Comparable Survival Observed With Regorafenib in HCC in Real-World Versus Clinical Settings

Richard S. Finn, MD

According to findings from the phase 3 RESORCE study (NCT01774344), regorafenib (Stivarga) demonstrated encouraging findings in patients with hepatocellular carcinoma (HCC), and these data ultimately led to the drug’s approval in 2017 for the treatment of patients with unresectable HCC who have previously received sorafenib (Nexavar).

Prior to this approval, sorafenib was the only approved therapy for patients with HCC, and regorafenib marked the first therapy approved in the second-line setting for this patient population. The addition of regorafenib to the armamentarium has been an exciting advance for the field over the last few years, but questions remain in regard to sequencing therapy and its overall use in the real-world setting.

The ongoing prospective observational REFINE study aimed to explore the safety and tolerability, as well as efficacy, of regorafenib in the real world compared with patients who received regorafenib in the clinical trial setting using data from patients in the RESORCE study, which is typically a uniquely selected group of patients and may not fully represent this patient population as a whole. Overall, the findings, which were presented during the 2020 European Society for Medical Oncology (ESMO) Virtual Congress, demonstrated tolerable safety in the real-world setting with overall comparable survival with patients treated with regorafenib in the RESORCE study.

In an interview with Targeted Oncology, Richard S. Finn, MD, an assistant professor of clinical medicine at the Geffen School of Medicine at the University of California, Los Angeles (UCLA), and director of the Signal Transduction and Therapeutics Program at the Jonsson Comprehensive Cancer Center at UCLA, discussed the real-world data from the REFINE study, which is exploring the outcomes of patients with unresectable HCC who received treatment with regorafenib.

TARGETED ONCOLOGY: What is the unmet need for patients with unresectable HCC?

Finn: There has been so much going on in advanced liver cancer over the past few years. For a long time, we only had sorafenib available for these patients. We say unresectable liver cancer is a group of patients who aren't curative. That can include patients who are getting chemoembolization or those that have advanced features and get systemic treatment upfront. However, as we know, many patients who get locoregional treatment will eventually progress and be candidates for systemic treatment. Even though we've had a lot of advances in advanced liver cancer/unresectable liver cancer, it's still not curable. A lot of the advances that we have come about in the last 3 years, an explosion of newly approved drugs. There's always the unmet need of better drugs that are more effective, better tolerated, but as we've had these new drugs, 1 of the unmet knowledge gaps is, how do these drugs perform outside of clinical trials? That's where real-world datasets can help and tell us what we're seeing in a clinical trial has relevance in the real-world.

TARGETED ONCOLOGY: What was the rationale for using regorafenib in this patient population?

Finn: It's still a work in progress, but this was launched shortly after the approval of regorafenib in second-line liver cancer. The RESORCE study was the first positive phase 3 study in liver cancer since sorafenib in 2007. This was also the first drug approved in second line, so with that approval, questions remain. How would this drug perform in the real-world? In the phase 3 RESORCE study, we saw that it improved survival versus placebo in patients who had prior exposure to ceramic nib ?!, as well as those that had tolerated a minimal dose of ssorafenib. In the RESORCE study, we saw a hazard ratio of 0.62, which is a 38% decrease in the risk of death. The median survival went from 7.8 months to 10.6 months, so right away, there was interest in developing a real-world experience with regorafenib, especially because its side effect profile has a lot of overlap with sorafenib. However, it is a different drug. The most common treatment-emergent AEs in phase 3 studies have been hypertension, hand-foot-skin syndrome, and some bilirubin changes, as well as fatigue. We still see GI toxicity among other things, so how would the real-world experience look with regorafenib, and that was 1 of the questions that REFINE is trying to address.

TARGETED ONCOLOGY: What were the methods of design for the REFINE study?

Finn: This is a single-arm study. It's a data collection study, so patients are not randomized in any way. It is a global study that has approved several hundred patients with the idea of seeing how the drug performs in the real-world setting in regards to the baseline characteristics of the patient who get it, so race and age; how it's used in different regions; etiology of the patients who get it; what prior treatments they have received; their Barcelona stage; child Pugh score; and things like that are real-world, as well as the dosing strategy taken by physicians when they start using regorafenib.

As we know, regorafenib is approved at 160 mg 3-weeks-on/1-week-off. By the time it came to the liver cancer space, the drug had been approved in colon cancer, where it's a very late-line drug after patients have had a lot of chemotherapy, and in that population, while it's an active drug, there have always been concerns about the dosing and side effect profile. Since that time, there have been publications that look at dose-escalation strategies, and so in looking at how doctors in real-world practice use regorafenib, 1 of the questions was also dosing, then obviously, side effects in the real-world and how long patients survive in the real-world as compared to the clinical trial setting, recognizing that clinical trial patients are fairly uniquely characterized by design.

TARGETED ONCOLOGY: What results did you present at this year's ESMO?

Finn: At this year's ESMO, I was a co-author on this poster where we presented some updated data, and what was very interesting is that this real-world data very much mimics the findings in the RESORCE study. Most importantly, the survival in this population was about 13 months, very comparable to what we saw in RESORCE. The side effect profile was very similar to what we saw in RESORCE patients. Almost all the patients had prior sorafenib before coming on, and that's where regorafenib was studied in RESORCE in patient who had prior sorafenib.

Some things that we learned were that in the real-world, just over half the doctors start patients on the full dose as prescribed, but others start patients at 120 mg or even 80 mg a day. Regardless of the dose, the efficacy seems to be very similar, and the side effect profile seems to be very similar. When we look and see, the length of time patients are on regorafenib, regardless of dose, it seems very comparable somewhere around 4 months plus or minus. Interestingly, dose reductions were fairly similar, regardless of the dose started, and if we look at what might have influenced the doctors' use of a lower dose, it did seem to relate to their dose on sorafenib, so were they on full dose sorafenib or less? Now in RESORCE, we did not have the leeway to do that, so patients were all started on a fixed dose of regorafenib, regardless of their prior dose of sorafenib. In a subsequent analysis from RESORCE, we showed that higher tolerance of sorafenib and the dose they were on did not affect the efficacy or the tolerability of side effects with regorafenib. If patients were on a shorter time with sorafenib, they still got a similar magnitude of benefit with regorafenib, and vice versa, if they were on a longer-term period of sorafenib, they got a similar benefit to regular revenue. Whether they were on full-dose or less than full dose of sorafenib, the magnitude of benefit from regorafenib was the same.

Now, the other thing that we showed in that retrospective analysis was that the sequence of sorafenib to regorafenib in that study provided a survival for that clinical trial population of about 26 months, which is a big number in liver cancer. I think that serves as proof of concept that now that we have so many drugs available in liver cancer, sequencing these drugs might be providing us with survival numbers which are much greater than we saw before. We look at where we were in 2008 with the approval of sorafenib; in general, survival was about 11 months from the SHARK study, and we've seen that gravitate over time. Even if we look at the CheckMate-459 study, which was the pivotal nivolumab versus sorafenib study and was a negative study, the survival with sorafenib in that study was 14.7 months. Part of the reason I think we're seeing patients live longer with advanced liver cancer is that we are sequencing therapies, and as we see from RESORCE and now with REFINE, the sequence of sorafenib to regorafenib, it looks like what we're seeing in the real-world is similar to what we saw on the phase 3 study.

TARGETED ONCOLOGY: What are the next steps now for this research?

Finn: The REFINE study is a work in progress. We're continuing to update the data and follow patients for their survival. This was an interim analysis, so I think we look forward to seeing these data as they mature and also probably following patients for the drugs they get after regorafenib. Now that we have other drugs available to maybe get a real-world sequence or what doctors are doing in the real-world as new drugs come online.