Sequencing Targeted Therapies and Immunotherapies in Hepatocellular Carcinoma

Lipika Goyal, MD

Lipika Goyal, MD

Both sorafenib (Nexavar) and lenvatinib (Lenvima) are approved frontline treatment options for patients with hepatocellular carcinoma (HCC). With several different agents approved in the second-line and later settings, sequencing remains an important topic in the treatment landscape of HCC.

Regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza) are all FDA-approved in the second-line setting and beyond for the treatment of patients with HCC. However, 3 randomized phase III clinical trials demonstrated the efficacy and safety of these agents in different patient populations, giving a clue to physicians as to which patient population may benefit more from each of these targeted therapies.

In addition, patients can also receive nivolumab (Opdivo) and pembrolizumab (Keytruda) as treatment of HCC in the later lines. Immunotherapies are available as well and are useful in select patient populations, such as those who rapidly progressed on the tyrosine kinase inhibitors (TKIs) sorafenib or lenvatinib, had poor tolerability of the agents, or are unable to receive third-line therapy, according to Lipika Goyal, MD.

Although there has not been an FDA approval yet, atezolizumab (Tecentriq) and bevacizumab (Avastin) are also under consideration for the treatment of this patient population. Earlier this year,a supplemental Biologics License Application was submitted to the FDAfor the approval of this combination. There are no data yet on how to sequence treatment following these agents yet.

In an interview withTargeted Oncology,Goyal, a gastrointestinal medical oncologist at Massachusetts General Cancer Hospital, discussed the first- and second-line treatment options for patients with HCC and shared her thoughts on how these agents should be sequenced.

TARGETED ONCOLOGY: What agents do we have available for the treatment HCC?

Goyal:There are multiple FDA-approved therapies for HCC in the advanced setting with another on the way. The 2 drugs that are approved in the frontline are sorafenib and lenvatinib. There was a noninferiority study that showed that lenvatinib was not inferior to sorafenib. In the second-line, we have regorafenib, cabozantinib, and ramucirumab for patients with an alpha-fetoprotein (AFP) greater than 400 ng/mL. We also have an accelerated approval for nivolumab and pembrolizumab.

TARGETED ONCOLOGY: How are we going about sequencing these agents?

Goyal:There are 2 scenarios to discuss. In 1 scenario, patients get a single-agent TKI of either sorafenib or lenvatinib in the first-line. The second scenario is patients who receive atezolizumab plus bevacizumab, which there was just a positive phase III trial, the IMbrave50 study, which we hope will lead to FDA approval this year.

For the first scenario, I think if there is a clinical trial available first. I always encourage patients to consider clinical trials so they could potentially get something that is not yet FDA approved and might be better than what is FDA approved. If they are not eligible or do not want to participate in a clinical trial, I think about if they have rapid progression on the TKI, if they had poor tolerability, or if they are unlikely to be able to go onto third-line therapy. If any of those are the case, I am more likely to recommend single-agent PD-1 inhibitor like nivolumab or pembrolizumab for the next line of therapy.

For patients who received atezolizumab and bevacizumab in the frontline setting, this is a data-free zone because all of the clinical trials were done in the post-sorafenib setting, but given that it is probably going to take some time for new data to emerge, we are talking about what we can do in clinical practice. Single-agent immunotherapy after someone has already received atezolizumab is unlikely to be effective, so there are other agents available in the next line. I always encourage these patients to consider clinical trials if that is available to them and they are eligible, but if not, we can think about the approved drugs for the first-line, such as sorafenib or lenvatinib, because neither atezolizumab or bevacizumab are TKIs.

If patients really need a response, lenvatinib is a reasonable choice because the response rate by modified RECIST was about 41% with lenvatinib versus 12% with sorafenib. If patients have certain comorbidities like uncontrolled hypertension, I would be more likely to move them to sorafenib because lenvatinib has a higher percentage of patients who have hypertension. Lenvatinib also has more nephrotic syndrome, a higher rate of hyperthyroidism, a higher rate of weight loss, so I look at the adverse event profile to determine which 1 a patient should go on to next.

The other thing I consider is if the patient had aVEGF-related complication on bevacizumab. I want to give these patients an agent that has less VEGF inhibition. When you compare lenvatinib and sorafenib, lenvatinib is a stronger VEGF inhibitor of VEGFR1/2/3. Sorafenib has a littleVEGFRactivity, so you want to be careful, but I would be more likely to recommend sorafenib over lenvatinib in the setting of prior complications to bevacizumab.

TARGETED ONCOLOGY: Are there other considerations you keep in mind when choosing the next line of therapy?

Goyal:I also think about concurrent medications. For example, in the post-transplant setting where we don’t really have a lot of data because a lot of these trials excluded patients who had a liver transplant, we do see recurrences in that setting. My usual practice is to consider giving sorafenib first because lenvatinib interacts with tacrolimus, and a lot of our patients are on tacrolimus as an anti-rejection medication. If the patients are on sirolimus and not tacrolimus, then it is very reasonable to use lenvatinib in that setting.

After lenvatinib or sorafenib, we also think about what the next line of therapy would be. The options we have in that space are regorafenib, cabozantinib, and ramucirumab in terms of targeted therapies, and then we have nivolumab and pembrolizumab. After someone has already had atezolizumab in the first-line, I think using a PD-1 inhibitor is unlikely to be efficacious, so I would recommend a targeted agent.

TARGETED ONCOLOGY: How do you choose between the 3 targeted therapies in this setting?

Goyal:In the RESORCE trial, which was the phase III trial of regorafenib versus placebo, patients had to have been on at least 400 mg daily of sorafenib for 20 out of 28 days. For patients who had tolerated sorafenib and were doing reasonably well on it, using regorafenib next is a reasonable option.

Ramucirumab was tested in the REACH2 trial against placebo in patients who had an AFP greater than 400. If someone has a high AFP, that would be a reasonable next option.

For the CELESTIAL trial, which is the randomized phase III trial of cabozantinib versus placebo, in patients who had received prior sorafenib, they could have had either 1 or 2 prior lines of therapy. That trial did not have any requirements for sorafenib tolerance or AFP, so cabozantinib is a reasonable drug to try regardless of how the patient did on sorafenib or their AFP.

TARGETED ONCOLOGY: What is your take home message?

Goyal:We need more high-level data to understand what the best sequencing is for these agents. It is wonderful that we are in this position where we have to think about what the next agent is because we have had multiple phase III clinical trials that were positive. If people had a TKI alone in the first-line setting, I would consider a clinical trial first, and after that, if they had progressed quickly, had poor tolerance, or were unlikely to make it to third-line therapy, I would consider single-agent immunotherapy.

If patients had atezolizumab and bevacizumab first, which we hope will get approved later this year, then I would choose a clinical trial or either lenvatinib or sorafenib. This is a data-free zone because we do not have trials yet on what to do after atezolizumab and bevacizumab, but given it will be some time before we collect that data, I would give lenvatinib versus sorafenib. To decide between these, I would look at if the patient needs a rapid response, their comorbidities if they had anyVEGF