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SAN FRANCISCO -- Dual therapy with pembrolizumab (Keytruda) and axitinib (Inlyta) improved survival over standard of care for patients with newly diagnosed or recurrent metastatic renal cell carcinoma (RCC), results of the phase III KEYNOTE-426 trial found.

At 12.8 months median follow-up, patients randomized to the PD-1 checkpoint antibody plus VEGF tyrosine kinase inhibitor combination had a 47% reduction in the risk of death compared to those treated with sunitinib (Sutent) alone, with the benefit seen regardless of PD-L1 status or risk group (HR 0.53, 95% CI 0.38-0.74, P<0.0001), reported Thomas Powles, MD, of the Barts Cancer Institute in London.

The 12- and 18-month overall survival (OS) rates were 89.9% and 82.3% with the combination, respectively, compared with 78.3% and 72.1% with sunitinib.

"Pembrolizumab and axitinib should be a standard care in this setting," Powles said during a press briefing ahead of the 2019 Genitourinary Cancer Symposium here.

Rate of overall response was significantly higher with pembrolizumab-axitinib (59.3% vs 35.7% with sunitinib, P<0.0001). Among those who responded, the median duration of response was not reached in the dual therapy arm versus 15.2 months in the sunitinib arm.

"This is a very significant trial," commented briefing moderator Robert Dreicer, MD, of the University of Virginia in Charlottesville and an American Society of Clinical Oncology (ASCO)-designated expert.

Dreicer told 番茄社区app that while upfront management of metastatic RCC in poorer-risk patients has shifted toward use of ipilimumab (Yervoy) plus nivolumab (Opdivo) following CheckMate 214, the pembrolizumab-axitinib data would quickly alter the management of RCC in favorable-risk patients.

“This is practice changing,” he said, adding that these results had the potential to be the most important of the meeting.

Dreicer explained that as pembrolizumab-axitinib showed benefit across all risk groups, there would likely be a “fair amount of discussion” about its role in higher-risk groups. He noted, for example, that in patients unlikely to tolerate the initial 4-week combination part of ipilimumab-nivolumab due to the potential for more acute toxicity, pembrolizumab-axitinib (and its reasonable toxicity profile) would offer an alternative.

“Assuming this passes regulatory muster, which I think most of us anticipate, you’re going to have a therapy that could theoretically be utilized across the clear cell kidney cancer spectrum for untreated patients with metastatic disease,” said Dreicer.

He added that while pembrolizumab-axitinib would not necessarily be the standard of care, “it’s certainly going to represent a standard of care.”

Median progression-free survival (PFS) was also improved with the combination, at 15.1 months versus 11.1 months with sunitinib (HR 0.69, 95% CI 0.57-0.84, P=0.0001).

"There's nothing from these data to suggest that the sunitinib arm underperformed in this trial," Powles said, noting that 11.1 months is quite long for a control arm with this agent.

In data presented at the 2018 European Society for Medical Oncology (ESMO) congress, another axitinib combination -- this time with the anti-PD-L1 agent avelumab (Bavencio) -- showed a significant PFS benefit in advanced RCC patients over sunitinib alone (13.8 vs 8.4 months, respectively), again irrespective of tumor PD-L1 expression status (HR 0.69, 95% CI 0.506-0.840, P=0.0001).

And at the 2018 Genitourinary Cancers Symposium, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) yielded a median PFS of 11.2 months versus 8.4 months with sunitinib in newly diagnosed metastatic RCC patients. OS data were not yet mature for either of these trials when they were presented.

In the current KEYNOTE-426 trial, the investigators randomized 861 newly diagnosed or recurrent stage IV clear cell RCC patients 1:1 to either:

• 50-mg sunitinib daily for the first 4 weeks of 6-week cycles
• 5-mg axitinib twice daily plus 200-mg pembrolizumab every 3 weeks for up to 35 cycles

Patients were required to have received no prior systemic therapy for advanced disease, have a Karnofsky performance status ≥70, adequate organ function, and have a tumor sample available for biomarker testing. Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group and geographic region.

Powles noted that there was no significant differences between the two arms in terms of patients who went on to second-line therapy with a checkpoint inhibitor following disease progression.

Rate of adverse events (AEs) were similar between the pembrolizumab-axitinib and sunitinib groups (96.3% vs 97.6%, respectively), as were rates of grade 3-5 AEs (62.9% vs 58.1%). Treatment-related deaths occurred in 0.9% of the pembrolizumab-axitinib group and 1.6% of the sunitinib group.

In the sunitinib arm, 10.1% of patients discontinued treatment because of AEs. In the combination arm, AEs led to discontinuation of one of the two treatments in 25.9% of patients and both treatments in 8.2% of patients.

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