Phase 3 REFLECT Trial in Patients with Unresectable Hepatocellular Carcinoma - Episode 4

Lenvatinib Combination Therapy for Treatment of HCC

An expert hematologist-oncologist considers the potential role of combination therapy with lenvatinib for patients with hepatocellular carcinoma.

Richard S. Finn, MD: When we think about a response, what has really gotten us excited in liver cancer, has been the data with immune checkpoints. Initially, with nivolumab and single-agent pembrolizumab, we saw response rates in the 15% to 20% range, a single agent. So, we know that both agents did not reach their primary endpoints in phase three studies, but they still maintain accelerated approval. At this time, The data with atezolizumab and bevacizumab from the IMbrave150 study, really established a new standard of care, for patients with advanced liver cancer. That study looked at the combination of the PD-L1 inhibitor atezolizumab in combination with VEGF antibody bevacizumab in the frontline setting, versus sorafenib in a randomized open-label study two to one of the active arm, versus control arm. And this study was stopped at its first interim analysis, because of the significant benefit in overall survival, with a hazard ratio of about 0.58. And similarly, PFS also demonstrated a significant improvement with the combination versus AtezoBev, again, with a PFS of about 0.59. Now, what was very intriguing about this combination, is that we now had objective response rates at the first analysis that was about 27% objective responders, with a number of those being complete responders. Specifically, we saw that five and a half percent of patients had a complete response. And at the first interim analysis, we didn't have the full duration of response. Earlier this year, we presented data with further follow-up. This was at the ASCO 2021 meeting, ASCO GI, I should say. And here we had, now objective response rate of 30% with 8% complete responses. And we had reached a median survival, in the combination of arms of 19.2 months. So, really this has established AtezoBev as the frontline treatment for most patients, who receive frontline treatment in advanced liver cancer. And again, all of these data are generated in patients for trial QA. Now, the NCCN guidelines have reflected this recommendation, but still, maintain TKIs as an option for patients of both sorafenib and lenvatinib. And I think clinically, most of us will look at patients in the frontline setting, and I think you really need to find a reason not to offer them AtezoBev. And what might be those reasons? Why would a patient not be a candidate for that combination, given its superior efficacy and actually a very favorable safety profile versus a TKI? Now, obviously, if patients have auto-immune diseases, that will give us pause and offering them a checkpoint inhibitor, like atezolizumab. But a lot of the contra-indications will probably become in practice related to bevacizumab. The one thing that has had us concerned somewhat, has been the theoretical bleeding risks with VEGF inhibitors. In IMbrave150 patients, had to have an upper endoscopy within six months of coming on study. And if they were at high risk for bleeding or had varices that had recently bled, they would have been excluded from the study. And those patients would be considered for a TKI. Now, keep in mind as a mechanism, all VEGF targeting drugs have a theoretical risk of bleeding, but high-grade bleeding events have not been seen really with sorafenib or lenvatinib, in the clinical studies. And therefore, patients who are not candidates for AtezoBev because of a contra-indication could be considered for the TKIs. And we've seen that for patients who have higher tumor burden or patients who have poor prognostic factors, such as high AFD, lenvatinib seems to offer better disease control than sorafenib.

This transcript has been edited for clarity.