Advanced HCC: Clinical Trial Data Behind First-Line Therapy Options

Expert oncologists take a look at clinical trial data as they pertain to prevalent first-line systemic therapy options in advanced hepatocellular carcinoma.


Josep Llovet, MD: Katie, I take advantage that now you give your opinion also to link that to what’s the new data for other options. For instance, the IMbrave150 trial for these patients. Not for this patient exactly, but in frontline [therapy], what are the new data? But first, what will you do with this patient?

Katie Kelley, MD: This patient did quite well with lenvatinib, so that turned out to be the perfect choice. If the patient hadn’t had a contraindication to immunotherapy, his comorbidity profile would have made me think about the STRIDE regimen if it were regulatorily approved by then. Because of the age, the ischemic cardiomyopathy, and the diabetes, those things make me nervous about a higher-risk profile from bevacizumab. This is a patient who, barring a contraindication to immune checkpoint inhibitor therapy, I would have considered for STRIDE.

Josep Llovet, MD: Can you brief us on the results of IMbrave150 and STRIDE, which you mentioned?

Katie Kelley, MD: We have updated results from IMbrave150 that have been recently published. They reaffirmed the initial presentation of results with the median overall survival of 19.2 months for the combination arm. From an oncologist’s perspective, talking to patients is striking. We have a very solid response rate, with tumor shrinkages occurring in 30% of patients in the IMbrave150 regimen. Among those, 8% of patients overall and almost a third of the responders are complete responses. When talking to patients, it’s a big deal to get to a point where tumors are not detectable. These responses are quite durable. Median duration originally was at reach, and now it’s over 18 months—I can’t remember the final number. Ultimately, the regimen has solidified itself as a legitimate, meaningful survival improvement, with a meaningful chance of tumor shrinkage that’s durable. As Josep already quoted, there was about a 43% rate of grade 3 or 4 toxicity related to the regimen.

One thing that was interesting about the updated data is that we see—in both treatment arms, in patients who eventually progress, with additional follow-up time—about 50% or more of those patients are going under safe subsequent therapies. This reassures us that even after first-line therapy, they’re able to be treated with further therapies.

Josep Llovet, MD: Do you want to say something about STRIDE?

Katie Kelley, MD: The STRIDE regimen comes from the HIMALAYA trial, which had 3 treatment arms: the combination of durvalumab plus tremelimumab, durvalumab alone, and sorafenib as the control arm. The combination of durvalumab plus tremelimumab in the STRIDE regimen is a very interesting approach to adding a CTLA4 inhibitor to an anti–PD-L1, like durvalumab. When we originally think about CTLA4 inhibitors in oncology, we think about a pretty high rate of immune-related toxicity, and that’s what we see with repetitive dosing over time. The STRIDE regimen, based on a precursor randomized phase 2 study called …, took advantage of the fact that a single higher dose of tremelimumab can elicit an immediate population of effector T cells in the tumor microenvironment in circulation in pharmacodynamic measurements. That translates to a higher rate of immune response but doesn’t bring with it the same degree of immune-related toxicity as sequential prolonged dosing. The single dose of tremelimumab of 300 mg on cycle 1, day 1 is what the STRIDE regimen uses with continuous dosing of durvalumab afterward. With that combination, durvalumab plus single-dose tremelimumab improved survival over sorafenib alone.

Josep Llovet, MD: With this trial, there have been issues comparing durvalumab-tremelimumab plus durvalumab. You say, “OK, durvalumab-tremelimumab is 20%, and durvalumab alone is 17%. Median survival is similar. Why should we add that?” The simple answer is because this combination was positive for superiority. Durvalumab was not positive for superiority, but it was positive for noninferiority. This is the plain answer to that issue.

Arndt Vogel, MD: The tail of the curve.

Katie Kelley, MD: The tail of the curve also separates with time. That’s the strongest argument, obviously in addition to the statistical plan, but we see that it’s bearing out with time.

Josep Llovet, MD: Absolutely. Let’s talk a bit about the REFLECT trial. Arndt, do you want to expand on what Andrea presented about lenvatinib? Generalize about what strikes you more using lenvatinib in these patients?

Arndt Vogel, MD: The REFLECT study, which looked at the efficacy of lenvatinib, was published a couple of years ago. The study was positive, which was good at that time. But as you mentioned, only noninferiority was shown. Nevertheless, the secondary end points—like PFS [progression-free survival], TTP [time to progression], response rate—by RECIST. 1.1 20% by RECIST 40%. It was really striking, at least for me. We’ve seen that the responders survive for a long time. The slogan “Response matters” is true, and the data have been accepted for publication. We’ll all be able to look at this in more detail. At that time, only noninferiority was shown.

The question is, does this reflect the true efficacy of lenvatinib? Maybe not. Jumping back to ESMO [European Society for Medical Oncology Congress], we’ve seen the LEAP-002 study. We have a median survival of 19 months. This isn’t a miraculous higher efficacy of lenvatinib, but with more effective options in the second line, this is what we can expect from lenvatinib. This is interesting. We can’t rely only on the Keytruda study. This drives the evidence, but it’s worthwhile to look at real-world data. We’ve seen very interesting data from Italy showing that lenvatinib was highly effective in patients with fatty liver disease, with a median overall survival of 22 months. In patients without NASH [nonalcoholic steatohepatitis]—correct me if I’m wrong—it was 17, 18 months.

Andrea Casadei-Gardini, MD: NASH or non-NASH?

Arndt Vogel, MD: Non-NASH.

Andrea Casadei-Gardini, MD: In non-NASH, in nonviral is 19 [months].

Arndt Vogel, MD: Right, 19. But it was clearly longer in the NASH cohort. We can’t say because that’s prognostic predictive. We had just had a single-arm study. This is in line with our own real-world data, which we just published. In the ELEVATOR study, we connect the data from 200 patients in the first-line setting who were treated with lenvatinib in Germany. We created 2 cohorts to reflect in and out, regardless of whether the patients fulfill the inclusion criteria. In the reflect in group, we had a median overall survival of almost 16 months, which was also already higher compared with the 13 months we observed in the REFLECT study. In our study, we did not observe a significant difference between nonviral and viral and NASH. In our hands, we observed so far with the retrospective study that lenvatinib was effective in all subgroups. Not only in NASH—it was effective in all subgroups. If you take all this together, there’s a noninferior phase 3 study showing the efficacy and the real-world data. With lenvatinib as a control arm, it suggests that the survival—at least today with more subsequent therapies—is higher. This makes it an interesting drug in the first-line setting, as you highlighted with your case.

Josep Llovet, MD: If you analyze all the control arms of the frontline trials—the more recent 1 is COSMIC-312—sorafenib has a ceiling.

Arndt Vogel, MD: It’s 15 months.

Josep Llovet, MD: But it’s an up-to-date ceiling. It’s not as if we’re talking about the SHARP trial, which was 11 months and moved to 14 months with CheckMate 459. Now it’s 15.5 months, but it has a ceiling with second-line effective drugs of 50%, of 15 months. Conversely, the LEAP-002 trial is negative because we’ll have another option. But the striking thing was the overperformance of lenvatinib. This can be explained: 55% of patients have second-line therapies that are effective, and around 25 were checkpoint inhibitors.

Second, the phenomenon that happened with sorafenib is that the physicians are more familiar with the drug. In REFLECT, that was the first-time physicians were exposed. Now they’re familiar, and they know how to handle the adverse event. This probably has an impact as well. There are other things in that population, but the ceiling for lenvatinib is 19 months. This is substantial. 

Transcript edited for clarity.

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