Hepatocellular Carcinoma: A Rapidly Evolving Treatment Landscape - Episode 5

Optimal HCC Frontline Treatments

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Richard S. Finn, MD: Tony, lead us off with some discussion about the impact of the 3 choices we have for frontline treatment—sorafenib, lenvatinib, and more recently atezolizumab and bevacizumab—based on the IMbrave150 trial.

Tony Bekaii-Saab, MD: Thank you, Rich. The landscape is getting more simplified. We have 3 options, but there is certainly a dominant option. The other 2 options are likely are going to be options for those who may be ineligible for immunotherapy. For the longest time, as you all recall, we had sorafenib, and most of us will remember the days before sorafenib where Megace [megestrol acetate], tamoxifen, or some other unproven agent would be used because we were so desperate for systemic agents in this disease. Then came sorafenib based on the SHARP trial, which showed an improvement in outcomes, but it was a tough drug. It was a tough drug to use.

The dose was challenging, and everyone came up with their own dosing schedule and regimen. For many years after that, there were attempts to displace sorafenib, mostly by agents with similar targets, plus or minus another drug on occasion with not much success. In fact, with sunitinib, we’ve seen the curve going in the wrong direction, until the REFLECT study with lenvatinib vs sorafenib, which was a noninferiority study. It certainly has limitations in terms of how to interpret the results, but it showed that we now have another option other than sorafenib, which appears to be noninferior for survival. It seemed to have trends favoring it for PFS [progression free survival] and maybe some response.

In the whole setting, it was just the noninferior option with the caveat that it was less toxic because it was primarily a VEGF-directed therapy, not so much as with sorafenib with all this background noise with the other kinases. It was easier to use, it got adopted, and it was becoming a favorite. We then got the IMbrave150 trial, which was designed to answer the question of immunotherapy plus a PD-L1 inhibitor, atezolizumab plus bevacizumab vs sorafenib. This couldn’t come more timely since we’ve had some setbacks with I/O [immuno-oncology], specifically with the nivolumab vs sorafenib study, which was negative. It had some trends, but overall it was a negative study.

Pembrolizumab in the second-line setting vs placebo was also negative, which was another setback. The big question was this: How can we move that field forward? There are patients who have tremendous responses to single-agent I/O, yet we’re not able to identify them. In the undiluted patient population, we’re not seeing those signals. Dr Finn presented a study at ESMO [European Society for Medical Oncology] Asia Congress, IMbrave150, which randomized atezolizumab plus bevacizumab vs sorafenib. This study was essentially powered for 2 coprimary end points, overall survival [OS] and PFS, and the secondary end point of response rate. There were a number of other end points to the study, including a PRO [patient-reported outcome] quality-of-life element.

This study came and hit every single 1 of the end points, from PFS to OS, with very impressive hazard ratios. In fact, the OS has not been reported yet, but it should be at some point later this year or maybe early next year. It seems to be tracking along close to the 2-year mark. Not knowing the results, we’ll see where they end up, but it’s quite an impressive movement in all the end points with the response rate between 25% and 30%. Most important, it preserves and improves the quality of life of the patients, so that certainly displaces sorafenib as a standard.

By default, because lenvatinib is a noninferior agent to sorafenib, and it has a similar survival, the same inference can be made for lenvatinib. This becomes our standard of care for patients with advanced disease and a Child-Pugh A score because that is what these studies have been looking at. Perhaps we can discuss later what that means for other stages, but for patients with Childs-Pugh A in the first-line setting with a good performance status, there are no contraindications for immunotherapy. This is now the standard.

Richard S. Finn, MD: We’ve seen some evolution. Sorafenib holds its line until the REFLECT study, where we saw lenvatinib was noninferior for overall survival. But it improved response rates, and it improved progression-free survival, which raised some interesting points for us in the liver cancer space on how we can affect these secondary end points. That didn’t necessarily translate into a survival advantage.

One of the things that came up was the potential impact of treatment beyond progression: There were more patients in the sorafenib arm who were able to get investigational agents, including I/O, which were not necessarily available to the lenvatinib patients. That study also had some interesting inclusion and exclusion criteria in that it excluded patients who had main portal-vein invasion or over 50% of their liver involved with tumor. Many of us interpreted that data as lenvatinib being perhaps a more active drug with a different adverse-effect profile, and you highlighted some of that. The VEGF readout from the event is much stronger than we see with sorafenib with regard to hypertension and proteinuria, whereas GI [gastrointestinal] toxicity is fairly similar between the 2 agents.

Hand-foot skin syndrome, which can be a dose limiting toxicity for sorafenib, was not all that relevant for patients receiving lithium lenvatinib. It then comes to atezolizumab-bevacizumab, which to your point, reassuringly hit all their end points: overall survival, progression-free survival, response rate, and quality of life. Peter, you did a more detailed quality-of-life readout from IMbrave150. Can you give us a top line of what you presented earlier this year?

Peter Galle, MD: The background of this patient-reported outcome analysis was a very solid one: More than 90% of patients reported, and it was a thorough assessment based on 2 questionnaires going to quality of life, role functioning, physical functioning. The difference for sorafenib in terms of quality-of-life deterioration in a meaningful way was between 3.7 months for sorafenib and almost a year for atezolizumab-bevacizumab. The significant difference here makes a difference in the life of our patients. They have a much better quality of life, and they can maintain their work and activity. In a situation where we are talking about palliation, their life span is still very limited. It makes quite a difference whether the quality of life is good or impaired, and this is very in favor of this combination in terms of improvement of quality of life and other aspects.

Transcript edited for clarity.