The greater LEAP program is investigating the combination of multikinase inhibitor lenvatinib and PD-L1 inhibitor pembrolizumab among patients with multiple solid tumor types, all of which have limited therapies available.(8) Other trials in this program have addressed endometrial carcinoma, melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma, as well as others.

The LEAP-002 study compared lenvatinib plus pembrolizumab to lenvatinib plus placebo in the first-line setting among patients with advanced HCC.(9,10) In 2023, results from the final analysis of LEAP-002 found that lenvatinib plus pembrolizumab did not meet the prespecified significance for improved overall survival (OS) and progression-free survival (PFS) vs lenvatinib plus placebo.(10)

In LEAP-002, 794 patients were randomized to receive either lenvatinib plus pembrolizumab (n = 395), or lenvatinib plus placebo (n = 399).(9-10) With a median follow-up duration of 32.1 months, the final analysis reported the median overall survival as 21.2 months in the lenvatinib-pembrolizumab arm vs 19 months in the lenvatinib-placebo arm (P = .023), and the median progression-free survival (PFS) as 8.2 months vs 8 months, respectively.(10) As lead author Josep M Llovet, MD, Tisch Cancer Institute, New York, NY, and coauthors wrote in this report, “Our findings do not support a change in clinical practice.”

Despite this negative study,(10) at the 2024 ASCO Gastrointestinal Cancers Symposium, longer-term data from LEAP-002 supported the continuation of the LEAP-012 study, an evaluation of TACE plus lenvatinib plus pembrolizumab for intermediate-stage HCC.(11) In the updated analysis, with a median follow-up of 43.6 months, lead author Richard Finn, MD, University of California, Los Angeles, and coauthors stated, “given the late separation of Kaplan-Meier survival curves of OS and PFS between treatment arms from 12 [months] onwards, outcomes with extended follow-up are of interest.” While the initial findings regarding OS and PFS in LEAP-002 were upheld with this additional follow-up, the activity shown in this patient population with the lenvatinib-pembrolizumab combination “supports the evaluation of TACE [plus/minus lenvatinib plus pembrolizumab] for intermediate-stage HCC in the ongoing phase 3 LEAP-012 study.”

LEAP-012 is a randomized, double-blind, international, active-controlled phase 3 trial comparing lenvatinib plus pembrolizumab plus TACE, to placebos plus TACE.(8,12,13) Eligible patients have HCC localized to the liver not amenable to curable treatment and have not received any previous systemic treatment for HCC, with a planned sample size of 950.(12,13) Response will be assessed every 9 weeks by imagining, and safety will be assessed throughout the study and up to 90 days post-treatment.(12) The dual primary endpoints for this study include PFS and overall survival at 60 months by blinded independent central review. Secondary endpoints include PFS, objective response rate, disease control rate, duration or response, and time to progression per both modified RECIST and RECIST v1.1.(12-13) Other exploratory endpoints are time from randomization to second/subsequent disease progression after initiation of new anticancer therapy or death from any cause, identification of molecular biomarkers, and health-related quality of life.(13)

EMERALD-1 was a phase 3 study comparing durvalumab plus bevacizumab and TACE to TACE alone among patients with embolization-eligible unresectable HCC.(14,15-17) There was an additional experimental arm examining durvalumab plus TACE.(14,15-17) At the 2024 ASCO Gastrointestinal Cancers Symposium, Riccardo Lencioni, MD, University of Pisa School of Medicine, Pisa, Italy, presented these results and stated, EMERALD-1 “is the first, global phase 3 study to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival with an immunotherapy and TACE-based regimen in unresectable HCC eligible for embolization.”(16)

In EMERALD-1, there were 616 patients randomized to receive either durvalumab plus bevacizumab plus TACE (n = 204), durvalumab plus TACE (n = 207), or TACE (n = 205).(15,16) The final PFS analysis reported a significant improvement of PFS in the durvalumab plus bevacizumab plus TACE arm when compared to the TACE arm (median PFS, 15 months vs 8.2 months; P = .032). The secondary end point comparing the PFS of the durvalumab plus TACE arm vs the TACE arm did not show a statistically significant improvement.(15-16)

In an interview with Oncology Learning Network regarding these results, Dr Lencioni highlighted, “The data is certainly very compelling. I think it opens a new horizon. For more than 20 years, we were trying to improve the embolization techniques…and all attempts to combine locoregional and systemic approaches failed to provide meaningful outcomes. This is the first trial that demonstrates that there is a potential synergistic effect and a significant prolongation of progression-free survival, as well as [time to progression], with the combination of durvalumab, bevacizumab, and TACE.”(17)

There is evidence that adjuvant therapy engaging the immune response, such as a PD-L1 inhibitor, can prolong recurrence-free survival (RFS) among patients with early stage HCC, and that inhibiting the VEGF pathway can improve the activity of the PD-L1 blockade among patients with advanced HCC.(18) In addition, when discussing the impact of EMERALD-1, Dr Lencioni noted, “We know that immune-based combinations have the potential to offer benefit across the entire spectrum of tumor stages, from the adjuvant to the intermediate to the advanced setting.”(17)

EMERALD-2 is a randomized, double-blind, international, placebo-controlled phase 3 study, evaluating the efficacy and safety of durvalumab with or without bevacizumab in the adjuvant setting.(18,19) Eligible patients have HCC and have successfully completed a curative therapy, either resection or ablation, with imaging confirming disease-free status no more than 28 days prior to randomization. Patients must not have received previous systemic anticancer therapy for HCC.(18) The planned sample size is 888, with patients randomized on a 1:1:1 basis to durvalumab plus bevacizumab, durvalumab plus placebo, or placebos. The primary endpoint is RFS for the durvalumab plus bevacizumab arm compared with the placebos arm, as assessed by blinded independent central radiology review using RECIST v1.1. Secondary end points include 2- and 3-year RFS, time to recurrence, OS, health-related quality of life measures, and safety.(18)

There is also on the horizon the potential of transarterial delivery of immunotherapy.1 As these combination therapies advance and potentially change practice, it is essential that interventional oncologists keep aware of the principles of immunotherapy, particularly when used in combination with existing locoregional therapies.