Checkpoint Inhibitor–TKI Combos Effective in RCC

The checkpoint inhibitors pembrolizumab (Keytruda; Merck) and avelumab (Bavencio; EMD Serono), in combination with the multi-tyrosine kinase inhibitor (TKI) axitinib (Inlyta; Pfizer), could become first-line treatments for clear-cell metastatic renal cell carcinoma (RCC) based on results of two separate phase III trials presented at the 2019 Genitourinary Cancers Symposium in San Francisco, CA, in February and published concurrently in The New England Journal of Medicine. Researchers reported that both combinations extended progression-free survival (PFS) compared with sunitinib (Sutent; Pfizer), a common first-line treatment.

Patients with newly diagnosed clear-cell advanced RCC who have a good prognosis typically receive TKIs such as sunitinib or pazopanib (Votrient; GlaxoSmithKline), whereas patients in intermediate- and poor-risk groups often receive Bristol-Myers Squibb's CTLA4 inhibitor ipilimumab (Yervoy) plus its PD-1 inhibitor nivolumab (Opdivo).

Approved as a second-line therapy for advanced RCC, axitinib, as well as pembrolizumab, have shown activity as first-line monotherapies. When assessed in combination in a phase Ib trial, the duo had a manageable safety profile and strong antitumor activity in patients with newly diagnosed disease (Lancet Oncol 2018;19:405–15).

Results of that trial prompted the randomized phase III study, says Thomas Powles, MD, of the Barts Cancer Institute in London, UK, who presented the findings (N Engl J Med 2019 Feb 16 [Epub ahead of print]). In KEYNOTE-426, Powles and colleagues assigned 861 patients with newly diagnosed clear-cell metastatic RCC from all risk groups to receive the PD-1 inhibitor pembrolizumab plus axitinib, or sunitinib. Overall, patients treated with the combination had an 18-month overall survival (OS) rate of 82.3%, a median PFS of 15.1 months, and a response rate of 59.3%, compared with 72.1%, 11.1 months, and 35.7%, respectively, in patients who received sunitinib.

“It's the first randomized trial to show a response rate, PFS, and OS advantage in the front-line setting—a 47% reduction in the risk of death in unselected patients is extremely good and has not been achieved previously,” says Powles, suggesting that it should become a new standard of care.

Also at the conference, researchers presented results of the phase III JAVELIN Renal 101 trial, which builds on a previous phase Ib trial of the PD-L1 inhibitor avelumab plus axitinib (N Engl J Med 2019 Feb 16 [Epub ahead of print]; Lancet Oncol 2018;19:451–60). In JAVELIN, 886 patients with newly diagnosed clear-cell advanced RCC received either avelumab plus axitinib, or sunitinib. Patients in the combination group had a median PFS of 13.8 months and an objective response rate of 51.4%, compared with 8.4 months and 25.7% in the sunitinib group.

In both phase III trials, almost all patients experienced side effects, with similar rates of grade 3 to 5 adverse events in the combination and sunitinib arms.

Notably, patients in both trials had a survival benefit regardless of PD-L1 status. Although the reason why isn't clear, Powles says that combining the drugs may have masked the effect of PD-L1 levels on response.

Robert Dreicer, MD, American Society of Clinical Oncology expert and deputy director of the University of Virginia Cancer Center in Charlottesville, considers both trials valuable but thinks that the OS benefit demonstrated by pembrolizumab plus axitinib makes this combination more likely to change clinical practice.

“These are very important studies because they show, in a front-line setting, across the risk spectrum, the potential to improve overall and progression-free survival, respectively,” he says. “Assuming the pembrolizumab–axitinib combination is approved, I think it enters rapidly into the front-line management of many patients with this disease—unambiguously in good-risk patients.”

However, Dreicer says it's unclear how the combinations will compare with ipilimumab plus nivolumab for first-line treatment of patients with intermediate- and poor-risk disease. “There's a fair amount of uncertainty about what's optimal,” he says. “We need to figure out whether or not there are certain groups of patients that may be better treated with certain approaches.” –Catherine Caruso

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