乌鸦传媒

Combining lenvatinib (Lenvima) with an immune checkpoint inhibitor in the first-line setting for unresectable hepatocellular carcinoma (HCC) failed to significantly improve survival outcomes in an international phase III trial.

In the so-called LEAP-002 study, overall survival (OS) and progression-free survival (PFS) showed numerical advantages for patients assigned to the multikinase inhibitor plus pembrolizumab (Keytruda) -- rather than lenvatinib plus placebo -- but neither of the trial's co-primary endpoint met prespecified criteria for statistical significance:

• OS: 21.2 vs 19 months, respectively (HR 0.84, 95% CI 0.71-1.00)
• PFS: 8.2 vs 8 months (HR 0.87, 95% CI 0.73-1.02)

The lack of difference in survival between arms could have multiple explanations, including the "substantial use of effective second-line therapies," according to researchers led by Josep Llovet, MD, PhD, of the Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai in New York City, who detailed their findings in .

For starters, the control group had a longer OS than expected, they said, and patients on lenvatinib plus placebo stayed on treatment for a median of 9.5 months, "longer than in other studies investigating front-line multikinase inhibitors."

The extended time on treatment could reflect clinicians' increasing familiarity with lenvatinib since its 2018 approval as a first-line monotherapy in HCC -- based on findings from , which proved it to be noninferior to sorafenib (Nexavar). In that trial, patients on single-agent lenvatinib had a median OS of 13.6 months.

"Moreover, unlike other open-label, front-line, phase III studies in advanced hepatocellular carcinoma, the longer exposure to lenvatinib in LEAP-002 might also be due to the double-blind design," added Llovet and colleagues.

In the U.S., approved first-line combination therapies for advanced HCC include the PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq) plus bevacizumab, an anti-VEGF antibody; and the PD-L1 inhibitor durvalumab (Imfinzi) plus tremelimumab (Imjudo), an anti-CTLA-4 immunotherapy.

Llovet told 乌鸦传媒 he would recommend either of those immunotherapy-based combinations in first-line, with the latter mostly for patients at high risk of bleeding.

Single-agent lenvatinib or sorafenib can still be considered in this setting "for advanced cases when there is a contraindication for immunotherapy (i.e., autoimmune diseases, liver transplantation)," he said, citing from the American Association for the Study of Liver Diseases.

The idea behind combining tyrosine kinase inhibitors or anti-VEGF antibodies with checkpoint blockade is they "can transform immunological cold tumors into hot tumors," the researchers explained, "thus expanding the patient population responding to checkpoint inhibitors because of distinct immunomodulatory effects."

Multikinase inhibitors -- such as lenvatinib, cabozantinib (Cabometyx), and others -- are clearly active in HCC "but their role as a combination partner with immunotherapy is less clear," according to Landon Chan, MBChB, and Stephen Chan, MD, both of the Hong Kong Cancer Institute.

"Notably, it has been shown that the dose of multikinase inhibitor might alter immunomodulation in hepatocellular carcinoma," they wrote in an . Yet in phase III trials testing these agents in combination with PD-1/L1 inhibitors, the dosing for the multikinase inhibitors "was determined from the approved monotherapy dose, without dedicated studies to evaluate the optimal dose when combining with anti-PD-1 or anti-PD-L1."

The double-blind phase III study randomized 794 patients with previously untreated unresectable HCC 1:1 to either oral lenvatinib (once-daily at an 8-mg or 12-mg dose based on body weight) plus IV pembrolizumab (200 mg every 3 weeks) or lenvatinib plus matching IV placebo. Median follow-up at data cutoff was 32.1 months.

Participants had a median age of 66 years and 81% were men, with most being Asian (43%) or white (43%). More than three-fourths had Barcelona Clinic Liver Cancer stage C disease, 82% had an A5 Child-Pugh score, two-thirds had macroscopic portal vein invasion or extrahepatic disease, and 62% were positive for hepatitis B/C.

Landmark analyses for OS favored the investigational arm both at 24 months (44% vs 40%) and 30 months (39% vs 31%).

Secondary efficacy outcomes showed improved objective response rates with the addition of pembrolizumab, reaching 26% as compared to 18% with placebo (per blinded central review). Complete responses were observed in 2% of each arm. Median time to response was similar between arms (about 4 months), while the median duration of response numerically favored lenvatinib-pembrolizumab, at 16.6 months versus 10.4 months.

Safety with the combination was consistent with the known toxicity profiles of the two agents, according to Llovet and his fellow investigators.

Grade ≥3 treatment-related adverse events (TRAEs) were more common with lenvatinib-pembrolizumab, at 62% versus 57% with lenvatinib-placebo, and the most common of these included hypertension (17% in each arm), increased aspartate aminotransferase (7% vs 4%, respectively), and diarrhea (6% vs 4%).

Serious TRAEs were reported in 25% of patients in the investigational arm and 16% of those in the control arm, while treatment-related deaths occurred in four and three patients, respectively.

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