Treatment Approaches for Advanced Hepatocellular Carcinoma: Insight From the 2022 Gastrointestinal Cancers Symposium

From January 20th to 22nd, clinicians gathered in San Francisco, California, and virtually for the 2022 American Society of Clinical Oncology (ASCO®) Gastrointestinal (GI) Cancers Symposium to discuss the latest innovative findings in GI cancer treatment, research, and care. This year’s conference included more than 600 abstracts.

Muhammad Shaalan Beg, MD, the director for GI Medical Oncology at University of Texas Southwestern Medical Center in Dallas, shared insight and key takeaways from the latest advances in treatment approaches for advanced hepatocellular carcinoma (HCC) presented at the meeting. Dr Beg is an associate professor of hematology and medical oncology and the medical director of the Clinical Research Office at University of Texas Southwestern. He conducts trials for new cancer treatments and is the principal investigator for the Simmons Comprehensive Cancer Center UM1 grant funded by the National Cancer Institute’s Experimental Therapeutics Clinical Trials Network (ETCTN).

What notable advances in first-line therapy for the treatment of advanced HCC were presented at the GI Cancers Symposium? How will these advances affect treatment of the disease going forward?

The practice-changing clinical trial was the HIMALAYA study (ClinicalTrials.gov Identifier: NCT03298451), which looked at combination immunotherapy (IO-IO), durvalumab with tremelimumab, as frontline therapy in patients with unresectable HCC.¹ This is the first trial to show that the combination of 2 immunotherapy medications is an effective treatment for HCC. Overall survival was significantly improved with the IO-IO combination compared with sorafenib monotherapy (16.4 vs 13.8 months; hazard ratio [HR], 0.78; 96% CI, 0.65-0.92; P =.0035). I am expecting this to become another approved frontline regimen for HCC. The investigators also demonstrated that durvalumab monotherapy was noninferior to sorafenib in overall survival (HR, 0.86; 96% CI, 0.73-1.03).

Atezolizumab with bevacizumab, a combination therapy approved for advanced HCC, consists of an immunotherapy option with a vascular endothelial growth factor (VEGF) blocker. If durvalumab with tremelimumab is approved, we’ll have 2 different combination regimens for HCC: an IO-IO combination and an IO-VEGF-targeted treatment.

This is important for 2 reasons. First, the atezolizumab with bevacizumab regimen has a higher risk of bleeding compared with sorafenib (all grade, 7% vs 4.5%), and patients with advanced HCC already have a high risk of GI bleeding compared with patients with other advanced cancers.^2,3 The IO-IO combination does not increase the risk of bleeding as much as sorafenib (all-grade hemorrhage standardized MedDRA query events, 1.8% vs 4.8%). The IO-IO combination could be a safer regimen from that perspective.¹ Second, the durvalumab and tremelimumab combination was administered by use of a novel dosing strategy referred to as the STRIDE (single tremelimumab regular interval durvalumab) regimen. The regimen begins with a single dose of tremelimumab plus durvalumab and then continues with durvalumab every 4 weeks. This resulted in a favorable adverse effect profile without too many immune-mediated adverse events (STRIDE vs durvalumab: grade 3-4, 12.6% vs 6.4%; leading to discontinuation, 5.7% vs 2.6%), which is a concern whenever we think about combining 2 different immunotherapy drugs.¹ I am excited about what these findings may mean for our patients with advanced HCC.

Another notable presentation was the phase 3 LAUNCH trial (ClinicalTrials.gov Identifier: NCT03905967), which compared the combination of lenvatinib with transarterial chemoembolization (TACE) to lenvatinib alone in an Asian population with advanced HCC.⁴ The early results of this trial indicated a higher median overall survival (17.8 vs 11.5 months; stratified HR for death, 0.45; P  <.001) and median progression-free survival (10.6 vs 6.4 months; HR, 0.43; P  <.001) in patients who received a combination therapy of lenvatinib-TACE compared with lenvatinib alone. There was some discussion of whether the trial participants are representative of the patients we see in the United States. There may be an opportunity for combinations such as lenvatinib with TACE or lenvatinib with pembrolizumab to be used with locoregional treatments or TACE.⁵ This is one area where there may be a lot of growth.

What notable advances in second-line therapy for advanced HCC were presented? How will these advances affect treatment of the disease going forward?

With the IO-VEGF and potentially the IO-IO combinations as first-line therapy, sorafenib, cabozantinib, and regorafenib will become second- or third-line treatments. The ASCO® guidelines recommend starting with the new therapies and then moving on to oral medications. This automatically creates a new sequence of treatments.⁶ My prediction is that patients with relapsed or refractory advanced HCC will be physically stronger after they receive the IO-IO or IO-VEGF combinations than they would have been if they had received the older oral medications first. In my experience, the oral medications cause a lot of adverse effects and weaken patients by the time they need second-line therapy. My hope is that with the new immunotherapy medicines, patients will be stronger when they receive a second-line treatment.

Can you comment on the initial findings of the DEDUCTIVE study presented at the meeting?⁷

The DEDUCTIVE study combined immunotherapy agents with oral tyrosine kinase inhibitors (TKIs). Currently, 2 IO-TKI combinations are being studied: tivozanib with durvalumab and pembrolizumab with lenvatinib (ClinicalTrials.gov Identifier: NCT05101629). These combinations are being evaluated in patients with advanced HCC who are refractory to atezolizumab with bevacizumab and offer a different strategy for people who may have intolerance to the previous regimens. In terms of adverse effects, the tivozanib data and the tivozanib combination data show more adverse effects than we see with the IO-IO combination. Thus, it is unlikely that these combinations will become a popular frontline regimen.

The place for these combinations in the second-line space is unclear because they also contain immunotherapy. If a patient has refractory or relapsed advanced HCC and is currently on the atezolizumab with bevacizumab or the HIMALAYA regimens, I do not know how excited people will be to continue an immunotherapy agent in second-line therapy. It is important to point out that these studies were initiated before results were available for the IO-IO combination. Currently, if a patient was intolerant to immune therapies in the first-line setting, we would likely choose a medication that is not an immune therapy, such as sorafenib. My inclination is that these IO-TKI combinations may end up having less of an impact in the treatment of advanced HCC.

What do you think are the most important unmet need in the treatment of advanced HCC?

We need to learn more about biomarkers in HCC so that we can better choose from the oral medications and various combination treatments available for individual patients.⁶ The biomarkers that have been found to be predictive of immune therapy response in other cancers, such as programmed death ligand 1 (PD-L1), are not predictive in HCC.⁸

There is also a need for treatments for patients with HCC whose liver is compromised. Everyone with HCC has cirrhosis. Participants in clinical trials usually have very mild cirrhosis, classified as Child-Pugh class A cirrhosis, with relatively healthy livers.⁶ But in the real-world setting, many patients with HCC have moderate cirrhosis and none of the trials we discussed included patients with Child-Pugh class B cirrhosis. We do not know how effective these treatments are going to be in people with HCC who have class A, B, or C cirrhosis. We need to determine which regimen is most effective and safest for this patient population.

What other potentially practice-changing trials are in progress that you and your colleagues are monitoring?

The early-stage trials combining systemic treatments with local treatments like TACE are interesting. The EMERALD-1 trial (ClinicalTrials.gov Identifier: NCT03778957) evaluated TACE in combination with durvalumab and bevacizumab therapy in patients with locoregional HCC and the EMERALD-2 trial (ClinicalTrials.gov Identifier: NCT03847428) studied durvalumab alone or in combination with bevacizumab in patients at high risk for recurrence of HCC after curative treatment. These trials could end up making a big difference. It may be possible to start systemic treatments sooner for many patients with HCC which could have a positive impact on their survival. These trials finished enrollment about 6 months ago, so we may start getting results at ASCO® 2022 or 2023.

You and your colleagues presented a study about serial analysis of circulating tumor DNA (ctDNA) for the identification of new actionable alteration in HCC. Can you comment on the findings?

This was an exploratory study of 106 patients with HCC who underwent prospective genomic analysis of ctDNA as part of routine clinical care between 2016 and 2021. Potentially actionable molecular alterations accounted for 19% (13/68) of new alterations. These included mutations in KIT and BRAF and amplifications in MET, BRAF, RAF1, PDGFRA, KIT, and FGFR2. There was a clear signal for people whose cancer was developing into a new clone as indicated by the ctDNA.⁹ This was our institutional experience, but a much larger study needs be done to confirm those findings. There are also many other studies evaluating whether ctDNA is predictive of disease progression.

Along these lines, exciting data were presented regarding ctDNA in colorectal cancer. An analysis from the GALAXY study showed that the presence or absence of ctDNA is more predictive of clinical outcomes than cancer stage.¹⁰ For example, a patient with stage 3 disease who is negative for ctDNA is not predicted to experience recurrence whereas a patient with stage 2 disease who is positive for ctDNA is predicted to experience cancer recurrence 90% of the time. I am excited about what these findings may mean for people with HCC. Even among patients who have had potentially curative surgery, at least 10% will experience recurrence within 1 year and approximately 70% after 5 years.¹¹ At this time, there is no known, effective, adjuvant treatment option for HCC. Some large trials are looking to study this. ctDNA may be able to identify a subgroup of patients with HCC who have “molecular residual disease.” The big question is: if we know that a patient has molecular residual disease that will likely recur, can we make a difference in their treatment? The colorectal cancer study was the first study in GI cancers to demonstrate the answer is yes. Depending on the stage of disease, chemotherapy can clear the molecular residual disease in 24% to 33% of patients.¹⁰

Are there any other abstracts or findings that you would like to highlight?

I think the ctDNA findings in general and the HIMALAYA study in advanced HCC were the most exciting in terms of updates. Another trial, which I hope will lead to an approved treatment, is the TOPAZ-1 trial (ClinicalTrials.gov Identifier: NCT03875235). The investigators found that first-line immunotherapy durvalumab in combination with chemotherapy (gemcitabine/cisplatin) improved overall survival over placebo plus chemotherapy in patients with advanced biliary tract cancer. The IO-chemotherapy regimen led to a 20% reduction in risk for death compared with placebo plus chemotherapy.¹² This was the first trial that showed improved overall survival with immunotherapy in patients with bile duct cancers. These findings could open a huge avenue for new treatments in bile duct cancers.