Encouraging Early Data of Atezolizumab/Bevacizumab Leads to Comparative Phase III Study

Michael S. Lee, MD

Michael S. Lee, MD

An early study of the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) in patients with unresectable hepatocellular carcinoma (HCC) showed significant activity and tolerable toxicity, according to Michael S. Lee, MD, who presented these data at the 2019 ESMO Congress.

The phase Ib study consisted of 2 phases. The non-randomized, single-arm phase (arm A) evaluated safety and efficacy of the combination therapy and the randomized phase of the study (arm F) compared the combination of atezolizumab and bevacizumab to atezolizumab alone.¹

After a median follow-up of 12.4 months, arm A saw durable responses. The objective response rate (ORR) was 36% (95% CI, 26%-46%) based on a review by RECIST v1.1. Additionally, 12% of patients had a complete response to the treatment. The secondary endpoint, progression-free survival (PFS) was 7.3 months in this arm (95% CI, 5.4-9.9). The duration of response (DOR), another primary outcome, was not reached. The safety profile of the combination was consistent with toxicities seen with either drug alone.

In arm F, the median PFS seen with the combination therapy was 5.6 months (95% CI, 3.6-7.4) versus 3.4 months (95% CI, 1.9-5.2) with atezolizumab monotherapy. The combination reduced the risk of disease progression or death by 45% compared with atezolizumab alone. These results showed that atezolizumab plus bevacizumab is superior to atezolizumab alone after a median follow-up of 6.6 months (HR, 0.55; 80% CI, 0.40-0.74;P= .0108).

Early results from the trial led to theFDA granting the combination a breakthrough therapy designationfor the frontline treatment of patients with advanced or metastatic HCC in July 2018.

Additionally, once investigators saw promising results in these early studies, a randomized phase III study (IMbrave150, NCT03434379) was initiated to compare atezolizumab plus bevacizumab to the standard-of-care sorafenib (Nexavar) in patients with locally advanced or metastatic HCC. IMbrave150 plans to randomize approximately 480 patients 2:1 to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxicity or loss of clinical benefit.²

The primary endpoints of IMbrave150 are investigator-assessed ORR by RECIST v1.1 and overall survival (OS). Secondary endpoints will either be investigator-assessed per RECIST 1.1 assessed by independent review facility and per RECIST v1.1 and HCC-modified RECIST and include; PFS, DOR, time to progression, and ORR.

Lee is hopeful about the combination and eagerly awaits the phase III data from IMbrave150. He stated, “I think that combination strategies may allow us a better chance at further shrinking that pool of patients who are progressing quickly, and by doing so, I think it may improve the overall outcome.”

In an interview withTargeted Oncology, Lee, assistant professor of medicine, University of North Carolina at Chapel Hill — School of Medicine, discussed the early data on the combination of atezolizumab and bevacizumab in patients with unresectable HCC. He also highlighted the importance of further validation, like the phase III IMbrave150 study, which is comparing the combination to the standard of care.

TARGETED ONCOLOGY:Can you discuss the rationale for the safety and efficacy study of atezolizumab and bevacizumab in unresectable HCC?

Lee: Unresectable, or metastatic HCC represents a huge area of need. Right now, the current standard of care is comprised of single-agent anti-angiogenic tyrosine kinase inhibitors such as lenvatinib (Lenvima) or sorafenib.

Although these are effective, and large randomized studies have shown that they prolong survival, they have modest response rates as single agents. They also have a significant toxicity profile. We [also] know that immune checkpoint inhibitors do show evidence of activity but as single agents they have modest response rates. However, a fair number of patients end up progressing quickly. Immune checkpoint inhibition may combine well with anti-angiogenic therapy. The VEGF that drives angiogenesis or blood vessel formation is immunomodulatory. It impacts immune effector cells and tumor stromal microenvironment in such a way that VEGF inhibition may improve immune cell trafficking to tumors and boost antitumor immunity. Several studies have also suggested that it would synergize in combination with an immune checkpoint inhibitor.

TARGETED ONCOLOGY: Can you discuss the study design and findings?

Lee: There were 2 arms of the study. The first arm was a non-randomized, single-arm study with the primary objective of assessing the efficacy and a primary endpoint of ORR. All patients in the study received a combination of atezolizumab and bevacizumab given every 3 weeks. Based on preliminary signals of efficacy in the non-randomized arm, we launch a 1:1 randomized arm where patients received the combination of atezolizumab and bevacizumab versus atezolizumab monotherapy.

In the non-randomized arm, the data are more mature with a median follow-up of a little over 12 months. We found that the ORR was 36% and there was an impressive 12% complete response rate. The disease control rate was about 71%.

In the randomized phase of the study, the primary endpoint was PFS and we did find that the combination of atezolizumab and bevacizumab resulted in a significant improvement in PFS compared to atezolizumab monotherapy. The hazard ratio is 0.55 and theP-value was 0.01. That translates to a 45% reduction in the risk of progression or death with the combination compared with atezolizumab monotherapy.

The median PFS in the non-randomized arm, where the data are more mature, exceeded 7 months. The OS data are much less mature but was about 17 months, and the results were comparable when we looked at them using a range of response criteria, including HCC-modified RECIST and investigator-assessed RECIST 1.1. The primary endpoint for the response rate, and the PFS was using an independent review facility assessed RECIST 1.1 criteria.

TARGETED ONCOLOGY: Can you explain the safety profile for atezolizumab plus bevacizumab?

Lee: The toxicities were manageable and not unexpected given the known toxicity profiles of either drug alone. When we looked at the toxicities in the combination arm versus the single agent in the randomized phase, we found that rates of toxicity were mostly comparable, except for toxicities that we would expect with bevacizumab, which is hypertension, and proteinuria. The majority of the toxicities were low-grade. Less than 5% to 10% of patients in either arm required steroids for immune-related adverse events. Overall, we found that toxicities were manageable and tolerable.

TARGETED ONCOLOGY: What are the next steps with this research?

Lee: The data were compelling enough that a large phase III randomized study was launched, IMbrave150, where the combination of atezolizumab and bevacizumab is being compared against the current standard of care. Those results are eagerly awaited, and I think will be the definitive data to help determine what will happen with the combination from a regulatory perspective. Although, given the results that we've seen here from this earlier phase study, we're very hopeful, and the results are promising. The response rate that we've seen is higher than what standard therapies can offer.

TARGETED ONCOLOGY: Do you see the results from the phase III changing the standard of care for HCC?

Lee: If it pans out like we've seen in these studies, I think it would.

TARGETED ONCOLOGY: What should community oncologist take away from this study and the ongoing phase III trial in relation to the treatment paradigm for HCC?

Lee: The role of checkpoint inhibitors is continuing to unfold, and I think the best way to combine or sequence immune checkpoint inhibitor antiangiogenic therapies is still a work in progress. We are all working on a better understanding.

The key here is that we know responses are durable and patients respond to immune checkpoint inhibition. In our study, we saw that among the 36% of the patients who responded, the median variation of response had not been reached. I think the trick is to figure out how to minimize the number of patients who aren't benefitting and who are progressing quickly. For example, in the randomized phase of our study, we saw that there was a higher proportion of patients who had progressive disease with atezolizumab monotherapy compared to the combination of atezolizumab and bevacizumab. I think that combination strategies may allow us a better chance at further shrinking that pool of patients who are progressing quickly, and by doing so, I think it may improve the overall outcome. What we'd all love to see is an improvement in PFS and OS. Improving on immune checkpoint inhibitor monotherapy is going to take that. Because our therapy combination was well tolerated, I'm hopeful that the toxicity profile is going to be something the majority of patients will be able to manage and that will be brought out by maintenance of the quality of life.

Reference:

1. Lee M, Ryoo B-Y, Hsu C-H, et al. Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA39.