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FDA approves Keytruda-Inlyta combination for first-line treatment of advanced renal cell carcinoma
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The FDA approved pembrolizumab in combination with axitinib for first-line treatment of advanced renal cell carcinoma.
Pembrolizumab (Keytruda, Merck) — an anti-PD-1 therapy — is approved for several oncologic indications, but this is its first approval for renal cell carcinoma.
Axitinib (Inlyta, Pfizer), a tyrosine kinase inhibitor, already had been approved for treatment of patients with advanced renal cell carcinoma who underwent one prior therapy.
Elizabeth R. Plimack, MD, MS — a researcher on the phase 1b and phase 3 trials that assessed the combination as first-line treatment of advanced renal cell carcinoma — told HemOnc Today the FDA granted approval sooner than she expected. Phase 3 data were presented in February at Genitourinary Cancers Symposium and published simultaneously in The New England Journal of Medicine.
“We are really happy about this approval because we have seen firsthand how effective this combination can be,” said Plimack, chief of the division of genitourinary medical oncology, associate professor in the department of hematology/oncology and director of genitourinary clinical research at Fox Chase Cancer Center.
“We still can’t promise patients that they can be cured, but we know this combination shrinks tumors in the vast majority of patients who take it,” Plimack added. “We also know it’s pretty safe. Some people have bad reactions, but most do really well on it. What we don’t know yet — and time will tell — is how long patients are going to do well on this combination. We hope it’s for many years, and we hope their cancer control persists even after we stop treatment.”
The FDA based the approval on results from the randomized phase 3 KEYNOTE-426 trial, which included 861 patients (median age, 62 years, range, 26-90; 73% men; 79% white) who had not received systemic therapy for advanced renal cell carcinoma.
The multicenter, open-label trial enrolled patients regardless of PD-L1 tumor expression. Approximately one-third (31%) of patients had favorable-risk disease; 56% had intermediate-risk disease and 13% had poor-risk disease.
Researchers randomly assigned 432 patients to pembrolizumab 200 mg IV every 3 weeks for up to 24 months plus axitinib 5 mg orally twice daily. The other 429 patients received sunitinib (Sutent, Pfizer) 50 mg orally once daily in a 4-weeks-on, 2-weeks-off schedule.
OS and PFS assessed by blinded independent review committee served as the primary outcome measures. Objective response rate served as an additional efficacy measure.
Median follow-up was 12.8 months (range, 0.1-22).
The pembrolizumab-axitinib combination was associated with significant improvement in OS (HR = 0.53; 95% CI, 0.38-0.74). Median OS had not been reached in either treatment group, but estimated 12-month OS rates were 90% with pembrolizumab-axitinib and 78% with sunitinib.
Patients assigned pembrolizumab-axitinib also achieved significantly longer PFS (median, 15.1 months vs. 11.1 months; HR = 0.69; 95% CI, 0.57-0.84).
Researchers reported ORRs of 59% in the combination group and 36% in the sunitinib group (P < .0001), with higher rates of complete response (6% vs. 2%) and partial response (53% vs. 34%) in the combination group.
The most common adverse reactions among patients treated with the combination included diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%) and decreased appetite (30%).
Forty percent of patients assigned the pembrolizumab-axitinib combination experienced serious adverse reactions, and 3.3% of patients experienced fatal adverse reactions. These rates were comparable to those observed in the control arm, Plimack said.
The most common serious adverse reactions among patients assigned the combination included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%) and pneumonitis (1%).
Thirty-one percent of patients assigned the combination discontinued treatment due to adverse reactions. The most common reactions that led to discontinuation were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%) and cerebrovascular accident (1.2%).
Per the KEYNOTE-426 protocol, pembrolizumab treatment ended at 2 years. However, not all patients had reached the 2-year mark a data cutoff. Some patients have continued on axitinib beyond the 2 year mark but others stopped both drugs, as the decision was left to the treating team.
Consequently, it remains unclear how long patients treated with this combination should remain on therapy, as well as which agent should be stopped when.
“Those are unanswered questions, and we are going to have to very rigorously collect those data over the next 3 to 5 years,” Plimack told HemOnc Today.
PD-L1 status did not appear to predict benefit from the combination, Plimack said. Researchers also observed benefit among patients with poor-, intermediate- or good-risk disease.
“We want patients who are doing well to do well for many years and perhaps permanently,” Plimack told HemOnc Today. “These early results suggest that may be the case, but we will need longer follow-up. For now, the majority of patients who have seen benefit from this combination feel well, and to see their cancer controlled scan after scan is huge for them. We’re really grateful to be able to offer this combination to patients as a standard first-line treatment.”
For more information:
Elizabeth R. Plimack, MD, MS, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111; email: elizabeth.plimack@fccc.edu.
Disclosure: Plimack reports a consultant role with Merck and a data safety monitoring role with Pfizer. She served as an author on phase 1b and phase 3 trials of the pembrolizumab-axitinib combination.