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Progression-free survival (PFS) in intermediate-stage hepatocellular carcinoma (HCC) improved by almost 5 months when a targeted agent and immunotherapy were added to transarterial chemoembolization (TACE), initial results from a randomized trial showed.

Median PFS increased from 10 months with TACE to 14.6 months with the addition of lenvatinib (Lenvima) and pembrolizumab (Keytruda). A subgroup analysis showed a consistent benefit with the combination therapy, while a preliminary survival analysis showed a trend toward improvement.

Grade 3/4 treatment-related adverse events (TRAEs) occurred more than twice as often with added lenvatinib/pembrolizumab, but relatively few patients discontinued treatment because of adverse events, reported Josep Llovet, MD, of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City, during the European Society for Medical Oncology congress in Barcelona.

"Early separation [of PFS curves] at the first 9-week scan was observed and continued beyond 24 months," said Llovet. "Although immature, a favorable OS [overall survival] trend was observed with lenvatinib plus pembrolizumab plus TACE, and OS will be tested at future analyses in accordance with the statistical analysis plan."

"Treatment with lenvatinib plus pembrolizumab plus TACE may be a new option for patients with intermediate-stage hepatocellular carcinoma," he added.

The trial provides more evidence for discussion of optimal treatment for intermediate-stage HCC, said invited discussant Angela Lamarca, MD, PhD, of the Hospital Universitario Fundación Jiménez Díaz in Madrid. The EMERALD-1 trial reported earlier this year demonstrated significant improvement in PFS with the addition of durvalumab (Imfinzi) and bevacizumab (Avastin) to TACE.

Acknowledging the limitations of cross-trial comparisons, Lamarca noted that LEAP-012 showed a larger reduction in the PFS hazard versus EMERALD-1 (34% vs 23%), but EMERALD-1 showed a larger absolute difference in PFS (6.8 vs 4.6 months in LEAP-012). The survival curves separated earlier in LEAP-012. Both trials showed improvement in objective response rate (ORR). EMERALD-1 had discrepancies in PFS and time to progression. Discontinuation rates because of toxicity were higher with the combination treatments compared with TACE alone in both trials.

"The LEAP-012 data may be more robust but I would like to see time to progression and more mature overall survival data and more granularity of data for discontinuation due to adverse events," said Lamarca.

"I agree with the conclusion that treatment with lenvatinib, pembrolizumab, and TACE may be a new option because we already have other treatments that have been reported, with a significant difference in progression-free survival," she noted. "In general, I feel LEAP-012 has more robust data. Other ongoing clinical trials are exploring other combinations. We will have to see whether we can get this to our patients."

"We are still facing the challenges of what to do when patients progress on this therapy. We are still missing biomarkers," she added. "Finally, is PFS a good enough surrogate endpoint for OS in HCC?"

TACE remains the standard of care for intermediate-stage HCC despite leading to a median PFS of only 7 to 8 months and median OS of 26 to 30 months, Llovet said in his introductory remarks. PD-(L)1 inhibition plus a VEGF or CTLA-4 inhibitor is the current standard for advanced HCC. Lenvatinib is a first-line option for patients with unresectable HCC who are TACE ineligible, unresponsive, or refractory.

The phase III LEAP-002 trial showed that first-line lenvatinib plus pembrolizumab led to numerically better OS for advanced HCC as compared with lenvatinib and placebo.

The accumulation of evidence provided a rationale for the multicenter, international LEAP-012 trial. Eligible patients had HCC not amenable to curative treatment and accessible to treatment with TACE in one or two sessions. Llovet and team randomized 484 patients to TACE plus lenvatinib and pembrolizumab or two placebos. The primary endpoints were PFS and OS, determined in hierarchical fashion.

The study population had a median age of 65-66, and men accounted for more than 80% of the patients. About three-fourths had a viral etiology, and alcohol was a contributing factor in 45%. Of the patients, 86% to 90% had .

The primary analysis showed a 4.6-month absolute difference in median PFS, which represented a 34% reduction in the hazard ratio (95% CI 0.51-0.84, P=0.0002). The 12-month PFS rate was 62.2% with the combination treatment and 43.4% with TACE-placebo, and 18-month PFS rates were 39.1% and 27.9%, respectively. The "profound difference" in PFS was evident across a prespecified subgroup analysis, said Llovet.

The actuarial OS rate at 24 months was 74.6% with combination therapy versus 68.6% for TACE-placebo, representing a 20% reduction in the hazard ratio (95% CI 0.57-1.11). The trend favoring the lenvatinib-pembrolizumab arm persisted across the subgroup analysis.

TACE plus lenvatinib and pembrolizumab led to an ORR of 46.8% versus 33.3% with TACE-placebo (P=0.0005). The disease control rate was 89.5% with TACE/lenvatinib/pembrolizumab and 81.5% with TACE-placebo.

Grade 3/4 TRAEs occurred in 71.3% of the combination arm versus 31.1% of the control group. Rates of serious TRAEs were 33.3% and 12.4%, respectively, and discontinuation rates were 8.4% and 1.2%. The most common all-grade TRAEs in the combination arm were hypertension (>50%), proteinuria (~40%), and increased liver enzymes, increased platelet count, hypothyroidism, and increased bilirubin (all ≥30% to <40%).

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