Phase III Trial Results Show PFS Advantage With Ramucirumab in Urothelial Carcinoma

Daniel P. Petrylak, MD

Daniel P. Petrylak, MD

Adding ramucirumab (Cyramza) to docetaxel improved progression-free survival (PFS) over docetaxel alone for patients with advanced or metastatic urothelial carcinoma who have progressed on platinum-based chemotherapy, results from the international phase III RANGE trial showed.

PFS was improved by 1.31 months and objective response rate (ORR) was nearly doubled by adding ramucirumab to docetaxel,¹lead investigator Daniel P. Petrylak, MD, said at the 2017 ESMO Congress.

“RANGE is the first phase III trial to demonstrate a PFS advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” said Petrylak. Further, the combination of ramucirumab and docetaxel did not result in significant additive toxicity or compromise quality of life compared with placebo plus docetaxel. Therefore, the combination represents a new treatment option for this patient population, he said.

Chemotherapy represents the standard of care for patients with metastatic urothelial cancer but, “unfortunately durable survivals are not common; about 5% of patients can survive 5 years with systemic chemotherapy. Thus, second-line treatment options are needed,” said Petrylak. “Chemotherapy itself is a second-line treatment; it generally gives a median survival of about 7 months. In the laboratory, we found that ramucirumab, which targets VEGF-R2, has activity in combination with docetaxel.”

For platinum-ineligible patients, pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are approved agents as first-line therapy. Five immune checkpoint drugs targeting PD-1/PD-L1 are approved for the treatment of platinum-refractory disease.

Response rates with immune therapy are in the range of 15% to 21%, and for many patients, progressive disease is the best response. “We don’t have other therapeutic options for patients who have failed checkpoint inhibition therapy or for patients who may not be eligible for checkpoint inhibition therapy,” said Petrylak, professor of medicine and urology, Yale School of Medicine and Yale Cancer Center.

The combination of ramucirumab and docetaxel displays synergy, doubling PFS compared with docetaxel as second-line treatment in an open-label phase II study of patients with locally advanced or metastatic urothelial carcinoma.²The phase II study was used as the basis for the RANGE trial, in which 530 patients were randomized 1:1 to ramucirumab (10 mg/kg) combined with docetaxel (75 mg/m²intravenously) or placebo plus docetaxel. Docetaxel was limited to 6 cycles, with up to 4 additional cycles allowed after trial sponsor approval.

Patients enrolled had locally advanced or unresectable metastatic bladder cancer that progressed within 14 months of prior chemotherapy, either a cisplatin- or carboplatin-based regimen. Patients were permitted to receive 1 prior immune checkpoint therapy—7% in the experimental arm and 10% in the docetaxel monotherapy arm received prior checkpoint inhibitor therapy.

Most patients enrolled had poor prognosis—61% had at least 2 adverse prognostic risk factors at baseline, noted Petrylak, “so this is a sick group of patients.”

Median follow-up in the full intent-to-treat population was 5.0 months. Median PFS as assessed by the investigators, the primary endpoint, was 4.07 months with the combination therapy compared with 2.76 months for patients who received docetaxel alone (HR, 0.757;P=.018). By independent blinded assessment, median PFS was 4.04 months versus 2.46 months in favor of ramucirumab/docetaxel (HR, 0.672;P= .0005).

At 1 year, by investigator assessment, 11.9% of patients randomized to ramucirumab and docetaxel were without progression versus 4.5% of those assigned to docetaxel alone. The corresponding percentages at 1 year by independent blinded assessment were 8.3% versus 5.1%, again favoring the combination. PFS outcomes were consistent across a variety of patient subgroups.

There was an approximate doubling of the objective response rate with combined ramucirumab and docetaxel versus docetaxel alone (24.5% vs 14.0%) and a tripling of the complete response rate (4.2% vs 1.4%). “The ORR in my mind is clinically significant and practice changing,” Petrylak said.

Despite administration of a second drug, there was no degradation in quality-of-life scores measured using either the EORTC QLQ-C30 Global Quality of Life or the EQ-5D-5L Index.

Toxicities were similar between groups, with slightly less anemia with ramucirumab/docetaxel (16%) compared with placebo/docetaxel (24%), including grade ≥3 anemia (3% vs 11%).

Treatment was discontinued, primarily due to progressive disease, in 209 patients on ramucirumab/docetaxel and 229 patients on placebo/docetaxel. Forty-nine patients in the combination arm remain on treatment compared with 36 in the docetaxel monotherapy arm. RANGE is designed to examine overall survival (OS) as a secondary endpoint, but OS data are still maturing. Petrylak 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.”

In a statement released by ESMO, Richard Cathomas, MD, deputy chief physician of oncology and hematology, Kantonsspital Graubünden, Chur, Switzerland, was a bit more cautious in his interpretation of the data. Data from RANGE alone should not change the standard-of-care treatment (immune checkpoint inhibition) in the second-line setting, he said. “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,” added Cathomas.

The 1.3-month magnitude of benefit was statistically significant, but “raises the question of whether it is clinically relevant,” he said. “We need to know if the improvement in PFS translates into an OS benefit. We have seen from other trials combining chemotherapy with angiogenesis inhibitors in different cancers that such a small PFS benefit often does not translate into OS.”

Invited discussant Yohann Loriot, MD, from Gustave Roussy, University of Paris Saclay, Villejuif, France, said that ramucirumab/docetaxel may be a treatment option after an immune checkpoint inhibitor, noting that many patients do not receive subsequent treatment after failure of immune checkpoint therapy. He added that the inclusion criteria for RANGE were rather restrictive: patients could not have brain metastases nor a recent cardiovascular or thromboembolic event and had to have an ECOG performance score of 0-1 to be eligible. He therefore questioned whether ramucirumab is active and well tolerated in unselected patients in daily practice.

References:

1. Petrylak D Chi KN, Drakaki A, et al. 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. Presented at 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA4_PR.
2. Petrylak DP, Tagawa ST, Kohli M, 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;34:1500-9.