Adjuvant Atezolizumab and Bevacizumab Delays Recurrence in Early-Stage HCC

Ahmed O. Kaseb, MD

Following its success as a standard-of-care (SOC) frontline approach in unresectable hepatocellular carcinoma (HCC), the use of atezolizumab (Tecentriq) and bevacizumab (Avastin) has now shown improved recurrence-free survival (RFS) in the adjuvant setting. This could be a practice-changing treatment option for patients with early-stage HCC who historically have poorer prognosis, according to Ahmed O. Kaseb, MD.

The phase 3 IMBrave050 trial (NCT04102098) evaluated adjuvant atezolizumab plus bevacizumab in patients with a high risk of HCC recurrence after resection or ablation with curative intent. In a prespecified interim analysis presented during the 2023 AACR Annual Meeting, 12-month independent review facility (IRF)–assessed RFS rates increased from 65% (95% CI, 60%-71%) with active surveillance to 78% (95% CI, 73%-82%) with the immunotherapy doublet.

Although median RFS was not evaluable (NE) for both arms at a median follow-up of 17.4 months, the hazard ratio of 0.72 favored the doublet (95% CI, 0.56-0.93; P = .012). Data regarding overall survival are still immature. Regarding safety, the regimen was consistent with both the known toxicity profile of each agent and the underlying disease.¹

This is the first phase 3 trial to demonstrate efficacy for an adjuvant immunotherapy combination in early-stage HCC. The combination was previously approved as frontline therapy for patients with unresectable or metastatic HCC based on findings from the phase 3 IMbrave150 study (NCT03434379).²

“Once the data have been combined, the next step is to look into pathways to approval [so] our patients in the clinic can access this regimen in the adjuvant setting,” Kaseb explained in an interview with OncLive^®. “We’re all excited to have an option in a setting where there is no standard of care or FDA approved drugs.”

In the interview, Kaseb discussed how the previous approval of atezolizumab and bevacizumab in HCC provided the impetus for the IMBrave050 study, discussed how data from this study could support the regimen’s approval in the adjuvant setting, and emphasized how this approval would substantially improve the treatment landscape for early-stage HCC.

Kaseb is a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

OncLive^®: Could you expand on the benefit that’s been seen with atezolizumab and bevacizumab since the regimen’s FDA approval in unresectable or metastatic HCC?

Kaseb: Since the approval of this regimen, we have witnessed a transformation in terms of patients’ tolerance to the regimen and [have also] mimicked the efficacy [seen in] the IMbrave150 study [in the early-stage setting]. [The combination] really transformed the field [by] introducing the first immunotherapy combination approach in the frontline setting for HCC. All physicians or oncologists involved were very familiar with the regimen, its tolerance level, and how to manage adverse effects [AEs]. [IMbrave050] was a natural [next step for] expanding the [regimen’s] indication to a different patient population through a phase 3 clinical trial.

What was the rationale for investigating this approach in the adjuvant setting for HCC?

HCC is a vascular tumor that is dependent on VEGF-mediated angiogenesis. It also [has] an immune-rich environment, [but does have] inhibitory signals. Therefore, there is a strong rationale to combine a checkpoint inhibitor [like] atezolizumab with the anti-VEGF [therapy] bevacizumab. The approval for atezolizumab and bevacizumab in [the advanced setting] validated this strategy. After surgery, we expect a surge [in the number of] immune cells in addition to VEGF. [In light of] these reasons, there is a strong rationale to [administer this combination] either before surgery [as neoadjuvant therapy] or after surgery in the adjuvant setting.

What was the clinical significance of interim efficacy and safety data from IMbrave050 that were shared at the meeting?

During the meeting, our team presented the results of the study [on the] integration of this approach in the adjuvant setting. [We shared] the study end points and walked through the study’s inclusion and exclusion criteria. The audience had the opportunity to [learn] exactly which patient population was included, the [study] outcomes, and the magnitude of benefit [observed]. It was a very nice introduction to the field. Down the line, these [data] could hopefully be the basis for [the regimen’s] FDA approval in this setting. For the first time ever, [we could] have an adjuvant regimen reviewed favorably by the FDA for patients with HCC.

Were any of these results particularly surprising?

When the study was reported to have met its primary end point in February, most of us in the field were not very surprised because of the regimen’s [known] activity in the frontline setting. There were [already] high expectations for the combination strategy, and the field was ready for it. The fact that we have been routinely using [atezolizumab and bevacizumab] in the frontline setting for HCC will make this easier to roll out [and incorporate into] the standard of care in clinical practice once it is officially approved by the FDA.

In general, [the regimen] was deemed to be safe. There were no new signals of AEs or toxicity in this study compared with [those reported in] the IMbrave150 study.

How have these findings inspired continued research in HCC, and what future directions do you envision for immunotherapy regimens in this patient population?

The field of HCC has been evolving so fast. We have witnessed a transformation of systemic therapy options for HCC since we started to see activity with immunotherapy, either alone or in combination strategies. Now more than ever, the field is ready to explore many new options in many new settings for HCC. This study is introducing the adjuvant approach and will hopefully lead to approval.

We’re also looking forward to combination strategies [that combine] immunotherapy and targeted therapy plus localized therapies as well. [We will] also see [investigations of this regimen] in the neoadjuvant setting as a preoperative treatment. These are the two areas that we’re excited about [exploring in the future].

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

References

1. Chow P, Chen M, Cheng AL, et al. IMbrave050: phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma at high risk of disease recurrence following resection or ablation. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, Florida. Abstract CT003.
2. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. Published May 29, 2020. Accessed April 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/