Significance of Lenvatinib/Pembrolizumab Vs Lenvatinib Outcomes in HCC

Amit Singal, MD

Medical Director of the Liver Tumor Program

Clinical Chief of Hepatology

Professor

UT Southwestern Medical Center

Dallas, TX

Targeted Oncology^TM: What was the purpose of the LEAP-002 trial (NCT03713593) and what were the key outcomes?

SINGAL: LEAP-002 enrolled patients who had a diagnosis of HCC [hepatocellular carcinoma]. This is a first-line trial. They needed to have Child-Pugh A [cirrhosis] and good performance status. All patients were required to have an esophagogastroduodenoscopy within 3 months of randomization, and like the REFLECT trial [NCT01761266], patients with main portal vein invasion were excluded from LEAP-002. Patients were randomly assigned to receive lenvatinib [Lenvima] plus pembrolizumab [Keytruda] versus lenvatinib plus placebo. Then the patients were treated until disease progression or intolerable toxicity with the primary end points of overall survival [OS] and progression-free survival [PFS] as dual primary end points. One thing that’s worth noting is that this is one of the first placebo-controlled, double-blind, randomized trials that we’ve had in HCC. Most of the other trials [in this setting] were open label, so I think that this is different in terms of study design from some of other trials you’ve seen, including that of REFLECT.

[There was] nothing too surprising about the baseline patient characteristics. The median age was 66, the majority were male.¹ There were 30% of patients from Asia, the rest of them from Western regions or Japan, and 30% of patients had ECOG performance status 1 [contrasted to 0]. There was viral etiology in about 60% of patients. There was alcohol etiology or non-alcoholic etiology in about 30% of patients, with 30% being nonviral. About 30% had an alfa-fetoprotein [AFP] level greater than 400 ng/mL. They all had Child-Pugh class A. These are patients with advanced tumor burden, but two-thirds of patients had macroscopic portal vein invasion or extrahepatic spread. Although about 22% were Barcelona Clinic Liver Cancer stage B and had failed locoregional therapy.

[Concerning the] top level results when you compare lenvatinib and pembrolizumab versus lenvatinib alone, the median OS with the combination was 21 months.¹ Median OS with lenvatinib alone was 19 months. There was a hazard ratio of 0.84, with a P value of .0227 so it did not meet the superiority threshold of .018.

I think the one thing that’s worth noting here is that lenvatinib/pembrolizumab performed as it should. The phase [1b] data for lenvatinib/pembrolizumab suggested a median OS of 22 months.² The median OS [in the phase 3 trial] was 21.2 months.¹ It’s not like we saw a big degradation in how lenvatinib and pembrolizumab performed. I think the interesting thing is this trial was negative because lenvatinib grew up ‘overnight’. Lenvatinib in the REFLECT trial had a median OS of approximately 13 months,³ and that was the assumption that went in when they were building LEAP-002. And, instead, you see a median OS of 19 months.¹

What did subgroup analysis show in this trial?

There was consistency across the different subgroups, although if you wanted to really tease, you can say that perhaps the combination of lenvatinib and pembrolizumab may have performed better if the patient had extrahepatic spread compared with no extrahepatic spread. Maybe in those patients it performs better. The same thing [is true] when you take a look at AFP greater than 400 ng/mL, you [could] say that lenvatinib/pembrolizumab performed better in that subgroup [HR, 0.67; 95% CI, 0.50-090].¹ So in patients with larger tumor burden or more aggressive disease, you may get a benefit from adding in pembrolizumab to lenvatinib. In these patients, clearly lenvatinib/pembrolizumab is a potent therapy, but it was a negative trial.

When you take a look at response by RECIST 1.1 criteria, the objective response rate was 26% with lenvatinib/pembrolizumab compared with 17.5% with lenvatinib monotherapy. Disease control rate was 81% [with lenvatinib-pembrolizumab] versus 78% [with lenvatinib], so it was relatively similar. If you take a look at objective response rate by modified RECIST criteria, they had a very similar disease control rate, although responses slightly higher with lenvatinib/pembrolizumab: 41% versus 34%.

One of the questions was, did those patients who received lenvatinib monotherapy receive more subsequent second-line therapies? When you take a look at overall second-line therapies, it was given to 44% of patients for lenvatinib and pembrolizumab versus 52% for lenvatinib monotherapy. When you take a look at [patients who received] immunotherapy in the second line, it was given to 14.5% [of those who received lenvatinib-pembrolizumab] versus 23% for the patients who were on lenvatinib monotherapy. So you do see a difference. I think the question is, is that enough to drive what we saw in terms of OS in terms of lenvatinib performing much better than expected?

What was seen in this trial in terms of duration and adverse events (AEs)?

Lenvatinib/pembrolizumab [had a duration of therapy] of 8.6 months versus 9.5 months for lenvatinib monotherapy. One thing that I believe personally is that duration on therapy for lenvatinib is one of the longest we’ve seen. When you take a look at REFLECT, the duration on therapy was closer to 5 months.³ This duration on therapy is quite long and, at least in my estimation, that’s in part because the investigators and patients were blinded, so they didn’t know if they were on combination therapy. There may have been providers that were more adamant about trying to keep their patients on therapy, dose reduce, etc, but work through treatment-related AEs to keep patients on therapy. When you take a look at grade 3/4 AEs, for lenvatinib/pembrolizumab it was 61% versus 57% for lenvatinib monotherapy.¹ Discontinuation from treatment-related AEs was 18% versus 10.5%, respectively. When you take a look at specific AEs, they were fairly similar between the 2 arms and there were no unexpected AEs that came out of the trial.

_REFERENCES:

_{1. Finn RS, Kudo M, Merle P, et al. LBA34 - 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/annonc/annonc1089}

_{2. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960-2970. doi:10.1200/JCO.20.00808}

_{3. 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}