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Can We Stop Debating First-Line Tx in Renal Cell Carcinoma?

For the treatment of advanced kidney cancer in first-line, the recently approved combination of pembrolizumab (Keytruda) plus axitinib (Inlyta) came out on top for overall survival, a network meta-analysis found.

Among the dozen available agents in this setting, this anti-PD-1 immunotherapy plus VEGF inhibitor regimen was most likely to yield the greatest overall survival (OS) benefit (posterior probability of 77%, surface under the cumulative ranking curve [SUCRA] of 95%), reported Zachary Klaassen, MD, of Medical College of Georgia at Augusta University, and colleagues.

And the multikinase inhibitor cabozantinib (Cabometyx) was most likely to confer the longest progression-free survival (PFS) benefit for these patients (probability of 38%, SUCRA of 84%), they said in a New England Journal of Medicine correspondence.

Likelihoods of longer PFS were similar for the combinations of avelumab (Bavencio) plus axitinib (20%) and pembrolizumab-axitinib (17%).

“Although randomized, controlled trials remain the standard for evaluating new treatments and direct comparative trials are ideal for guiding treatment choice, this network meta-analysis provides contemporary guidance for clinicians who are treating patients with metastatic renal cell carcinoma,” Klaassen’s group wrote.

Over the past year, results of three positive phase III trials involving immunotherapy-based combinations in frontline renal cell carcinoma (RCC) have stirred debate as to which is most effective, and for which patients. Single-agent sunitinib (Sutent), the prior standard of care, was the comparator for all three.

First, CheckMate 214 showed that ipilimumab (Yervoy) plus nivolumab (Opdivo) improved overall survival in intermediate- and poor-risk patients, as defined by the International Metastatic RCC Database Consortium (IMDC).

Subsequently, JAVELIN Renal 101 reported a PFS advantage with avelumab plus axitinib across all IMDC groups, but with immature OS data.

Finally, KEYNOTE-426 showed an improvement in PFS with pembrolizumab plus axitinib and, more importantly, an improvement in OS, with the benefits seen across all IMDC risk groups.

Responding to the network meta-analysis findings, JAVELIN Renal 101 trial investigators Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City, and Bo Huang, PhD, of Pfizer, cautioned that the phase II study that led to the first-line approval of cabozantinib in metastatic RCC included only 157 patients, and all were intermediate- or poor-risk. Conversely, JAVELIN Renal 101 enrolled nearly 900 patients and also included good-risk patients, who made up 21% of the study population.

“A cross-trial comparison has limitations that cannot be overcome by a network meta-analysis because of a lack of patient-level data to adjust for differences in baseline characteristics (e.g., prognostic risk factors and geographic region), follow-up time, subsequent anticancer therapies, and other factors that may affect the efficacy results in trials involving patients with advanced renal cell carcinoma,” Motzer and Huang said.

And though the meta-analysis from Klaassen and colleagues favored pembrolizumab plus axitinib when it came to OS, KEYNOTE-426 investigators Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, and Thomas Powles, MD, of Royal Free NHS Trust in London, also expressed caution over the findings and said that each randomized trial should be assessed on its own merits.

“The quality of network meta-analyses is strongly influenced by the included trials — the more heterogeneous the trials, the more statistical ‘noise’ is introduced,” they wrote.

Citing the “very heterogeneous” populations in the current metastatic RCC studies, Rini and Powles argued that the conclusions of the analysis “could be based on groups as small as 50 patients.”

Klaassen and co-authors disclosed no relevant relationships with industry.


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