Choosing the Optimal First-Line Regimen for Patients With Advanced HCC

Richard S. Finn, MD

Multiple frontline regimens are approved for patients with hepatocellular carcinoma (HCC). Therefore, the treatment selected for each patient is based on specific disease characteristics, according to Richard S. Finn, MD.

“When we have an appropriate patient for first-line therapy, there are several things we need to consider. These are going to be patients who are staged as Barcelona C. These are patients who have extra hepatic spread or tumor in the liver that's invading into the vasculature or what we call portal venous invasion or macrovascular invasion. These might also be patients who have intermediate liver cancer, that are not good candidates for local regional treatments, such as transarterial chemoembolization or radioembolization, or Y90, and these are patients who have very large diffuse bilobar tumors, who might still be intermediate because they don't have vascular invasion or extra hepatic spread,” explained Finn, professor of Medicine at the Geffen School of Medicine at UCLA in the Department of Medicine, Division of Hematology/Oncology, in an interview with Targeted Oncology™.

At the recent International Live Cancer Association (ILCA) Annual Conference 2023, Finn gave a presentation during a debate session in which he supported the use of atezolizumab (Tecentriq) in combination with bevacizumab (Avastin; atezo/bev) for a patient with a large tumor, and high tumor burden.¹

Atezo/bev was established as a standard-of care frontline treatment for unresectable or metastatic HCC back in 2020. Updated findings from the IMbrave150 study (NCT03434379), which supported the FDA approval, showed that the clinical meaningful survival benefit demonstrated with atezo/bev vs sorafenib (Nexavar) was maintained after 12 months of additional follow-up.²

Results came from 501 patients in the intention-to-treat population of IMbrave150, 336 of whom were treated with atezo/bev and 165 who were treated with sorafenib. The median overall survival observed with additional follow-up was 19.2 months (95% CI, 17.0-23.7 months) vs 13.4 months (95% CI, 11.4-16.9) with sorafenib (HR, 0.66; 95% CI, 0.52-0.85; P <.001). The median progression-free survival (PFS) in the atezo/bev arm was 6.9 months (95% CI, 5.7-8.6 months) vs 4.3 (95% CI, 4.0-5.6 months) with sorafenib (HR, 0.65; 95% CI, 0.53-0.81; P <.001).

The study also showed that the safety profile of the combination was consistent with the primary analysis. Treatment-related grade ¾ adverse events (Aes) were observed in 43% of patients treated with atezo/bev compared with 46% of the sorafenib arm. Further, treatment-related grade 5 Aes were observed in 2% vs <1%, respectively.

According to Finn, only 1 clinical trial is ongoing that is challenging atezo/bev as a standard of care regimen. The SKYSCRAPER-14/Imbrave152 study (NCT05904886]) is evaluating the use of at atezo/bev vs atezo/bev and tiragolumab (RG6058, MTIG7192A) in patients with untreated locally advanced or metastatic HCC.

In the interview, Finn discussed his ILCA 2023 presentation on optimal frontline treatment in HCC and how the standard of care could evolve in the future.

Targeted Oncology: Can you talk about HCC treatment over the past 5 years? What were the key events in research leading up to where we are now?

Finn: In the last 5 years or so, we’ve really seen a revolution in the management of our patients with advanced liver cancer. That’s from the impact of all the new approvals we’ve had. I would say it all started with lenvatinib [Lenvima] in 2017, which became a new frontline option based on the REFLECT study [NCT01761266], and then we had a number of readouts in the second line as well, with regorafenib [Stivarga] and cabozantinib [Cabometyx] being approved for patients who had progressed after sorafenib.

We had accelerated approvals of pembrolizumab [Keytruda] and nivolumab [Opdivo] in the second-line setting as well as the accelerated approval of ipilimumab [Yervoy] and nivolumab [ipi/nivo]. Perhaps the biggest impact came in 2020 aith the approval of atezolizumab and bevacizumab in the frontline setting, which was the first time we improved survival over sorafenib since its initial approval around 2008. This approval was associated with not only an improvement in survival, but now double-digit responses, with objective response rate of 30%. These responses are quite durable with a significant improvement in progression-free survival, quality-of-life, and a very favorable [adverse] effect profile.

HCC | Image Credit: © Reema - www.stock.adobe.com

After the approval of atezolizumab/bevacizumab, we saw data with dual checkpoint inhibition with tremelimumab [Imjudo] and durvalumab [Imfinzi; durva/treme] based on the HIMALAYA study [NCT03298451], which is a single dose of tremelimumab in combination with durvalumab monthly or every 4 weeks. This also improved survival vs sorafenib. It did not have any PFS advantage, but it did have an objective response rate of 20%, and a favorable [adverse] effect profile that we see with dual checkpoint inhibition.

Then, in the past year, although we have not seen approvals yet, we had the positive readout of camrelizumab [AiRuKa] in combination rivoceranib [YN968D1], which also improved survival, objective response, and PFS vs sorafenib. We're waiting to see a decision from the FDA on that study, as most of the accrual did come from non-United States-based patients. It’s a very exciting time in the liver cancer landscape, and at the end of the day, our patients are benefiting from all these options.

Can you discuss some of the factors that you consider when selecting a treatment for a patient with HCC?

When we have an appropriate patient for first-line therapy, there are several things we need to consider. These are going to be patients who are staged as Barcelona C. These are patients who have extra hepatic spread or tumor in the liver that's invading into the vasculature or what we call portal venous invasion or macrovascular invasion. These might also be patients who have intermediate liver cancer, that are not good candidates for local regional treatments, such as transarterial chemoembolization or radioembolization, or Y90, and these are patients who have very large diffuse bilobar tumors, who might still be intermediate because they don't have vascular invasion or extra hepatic spread. These patients are probably better served with medical treatment than locoregional treatments. There are also patients who stage migrates. These patients have locoregional treatments for their intermediate disease, and they become refractory to those. They might not develop extra hepatic spread or vascular invasion, but their tumor keeps recurring in the liver despite efforts to control at local regional treatment. All 3 of those groups would be appropriate for systemic treatment.

Now, the question is how we choose, given we have sorafenib, lenvatinib, atezolizumab plus bevacizumab and durvalumab plus tremelimumab all approved. I think looking at all these data objectively, the most active regimen we have is atezolizumab and bevacizumab. This is based on a hazard ratio of 0.58 for overall survival, 0.59 for PFS, a median overall survival of over 19 months, and objective response rate of 30%. Now, there are some contraindications to this regimen. These patients who would receive this require upper endoscopy to rule out any high risk for bleeding with bevacizumab. Certainly, patients who have varices that have these banded would be considered appropriate. However, there are going to be some patients who are felt to be too high-risk for bleeding, in which case, bevacizumab would not be appropriate. Then the question is, can they get a checkpoint inhibitor upfront? I would say if they have contraindications to bevacizumab, then durvalumab plus tremelimumab would be our next best option given that it was superior to sorafenib.

However, again, the hazard ratio in that study was 0.78 with a median survival of 16.4 months, and no change in PFS. But, the objective response rate was 20% and these are quite durable. We've seen with recent data from long-term follow-up of that study, that there is a 4-year survival of about 25% for patients who got durvalumab plus tremelimumab in the HIMALAYA study [NCT03298451]. Now, if a patient is not a candidate for [immunotherapy], then I think lenvatinib has demonstrated that it is a very active agent in liver cancer. Recent data from the LEAP-002 study [NCT03713593] where lenvatinib was the control arm, the survival is 19 months. But even in the REFLECT study we saw, while it was non-inferior to sorafenib for overall survival, it did improve progression-free survival, and has a pretty solid response rate for a [tyrosine kinase inhibitor] at about 19%, which has been reproducible as well, in the LEAP-002 study [NCT03713593].

We cannot ignore a patient's underlying liver function. Certainly for patients who have decompensated liver disease, we need to ask ourselves, can we even help them with systemic treatment? Is their cancer the main problem? Or are these patients just going to run into problems and unfortunately, maybe pass from end-stage liver disease and not cancer? That is why assessing liver function and performance status is important. When we look at patients and consider them for frontline treatment, however, we now have drugs that are active in liver cancer. Sometimes patients might have liver dysfunction from a large tumor burden and they're not from their underlying liver disease, and these are patients who might benefit from these treatments where we can induce an objective response and improve their liver function.

Your debate at ILCA asked which is the best first option of HCC. Can you talk about your stance in the debate some of the key points from your presentation?

At the ILCA 2023 meeting, there was a debate on the optimal choice for frontline therapy. I had a very formidable opponent here, my good friend, and colleague Katie Kelley, MD, who I think put up a good argument. Both of us started with a case and then decided how we would approach that. My case involved a patient of mine who I met back in 2021 and is now approaching 2 years on treatment.

The patient presented with hepatitis B, a very large tumor burden with pain, liver dysfunction, and significant weight loss. His scan showed a very large tumor, and his liver dysfunction was a result of this tumor. We also saw that his AFP was elevated at over 600, he had an endoscopy with showed varices that were banded, and my choice for him was the use of atezo/bev. The reason for that is that this patient needed an objective response. He was in a so-called visceral crisis, if I could borrow language from our breast cancer colleagues, where he had end organ dysfunction from a large tumor burden, and he needed a response. The best way to get a response is with atezo/bev. The objective response rate is 30% in the phase 3 study.

We know atezo/bev is the most active agent in improving survival with a hazard ratio of 0.58. It delayed PFS, and even though my patient had a history of varices, and these were treated, he had a distant history of coronary disease as well. However, we know that bleeding events with HCC from the IMbrave150 study are still relatively low. As far as high-grade events, when they do occur, they were more common in patients who had main portal vein invasion. I think that risk benefit very much favored atezo/bev.

We also now have real-world data from the community setting that demonstrates that the use of atezo/bev in patients who are child Pugh A or child Pugh B disease has a very similar risk of bleeding. I had follow-up on this patient, which showed that he had a significant response. His liver function normalized, he has gained about 30 or 40 pounds since his treatment course as he's felt better, he's gone back to work, and his AFP is now undetectable. His life has been saved by this active regimen which induced this rapid response.

Katie Kelley presented a case where she used durva/treme in a patient who she had some concerns about coronary disease and the use of bevacizumab in that patient. Her argument there, besides toxicity, was largely focused on the tail of the curve from the durva/treme study. That recent data suggests a survival rate of 25% in the durva/treme arm. However, we got to keep in mind with a landmark analysis, patients must live long enough to get to that benchmark. When we look at the hazard ratio for overall survival from HIMALAYA, that was 0.78 vs 0.58 with IMbrave150. In addition, IMbrave150 took patients who had main portal vein invasion, which HIMALAYA did not. Taken together, I would argue even for her patient, I would have used the atezo/bev, because it is really a more active regimen and is very well-tolerated.

What is the key takeaway from your argument?

I think the take home points from my presentation was the patient I presented was in visceral crisis from his tumor burden, and they needed a response as soon as possible. Despite having child Pugh B disease, this was a result of his large tumor burden. The most active regimen here for him would have been atezo/bev, and this is based on overall survival, progression-free survival, objective response rate in patients who are at high-risk based on high AFP tumor burden vascular invasion.

The risk-benefit for atezo/bev, considering that he had his varices these banded, and he had distinct coronary disease, favored the choice of atezo/bev for this patient. Now, taking care of him 2 years later, it's gratifying to see how well he is doing.

Which ongoing studies could potentially change standard of care frontline treatment for HCC?

The landscape has changed very rapidly for frontline HCC. What the next frontline HCC regimen will be is not known yet. Interesting data is what I presented at ASCO this year atezo/bev in combination with tiragolumab, and anti-TIGIT antibody.

The data showed an objective response rate in this phase 1 study of over 40% This regimen is now going into phase 3, the SKYSCRAPER-14/IMbrave152 study. This study will look at atezo/bev vs atezo/bev and tiragolumab. If positive, which will take some time to accrue and read out, this might become a new standard of care. Right now, there are no other frontline phase 3 studies going up against atezo/bev.

Another study we're waiting to see data on in earlier-stage liver cancer is Imbrave050 [NCT04102098]. This study demonstrated that the use of atezo/bev after curative resection for liver cancer, decreased recurrence-free survival. We're waiting for regulatory approval for that regimen for these patients at high-risk disease after surgery.

But still, there are several other adjuvant studies that we're waiting to see results from, including studies looking at durvalumab and bevacizumab in this population, as well as studies with nivolumab and pembrolizumab. Also, there are important studies in intermediate-stage disease where we have several phase 3 studies waiting to read out about the combination of immunotherapy regimens with chemoembolization. I should also mention the frontline study that we're waiting to read out that has completed enrollment and is the study of ipi/nivo vs sorafenib and /or lenvatinib, and we're waiting for those results.

REFERENCES:

• ^{Finn, R. Which should be first option in HCC? Presented at: ILCA Annual Conference 2023; September 7-9, 2023; Amsterdam, Netherlands.}
• ^{FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. FDA News release. May 29, 202. Accessed September 26, 2023. https://tinyurl.com/5n9b7bp7}
• ^{Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2021;76(4):862-873. doi:10.1016/j.jhep.2021.11.030}