Targeting Angiogenesis in Bladder Cancer

According to the phase III RANGE study, adding ramucirumab (Cyramza; Eli Lilly) to docetaxel may improve progression-free survival (PFS) for patients with advanced or metastatic urothelial carcinoma whose disease is refractory to platinum chemotherapy. The findings were presented by Daniel Petrylak, MD, of Yale Cancer Center in New Haven, CT, during the ESMO 2017 Congress, the annual meeting of the European Society for Medical Oncology, in Madrid, Spain.

Ramucirumab, a VEGFR2 inhibitor, was first approved in 2014 to treat advanced or metastatic gastric and gastroesophageal adenocarcinomas. It has since received the FDA's nod for two additional tumor types: platinum-resistant metastatic non–small cell lung cancer and metastatic colorectal cancer.

Investigators randomly assigned 530 patients to receive either ramucirumab plus docetaxel or placebo plus docetaxel. Among 437 evaluable patients, the median investigator-assessed PFS was 4.07 months and 2.76 months, respectively; the objective response rates were 24.5% and 14%. At 6 months, 28.5% of patients in the ramucirumab cohort showed no signs of disease progression, compared with 18.9% of patients in the placebo arm.

An independent blinded analysis yielded similar results, Petrylak noted, and the addition of ramucirumab to docetaxel “did not lead to significant additive toxicity or compromise patients' quality of life.” This treatment regimen is also “the first to show superior PFS over chemotherapy alone in platinum-refractory bladder cancer,” he added.

Discussing RANGE's data at ESMO, Yohann Loriot, MD, of Institut Gustave Roussy in Villejuif, France, said “the evidence indicates targeting angiogenesis in bladder cancer could be a good strategy.” He did question, however, whether the 1.3-month improvement in median PFS seen with the ramucirumab–docetaxel combination was clinically relevant. Given that five immune checkpoint inhibitors (ICI) have been approved for platinum-refractory urothelial carcinoma within the last 2 years, these agents “may be the preferred second-line option for the majority of clinicians,” Loriot said—particularly pembrolizumab (Keytruda; Merck), the only one so far to demonstrate an overall survival benefit in these patients.

That said, ramucirumab–docetaxel could be deployed following PD-1 blockade, Loriot suggested. He also recommended exploring the combination's utility in patients whose disease is of the basal, not luminal, subtype.

“Post-ICI is where I think it's going to be positioned,” Petrylak agreed. “For now, though, it's difficult to determine whether such patients would do better, because only about 10% of our study participants received prior checkpoint blockade.”

Compared with the luminal subtype, basal bladder tumors respond more poorly to anti–PD-1 therapy, Petrylak explained, “so whether ramucirumab–docetaxel might benefit these patients could be answered later” via a retrospective analysis of tumor tissue samples from RANGE. Further trials are also under consideration, he added, to better suss out just where ramucirumab–docetaxel may fit in platinum-refractory urothelial carcinoma's growing therapeutic arsenal. –Alissa Poh