Phase 3 LEAP-012 Trial Offers A New Option for Intermediate-Stage HCC Management

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with limited treatment options for patients in intermediate stages. Traditionally, transarterial chemoembolization (TACE) has been the cornerstone of treatment for intermediate-stage HCC for the last 20 years, with median progression-free survival (PFS) of 7 to 8 months and overall survival (OS) ranging from 26 to 30 months. However, the efficacy of TACE alone has plateaued over the years, necessitating newer treatment combinations to improve survival outcomes.

The phase 3 LEAP-012 trial (NCT04246177), presented at European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain by Josep M. Llovet, MD, PhD, may be a valuable step in this direction, as the combination therapy showed a higher response rate and disease control rate (DCR) compared to TACE alone.

LEAP-012 and HCC Treatment Advances

Hepatocellular carcinoma is a leading cause of cancer-related mortality globally. Image Credit: © Best - stock.adobe.com

Llovet, director of the Liver Cancer Program and professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai; professor of medicine-hepatic oncology at the University of Barcelona; professor of research at the Catalan Institution for Research and Advanced Studies; and professor at the Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic of Barcelona in Spain, presented the LEAP-012 trial at ESMO Congress 2024. Llovet explained that the phase 3 LEAP-012 trial investigated the use of lenvatinib (Lenvima; Eisai and Merck), a tyrosine kinase inhibitor, and pembrolizumab (Keytruda; Merck Sharp and Dohme), an anti-PD-1 monoclonal antibody, in combination with TACE for intermediate-stage HCC.

Llovet explained that although TACE has been the standard of care for decades, in advanced stages, lenvatinib and pembrolizumab have shown promise, and combining them with TACE for intermediate-stage disease presents a valuable step forward.

Llovet outlined the design of the LEAP-012 trial, a double-blind, placebo-controlled study that randomized patients with intermediate-stage HCC 1 to 1 to receive either lenvatinib plus pembrolizumab with TACE or dual placebo with TACE. Importantly, these patients had confirmed HCC that was confined to the liver, with no portal vein thrombosis or extrahepatic spread, and were not amenable to curative treatments such as resection or ablation.

The trial's primary end points were PFS and OS, while secondary end points included objective response rate (ORR), duration of response, DCR, time to progression, and safety. A total of 480 patients were enrolled, with 237 patients assigned to the lenvatinib-pembrolizumab-TACE arm and 243 to the dual placebo-TACE arm.

Key Findings of LEAP-012

After a median follow-up of 25.6 months, the first interim analysis revealed significant differences between the 2 groups. Llovet explained that the median PFS was 14.6 months for the combination arm, compared to 10 months for the placebo arm. The hazard ratio (HR) was 0.66 (95% CI: 0.51-0.84) with a P value of 0.0002, demonstrating a substantial reduction in the risk of progression. This profound improvement was also seen across various pre-specified subgroups.

Although OS data were still immature, the 2-year survival probability favored the combination arm, with a survival rate of 74.6% compared to 68.6% in the dual placebo arm. However, this difference did not reach statistical significance at the time of the interim analysis (HR: 0.80; P value: 0.086). The ORR was another notable result, with 46.8% of patients in the combination arm achieving a response compared to 33.3% in the placebo arm, underscoring the clinical activity of lenvatinib and pembrolizumab.

From a safety perspective, treatment-related AEs were observed more frequently in the combination arm, with 71% of patients experiencing grade 3/4 AEs compared to 31% in the placebo arm. Common AEs included hypertension, proteinuria, and elevated liver enzymes, which are consistent with the known safety profiles of lenvatinib and pembrolizumab. However, the toxicity was considered manageable, and only 8.4% of patients discontinued both drugs due to AEs, with a low incidence (1.7%) of grade 5 toxicity.

LEAP-012 in the HCC Treatment Landscape

Angela Lamarca, MD, PhD, MSc, a medical oncologist at the Fundacion Jimenez Diaz University Hospital in Madrid, Spain, offered further insights into the LEAP-012 trial by placing it within the broader context of HCC treatment advancements. She acknowledged the profound transformation in HCC management over the past decade, especially with the introduction of immune checkpoint inhibitors and anti-angiogenic agents in advanced-stage disease.

“I think it's important to realize how much of a change we are seeing in the management of HCC over the last years. For many, many years, TACE has been the standard of care, but we do know that this is an area of unmet need, so new combination strategies are being tested with TACE to see whether we can improve the outcome,” Lamarca said. “We recently heard the data from the EMERALD-1 [NCT03778957] clinical trial testing durvalumab [Imfinzi; AstraZeneca] and bevacizumab [Avastin; Genentech] with TACE also in the intermediate stage, and I will try and place the EMERALD-1 trial in context with the LEAP-012 trial.

Lamarca highlighted that, despite the success of lenvatinib and pembrolizumab in the advanced setting, the combination failed to meet the OS end point in the LEAP-002 trial, raising questions about its potential in earlier stages of the disease. In the EMERALD-1 trial, Lamarca explained that durvalumab and bevacizumab with TACE were tested in a similar patient population as LEAP-012. While cross-trial comparisons are not ideal, Lamarca provided analysis of the results of both, noting that LEAP-012 and EMERALD-1 showed improvements in PFS. However, LEAP-012 demonstrated a more robust reduction in progression risk, with a HR of 0.66 compared to 0.77 in EMERALD-1.

Can TACE Efficacy Be Improved?

One of the central questions posed by Lamarca was whether adding lenvatinib and pembrolizumab to TACE could improve outcomes without compromising safety. The LEAP-012 trial results suggest that this combination can indeed enhance PFS and ORR compared to TACE alone, offering patients a more effective treatment option in the intermediate stage. Lamarca noted the importance of biomarkers in HCC, as the current lack of reliable biomarkers for the disease makes predicting which patients will benefit most from combination therapies a challenge.

The early separation of the PFS curves, as observed in LEAP-012, is promising and indicates that patients could experience earlier and more durable responses, according to Lamarca. However, the lack of mature OS data leaves some uncertainty in this regard, although Lamarca expressed optimism that future analyses may confirm the observed positive trend.

Safety Considerations and Practical Application

In terms of safety, Lamarca echoed Llovet's points regarding the AEs of the regimen, as the AEs associated with lenvatinib and pembrolizumab were consistent with previous studies. Hypertension, proteinuria, and liver enzyme elevations were common but manageable, and while there was a higher rate of treatment discontinuation in the experimental arm, Lamarca explained that the overall safety profile would be manageable for patients.

From a clinical practice perspective, Lamarca acknowledged the complexity of managing patients who receive TACE. Decisions on when to re-TACE, how to define progression, and whether to switch treatments remain challenging and highly variable between institutions. Additionally, although the LEAP-012 trial demonstrated strong efficacy of the regimen, Lamarca noted that there remain some unanswered questions regarding the optimal sequencing of the therapies and the timing of re-TACE procedures.

Comparison With EMERALD-1 and Future Directions

The LEAP-012 and EMERALD-1 trials demonstrated positive PFS outcomes, but LEAP-012 showed a more significant separation of PFS curves early in treatment, according to Lamarca. This could suggest that lenvatinib and pembrolizumab are a more potent in combination with TACE than durvalumab and bevacizumab.

Looking ahead, Lamarca noted that there is a need for continued research investigating treatment options for intermediate-stage HCC, particularly in relation to identifying biomarkers that can predict response to combination therapies. While OS remains a valuable end point, Lamarca noted that the oncology community does accept PFS as a surrogate for OS in certain cancers, such as HCC. Therefore, the PFS benefit seen in LEAP-012 may be sufficient to recommend this regimen to patients even before OS data mature.

“A very important question that comes to mind when we are discussing OS after discussing a positive PFS is whether I will, as a clinician, accept this regimen as a new standard in intermediate-stage HCC, as it’s a treatment showing benefit in PFS, but not yet in OS,” Lamarca said. “My personal opinion is that, yes, I will probably recommend to my patients a treatment that is showing benefit in PFS, even though I don't have a full confirmation of benefit in OS.”

Conclusion

The LEAP-012 clinical trial represents a significant advancement in the treatment of intermediate-stage HCC, demonstrating that the combination of lenvatinib, pembrolizumab, and TACE can significantly improve PFS and ORR. While OS data remain immature, the observed trends are encouraging, and the manageable safety profile makes this regimen a potential new standard of care.

“In combination with TACE, the safety profile of lenvatinib plus pembrolizumab was manageable and consistent with the known safety profiles of lenvatinib plus pembrolizumab and TACE, with no new safety concerns identified,” Llovet said. “Overall, treatment with lenvatinib plus pembrolizumab and TACE may be a new option for patients with intermediate-stage hepatocellular carcinoma.”

REFERENCE

Llovet JM, Lamarca A. Presidential Symposium I: Practice-changing trials. ESMO Congress 2024; Barcelona, Spain; September 13-17, 2024.