Amit Singal, MD, medical director, Liver Tumor Program, clinical chief, Hepatology, professor, Department of Internal Medicine, Dedman Family Scholar in Clinical Care, Willis C. Maddrey, MD, Distinguished Chair in Liver Disease, University of Texas (UT) Southwestern Medical Center, discussesthe FDA approval of durvalumab (Imfinzi) with tremelimumab (Imjudo) in unresectable hepatocellular carcinoma (HCC).

FDA approved durvalumab in combination with tremelimumab

 for the treatment of adult patients with unresectable HCC, administered via the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen.

The approval of the STRIDE regimen is a notable advance in the field of HCC amid the growing treatment landscape for patients, Singal says. Moreover, there has been a marked improvement with this regimen in the survival of patients with advanced stage HCC extending over a year, Singal adds.

As more therapies become available, a complexity lies in deciding between the first-line therapies thatare available, Singal continues. For example, when treating patients with atezolizumab (Tecentriq) and bevacizumab (Avastin), it is important to be aware of those with contraindications to bevacizumab, Singal says. Moreover, these patients have a higher risk of gastrointestinal bleeding with bevacizumab, making it important to consider other options or regimens for this patient population, Singal emphasizes.

The STRIDE regimen can be a reasonable option to consider in these patients, Singal adds. Overall, inpatients who are at high risk of bleeding or have a history of bleeding should be considered for the STRIDE regimen, Singal concludes.

Videos

Amit Singal, MD, discusses the FDA approval of durvalumab with tremelimumab (Imjudo) in unresectable hepatocellular carcinoma.


Dr. Singal on the FDA Approval of Durvalumab With Tremelimumab in Unresectable HCC

Richard Kim, MD, professor, Moffitt Cancer Center, discusses the evaluation of TKI and immunotherapy combination regimens in hepatocellular carcinoma (HCC).

The phase 3 LEAP-002 trial (NCT03713593) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) failed to meet the coprimary end points of progression-free survival (PFS) and overall survival (OS) vs lenvatinib plus placebo, Kim says. The phase 3 COSMIC-312 trial (NCT03755791) that examined cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) met a coprimary end point of PFS; however, it missed the coprimary end point of OS, Kim adds. Although TKI/immunotherapy combinations failed to meet all their primary objectives in these 2 trials, there are some nuances for comparing these data with traditional immunotherapy/VEGF inhibitor combinations, according to Kim.

For example, LEAP-002 used single-agent lenvatinib in its control arm, and those patients who received the TKI alone did well, Kim says. If the trial investigated lenvatinib plus pembrolizumab vs sorafenib (Nexavar) in the control arm, it is possible that it would have been a positive study, according to Kim.

Another phase 3 study (NCT03764293) examined the combination of the TKI rivoceranib and the checkpoint inhibitor camrelizumab vs sorafenib alone. The doublet provided improvements in PFS and OS in patients with unresectable HCC, Kim concludes.

Richard Kim, MD, discusses the evaluation of TKI and immunotherapy combination regimens in hepatocellular carcinoma.


Dr. Kim on The Evaluation of TKI/Immunotherapy Combos in HCC

Rachna T. Shroff, MD, MS, medical director, Clinical Trials Office, chief, Section of GI Medical Oncology, director, Arizona Clinical Trials Network, associate director of clinical investigations, Clinical and Translational Oncology Program, University of Arizona, discusses the utility of combining anti–CTLA-4 and anti–PD-1 therapies in hepatocellular carcinoma (HCC).

The phase 3 HIMALAYA trial (NCT03298451) assessed the safety and efficacy of durvalumab (Imfinzi) with or without tremelimumab (Imjudo) vs sorafenib (Nexavar) alone in previously untreated patients with unresectable HCC. On October 24, 2022, 

the FDA approved durvalumab in combination with tremelimumab

 for the treatment of adult patients with unresectable HCC, based on data from HIMALAYA.

The investigative arm of HIMALAYA evaluated the STRIDE regimen, which is comprised of a single dose of tremelimumab, an anti–CTLA-4 agent, plus doses of durvalumab administered every 4 weeks, Shroff says. Using a single dose of an anti–CTLA-4 therapy in combination with a checkpoint inhibitor reduces the risk of immune-related adverse effects that are typically associated with combining those types of agents, Shroff explains. Data from HIMALAYA have shown that this regimen provided an overall survival benefit over sorafenib alone, Shroff adds. The efficacy benefits of the combination and its manageable safety profile make it a promising frontline option for patients with HCC, Shroff says.

Although the emergence of the STRIDE regimen and other options have shifted the HCC treatment landscape, advancements are still needed to further improve patient outcomes, according to Shroff. Further understanding of which patients benefit most from immunotherapy will allow for more individualized care in HCC, Shroff concludes.

Rachna T. Shroff, MD, MS, discusses the utility of combining anti–CTLA-4 and anti–PD-1 therapies in hepatocellular carcinoma. 


Dr. Shroff on the Utility of the HIMALAYA Regimen in HCC

Ghassan K. Abou-Alfa, MD, a medical oncologist, Memorial Sloan Kettering Cancer Center, discusses areas ripe for further exploration in hepatocellular carcinoma (HCC).

Efforts are underway to examine the immune microenvironment in patients with HCC, according to Abou-Alfa. Researchers at Memorial Sloan Kettering (MSK) Cancer Center are collecting tissue samples, along with demographic and treatment information, from patients with HCC around the world to better understand the molecular components of the immune microenvironment, Abou-Alfa says.

Advancements in cellular therapies for HCC and other solid tumors will be another area of interest in the coming years, Abou-Alfa adds.

Ensuring all patients with HCC have access to treatment remains a priority, Abou-Alfa says. The highest rates of liver cancer due to hepatitis C are found in Africa, particularly Egypt, according to Abou-Alfa. The highest incidence rates of liver cancer stemming from hepatitis B are also in Africa, Abou-Alfa adds. Bearing this in mind, in conjunction with colleagues in Africa, MSK researchers conducted a study to examine access to therapy across the continent for patients with liver cancer, Abou-Alfa concludes.

Ghassan K. Abou-Alfa, MD, discusses areas ripe for further exploration in hepatocellular carcinoma.


Dr. Abou-Alfa on Areas Ripe for Further Exploration in HCC

Ghassan K. Abou-Alfa, MD, a medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the analysis of disease and patient factors to inform clinical decisions in hepatocellular carcinoma (HCC). 

Although examining an individual patient’s disease factors can aid in treatment decisions within HCC, current guidance is lacking, Abou-Alfa says. For example, with the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin), there is serious concern about bleeding due to varices that can occur in certain patients, Abou-Alfa explains. As such, if this regimen is selected for use, it is important to perform an endoscopy in the patient, according to Abou-Alfa, who adds that the regimen should be stopped if there is any safety concern.

Due to the eligibility criteria of certain studies, questions remain regarding patients with major blood vessel involvement with their tumors, as this can affect the functionality of the liver and the benefit derived with a therapy, Abou-Alfa says. Patients with heavy vessel involvement typically would be classified as Child-Pugh class B, which would make them ineligible for most clinical trials, so it is important to gain an understanding of how certain treatments can affect this group of patients, Abou-Alfa concludes. 

Ghassan K. Abou-Alfa, MD, discusses the analysis of disease and patient factors to inform clinical decisions in hepatocellular carcinoma. 


Dr. Abou-Alfa on Analyzing Disease Factors to Inform Clinical Decisions in HCC

Laura Goff, MD, associate professor of Medicine, Hematology/Oncology, executive medical director, Vanderbilt-Ingram Cancer Center Patient Care Center, co-chair, Data and Safety Monitoring Committee, Vanderbilt-Ingram Cancer Center, discusses how to consider clinical trial information to inform treatment decisions in patients with hepatocellular carcinoma (HCC).

Safety is a key aspect when considering clinical trial inclusion criteria and how they will relate to real-world treatment decisions in this population, Goff says. Checking to see whether a platelet count threshold was included or whether patients were screened for varices can be important, especially if the trial was evaluating a VEGF-targeted agent, Goff adds.

However, other factors allow for more flexibility, such as Child-Pugh score for cirrhosis. It is important to evaluate individual factors that may contribute to a patient’s ability to tolerate a specific treatment, Goff explains. For example, Goff shares that she would still consider to use all or part of a regimen in an otherwise functional patient with Child-Pugh B cirrhosis if there is no clear indicator that they may experience excessive toxicity with the regimen—even though these patients may not have been included in clinical trials. Additionally, it is known that patients with severe cirrhosis can have significant functional impairment, either to the liver or their performance status, limiting their ability to derive benefit from treatment, Goff explains.

It is important to practice caution when making cross-trial comparisons of overall survival (OS) data reported with different regimens in HCC, Goff says. Progress has been made with extending OS in this population, as has been demonstrated with different agents and trials, according to Goff. Investigators continue to evaluate which patients go on to receive subsequent treatment and how much that relates to outcomes, Goff says. Newer agents in different lines of treatment can affect the ability to use OS as a single marker to demonstrate the benefit of a specific regimen, Goff concludes.

Laura Goff, MD, discusses how to consider clinical trial information to inform treatment decisions in patients with hepatocellular carcinoma.


Dr. Goff on Leveraging Clinical Trial Information to Inform Treatment Decisions in HCC

Rachna T. Shroff, MD, MS, medical director, Clinical Trials Office, chief, Section of GI Medical Oncology, director, Arizona Clinical Trials Network, associate director of clinical investigations, Clinical and Translational Oncology Program, University of Arizona, discusses remaining unmet needs for patients with hepatocellular carcinoma (HCC).

Although data from the phase 3 IMbrave150 (NCT03434379) and HIMALAYA (NCT03298451) trials have served to potentially shape frontline treatment in this population, additional questions remain with regard to how to proceed in the second line and beyond, Shroff says. Moving forward, many patients will likely receive an immunotherapy-based approach in the frontline setting, and investigators will need to evaluate whether rechallenging with immunotherapy is feasible in later lines, Shroff explains.

Although strides have been made in the metastatic setting, it is unknown whether combinations such as atezolizumab (Tecentriq) and bevacizumab (Avastin) or durvalumab (Imfinzi) plus tremelimumab could play a role in the perioperative setting, Shroff adds.

Considering how these therapies work in the real-world setting is also critical, as many patients do not have Child-Pugh A cirrhosis, Shroff notes, adding that another key area to investigate is whether these combinations are applicable for those with Child-Pugh B early cirrhosis.

Rachna T. Shroff, MD, MS, discusses remaining unmet needs for patients with hepatocellular carcinoma.


Dr. Shroff on Remaining Unmet Needs for Patients With HCC

Richard Kim, MD, professor, Moffitt Cancer Center, discusses the evolution of frontline treatment in hepatocellular carcinoma (HCC).

Until recently, the standard first-line treatment for patients with advanced HCC was the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin), based on data from the phase 3 IMbrave150 study (NCT03434379), Kim says. However, other positive data have since read out in this space, according to Kim. One such example is the phase 3 HIMALAYA trial (NCT03298451), which is examining durvalumab (Imfinzi) plus tremelimumab in this population; these data may change the current treatment landscape, Kim explains.

In HIMALAYA, the safety and efficacy of a single priming dose of tremelimumab followed by regular interval durvalumab, also known as the STRIDE regimen, was compared with that of sorafenib (Nexavar) in the first-line setting for patients with advanced HCC, Kim adds. Data showed that those who received the STRIDE regimen experienced a longer overall survival (OS) and progression-free survival than those who were given sorafenib. Three-year follow-up data showed that the 36-month OS rate was 30.7% for patients treated with the STRIDE regimen, Kim says. Although this regimen is not yet approved by the FDA, it is anticipated that approval will be granted in the near future, according to Kim.

Another arm of the trial investigated durvalumab as a single agent compared with sorafenib in this population, Kim adds. Although durvalumab monotherapy did not result in a statistically significant OS improvement vs sorafenib, the benefit derived with the agent appeared to be greater than what has been observed with TKI monotherapy in this setting, Kim notes. Since durvalumab monotherapy proved to be noninferior to sorafenib and to have favorable safety, it could be an alternative option for patients who are not candidates for doublet therapy with dual immunotherapy or immunotherapy plus a VEGF TKI, Kim concludes.

Richard Kim, MD, discusses the evolution of frontline treatment in hepatocellular carcinoma. 


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