biomarker data reported.

So how can we use these data in clinical practice? Most clinicians will choose to use ramucirumab plus docetaxel following immune checkpoint inhibitors. But there are many open questions we must address.

First, we have an insufficient number of patients in subgroup analyses to suggest that ramucirumab and docetaxel may work after immune checkpoint inhibitors. Only 10% of patients in the study received prior immune checkpoint inhibition, and many patients (60%) did not receive any subsequent treatment after immune checkpoint inhibition failure. There is also no evidence of efficacy of ramucirumab on visceral disease.

This raises the question: Could ramucirumab and docetaxel be a better option for basal tumors? Translational investigation would be key. We have trials in lung cancer and bladder cancer suggesting that anti-PD-L1 therapy can sensitize tumors to antiangiogenetic therapy and, conversely, antiangiogenic therapy can improve anti-PD-L1 treatment.

Of course, it’s easier to predict the past than to predict the future. However, for the majority of patients, the first-line treatment of metastatic urothelial cancer should include platinum-based chemotherapy and immune checkpoint inhibitors. For patients with short response to first-line therapy and those with platinum-resistant metastatic urothelial cancer, docetaxel and ramucirumab may be given.

Yohann Loriot, MD

Institut Gustave Roussy

Villejuif, France

Disclosures: Loriot reports no relevant financial disclosures.