Cora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo Forlanini Hospital in Rome, Italy, formally discussed CheckMate 025 at the Presidential Session of the 2015 European Cancer Congress as well as findings from the METEOR trial of cabozantinib (Cometriq) in metastatic renal cell carcinoma (see full details of the METEOR trial in this article).

“We now have two new interesting agents with different mechanisms of action,” she noted. “This is an exciting time for immunotherapeutics and for drugs targeting VEGF [vascular endothelial growth factor] resistance.”

The overall survival benefit of 25 months with nivolumab, she said, “sets a new benchmark for patients with previously treated metastatic renal cell carcinoma.”

Immunotherapy not only provides significant tumor shrinkage but can also stabilize disease, which translates into long-term survival benefits, she pointed out.

“We know that with immunotherapy, the kinetics of response differ from [those of] targeted therapy, and we can often see responses after therapy has been stopped,” added Dr. Sternberg.

First-Time Survival Difference

Because of this observation, patients in CheckMate 025 were allowed to remain on nivolumab even when they appeared to be progressing, “which was wise,” and the study’s endpoint was, “correctly,” overall survival, she commented.

She emphasized that the median overall survival of 25 months—a 5.4-month difference vs everolimus—is the first time a survival difference has been observed in the second-line treatment of metastatic renal cell carcinoma. “This is an important new result,” she remarked.

Clinical Implications

Dr. Sternberg further indicated that the lack of difference in progression-free survival is not surprising when viewed in context with ipilimumab (Yervoy) data in melanoma. “You see no separation of the curves in the first 3 months, but separation starts to occur after that, and overall survival is increased…. The progression-free survival may not reflect the clinical benefit of nivolumab, due to its mechanism of action. This is what we can expect to see with immunotherapy.”

This pseudoprogression, and the challenges in evaluating response on treatment, could prove problematic for clinicians “in deciding how to counsel patients and on when to stop therapy,” she predicted.

She also noted that perhaps not all patients will benefit equally from immunotherapy. In CheckMate 025, the most benefit was seen in patients with only one prior antiangiogenic regimen and in poor-risk patients. Little to no benefit was observed among favorable-risk patients, those treated in the third-line setting, and the elderly (> 75 years). The reasons for these differences are not clear.

Also unclear is why PD-L1 (programmed cell death-ligand 1) expression did not predict survival. More information on PD-L1 as a potential biomarker in this tumor would be of real interest, she said, especially in light of the intratumoral heterogeneity of this malignancy.

Referring to possibly having nivolumab and also cabazantinib in the treatment arsenal, Dr. Sternberg concluded: “Our task is to integrate the results of drugs with novel mechanisms of action—to understand whether we should use them in combination, in sequence, as maintenance therapy, or as adjuvant or neoadjuvant treatment. We also need proper patient selection.”  ■

Disclosure: Dr. Sternberg has received research funding or honoraria from Pfizer, Novartis, Bayer, AVEO, Roche, BMS, Exelexis, and GSK.