Doublet immunotherapy consolidates its role in hepatocellular carcinoma

Angela Lamarca

Angela Lamarca

Fundacion Jimenez Diaz University Hospital, Madrid


Benefits reported for the combination of ipilimumab and nivolumab further expand alternative therapeutic options for patients with unresected advanced disease

Immune-based combination therapies for the first-line treatment of hepatocellular carcinoma (HCC) are gaining growing attention from research, and both atezolizumab plus bevacizumab and durvalumab and tremelimumab are today new standard of care options for advanced disease following the IMbrave150 and the HIMALAYA trials demonstrating the superiority of these combinations over tyrosine-kinase inhibitor (TKI) monotherapy (N Engl J Med. 2020 May 14;382(20):1894-1905; NEJM Evid. 2022 Aug;1(8):EVIDoa2100070).

As presented at the 2024 ASCO Annual Meeting, the CheckMate-9DW randomised phase III clinical trial explored the role of a novel combination with ipilimumab and nivolumab for patients diagnosed with untreated unresectable HCC - 335 to experimental arm and 333 to the control arm with a TKI, lenvatinib or sorafenib (J Clin Oncol 42, LBA4008-LBA4008(2024)). The study met its primary endpoint showing a benefit in terms of overall survival (OS) in favour of the experimental arm.

The relevance of this study for clinical practice is clear, while it opens up new discussions in this setting.

Firstly, the study results provide further confirmation of the key role of doublet-immunotherapy approaches with CTLA-4 inhibitors replacing antiangiogenic agents in advanced HCC, in keeping with the benefit to that observed in the HIMALAYA trial with a different double therapy - durvalumab plus tremelimumab (NEJM Evid. 2022 Aug;1(8):EVIDoa2100070).

Secondly, the study highlights the challenge of finding the right balance between activity and toxicity, both likely to be driven by the CTLA-4 inhibition. In the CheckMate-9DW, the response rate was the highest reported to date in a randomised phase III study in the first-line setting for advanced HCC (36%) compared to response rates previously reported for the combinations atezolizumab-bevacizumab and durvalumamb-tremelimumab (30% and 20% respectively) in other studies (J Hepatol. 2022 Apr;76(4):862-873; Ann Oncol. 2024 May;35(5):448-457). Interestingly, the responses with ipilimumab plus nivolumab were both early responses (time to response of 2.2 months) and durable responses (median duration of response of 30 months). However, the CheckMate-9DW also reported the highest toxicity profile for a doublet immunotherapy regimen, with 30% of patients requiring high dose steroids and a shorter duration of treatment over TKI (4.7 months vs 6.9 months). Whether this toxicity profile could explain the shape of the curve and the shorter duration of treatment despite overall benefit in progression-free survival (PFS) and OS is still to be determined, and a better understanding of number of cycles administered, a detailed review of the full publication and additional data are needed.

Finally, it is interesting to highlight that the control arm overperformed in the CheckMate-9DW. Most patients were treated with lenvatinib (85%) and only a minority with sorafenib, reflecting current clinical practice across the globe. The overperformance was especially clear at the beginning of the follow up, with the TKI arm showing a better performance both in terms of PFS and OS. I believe this could imply both a better toxicity profile of the doublet regimen and that some patients with HCC may be more responsive to TKI - even though we still do not know how to identify those patients.

As of today, the combination with ipilimumab and nivolumab could represent a new alternative therapeutic option for HCC, especially when response may be the primary aim and in presence of contraindications for using antiangiogenic agents. However, patient selection is likely to be crucial.

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