Optimized Sequencing Remains a Top Priority in HCC

The approvals of multiple regimens in hepatocellular carcinoma (HCC) have brought questions regarding optimal treatment sequencing to light in the field, said Gagandeep Brar, MD, who added that identifying an optimal sequencing strategy could depend on the results of ongoing phase 3 clinical trials.

“Prior to 2017, [patients with] HCC had a fairly dismal prognosis,” explained Brar. “Since then, there has been a lot of enthusiasm to help these patients. Now, it comes down to, How do we treat our patients, and how do we sequence our [treatments]? We are not going to figure out how to sequence these [therapies] until several [ongoing] first-line trials read out.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Brar, an assistant professor of medicine within the Division of Hematologic and Medical Oncology at Weill Cornell Medicine, discussed how the treatment paradigm has expanded in HCC, continuing sequencing challenges, and ongoing trials that are expected to impact the landscape.

OncLive^®: What are some of the nuances with regard to treatment in HCC, and how has the field evolved?

Brar: The treatment landscape of HCC has changed since 2017. Prior to that, for a decade, we only had sorafenib [Nexavar] as a first-line agent. That was about it. [Although sorafenib] was efficacious compared with placebo or best supportive care, it did come with a lot of toxicities and it was limited in terms of which patient populations we could use it in.

A majority of patients with HCC have some underlying liver dysfunction. We are almost trying to compete with 2 things: the degree of their liver dysfunction and the cancer that we are trying to treat. It can be challenging to try to navigate this whole field.

Around 2017, lenvatinib [Lenvima] was evaluated in a noninferiority study compared with sorafenib. We found that [lenvatinib] was noninferior, so we had a second first-line agent for patients with advanced HCC. That was a big deal in the HCC landscape. There are differences in [toxicity] profiles, so when looking at which patient is eligible for which [agent], I [think about how the patient will] tolerate the [toxicity].

More recently, the IMbrave150 data [led to] the FDA approval of atezolizumab [Tecentriq] and bevacizumab [Avastin] in the first-line setting, which is now the new standard of care. That study compared [atezolizumab/bevacizumab] with sorafenib. Although the survival data aren’t mature yet, in terms of progression-free survival (PFS), response, and safety, [IMbrave150] was really the landmark study of HCC in this treatment space.

What was unique about the findings from the IMbrave150 trial?

IMbrave150 was a phase 3 trial of several hundred patients, comparing atezolizumab and bevacizumab with sorafenib in the first-line setting for patients with advanced HCC. The study had 2 co-primary end points: PFS and overall survival [OS]. Patients had to have Child-Pugh A performance scores, and their liver dysfunction had to be fairly normal. Again, the survival data aren’t mature yet, but the study did meet its primary end points of PFS and OS.

One would imagine that combination therapy in a space like HCC would come with a lot of toxicity. Interestingly, [atezolizumab/bevacizumab] was fairly well tolerated. An important caveat of this trial is that patients with active or untreated esophageal varices were excluded because there is a bleeding risk with bevacizumab.

What I really appreciated about this study is that the study personnel included quality of life (QOL) and time to deterioration [in the analysis]. There was a very large difference between the combination versus sorafenib in those regards. Also, it is challenging as a person who runs clinical trials to get patients to do [QOL assessments] consistently. [The investigators] did a good job because the patient response was over 70%. The QOL is a real marker of this study, supporting that atezolizumab and bevacizumab did better than sorafenib.

With multiple agents approved in the second-line setting, how do you approach sequencing for patients with HCC?

The next big question for everyone in the HCC space is: how do we sequence [our treatments]? Evidence-based data will be coming out in the next few years as we all get a little more experienced and comfortable using these agents for patients who, just a few years ago, would have had a median OS of less than 1 year.

This is a learning space for all oncologists who treat [patients with] HCC. Some exploratory studies are looking at differences in responses [to our available agents]. Second-line regorafenib [Stivarga] was studied in patients who tolerated sorafenib in the first-line setting; there was definitely efficacy [with that sequence]. One sequencing strategy would be to use sorafenib in the first-line setting, followed by regorafenib. A lot of patients who are eligible for atezolizumab and bevacizumab will receive atezolizumab and bevacizumab. After that, the logical thing to do would be to switch to a TKI of some sort––that could be lenvatinib or sorafenib in the second-line setting. From there, [you could determine a sequence] based on first-line data.

Other data that have come out [showed] that lenvatinib followed by sorafenib has some signal of [efficacy].

Using immunotherapy up front is [preferred] because it is unlikely to have a benefit in the second-line setting. The combination of nivolumab [Opdivo] and ipilimumab [Yervoy] is approved in the second-line setting. I would probably use those [agents] if a patient were on a frontline TKI, but that is at the cost of reasonable toxicity. We have to have the right patient selection when we think about sequential therapy, and we have to look at the safety profile of the drugs.

I should also mention that we have ramucirumab [Cyramza] in the second-line setting as well. [Ramucirumab was evaluated] in more of a biomarker-driven study. Patients have to have a serum alpha-fetoprotein (AFP) of more than 400 [ng/mL to use that agent], but it is an option. We also have cabozantinib [Cabometyx], which is also approved in the second-line setting. In that trial, about 30% of patients were in more of the third-line setting, and they had an advantage in efficacy. Perhaps cabozantinib [should be given] in the second- or third-line setting, as there is some actual evidence [to support that approach]. We will determine the rest [of the optimal sequencing strategy] with time.

How is AFP informing treatment selection within this patient population? Are there other biomarkers of interest in HCC?

AFP is the only biomarker that we have in HCC. To be honest, it is not the greatest biomarker because there are patients who are AFP negative but have HCC. In the advanced-stage setting, ramucirumab [was evaluated in] a biomarker-driven study where we found, through subgroup analyses, that patients with an AFP of more than 400 ng/mL tolerate and have a survival advantage with ramucirumab.

Beyond AFP, we haven’t seen other strong [biomarker] signals. There were a few promising ones, including FGFR and MET, but those did not pan out. There is a lot of work to be done in the biomarker-driven clinical trial space.

When we only had sorafenib, I didn’t know if biomarkers were important because we didn’t have anything else to give but sorafenib. Now that we have all of these options, I think this is the time to dig deep and look for these markers. The caveat is that HCC is a very complex disease. Are we going to find 1 home-run biomarker? Probably not, but we can probably find certain biomarkers for each of the systemic therapies that we have.

What ongoing trials are you waiting to hear the results of?

There are different trials that I am looking forward to. There is the LEAP-002 study, which is looking at pembrolizumab [Keytruda]. Then, there is the HIMALAYA study, which is an immunotherapy combination study. There is also the COSMIC-312 study, which is evaluating atezolizumab in combination with cabozantinib. [There is also a study] trying to bring nivolumab and ipilimumab into the first-line setting.

Until we know what our first-line strategy is and how to delineate which we are going to pick, we are not going to know how to sequence [treatments in] the second-line setting and beyond. If all of these [ongoing trials] are positive, how are we going to sort out which patients should get which sequence of therapies? I don’t think anyone knows the answer to that yet.