Expert Shares Views on RESORCE Data

Richard Finn, MD

The paradigm-changing findings of the phase III RESORCE trial will likely lead researchers to change how they treat patients with unresectable hepatocellular carcinoma (HCC) in the second-line setting, according to Richard Finn, MD.

In the study, second-line treatment with regorafenib (Stivarga) demonstrated a 2.8-month improvement in overall survival (OS) versus placebo for patients with unresectable disease who progressed on sorafenib (Nexavar), leading to a 38% reduction in the risk of death with the multikinase inhibitor (HR, 0.62; 95% CI, 0.50-0.78;P<.001). The median OS was 10.6 versus 7.8 months with regorafenib and placebo plus best supportive care, respectively.

&ldquo;Certainly, this is practice changing,&rdquo; says Finn, an assistant professor of Medicine at the Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology at UCLA Jonsson Comprehensive Cancer Center. &ldquo;There is now an option for these patients. Three months is a strong start and, hopefully, we will continue to improve on that. This lends credence to the idea that systemic therapy does play a role in advanced liver cancer.&rdquo;

These clinical findings are to be submitted to the FDA and European Medicines Agency for potential approval of regorafenib in this setting. In an interview, Finn discussed his perspective on the RESORCE results, when patients with HCC should make the switch to regorafenib, and what further refinements the field could still use.

HCC Monitor: What were your first reactions to the RESORCE data?

FINN:Like many others, when first seeing the RESORCE survival data, we were all very happily or pleasantly surprised. A 3-month median improvement in OS is not only statistically significant but also clinically significant. This is especially in the context of what has been going on in liver cancer research from the past decade. As many people are aware, sorafenib has been the only drug that&rsquo;s been approved. Despite many efforts to improve on sorafenib in the frontline setting, essentially all approaches have not met their endpoints.

Similarly, in second-line—an area that we thought was a &ldquo;low-hanging fruit&rdquo; or a low hurdle for improvement, being that placebo has been the control arm&mdash;all of the agents looked at in large phase III studies have failed. Then, we have the RESORCE study, and not only is it the first positive study but it&rsquo;s very positive. We are all very excited about that. The field needed some new positive data, and this incremental improvement will be good for patients and good for the field.

We have been trying to improve outcomes for patients with advanced liver cancer for several years. There have been numerous phase III studies done, and all of them were unsuccessful in achieving their goal of improving OS. Now, we have the RESORCE study which, for the first time, has a significant improvement in median OS, improving survival by 3 months with the addition of regorafenib plus best supportive care versus best supportive care alone. For sure, this is going to change the way we manage patients with advanced liver cancer.

Just as the data from the SHARP study influenced how we managed patients with systemic therapy, the positive data from RESORCE is going to continue to change that landscape.

RCC Monitor:Would these findings provide an incentive for physicians to stop using other locoregional therapies?

FINN:There is no question that chemoembolization plays a significant role in the management of patients with unresectable liver cancer. We need to keep in mind that unresectable liver cancer is not 1 disease, but several subgroups of patients. For those patients who fit within the Barcelona Clinic Liver Cancer stage B or intermediate-multifocal tumors in the liver, good performance status, and no extrahepatic spread or vascular invasion, chemoembolization is a very appropriate and effective way to manage those patients.

The challenge over the past several years, as sorafenib came into play, was that transition from intermediate to advanced disease in which systemic therapy has proven to be of benefit. There has still been some hesitancy to go to systemic therapy, even when patients are progressing on chemoembolization. They develop a contraindication, or what is felt to be a perceived contraindication to chemoembolization—such as vascular invasion.

Still, the tumor is confined to the liver. Some clinicians will say, &ldquo;Well, we can do chemoembolization in those patients. It&rsquo;s safe.&rdquo; The question is, &ldquo;Does it help them?&rdquo; That has never been well defined in randomized studies with chemoembolization. Now, you have an experience where you&rsquo;ve gone from sorafenib improving survival by a median of 3 months from the phase III studies to now regorafenib with another incremental increase of 3 months versus placebo.

That speaks to the fact that these agents are active in liver cancer; we are not just improving response rates or time to progression but we&rsquo;re improving OS. This continuum should hopefully build on the high level of evidence that systemic therapy plays a role in patients with advanced liver cancer. Our definition of advanced disease needs to go back and question the role of continuing chemoembolization when patients present with criteria that would fit into the clinical studies, such as SHARP and RESORCE.

The fact that for the past decade we have had only had 1 positive phase III study—SHARP, with a median overall survival of 3 months&mdash;has made people a little discouraged with the role of systemic therapy. Three months is significant; it is not a cure, but it is significant. At the same time, there was room for improvement and there continues to be room for improvement.

The RESORCE data gives credence to the idea that systemic therapy plays a role in the treatment of advanced liver cancer. This idea that [patients receive] chemoembolization until decompensation or extrahepatic metastatic disease and then go to systemic therapy might not be the exact transition points.

HCC Monitor: When would be an appropriate time for physicians to switch treatment?

FINN:It has been noted that if a patient does not die of cirrhosis their cancer will become refractory to chemoembolization. Or, they will develop a new site of disease or some other clinical symptom that makes chemoembolization less attractive.

What makes it even less attractive is the data that supports that it works. When we have large phase III randomized studies, regardless of whether it was with local regional therapy or with a systemic therapy, large randomized placebo-controlled studies are high levels of evidence and should dictate treatment decisions more so than individual experience.

In the context of the SHARP, ASIA-PACIFIC, and RESORCE studies, there is very strong data that for patients who are Barcelona Clinic Liver Cancer stage C are appropriate and should be triaged to systemic therapy.

However, there are still a group of patients with Barcelona Clinic Liver Cancer stage B intermediate disease who are candidates for systemic therapy. This is a group of patients who are getting local regional therapy, but that therapy cannot keep up with the pace of their disease. They have rapid recurrence, and their disease is not completely controlled with TACE [transcatheter arterial chemoembolization]. It is those patients who would also be considered appropriate for that transition to systemic therapy.

HCC Monitor: Can you discuss regorafenib&rsquo;s adverse event profile?

FINN:One of regorafenib&rsquo;s first approvals was in advanced colorectal cancer (CRC) in the later line therapy. There was a fairly high incidence of grade 3/4 adverse events, which remarkably were toned down in the RESORCE data. We always need to measure the efficacy versus the safety and tolerability.

What was surprising was how well the drug was tolerated in this group of patients. There&rsquo;s a very low incidence of grade 3/4 events in the RESORCE study versus the CRC study. There are some ideas on why that might be the case. Obviously, the RESORCE study took patients who had a prior multikinase inhibitor with some overlapping toxicities.

There is always a leap from a research study to clinical practice, and we will see how that data shapes up in anyone&rsquo;s clinical experience. There is also a learned experience to managing the toxicities. Sorafenib has been around a long time and clinicians have become a little more experienced on how to manage the multikinase inhibitor side effect profile, which also might explain the lower incidence of adverse events.

HCC Monitor: What advice would you give clinicians regarding the best time to switch treatments, in order to maximize the benefit for patients?

FINN:The challenge is, how do we identify patients for whom sorafenib isn&rsquo;t working? For those patients, what do we do after? This has obviously been an area of great clinical research, and we need to still encourage patients to go on clinical studies to help move things forward. To me, there&rsquo;s always been somewhat of a sweet spot between progression on sorafenib and the opportunity to get someone into a clinical trial to consider him or her for second-line treatment.

There&rsquo;s always going to be a few different groups of patients. There are patients who will receive sorafenib and get sick very quickly because their disease progresses. There will be a group of patients who get a benefit from sorafenib for some period of time, and then their disease slowly starts to progress.

We know that the response rate with sorafenib is very low and that most of its benefit is by slowing progression. The SHARP study was done in such a way that patients could continue on sorafenib beyond radiographic progression until symptomatic progression; a subset of patients did that. Now in clinical practice, how do we incorporate the RESORCE data?

We need to first, give patients the benefit of the doubt with sorafenib. It&rsquo;s proven to work in the frontline and there&rsquo;s going to be some clinical judgment. In my practice, I have historically always given patients the benefit of the doubt, even if there is a little increase from scan to scan. If it&rsquo;s not life threatening, then we can give it to them a little longer.

At some point, there is the feeling that we need to try something else—whether that will be a clinical study or a transition to regorafenib.

When you see that patient and their scan suggests progression, there has to be the question of, &ldquo;Do I have time to watch this patient a little longer on sorafenib? If I wait another 2 or 3 months when they get imaged again, am I going to lose the opportunity to give them a second-line treatment?&rdquo; That really depends on where and how they progress.