Targeting Cancer With Tyrosine Kinase Inhibition in Frontline HCC

Discussing the LEAP-002 Trial of Lenvatinib Plus Pembrolizumab in HCC

During a Targeted Oncology case-based roundtable event, Ghassan K. Abou-Alfa, MD, MBA, discusses with participants the unexpected results of the LEAP-002 trial of lenvatinib plus pembrolizumab versus pembrolizumab alone for patients with hepatocellular carcinoma. This is the second of 2 articles based on this event.

GHASSAN K. ABOU-ALFA, MD, MBA: [In summary], lenvatinib/pembrolizumab versus lenvatinib was a study that was negative.1 It did not show any difference between lenvatinib/pembrolizumab versus lenvatinib. Median OS was [21.2] months for lenvatinib/pembrolizumab, but also, shockingly, median OS was 19.0 months for single-agent lenvatinib. It was well tolerated with a great response…same as we expected. At the same time, only about 20% of patients received second-line immune checkpoint inhibitors after lenvatinib. What do you think of those data, or do you want to talk particularly in regard to that 19-month shocking result of lenvatinib alone?

GABOR VARADI, MD: It's very shocking. The problem is that in other tumors, for example, renal cell carcinoma [RCC], although RCC may be much more immunogenic than hepatocellular carcinoma [HCC], [lenvatinib plus pembrolizumab] is one of the prime treatments nowadays.2 And [yet], in HCC, there was no significant OS or even progression-free survival advantage.1 It’s also a question of how it was possible that with lenvatinib alone, such a long and good OS result was achieved.

ABOU-ALFA: I agree with you, Dr Varadi. We’re talking about 19-month median OS for single-agent lenvatinib compared with what we [expected to be] 13 or 14 months. I would love to hear more thoughts. Dr Malik, what are your thoughts?

SANDEEP MALIK, MD: I have limited experience on use of these agents in HCC. I can only quote what's in the studies or what's reported. A few patients that I have treated may not do full justice to what the benefits might be.

ABOU-ALFA: No problem. Dr Li, any thoughts in regard to this 19-month median OS? Does it surprise you?

ZUJUN LI, MD: It's a little bit surprising for me, yes. There's so many things to try. But either this is an experimental arm doing worse than expected or it's a comparator doing better than expected. I think the comparator is doing better than expected.

ABOU-ALFA: I agree with you. Frankly, it has been shocking to almost everybody, because after all, it is not what we expected. But if anything, it gives us an invitation to think about whether single-agent lenvatinib might not be a bad idea after all, because we have 2 studies that are positive and 1 of them even shows way more positive results, per se. So it can be an argument for that purpose.

ASHISH KHOT, MD: You can’t compare across trials, but the trials which have been positive in HCC are the PD-L1 agents. And the PD-1 agents have not done well, which is the opposite with RCC and bladder cancer, where you see more PD-1 [efficacy]. Is there any change in mechanism of action?

ABOU-ALFA: I love your question, Dr Khot. You're right: clearly, in HCC, there's no question about it, you need a combination. But interestingly, all of us thought that any combination is good. That is probably not [true]. In other words, maybe lenvatinib/pembrolizumab might be [more effective] as a sequential [treatment]: lenvatinib followed by pembrolizumab rather than lenvatinib plus pembrolizumab. On the other hand, atezolizumab [Tecentriq] plus bevacizumab [Avastin] is a positive story,3 which now has more updated data that was reported [in September 2022].4

In regard to durvalumab [Imfinzi] plus tremelimumab [Imjudo], you're probably right, as well. But remember, the cabozantinib [Cabometyx] plus atezolizumab study was negative [for OS benefit].5 Now we have the lenvatinib/pembrolizumab study that is negative.1 So it's not every combination, only the ones that will affect the immune microenvironment. But it’s definitely a good point that you bring up.

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. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2023. Accessed October 25, 2022. https://bit.ly/2TAx1m3

3. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

4. D’Alessio A, Cheon J, Fulgenzi CAM, et all. Treatment-related adverse events and improved survival with atezolizumab plus bevacizumab; a global, real-world study. Poster presented at: 16th Annual International Liver Cancer Association Conference; September 1-4, 2022; Madrid, Spain. Accessed October 25, 2022. https://bit.ly/3RrpXHf

5. Kelley RK, Rimassa L, Cheng AL, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(8):995-1008. doi:10.1016/S1470-2045(22)00326-6