The FDA on Friday for the first-line treatment of metastatic renal cell carcinoma.
Approval of the PD-1 immune checkpoint inhibitor pembrolizumab plus VEGF tyrosine kinase inhibitor axitinib was based on findings from KEYNOTE-426, which at first interim analysis demonstrated a survival advantage over single-agent sunitinib (Sutent) and improved response rates. Results were presented earlier this year at the Genitourinary Cancers Symposium in San Francisco.
For overall survival, patients on the combination had a 47% reduction in the risk of death compared to those treated with standard-of-care sunitinib (HR 0.53, 95% CI 0.38-0.74, P<0.0001), and this was seen across all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups:
- Favorable: HR 0.64, 95% CI 0.24-1.68
- Intermediate: HR 0.53, 95% CI 0.35-0.82
- Poor: HR 0.43, 95% CI 0.23-0.81
"Pembrolizumab in combination with axitinib offers an important new therapeutic option for physicians to consider when approaching initial treatment for patients newly diagnosed with advanced renal cell carcinoma," lead investigator Brian Rini, MD, of the Cleveland Clinic Cancer Center in Ohio, said in a .
Median progression-free survival was 15.1 months with the combination versus 11.1 months with sunitinib alone (HR 0.69, 95% CI 0.57-0.84, P=0.0001), with the advantage again seen in all IMDC risk groups.
Rates of overall response were also better with pembrolizumab-axitinib (59.3% vs 35.7% with sunitinib). 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.
Ipilimumab (Yervoy) plus nivolumab (Opdivo) is currently approved for intermediate- and poor-risk patients, and another first-line combination that combines an immunotherapy with axitinib is expected to join the mix.
KEYNOTE-426 randomized 861 patients 1:1 to 200 mg pembrolizumab every 3 weeks for up to 2 years in combination with 5 mg oral axitinib administered twice daily (n=432) or to 50 mg oral sunitinib once daily every 4 weeks with 2 weeks off (n=429).
Adverse events (AEs) rates were similar between the pembrolizumab-axitinib and sunitinib arm (96.3% vs 97.6%, respectively), as were rates of grade ≥3 AEs (62.9% vs 58.1%). The most common AEs of any grade (>20%) in the combination arm included diarrhea, fatigue, hypertension, liver toxicity, hypothyroidism, decreased appetite, hand-foot syndrome, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
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. Treatment-related deaths occurred in 0.9% of the pembrolizumab-axitinib group and 1.6% of the sunitinib group.