Adding Keytruda (pembrolizumab) to Lenvima (lenvatinib) led to better duration of response outcomes than Lenvima plus placebo in patients with advanced liver cancer (hepatocellular carcinoma; HCC), according to findings from the phase 3 LEAP-002 trial.
However, 35% of responders to the frontline regimen experienced an extended duration of response (DOR) of three years or more, according to an extended follow-up of the trial, presented at the 2024 Gastrointestinal Cancers Symposium.
As a result, the study authors, led by Dr. Richard S. Finn, of UCLA Health, noted that Lenvima monotherapy remains a standard-of-care first-line treatment for patients with advanced HCC.
The trial failed to meet its co-primary endpoint of overall survival (OS; time from treatment until death of any cause) at the final analysis, and progression-free survival (PFS; time patients live after therapy without their disease getting worse) at the first interim analysis. The median OS for the combination regimen was 21.2 months, compared with 19 months with the placebo regimen, while the median PFS was 8.2 months and eight months, respectively.
Additional Follow-Up
After 12 months of additional follow-up (median, 43.6 months; range, 37.3-52.6), 24-month DOR rates with Lenvima plus Keytruda versus placebo were 43% and 24%, respectively, while 36-month rates were 35% versus 4%. “…DOR results were encouraging,” the study authors added.
Median time to response with Lenvima plus Keytruda was 4.1 months (range, 1.3 to 39.6), compared with four months (range, 0.3 to 18.6) with the placebo regimen, while median DOR was 16.6 months (range, 2.0+ to 45.3+) and 10.4 months (range, 1.9 to 37.0+), respectively.
Median OS with Lenvima plus Keytruda was 21.1 months, compared with 19.0 months with Lenvima plus placebo. The 24-month OS rates with the combination vs placebo were 43% versus 40%, respectively, while the 36-month OS rates were 33% versus 24%.
The addition of Keytruda to Lenvima induced a median PFS of 8.2 months, compared with 8.1 months with placebo, with 24-month PFS rates of 16% versus 10%, respectively and 36-month PFS rates of 14% versus 3%.
The objective response rate (ORR) was 26% for those administered Lenvima plus Keytruda, compared with 18% for those given Lenvima plus placebo. Disease control rates (DCRs) were 81% and 78%, respectively.
Complete responses occurred in 3% of patients treated with Lenvima plus Keytruda, compared with 2% treated with Lenvima plus placebo, whereas 24% and 16%, respectively, experienced partial responses, and 55% and 61% had stable disease. Further, 12% and 15% of those in the combination and control arms, respectively, reported progressive disease.
Treatment-related deaths occurred in four patients in the combination arm and three patients in the placebo arm. Grade 3 to 5 (moderate to fatal) treatment-related side effects occurred in 62.8% and 58.0% of patients, respectively, with the most common including hypertension (43.8% versus 46.8%), diarrhea (40.8% versus 34.2%) and hypothyroidism (40.0% versus 35.9%).
Lastly, 46.6% of patients in the Lenvima plus placebo group received one or more post-study systemic anticancer treatments, versus 55.4% of patients in the Lenvima plus placebo group.
Phase 3 LEAP-002 Trial
In the randomized, double-blind trial, investigators aimed to evaluate the safety and efficacy of first line Lenvima plus Keytruda (395 patients), compared with Lenvima plus placebo (399 patients), in patients with advanced HCC.
PFS and OS served as the primary endpoints. Secondary endpoints included ORR, DOR, DCR and safety and tolerability.
Those eligible for the trial included adults with a confirmed diagnosis of HCC; no prior systemic therapy for their disease; BCLC stage C or B not amenable to or refractory to locoregional therapy and not amenable to curative therapy; Child-Pugh liver class A, measurable disease; ECOG performance status of 0 or 1, indicating that they could perform all or most of their daily tasks independently; no main portal vein invasion; and esophagogastroduodenoscopy within three months of randomization.
Patients were stratified by geographic region, macroscopic portal vein invasion and/or extrahepatic spread, AFP level and ECOG performance status.
In total, 369 patients in the combination arm and 385 patients in the control arm discontinued treatment, with 10 and 1, respectively, completing treatment and 16 and nine still ongoing with treatment.
“The activity of (Lenvima) plus (Keytruda) for patients with advanced HCC observed in this study supports the evaluation of transarterial chemoembolization with or without (Lenvima) and (Keytruda) for the treatment of patients with intermediate-stage HCC in the ongoing phase 3 LEAP-012 study,” the study authors concluded.
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