Ahmed O. Kaseb, MD, professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine,The University of Texas MD Anderson Cancer Center, discusses the significance of results from the phase 3 IMbrave050 trial (NCT04102098) of adjuvant atezolizumab (Tecentiq) and bevacizumab (Avastin) for patients with early-stage hepatocellular carcinoma (HCC).

HCC is characterized as a vascular tumor that is dependent on VEGF-mediated angiogenesis, and has an immune-rich microenvironment, Kaseb begins. However, this tumor type is also associated with a high level of PD-L1 expression. Accordingly, patients with this tumor type may benefit from an immune checkpoint inhibitor (ICI) combined with a VEGF inhibitor, Kaseb explains.

The prior FDA approval for the ICI atezolizumab and VEGF inhibitor bevacizumab in unresectable or metastatic HCC validated the benefit of this approach, and subsequently transformed the frontline treatment landscape, Kaseb continues. This approval was based on data from the phase 3 IMbrave150 study (NCT03434379).

Based on the safety and efficacy of frontline atezolizumab and bevacizumab, researchers sought to expand the regimen's indication for patients with a high risk of HCC recurrence after resection or ablation through the phase 3 IMbrave050 trial. Patients undergoing surgery typically experience an increase in the number of immune cells and VEGF expression, Kaseb says. Therefore, it was hypothesized that atezolizumab and bevacizumab may be particularly beneficial pre- or postsurgical resection in the adjuvant setting, Kaseb details.

IMbrave050 was reported to have met its primary end point in a prior press release, Kaseb reports. This outcome was expected, since the regimen's activity and safety in the frontline setting was well-established, and its performance in the adjuvant setting was thus highly anticipated, he notes.

Results from a prespecified analysis were presented at the 2023 AACR Annual Meeting and showed that the doublet increased 12-month recurrence-free survival (RFS) rates compared with active surveillance consistently across all subgroups. Moreover, the hazard ratio of 0.72 for recurrence-free survival (RFS) in the experimental and surveillance groups favored the doublet, although these data were not evaluable at the time of data cutoff. However, the overall survival analysis for this trial is still highly immature. The safety of this regimen was deemed to be in line with its known toxicity profile in the prior research.

These data will be discussed with regulatory agencies and could support the regimen's FDA approval in early-stage HCC, Kaseb says. As atezolizumab and bevacizumab are already routinely used as a frontline treatment in clinic, it will be easier to incorporate the agent into standard practice if it gains approval, Kaseb concludes.

Dr. Kaseb reports receiving honoraria from Roche/Genentech, Bayer, Exelixis, Eisai, Merck, Bristol-Myers Squibb, and AztraZeneca; he received grants from Roche/Genentech, Exelixis, Merck, Bristol-Myers Squibb, and AztraZeneca; he received travel funding from Roche/Genentech.

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Ahmed O. Kaseb, MD, discusses the significance of results from the phase 3 IMbrave050 trial of adjuvant atezolizumab and bevacizumab for patients with early-stage hepatocellular carcinoma.
 


Dr Kaseb on the Investigation of Adjuvant Atezolizumab and Bevacizumab in Early-Stage HCC

Ahmed O. Kaseb, MD, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discusses the safety profile of the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) in hepatocellular carcinoma (HCC).

The phase 3 IMbrave150 trial enrolled patients with unresectable HCC and randomized them to receive treatment with atezolizumab in combination with bevacizumab or sorafenib. The adverse events (AEs) reported in both arms of the trial were expected, says Kaseb. More gastrointestinal and skin manifestations were observed in the sorafenib arm, whereas more bleeding episodes, hypertensive episodes, and proteinuria were reported in the combination arm. Grade 3 to 4 AEs occurred in 57% of patients in the combination arm versus 55% of patients in the sorafenib arm. Grade 5 AEs occurred in 5% and 6% of patients, respectively. The risk-benefit ratio must be weighed for the combination. Comorbidities and the current tumor burden must also be considered to determine which regimen to start with, concludes Kaseb.

Ahmed O. Kaseb, MD, discusses the safety profile of the combination of atezolizumab and bevacizumab in hepatocellular carcinoma.

Dr. Kaseb on Safety Profile of Atezolizumab Plus Bevacizumab in HCC

Ahmed O. Kaseb, MD, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discusses research with targeted therapy in hepatocellular carcinoma (HCC).

FGF inhibitors and TGF-β inhibitors are being evaluated, says Kaseb. Notably, tumors with advanced cirrhosis tend to have molecular alterations in TGF-β. Additionally, some studies have looked at 

 alterations. However, the overall percentage of patients with potentially targetable alterations is less than 5%, says Kaseb. One Asian study evaluated the use of RAS inhibitors in only 1% of the 2000 patients screened. TKIs, however, could have greater utility because they cause a downstream effect that could augment the effect of immunotherapy.

If TGF-β or STAT3 inhibitors, which are associated with immune suppression, can also be combined with immunotherapy, it could lead to greater utility in the field, explains Kaseb. At The University of Texas MD Anderson Cancer Center, investigators are planning a study that will evaluate STAT3 inhibitors plus checkpoint inhibitors, which could also help overcome acquired resistance mechanisms to immunotherapy, concludes Kaseb.

Dr. Kaseb on Research With Targeted Therapy in HCC

Ahmed O. Kaseb, MD, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discusses the progression of therapeutic options for patients with hepatocellular carcinoma (HCC).

Sorafenib (Nexavar) and lenvatinib (Lenvima) will still have a role in the treatment of patients with HCC despite the approval of atezolizumab (Tecentriq) plus bevacizumab (Avastin). Results from a meta-analysis that was published in the 

 in 2017 examined all phase III studies with sorafenib and showed a trend toward improved survival and outcomes in patients with hepatitis C—related HCC. If a patient with a history of hepatitis C receives frontline atezolizumab plus bevacizumab and progresses, they can then receive sorafenib because of its potential increased efficacy in those with hepatitis C, explains Kaseb.

If a patient has a history of hepatitis B, then lenvatinib, cabozantinib (Cabometyx), or another second-line agent may be effective, as lenvatinib has been shown to have benefit in those with hepatitis B, explains Kaseb. Choosing the appropriate drug to start with will depend largely on the patient’s risk factors, adds Kaseb.

Down the line, more studies will be launched, and more approved doublets will emerge in HCC, predicts Kaseb. For example, one study is evaluating the use of pembrolizumab (Keytruda) plus lenvatinib. Another study is evaluating atezolizumab plus cabozantinib; yet another is examining durvalumab (Imfinzi) and tremelimumab. Many ongoing studies are expected to read out by the end of next year, and those data will hopefully lead to more available options for patients with HCC, concludes Kaseb.

Ahmed O. Kaseb, MD, discusses the progression of therapy options for patients with hepatocellular carcinoma.

Ahmed O. Kaseb, MD

Articles

Dr Kaseb on the Investigation of Adjuvant Atezolizumab and Bevacizumab in Early-Stage HCC

Dr. Kaseb on Safety Profile of Atezolizumab Plus Bevacizumab in HCC

Dr. Kaseb on Research With Targeted Therapy in HCC

Dr. Kaseb on the Progression of HCC Research