A New Option to Treat Intermediate Hepatocellular Carcinoma?

BARCELONA — Adding lenvatinib and pembrolizumab to transarterial chemoembolization (TACE) led to a significant improvement in progression-free survival in patients with intermediate-stage hepatocellular carcinoma compared with TACE plus placebo, according to findings from the first interim analysis of the phase 3 LEAP-012 study.

The results, presented here at the European Society for Medical Oncology, could represent a practice-changing shift in the treatment of intermediate-stage hepatocellular carcinoma, commented lead investigator Josep Llovet, MD, PhD, from the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York City. 

Although overall survival results for the LEAP-012 study remain immature at this time, a “favorable trend” in the current analysis suggests the new combination treatment may improve survival and could become “a new option” for patients with intermediate-stage hepatocellular carcinoma, Llovet said during a symposium on practice-changing trials.

For the last 20 years, the standard treatment option for this patient population has been TACE alone, and patient outcomes have remained poor, explained Llovet. The latest randomized controlled trials have established a median progression-free survival (PFS) of about 7 to 8 months and a median overall survival (OS) of around 26 to 30 months with TACE. 

Adding lenvatinib (Lenvima) and pembrolizumab (Keytruda) has the potential to improve patient outcomes. In advanced disease, lenvatinib plus pembrolizumab led to a 2-month improvement in OS compared with lenvatinib alone (21.1 months vs 19 months; hazard ratio [HR], 0.84; P = .023)

The current LEAP-012 trial randomly assigned 480 patients (median age 65 years) with intermediate-stage hepatocellular carcinoma not amenable to curative treatment to either TACE plus the lenvatinib/pembrolizumab combination (n = 237) or TACE plus placebo (n = 243) for up to 2 years. The dual primary endpoint was PFS and OS. 

The rate of treatment discontinuation was high in both arms — 78% (n = 185) in the treatment arm and 89% (n = 215) in the placebo arm — mostly due to progressive disease.

Baseline characteristics were well-balanced between groups overall, though more than 80% of patients were men. 

The main etiology of the disease was viral, particularly hepatitis B and C infection followed by alcohol, Llovet said. In terms of tumor stage, 30% of patients were BCLC stage A (earliest) and another 60% were stage B.

This first interim analysis represents the final analysis for PFS.

Patients who received the combination therapy had significantly longer PFS — a median of 14.6 months vs 10 months in the control arm (HR, 0.66; P = .0002) at a median time from randomization to data cut-off of 25.6 months. At 18 months, 39.1% of patients in the combination group remained progression-free compared with 27.9% in the TACE-only group.

“This profound difference in progression-free survival was also observed in the prespecified subgroups,” Llovet added.

The OS findings showed a trend in favor of the treatment group. The probability of being alive at 2 years was 74.6% in the combination group vs 68.6% in the TACE-only group (HR, 0.80; P = .0867).

The per RECIST objective response rate (ORR), a secondary endpoint, was 46.8% in the combination drug group compared with 33.3% in the TACE-only group. Overall, 3.4% of patients in the combination arm had complete responses vs 4.1% in the TACE-only arm, and 43.5% vs 29.2%, respectively, had partial responses. 

The median duration of response for the combination group was about 2 months longer — 12.6 months vs 10.7 months — and the disease control rate was higher in the combination group — 89.5% vs 81.5%.

The modified RECIST ORR was 71.3% in the combination drug group vs 49.8% in TACE-only, with complete response rates of 56.1% vs 33.7%, respectively, and partial response rates of 15.2% vs 16%, respectively. In this case, the median duration of response was 14.6 vs 12.5 months, respectively, and the disease control rate was 90.3% vs 81.1%.

Grade 3 or 4 treatment-related adverse events were higher in the combination drug group — 71.3% vs 31.1% in the TACE-only group. Adverse events led to treatment discontinuation in 8.4% of patients in the combination group and 1.2% in the TACE-only group. However, no new safety concerns were identified.

Despite the immature OS data, Angela Lamarca, MD, PhD, the invited discussant for the study, said she still feels “quite optimistic” about the results. 

” Would I accept this treatment as a new standard in intermediate-stage disease? My personal opinion is that probably yes I would recommend to my patient a treatment that is giving benefit in progression-free survival, even though I don’t have a full confirmation of benefit in overall survival,” said Lamarca, from the UAM Fundación Jiménez Díaz University Hospital in Madrid, Spain. 

Improving outcomes in intermediate-stage hepatocellular carcinoma “remains a huge unmet need,” she added, citing similarly promising results from the EMERALD-1 trial, presented earlier this year at the American Society of Clinical Oncology meeting. This trial showed increased PFS in intermediate-stage hepatocellular carcinoma with a combination of durvalumab and bevacizumab. 

“What is good news is that within 9 months we’ve had two clinical trials in hepatocellular carcinoma reporting a positive progression-free survival outcome in this setting, something that is very welcome news to the field,” she said. 

While acknowledging the pitfalls of making trial-to-trial comparisons, she emphasized the similar PFS benefits seen in both of these recent trials — median increases over controls of 4.6 months in LEAP-012 and 6.8 months in EMERALD-1.

“I do agree with the authors that this may be a new option for patients with intermediate-stage hepatocellular carcinoma,” she concluded.

Funding for the study came from Merck Sharp & Dohme LLC, and Eisai Inc. Llovet disclosed principal investigator relationships with Eisai Inc, Nutley, Merck Sharp & Dohme LLC, among other disclosures. Lamarca disclosed speaker honoraria from Merck, Eisai, Pfizer, Ipsen, Incyte, AAA/Novartis, AstraZeneca, Roche, and others; advisory and consultancy honoraria from Eisai, Nutricia, Roche, Servier, Boston Scientific, and others; as well as principal investigator-associated institutional funding from Merck, Boehringer Ingelheim, Servier, AstraZeneca, and others.