LEAP-002 Trial of Lenvatinib/Pembrolizumab Combo Misses Key End Points in uHCC

In an interview with Targeted Oncology Richard Finn, MD, discussed the implications of the LEAP-002 trial.

Though the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) achieved the longest median overall survival (OS) ever reported in the first-line for unresectable hepatocellular carcinoma (uHCC), the primary end points of OS and progression-free survival (PFS) did not meet pre-specified statistical significance in the phase 3 LEAP-002 trial (NCT03713593).

Findings from the final analysis of the study were presented at the 2022 European Society of Medical Oncology (ESMO) Congress, and showed that after a median follow-up of 32.1 months (range, 25.8-41.1) for OS, the median was 21.2 months (95% CI, 19.0-23.6) with lenvatinib plus pembrolizumab vs 19.0 months (95% CI, 17.2-21.7) with lenvatinib monotherapy.

The 24-month OS rates were 43.7% vs 40.0%, respectively (HR, 0.840; 95% CI, 0.708-0.997; P = .0227), and ultimately did not reach the secure threshold of 0.0185. Still, these results support the use of lenvatinib as first-line treatment of patients with uHCC, according to Richard Finn, MD.

Patients in the global, randomized, double-blind phase 3 study, were randomized 1:1 and were eligible to enroll if they had 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 no main portal vein invasion.

Those enrolled receive lenvatinib at 12 mg orally once a day for patients with a screening body weight of at least 60 kg or at 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). The other option was the lenvatinib regimen plus placebo which was administered on day 1 of each 3-week cycle (n = 399). The agent was administered until progressive disease or unacceptable toxicity, and pembrolizumab and placebo were given to patients for up to 35 cycles.

Findings also showed the safety profile of the combination regimen to be consistent with previously reported data with any grade adverse events (AEs) occurring in 381 patients (96.5%) in the combination arm and 378 patients (95.7%) in the monotherapy arm. There were a total of 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.

In an interview with Targeted OncologyTM, Finn, professor of medicine in the Division of Hematology Oncology at the Geffen School of Medicine at UCLA in Los Angeles, Johnson Comprehensive Cancer Center, discussed the implications of the LEAP-002 trial.

Can you provide some background on lenvatinib and the basis of the LEAP-002 trial?

Lenvatinib is a multikinase inhibitor that has been approved in the United States for some years now, globally, based on the results of the REFLECT study [NCT01761266], which demonstrated it to be non-inferior to sorafenib [Nexavar] in terms of overall survival. In that study of advanced liver cancer patients, lenvatinib had a survival of just over 13 months, but was superior to sorafenib in terms of secondary end points, progression-free survival and objective response rate.

At the same time, pembrolizumab is a PD-1 antibody which is approved in the United States from an accelerated approval mechanism based on objective response rate, duration of response, and safety. That is in a second line setting, and its activity has been confirmed and phase 3 studies, KEYNOTE-240 [NCT02702401], and KEYNOTE-394 [NCT03062358], 2 studies of pembrolizumab in the second-line setting vs placebo. KEYNOTE-240 just missed its primary end point, whereas KEYNOTE-394 confirmed its activity.

Given that there's evolving data that there could be a synergistic interaction between a kinase inhibitor like lenvatinib and its effect on multiple kinases in the immune microenvironment, it was evaluated in combination with lenvatinib initially in a phase 1B study. This phase 1B study was in advanced liver cancer in the frontline setting. We published this in Journal of Clinical Oncology in 2020 and showed that the combination had an objective response rate of about 36% and an overall survival of over 21 months. That was the basis for LEAP-002.

Can you discuss the key study pools and what methods were used to carry out the LEAP-002 study?

The results of which we presented at the ESMO 2022 meeting were for a global phase 3 study designed to confirm that lenvatinib and pembrolizumab in combination would be better than lenvatinib alone in the treatment of advanced liver cancer in the first-line setting. This was a global study, double-blind, placebo controlled. About 400 patients in each arm were randomized to receive lenvatinib and pembrolizumab or lenvatinib and placebo. The dual primary end points were overall survival and progression-free survival.

Like most studies in advanced liver cancer, we took patients who were well compensated with Child-Pugh A liver disease, good performance status, and those who had not been treated in the frontline setting. Importantly, we did exclude patients who had extra paddock venous invasion or main portal vein invasion, also known as Vp4 invasion.

Can you discuss the findings of LEAP-002 which were presented at ESMO 2022?

At this meeting, we presented the final analysis from this study, and this includes the primary end points of overall survival and progression-free survival. Unfortunately, the study did not show a statistical improvement in overall survival. It's interesting to see why that was the case. The combination of lenvatinib and pembrolizumab performed as expected in regard to the overall survival being over 21 months, 1 of the longest survivals ever reported and a liver cancer study. We improved our objective response rate. As expected, the objective response rate with the combination was just over 25% There were no new safety signals. Progression-free survival was over eight months.

What was unexpected was how well the control arm performed. Survival advantage alone was 19 months which is almost 6 months greater than how it performed in the REFLECT study where survival was about 13 and a half months. Other than that, lenvatinib performed as expected. Its objective response rate was around 17%, very similar to what was in REFLECT. But this overall survival of 19 months is what limited us from showing a significant difference in survival with the combination.

There were no new safety signals. The safety was as expected and mostly driven by lenvatinib. There was no real increase in toxicity with the addition of pembrolizumab. PFS, one of the other coprimary end points, also was not statistically improved, but over time, you can see at the PFS curve that there is a separation that is maintained over time at the 2-year benchmark. Still 16% of patients had not progressed that received lenvatinib and pembrolizumab vs 9% in the lenvatinib alone arm.

What are the implications of these findings?

A few things we learned from this study is that lenvatinib and pembrolizumab are safe. It's active in liver cancer but was not statistically better than lenvatinib alone. What we did learn is that lenvatinib alone is a very active regimen for patients in the frontline setting, giving a survival of 19 months. It's important to note that the 19 months is in a population that did not have a main portal vein invasion. If we look at other phase 3 studies in space, these results compare to the HIMALAYA study [NCT03298451] where durvalumab [Imfinzi]and tremelimumab had a survival of around 16 months. But when the IMbrave-150 study [NCT03434379] of a atezolizumab [Tecentriq] and bevacizumab [Avastin] reports a survival of over 19 months, that is in a higher-risk population and patients who did have included main portal vein invasion.

Lenvatinib is an important option for our patients with advanced liver cancer, it's important to keep that in mind. This combination is being evaluated in another phase 3 study of lenvatinib and pembrolizumab plus transarterial chemoembolization [TACE] for patients with intermediate liver cancer as well. That's a phase 3 study of that combination vs TACE alone.

This combination was intended for FDA approval based on KEYNOTE-524. What's different about this trial that may push that combination?

Unfortunately, I don't think this study will support regulatory approval of this combination. The phase 1b study, also known as KEYNOTE-524 [NCT03006926], was a large, 100 patient study that we hoped would possibly get accelerated approval. It read out right about the time of IMbrave-150 which was a large phase 3 study, which proved that atezolizumab and bevacizumab was better than sorafenib.

Therefore, we were relying on LEAP-002 for the registration. Again, given that we did not meet our primary end points, I think it's going to be hard to see this getting registered as a combination, though I think it does serve as a benchmark or a baseline for further development for potentially a triplet combination. We're still waiting for LEAP-001 [NCT03884101] to read out.


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.

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