IMbrave050: Adjuvant atezolizumab plus bevacizumab provides landmark recurrence-free survival for HCC

Adjuvant therapy with atezolizumab and bevacizumab improved recurrence-free survival in patients with hepatocellular carcinoma (HCC) following surgical resection or ablation, according to results from the phase 3 IMbrave050 clinical trial , which were presented by Prof. Masatoshi Kudo (Kindai University, Japan) at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023, held 2-6 June 2023 in Chicago, IL, USA [1]. Medicom interviewed Prof. Kudo to learn more.

The standard-of-care for curative intent therapy for early-stage HCC includes surgical resection and thermal ablation. However, 5 years after resection or ablation, the risk of recurrence is about 70–80%. There is an unmet need in HCC patients for effective adjuvant approaches.

The randomised-controlled, phase 3 IMbrave050 trial (NCT04102098) researched the efficacy of an adjuvant combination treatment of the checkpoint inhibitor atezolizumab and the targeted therapy bevacizumab in delaying or preventing recurrence compared with active surveillance, which is the current standard-of-care for patients who have undergone surgical resection or ablation [2].

The trial enrolled patients with HCC who were at high risk of recurrence following tumour resection or ablation based on criteria such as size and number of tumours, presence of cancer cells within the lumen of blood and/or lymphatic vessels, and tumour grade. Study participants were randomly assigned 1:1 to receive atezolizumab plus bevacizumab every 3 weeks for a period of 1 year (or 17 cycles) or undergo active surveillance for 1 year. Patients in the control arm were eligible to switch to the experimental arm in case of recurrence. The primary endpoint was independent review facility-assessed recurrence-free survival (RFS).

After a median follow-up of 17.4 months, the trial met its primary endpoint, as the combination of atezolizumab and bevacizumab significantly increased RFS when used as adjuvant therapy following surgical resection or ablation. Participants who received the combination treatment had their risk of recurrence or death reduced by 28% compared with those in the active surveillance arm. The median RFS was not reached for either arm at this timepoint. Because the primary endpoint was met earlier than expected, the data for the trial’s secondary endpoints, including overall survival, are not yet sufficiently mature. Subsequent analyses will supply these data at a later timepoint.

 

Medicom spoke with Prof. Kudo:

Could you tell us a little bit about why this trial was important?

“There is simply no standard care for the adjuvant setting in HCC after resection or ablation. Several pervious trials have failed to meet the endpoint to suppress the tumour occurrence after curative treatment. This is very important because this is the first positive trial so far.”

What was the rationale behind combining bevacizumab and atezolizumab?

“As you know, the IMbrave150 trial (NCT03434379) for unresectable, advanced-stage HCC showed that atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib [3]. The rationale is that combining a checkpoint inhibitor PD-L1 antibody with the anti-VEGF antibody bevacizumab, which improves the immune microenvironment, will shift the environment from immune-suppressive to immune-permissive. The response rate was 30% in advanced-stage HCC; with a median survival of 19.2 months, which is the best outcome available for unresectable HCC. It follows that atezolizumab plus bevacizumab is first choice for frontline treatment of unresectable HCC. The next obvious question is whether we could employ this combination in earlier stage disease; in other words, does this combination improve the recurrence after resection or ablation, even in the absence of evident disease? It is very well known that the recurrence rate in this situation is around 60– 80%, even after curative resection, because at the time of resection, micrometastases have already been seeded in the remaining liver. It will take some time after resection or ablation, before those metastatic tumours become visible by CT or MRI imaging.”

“In that sense, the adjuvant therapy suppressing the recurrence is very important. And it is generally believed that a single checkpoint inhibitor monotherapy is not strong enough to suppress recurrence. That is based on the understanding that the micrometastases will have the same immune microenvironment as the primary resected tumour; thus PD- L1 antibody monotherapy will likely only achieve approximately 50% response rate. Combining PD-L1 checkpoint inhibition with a targeted therapy like bevacizumab is more potent; this combination should suppress or kill the remaining microtumours.”

What were the patient-reported outcome (PRO) results?

“We use the IL42 tool, which is a version of the EORTC QLQ-C30 questionnaire, with 5 domains: (1) health-related quality-of-life, (2) physical functioning, (3) role functioning, (4) emotional functioning, and (5) social functioning. In total, the participants answered 15 questions at baseline and thereafter at every other visit.”

“The response rate was greater than 93%, which we were very pleased with. Treatment was continued until recurrence or unacceptable toxicity for 1 year, or about 17 cycles. At the time of the 17th cycle, or at 1 year, more than 94% were under active surveillance; 96% of whom answered our questions.”

“In terms of baseline scores, the questionnaire was designed to measure the change on a scale of 0–100 points. There were no differences at baseline between the atezolizumab plus bevacizumab arm and the active surveillance arm. There were very high scores at baseline in both arms, around 80 to 90 for health-related quality-of-life, 81 points for physical function, and so on. We compared the intervention arm with the general population baseline scores, using published data from a general healthy population. We found that the intervention arm reported very similar scores to those scores: 71 to 89. We concluded that there was no deterioration in the quality-of-life at the outset of the adjuvant therapy after resection or ablation.”

“The pre-specified deterioration definition was a drop by -10 points, which we determined would be a significant deterioration drop due to adjuvant therapy. But compared with the baseline scores, the treatment arm was very stable, and showed no evidence of deterioration up to, and including, cycle 17. The intervention arm PRO scores also overlapped entirely with those from the active surveillance arm in terms of a 95% competence interval. The line is almost similar, comparable throughout the 17 cycles. We could therefore conclude from this PRO-based health-related quality-of-life tool and functioning score that this did not deteriorate at all.’’

Will these results change guidelines?

“Of course, this is a practice-changing result. Yes, absolutely, all international guidelines will be changed.”

Any safety concerns?

“Treatment-related grade 3–4 adverse events occurred in around 35% in the atezolizumab plus bevacizumab group. Treatment-related serious adverse events occurred in 13% of the participants. Treatment-related grade 5 occurrence was 0.6%. Two participants died, but 1 participant in the active surveillance group also died because of bleeding. The groups did not differ very much and we felt that this combination was safe and tolerable.”

What are the next steps?

“The next step, of course, is that we have to extend the follow up to accumulate more data, including overall survival. That will be exciting to see!”

1. Kudo M, et al. Efficacy, safety and patient reported outcomes (PROs) from the phase III IMbrave050 trial of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation. Abstract 4002, ASCO Annual Meeting, 2–6 June 2023, Chicago, IL, USA.
2. Hack SP, et al. Future Oncol. 2020 May;16(15):975-989.
3. Finn RS, et al. N Engl J Med 2020;382:1894-1905.

Photo courtesy of https://www.kindai.ac.jp/

 

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Posted on 17 July 20232 August 2023