LEAP-002 Trial Misses Primary End Points, But Data Support Role of Lenvatinib Monotherapy as SOC in Frontline HCC

Although the primary end points of the phase 3 LEAP-002 trial (NCT03713593) did not meet prespecified statistical significance with regard to survival benefit achieved with lenvatinib (Lenvima) plus pembrolizumab (Keytruda), the median overall survival (OS) observed with lenvatinib monotherapy supports its role as a standard of care in frontline advanced hepatocellular carcinoma (HCC) treatment.^1-2

“Lenvatinib continues to demonstrate its importance as a treatment option for advanced HCC,” Richard S. Finn, MD, professor of medicine, Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, said in a presentation of the data.

After a median follow-up of 32.1 months (range, 25.8-41.1) for overall survival (OS), the median was 21.2 months (95% CI, 19.0-23.6) with lenvatinib plus pembrolizumab, compared with 19.0 months (95% CI, 17.2-21.7) with lenvatinib monotherapy. Similarly, 24-month OS rates were 43.7% vs 40.0%, respectively (HR, 0.840; 95% CI, 0.708-0.997; P = .0227). Finn noted, “However, this did not reach the secure threshold of 0.0185.”

A subgroup analysis favored the combination regimen as demonstrated in a forest plot; in particular, Finn highlighted those associated with high-risk features such as macrovascular invasion/extrahepatic spread (HR, 0.78; 95% CI, 0.63-0.95) and elevated AFP [alpha-fetoprotein] status (HR, 0.67; 95% CI, 0.50-0.90).

After a median follow-up of 17.6 months (range, 11.3-26.6) for progression-free survival (PFS), the median was 8.2 months (95% CI, 6.3-8.3) with the combination regimen, compared with 8.1 months (95% CI, 6.3-8.3) with the monotherapy. The 12-month PFS rates were 34.1% and 29.3%, respectively, and 24-month rates were 16.7% and 9.3% (HR, 0.834; 95% CI, 0.712-0.978). These results did not meet statistical significance per the pre-specified statistical plan.

However, Finn explained, although the trial failed to meet its co-primary end points, the trial demonstrated trends toward improved OS and PFS among those who received the combination regimen.

In addition, he added that the median OS induced from lenvatinib monotherapy in the trial was longer than that observed in previously reported clinical trials evaluating the agent alone in HCC.

“The median OS of 19.0 months with lenvatinib supports its role as a standard of care in first-line advanced HCC,” Finn said.

In the final analysis, median duration of response (DOR) per RECIST v1.1 by blind independent committee review (BICR) in the lenvatinib plus pembrolizumab arm was 16.6 months (range, 2.0+ to 33.6+), compared with 10.4 months (range, 1.9-35.1+) with lenvatinib alone. Median DORs per modified RECIST v1.1 by BICR were 11.2 months (range, 1.4+ to 35.3) and 8.5 months (1.9+ to 35.3+), respectively.

The combination regimen induced an overall response rate (ORR) of 26.1%, compared with 17.5% with lenvatinib alone—including a complete response (CR) rate of 1.5% in both arms, progressive disease (PD) rates of 12.2% vs 15.0%, respectively, and stable disease (SD) rates of 55.2% and 60.9% per RECIST v1.1 by BICR. Per modified RECIST v1.1, the ORR with lenvatinib plus pembrolizumab was 40.8%, vs 34.1% with lenvatinib alone—including CR rates of 9.4% and 9.5%, respectively, PD rates of 9.4% and 10.3%, respectively, and SD rates of 43.5% and 49.1%, respectively.

The safety profile of the combination regimen was consistent with previously reported data.

Any grade adverse events (AEs) occurred in 381 patients (96.5%) in the combination arm, compared with 378 patients (95.7%) in the monotherapy arm. In total, there were 4 grade 5 events with lenvatinib plus pembrolizumab, and 3 with lenvatinib alone. The combination regimen led to discontinuation of any treatment in 71 patients (18%), compared with 42 patients (10.6%) in the monotherapy arm.

The most common AEs in the combination vs the monotherapy arms included hypertension (43.3% vs 46.8%, respectively), diarrhea (40.3% vs 33.9%), hypothyroidism (40.0% vs 35.7%), PPE syndrome (33.2% vs 30.6%), proteinuria (30.6% vs 34.9%), decreased appetite (30.1% vs 23.3%), fatigue (27.3% vs 20.8%), increased aspartate aminotransferase levels (22.0% vs 15.4%), decreased platelet counts (21.0% vs 21.0%), decreased weight (20.3% vs 13.4%), increased alanine transaminase levels (19.2% vs 14.9%), increase blood bilirubin (19.2% vs 16.7%), dysphonia (19.0% vs 17.2%), and nausea (17.7% vs 14.4%).

The most common immune-mediated AE in both arms was hypothyroidism (42.3% vs 39.5%, respectively).

In total, 174 patients in the lenvatinib/pembrolizumab combination arm went on to receive subsequent systemic anti-cancer therapy, compared with 208 patients on lenvatinib alone.

“The treatment landscape has changed significantly for advanced liver cancer in the past several years, and, therefore, there will be an impact of post-progression treatment,” Finn explained. “Both arms went on to receive some post-systemic treatment. It was higher in the lenvatinib-alone arm, but the majority of patients did get either a tyrosine kinase inhibitor or a VEGF-focused agent. If you look at any immunotherapy (administered) post-progression, 23% of patients in the (monotherapy arm) versus 14% (in the combination arm received immunotherapy after treatment on the trial)," Finn said.

In the global, randomized, double-blind phase 3 study, patients were randomized 1:1 to receive either lenvatinib at a dose of 12 mg orally once daily for patients with a screening body weight of at least 60 kg or a dose of 8 mg orally once daily for patients with a screening body weight less than 60 kg plus 200 mg pembrolizumab IV on day 1 of each 3-week cycle (n = 395); or the lenvatinib regimen plus placebo administered on day 1 of each 3-week cycle (n = 399). Lenvatinib was administered until progressive disease or unacceptable toxicity, whereas pembrolizumab and placebo were given for up to 35 cycles.

“Now, there's this evolving preclinical data to suggest that combining a multikinase inhibitor such as lenvatinib in combination with IO [immuno-oncology]may be synergistic,” Finn said. “The single-arm phase 1b 116/KEYNOTE-524 study [NCT03006926]³ evaluated this combination in a frontline setting that demonstrated very exciting activity, with an objective response rate of about 36% by RECIST v1.1, and a median survival of just over 21 months. With that in mind, LEAP-002 was launched as a double-blind, placebo-controlled study in the frontline.”

To be eligible, patients had to have a confirmed diagnosis of HCC, no prior systemic therapy for advanced HCC, were not amenable to curative therapy, had Child-Pugh class A disease, an ECOG performance status of 0 or 1, undergone an esophagogastroduodenoscopy within 3 months of randomization, and of note, according to Finn, no main portal vein invasion.

PFS per RECIST v1.1 by BICR and OS served as the co-primary end points. Secondary end points included ORR, DOR per RECIST v1.1 and modified RECIST by BICR, and safety/tolerability. Post-treatment follow-up assessed safety, disease status, and survival status.

In the combination arm, median age was 66.0 years (range, 19-88), and the majority of patients were male (80.3%).

Lenvatinib monotherapy is FDA-approved for the first-line treatment of patients with HCC based on data from the phase 3 REFLECT trial (NCT01761266), which demonstrated the multiple receptor tyrosine kinase inhibitor was non-inferior to sorafenib (Nexavar) in OS.⁴

Lenvatinib in combination with pembrolizumab plus transarterial chemoembolization is now under investigation in the phase 3 LEAP-012 study (NCT04246177), Finn concluded.

Invited discussant, R. Kate Kelley, MD, professor, clinical medicine, Department of Medicine (Hematology/Oncology), UCSF, noted that prognosis has improved for patients with first-line, advanced HCC. “The advent of multiple first- and later-line treatment options marks enormous progress in HCC and provides new opportunity to individualize treatment decisions,” she said.

References

1. Finn RS, Kudo M, Merle P, et al. Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first- line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33(suppl_7): S808-S869. doi:10.1016/j.annonc.2022.08.031.
2. Merck News Release. Merck and Eisai provide update on phase 3 LEAP-002 trial evaluating Keytruda (pembrolizumab) plus Lenvima (lenvatinib) versus Lenvima monotherapy in patients with unresectable hepatocellular carcinoma. Published: August 3, 2022. Accessed: September 10, 2022. https://bit.ly/3d1kx6P
3. Finn RA , Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38:2960-2970. doi:10.1200/JCO.20.00808.
4. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1.