Targeting Cancer With Tyrosine Kinase Inhibition in Frontline HCC
During a live virtual event, Ghassan K. Abou-Alfa, MD, discussed the results of the REFLECT trial of lenvatinib versus sorafenib and the LEAP-002 trial of lenvatinib/pembrolizumab versus lenvatinib in patients with hepatocellular carcinoma.
Targeted OncologyTM: What data support the use of lenvatinib (Lenvima) for patients with HCC?
GHASSAN K. ABOU-ALFA, MD, MBA: The REFLECT study [NCT01761266] looked into sorafenib [Nexavar] versus lenvatinib. [The design] was standard, with nothing particular about this study. Patients with Child-Pugh score A were treated in the first line, [and had] appropriate eligibility for systemic therapy. Patients were randomly assigned to lenvatinib or sorafenib. The primary end point was overall survival [OS]. Interestingly, the patients were stratified by region, by the extent of vascular involvement or extent of the disease, performance status, and body weight.
This was a study looking for noninferiority. [The goal was] to see the 2 Kaplan-Meier curves hugging each other, and that's exactly what we had, with 13.6 months median OS for lenvatinib versus 12.3 months median OS for sorafenib. [Almost] no difference at all with the hazard ratio of 0.92 [95% CI, 0.79-1.06], which is close to 1, exactly what you want it to be.1
Interestingly, the progression-free survival [PFS] in this study was 3 times higher for lenvatinib compared with sorafenib. On top of that, the benefit addressed all patients, independent of what they had for disease in regard to the different demographics. But more importantly, even through locally advanced disease, it might sometimes benefit patients. Patients with Barcelona Clinic Liver Cancer [BCLC]-B stage disease do very well. And this is a very important message, because not all patients with stage BCLC-B are going to get embolization.
What did patients in this study receive as therapy in the second line following progression?
In the lenvatinib arm, post-study, about one-third got sorafenib [or another therapy] and the others did not get any therapy. But for sorafenib, this was early in the story of all of those therapies, so 12% remained on sorafenib [since] there were no other choices. When we didn't have anything else, we slowed down the disease by keeping the sorafenib on. We are not doing it anymore, because we have choices. Patients may have gotten tired of sorafenib after lenvatinib, but there was no immunotherapy at that time.
What were the results of the phase 3 LEAP-002 trial (NCT03713593) of patients with HCC?
This is a very straightforward study; it was first line. We established lenvatinib as a standard of care [in the REFLECT trial]. This trial investigated lenvatinib plus pembrolizumab [Keytruda], the combination of a TKI plus immune checkpoint inhibitor, compared with lenvatinib plus placebo. It was a randomized, blinded study…and the primary end point was OS. There were the same standard requirements for the study.
This was presented at the 2022 European Society for Medical Oncology Congress in Paris [in September 2022].2 The patient population had a median age of approximately 66 years, close to 50% of patients had hepatitis B, about 20% had hepatitis C, and about 78%, which is similar to what we see in every study, were BCLC-C—in other words, with metastatic disease, and the rest are BCLC-B, which is locally advanced disease.
The results show that the median OS for the lenvatinib plus pembrolizumab was 21.2 months and single-agent lenvatinib was 19.0 months.2 The hazard ratio was 0.84, [indicating] no [significant] difference between the 2 results [95% CI, 0.708-0.997; P = .0227]. All the excitement and anticipation about the use of the lenvatinib/pembrolizumab combination did not pan out. But more intriguingly, single-agent lenvatinib had an [unexpectedly high] median OS of 19.0 months. Even though there was a [slight] improvement favoring the lenvatinib/pembrolizumab arm, at the end of the day, lenvatinib was as good.
The ORR [by RECIST 1.1] for lenvatinib/pembrolizumab was 26% and 17% with lenvatinib alone. There was quite a high rate of stable disease [in both arms]. By modified RECIST criteria, where you are looking into [treatment-induced tumor] necrosis, ORR was 40% for lenvatinib/pembrolizumab versus 34% with lenvatinib. There was [some improvement] with pembrolizumab added to lenvatinib, but not that much difference compared with single-agent lenvatinib.
What treatments did these patients receive after disease progression?
On the lenvatinib/pembrolizumab arm, about 14% got immunotherapy, and then in the lenvatinib/placebo arm, 22% received immunotherapy. It wasn’t a huge number of patients. You might have argued that the median OS for lenvatinib alone was 19.0 months because everybody received pembrolizumab or [other immunotherapy] afterwards. But only about 20% got that.
1. 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
2. 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