How Will the Combination of Bevacizumab/Atezolizumab and Novel IO Therapies Be Utilized in HCC?

Key Takeaways

• Advanced liver cancer treatments have expanded in recent years, including Immuno-Oncology (IO) and IO-IO therapies.

  • Atezolizumab and bevacizumab combination therapy increased median overall survival to 19.2 months, compared to 13 months with sorafenib.

  • Among patients who responded to treatment, the median duration of response was more than 18 months.

• Nivolumab and pembrolizumab combination response in difficult to treat cancers is often excluded from study.

• Safety, including expected bleeding events, may be managed with screening activities.

• New combinations are being studied with encouraging results, including lenvatinib and pembrolizumab, atezolizumab and cabozantinib, nivolumab and ipilimumab, and durvalumab and tremelimumab.

This transcript has been edited for clarity.

So, one of the big advances in the management of advanced liver cancer in the recent past was the readout from the IMbrave150 study.^[1] This phase III study supported the US and global approval of atezolizumab and bevacizumab in advanced liver cancer. And the US approval was in June of last year, shortly after the publication in the New England Journal of Medicine in May 2020.^[1] 

And at the time of the primary analysis from the study, we did not have fully mature data in regard to the overall survival (OS) benefit. We know that the hazard ratio for OS was significantly reduced with the addition of atezolizumab and bevacizumab. The hazard ratio was 0.58. And this year at ASCO GI 2021 (American Society of Clinical Oncology – Gastrointestinal Cancers Symposium 2021), we presented data with an additional year of follow-up.^[2] So, the median follow-up time at the updated data analysis was over 15 months as compared to about 8 months at the initial presentation. 

And the data was quite striking, in that we now see that the median OS in frontline liver cancer is 19.2 months. And again, at the time of the initial analysis, because the study was stopped at its first interim analysis, so now with a median overall survival with atezolizumab and bevacizumab of just over 19 months, as compared to sorafenib just over 13 months, we see that combination immunotherapy is clearly establishing itself as the standard of care for most patients with advanced liver cancer. The other striking thing that came out of the longer follow-up is an increase in the response rates. Initially, we presented an objective response rate of 27 months, and we didn’t have the median duration of response. And now with longer follow-up, we have more responses. That is to say, the objective response rate is 30%, and that includes 8% complete responses. And for those patients who do respond, the median duration of response is about 18 months, just over 18 months. So very durable responses for those patients who do respond and a very good chance of responding. 

We now see with this doublet, we’ve increased the responses we saw from single agent IO (Immuno-Oncology), such as nivolumab or pembrolizumab where response rates are around 15-20%. Also, there were no new safety signals with longer follow-up. And a little more analysis—and this was actually presented at AACR (The American Association for Cancer Research) this year—that in patients who have high-risk features, so those who have been excluded from some other phase III studies, such as having more than 50% of their tumor involving their liver, or 50% of their liver involved with tumor, bile duct invasion, or main portal vein invasion, we see still a consistent benefit for those patients in terms of survival, PFS (progression-free survival), and response as compared to sorafenib.^[3] 

And also, highlighted that for those patients when we did see high-grade bleeding events in the IMbrave study, which was always a concern with bevacizumab, that those events occurred largely in patients who had main portal vein invasion. And that helps us identify patients who might be at higher risk for bleeding with atezolizumab and bevacizumab or high-grade bleeding events. All patients had upper endoscopies before coming on study. And so, I think there’s still a favorable risk-benefit profile with the atezo–bev across various patient characteristics. 

In the next several months, it will be very interesting to see the readout from other combinations. The combination of lenvatinib and pembrolizumab looks very promising. Published in JCO (Journal of Clinical Oncology) last year was a phase I B2 study that showed response rates of 36%, objective response rate, with this combination with a very durable response.^[4] And then also in development is the combination of atezolizumab with cabozantinib, the multikinase inhibitor that is approved in second line, being looked at in combination with atezolizumab versus TKIs (tyrosine kinase inhibitors) in the frontline setting.^[5]

And then novel IO-IO combinations—nivolumab and ipilimumab and durvalumab and tremelimumab—two regimens that show very significant response rates, about 30% with ipi–nivo. And as you know, ipi–nivo is approved in the second line setting in the United States based on accelerated approval. And that data were published in JAMA Oncology by Dr. Yau and colleagues in 2020.^[6] And durvalumab and tremelimumab had data at ASCO last year where we see response rates around 25%. And again, both these IO-IO combinations are being compared to TKIs in the frontline setting.^[7]

So, in summary, liver cancer’s come a far way. IO now is frontline in combination, right now with atezo–bev being that combination partner. But in the next several months, hopefully, we’ll see additional data with other IO-based combinations and, at the end of the day, improving the options and survival and quality of life for our patients with liver cancer. And then, also moving these regimens to earlier stage disease, such as in combination with locoregional treatment or even truly adjuvant after curative resection or RFA (radiofrequency ablation). 

So, please continue to have your patients enrolled in clinical studies, and keep track of the upcoming data. Thank you for your attention.