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, an American Society of Clinical Oncology (ASCO)-designated expert, who added that the combination would have an impact on patient management once it makes its way through the regulatory process.
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.
The study was funded by Merck.
Powles disclosed relevant relationships with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, AstraZeneca, and Ipsen. Co-authors reported multiple relevant relationships with industry, including Merck and Pfizer.
Dreicer disclosed relevant relationships with Astellas Pharma, AstraZeneca, Genentech/Roche, EMD Serono, Incyte, Pfizer, Seattle Genetics, BioClin Therapeutics, Janssen, and Merck.
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Bristol-Myers Squibb Company (BMY) : Free Stock Analysis Report. At a median follow-up of 22 months in the nivolumab monotherapy group and 16 months for combination therapy, the rate of any treatment-related adverse event leading to study withdrawal was 12 with monotherapy and 18 with combination therapy. We remind investors that the company received a significant boost in April 2016 when the FDA approved the tablet formulation of cabozantinib (distinct from the capsule form) under the brand name Cabometyx for the treatment of RCC in patients who have already received anti-angiogenic opioid OD Deaths Are Saving Lives Through Transplantation therapy. (PFE) : Free Stock Analysis Report. This doubling of progression-free survival (PFS) applied to all comers regardless of whether or not their tumor expressed programmed death-ligand 1 (PD-L1). There were no neurotoxicity or cutaneous side effects, which we would not expect with radiation treatment alone.