Ongoing Challenges and Future Directions of Therapy in HCC

Transcript:

Joseph Llovet, MD, PhD: We can now, if you want, recap and provide a picture of what we think our current challenge is and where the field is moving to in the next 5 years. Certainly, the main challenges, in my mind, are in the area of adjuvant therapy after resection, local ablation. Now, 40% of the patients are receiving resection, local ablation, as a primary treatment. And in spite of that, we have 70% recurrence at 5 years, and we don’t have any single adjuvant therapy at this point. So sorafenib was negative, the STORM trial. Certainly now there are phase III studies testing nivolumab, for instance, versus placebo, as well as other checkpoint inhibitors. And there’s maybe a window of opportunity.

Another challenge is in intermediate disease; we are stuck with the old data we published years ago. I remember the meta-analysis of chemoembolization was published in 2003, and it still is the standard of care. Nothing has changed, so certainly I think for this area, now is the time when systemic therapies will come to the intermediate field, in combination with TACE [transarterial chemoembolization, as a single agent, or as a combination of systemic therapies, head-to-head with locoregional. And then in advanced disease, as I said, I think we are not looking for third-line therapy. This will come naturally. So the need is to raise the bar and try to reach the 2-year survival for patients in frontline advanced. And, certainly, I think this will come from combinations with very appealing preliminary data. Do you want to discuss the preliminary data of the combinations that have been released? There are not so much data, but some appealing data are out there at this point.

R. Kate Kelley, MD: I think absolutely there are very promising data—or provocative data, the right word to use—in the phase I and phase II settings. You’ve alluded to the TKI [tyrosine kinase inhibitor] plus PD-1 inhibitor, PD-L1 inhibitor data. We saw a promising confirmed response rate from the pembrolizumab plus lenvatinib combination at ASCO [American Society of Clinical Oncology] 2018, and admittedly a small cohort, and that requires expanding to a larger study. In fact, it has already launched a phase III trial comparing that combination with lenvatinib.

And then likewise, the combination of atezolizumab plus bevacizumab in phase I showed a striking response rate in the initial cohort of up to 65% at some analyses, but actually with some decrement in the expanded cohort at ESMO [European Society for Medical Oncology] 2018 to the 27%, 30% range, depending on central versus local review. But that is also looking ahead to the IMbrave150 trial, which will give us a randomized phase III context for this combination of atezolizumab plus bevacizumab versus sorafenib. And then I think the HIMALAYA trial of durvalumab plus tremelimumab as the checkpoint inhibitor combination, CTLA-4 plus PD-L1 inhibition, is also due to report in the coming year or 2, to complete, I should say, and who knows when we’ll see the results? But those are eagerly awaited.

Masatoshi Kudo, MD, PhD: The most important profile of HCC is recurrence after curative therapy, like surgery or ablation. So adjuvant setting, if we introduce the combination therapy, immuno-combination, immunotherapy, as adjuvant setting, the complete or real cure is obtained. And the recurrences are the biggest problem, but recurrence may be suppressed by adjuvant combination therapy or TACE combination, as well, or TACE replacement. In the multifocal tumor, usually standard care is TACE, but the TACE impairs liver function and the response is not good. But that being replaced by systemic therapy, especially combination immunotherapy, will be a promising method.

Transcript Edited for Clarity