What can real-world evidence teach us about atezolizumab plus bevacizumab in 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 (NCT04102098) [1], presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023, held 2-6 June 2023 in Chicago, IL [2]. As this combination therapy is finding its way into practice, Dr Cha Len Lee (University of Toronto, Canada) performed a study to assess the efficacy, safety, and value of esophagogastroduodenoscopy with regard to this combination therapy in the real world [3]. Medicom Medical Publishers spoke with Dr Lee to discuss the findings.

Can you tell me about the unmet need in patients with HCC and why it's important that we have real-world data on the combination of atezolizumab and bevacizumab?

“HCC is a significant global health concern, currently ranking the fourth leading cause of cancer-related death worldwide,” said Dr Lee. “Since 2008, there has been a huge search for novel treatments targeting this disease, particularly in the area of immunotherapy. When the IMbrave150 trial showed the superiority of atezolizumab with bevacizumab in terms of overall survival, progression-free survival, and response rate against sorafenib, this combination treatment was recognized as the first-line treatment option [4]. Furthermore, the IMbrave150 trial reported that the treatment-related gastrointestinal bleeding rate was 7% compared with 4.5% in the sorafenib group. As a result, the trial recommended that all the patients should have endoscopic esophagogastroduodenoscopy (EGD) within six months prior to the treatment with atezolizumab plus bevacizumab in order to identify any viruses, which may increase the likelihood of bleeding when undergoing this treatment. Three years have passed and it is evident that this treatment has significantly impacted the landscape of HCC. However, the value of performing pre-treatment EGD in all the patients remains uncertain, and the efficacy and bleeding risk of atezolizumab with bevacizumab in the real-world setting are still unclear. With all those unanswered questions, we decided to perform a retrospective analysis on this topic.”

Can you tell us about the methodology of and results you obtained with the analysis?

“In Canada, we have the HCC - Cancer Health Outcome Research Database, which is a consortium across 10 cancer centres in different provinces. For this specific retrospective analysis, we collaborated with five cancer centres from the provinces of Ontario, Alberta, and Manitoba. Our analysis focused on the efficacy, safety, and uptake of EGD. In total, we managed to recruit 112 patients who have been treated from the 1^st of July, 2020 to the 31^st of August, 2022. Overall, our patient baseline characteristics were similar to those of the patients that were enrolled in the IMbrave150 trial, but we included more patients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC and patients who previously underwent local therapy. Additionally, all our patients received atezolizumab with bevacizumab outside the clinical trial setting: 90% of them received the treatment as a first line therapy, 9% of the patients received it as a second line treatment, and 1% received this combination therapy as a third line treatment.”

“In terms of efficacy, after a median follow-up of 10.4 months, the reported overall survival in our study population was 20.3 months and the median progression-free survival was 9.6 months. Moreover, the disease control rate achieved with the treatment was 76.8 months. Altogether, these numbers are comparable with those that have been reported in the IMbrave150 trial.

The second part of the study focused on the uptake of EGD and treatment-related bleeding. We discovered that 70% of the patients completed EGD within six months before starting treatment, while the other 30% proceeded with the treatment without EGD or any invasive determinations of portal hypertension or compensated advanced chronic liver disease. For those who had undergone EGD, 41% did have evidence of viruses seen on their endoscopic investigations and 20% of those required treatment with either ligation or beta blockers. Those numbers were two times higher than the rates that were reported in the IMbrave150 trial. This is not surprising; these results are reflecting the real-world high-risk population that we are treating in this study.”

“Overall, the treatment-related bleeding rate observed in this study was 15%. Stratified by EGD status, the rate in the EGD group was higher, with 18%, compared with the non-EGD group (9%). Again, this is not surprising as the EGD group might be the higher risk group sent for some investigation before they received their treatment. However, when we further analysed the data, 10% of the bleeding complications were actually non-gastrointestinal bleedings, like bruises and gum bleedings. The other 5% of the bleedings were specific gastrointestinal bleedings. When we compared patients who had gastrointestinal bleedings with those who had non-gastrointestinal bleedings, there wasn't a meaningful overall survival or progression-free survival difference between the EGD and non-EGD groups.”

What are the implications of these results, especially with regard to bleeding risk?

“It's still a very small study and I can't make any firm conclusion based on the results. However, our study does show potential for the selective use of EGD in patients with low risk of hepatic decompensation. In addition, our study showed that the approach of selective EGD, based on patient characteristics and risk factors, is useful in certain patients. The patient can start his or her treatment sooner without having to wait for EGD.

There might also be a potential for clinical cost-saving; however, we need to err on the side of caution with respect to not investigating our patients with pre-treatment EGD before they receive atezolizumab with bevacizumab, as this combination therapy involves a high dose of bevacizumab.”

What are the next steps for your research?

“At the moment the sample size of our study is definitely small, but we are excited about the results. Therefore, we are in the process of publishing our findings. In addition, the community needs to have real-world data with regard to the combination therapy of atezolizumab plus bevacizumab. Meanwhile, we want to expand the sample size of this retrospective analysis by collaborating with more Canadian cancer centres in the consortium. Next, in the long run we are considering to conduct a prospective study with our multidisciplinary team, including hepatologists, to create a better guideline with respect to stratifying patients with HCC around the area of variceal bleeding related to cirrhosis and atezolizumab with bevacizumab.”

1. Hack SP, et al. Future Oncol. 2020 May;16(15):975-989.
2. 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. ASCO, June 2-6, 2023, Chicago, USA. Abstract: 4002.
3. Lee CL, et al. Real-world multicentre analysis of patients with hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (A+B): Efficacy, esophagogastroduodenoscopy (EGD) uptake and bleeding complications. ASCO, June 2-6, 2023, Chicago, USA. Abstract: 4105.
4. Finn RS, et al. N Engl J Med 2020;382:1894-1905.

 

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Posted on 17 July, 20232 August, 2023