In his discussion of KEYNOTE-361 and the DANUBE trial, Richard Cathomas, MD, of Kantonsspital, Graubünden, Switzerland, said both studies yielded disappointing results. Overall, in these trials as well as current evidence from other trials, treatment of platinum-eligible (cisplatin or carboplatin) patients with metastatic urothelial cancer is more clear-cut at present, whereas “the fog is not cleared” for patients not fit for platinum-based chemotherapy.
“For a long time, there has been no change in the first-line treatment for metastatic urothelial cancer. Patients are divided into fit and unfit for platinum chemotherapy based on renal function and performance status. In case of platinum-ineligible patients best supportive care is advised,” he said.
Dr. Cathomas continued: “Recently, the checkpoint inhibitors atezolizumab and pembrolizumab have been approved as first-line treatment for cisplatin-unfit patients, but this is only based on two single-arm trials, and their use is restricted to PD-L1–overexpressing patients. Checkpoint inhibitors have also been approved by [the U.S. Food and Drug Administration] for patients not eligible for any platinum-based chemotherapy.”
Richard Cathomas, MD
Comparison Across Trials
“These two trials have similar designs and similar populations. Overall, survival results for the intent-to-treat population did not reach significance in both trials—either for pembrolizumab plus chemotherapy or durvalumab plus tremilimumab—even after adjusted analyses were performed based on subsequent therapy,” Dr. Cathomas explained.
“The only phase III trial to report an overall survival benefit for front-line immune checkpoint inhibitor was JAVELIN 100. In KEYNOTE-361, no subgroup benefited from the combination, and no difference in survival was seen using PD-L1 expression as a biomarker or in choice of platinum agent. In the DANUBE trial, the PD-L1–positive group treated with the durvalumab/tremelimumab combination appeared to gain a survival benefit, but this is solely hypothesis-generating,” he proposed.
Uncertainty Remains for Platinum-Ineligible Patients
“In hindsight, what may account for these disappointing trials is the one-size-fits-all approach and the complex sequential testing in KEYNOTE-361,” noted Dr. Cathomas.
“PD-L1 does not appear to be a useful biomarker for first-line treatment decisions. The PD-L1 situation is difficult and unclear, which is also highlighted by the plethora of diagnostic tests,” he added.
“We are left with uncertainty for platinum-ineligible patients. Future trials will give us more insights, and it is crucial that we identify subgroups for further investigation. Drugs on the horizon may be an improvement—such as antibody-drug conjugates and FGFR inhibitors,” he said.
DISCLOSURE: Dr. Cathomas has received honoraria from Astellas Pharma, Bristol Myers Squibb, Debiopharm Group, and Janssen-Cilag; has served as a consultant or advisor to Janssen-Cilag and MSD Oncology; has served as an institutional consultant or advisor to Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Pfizer, Roche, and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca.
Two different phase III studies found that combining an anti–PD-1/PD-L1 checkpoint inhibitor (pembrolizumab in KEYNOTE-361) with platinum-based chemotherapy or with another checkpoint inhibitor (the anti–CTLA-4 antibody tremelimumab in DANUBE) failed to significantly improve overall or...