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Atezolizumab + Bevacizumab in Treatment-Naive mRCC

Insights From: Dan J. George, MD, Duke Cancer Institute
Published: Wednesday, Oct 04, 2017



Daniel James George, MD: So, IMmotion 150 was a randomized phase II study looking at the comparison of sunitinib versus atezolizumab, a PD-L1 inhibitor, versus the combination of atezolizumab with bevacizumab, a VEGF-targeted antibody. And this was done in the frontline setting of renal cell carcinoma patients previously untreated. The rationale for this is that PD-L1/PD-1 strategies have shown activity in patients previously treated with VEGF-targeted therapies in renal cell carcinoma. And the idea of combining a PD-L1 strategy with an anti-VEGF strategy is attractive because of some of the immune modulatory effects of VEGF inhibition, particularly on cellular effects, such as tissue-associated macrophages and T-regulatory cells. So, for that reason, combining these 2 might have an even greater effect on immune stimulation while also creating perhaps some greater anti-tumor recognition by causing some hypoxia by blocking VEGF.

The problem with the strategy, of course, is the increased toxicity—2 agents compared with 1—in particular, overlapping toxicities that might occur, including fatigue and diarrhea. Bevacizumab is very attractive for the reason that it’s the most targeted and specific VEGF strategy, and it has probably the least amount of GI toxicity. And, in fact, in this study, the combination of atezolizumab and bevacizumab was really well tolerated. In fact, one of the reasons I think we’re excited about that regimen is because of the ability to treat patients for a long period of time, particularly patients who might have difficulty with other combination strategies.

The overall study was interesting in that it showed an improvement when compared to sunitinib, really our control for this population, for atezolizumab and bevacizumab, particularly in patients that had PD-L1–positive tumors. And if you think about it, the PD-L1–positive tumors are more likely to track with aggressive disease. It’s a poor prognostic indicator, and we see higher levels of expression in patients with intermediate- and poor-risk features. And interestingly, that’s the population of patients who got the greatest progression-free survival benefit associated with the combination of atezolizumab and bevacizumab of 12 months’ median progression-free survival versus only about 5 or 6 months with the sunitinib arm, so really suggesting that’s a group of patients we’d want to target with this strategy.

What’s also interesting is looking at how we judge progression in this era of immune strategies. So, traditionally, we’ve used RECIST 1.1 criteria, which doesn’t take into account possible flare or growth effects or some discordant effects that could happen with the appearance of some lesions and disappearance of others. These immune-modified RECIST criteria have been developed. What’s really, I think, comforting is to know that regardless of which approach you use—the RECIST 1.1 or the immune-modified—we still saw the same overall benefit associated with the PD-L1–positive tumors, overall for the population in favor of the combination over sunitinib but even more so in the PD-L1–positive tumors. So, I think it justifies that whatever means we use to judge these tumors, we’re going to be able to translate these study results into our real-world practice.

Transcript Edited for Clarity 
 
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Daniel James George, MD: So, IMmotion 150 was a randomized phase II study looking at the comparison of sunitinib versus atezolizumab, a PD-L1 inhibitor, versus the combination of atezolizumab with bevacizumab, a VEGF-targeted antibody. And this was done in the frontline setting of renal cell carcinoma patients previously untreated. The rationale for this is that PD-L1/PD-1 strategies have shown activity in patients previously treated with VEGF-targeted therapies in renal cell carcinoma. And the idea of combining a PD-L1 strategy with an anti-VEGF strategy is attractive because of some of the immune modulatory effects of VEGF inhibition, particularly on cellular effects, such as tissue-associated macrophages and T-regulatory cells. So, for that reason, combining these 2 might have an even greater effect on immune stimulation while also creating perhaps some greater anti-tumor recognition by causing some hypoxia by blocking VEGF.

The problem with the strategy, of course, is the increased toxicity—2 agents compared with 1—in particular, overlapping toxicities that might occur, including fatigue and diarrhea. Bevacizumab is very attractive for the reason that it’s the most targeted and specific VEGF strategy, and it has probably the least amount of GI toxicity. And, in fact, in this study, the combination of atezolizumab and bevacizumab was really well tolerated. In fact, one of the reasons I think we’re excited about that regimen is because of the ability to treat patients for a long period of time, particularly patients who might have difficulty with other combination strategies.

The overall study was interesting in that it showed an improvement when compared to sunitinib, really our control for this population, for atezolizumab and bevacizumab, particularly in patients that had PD-L1–positive tumors. And if you think about it, the PD-L1–positive tumors are more likely to track with aggressive disease. It’s a poor prognostic indicator, and we see higher levels of expression in patients with intermediate- and poor-risk features. And interestingly, that’s the population of patients who got the greatest progression-free survival benefit associated with the combination of atezolizumab and bevacizumab of 12 months’ median progression-free survival versus only about 5 or 6 months with the sunitinib arm, so really suggesting that’s a group of patients we’d want to target with this strategy.

What’s also interesting is looking at how we judge progression in this era of immune strategies. So, traditionally, we’ve used RECIST 1.1 criteria, which doesn’t take into account possible flare or growth effects or some discordant effects that could happen with the appearance of some lesions and disappearance of others. These immune-modified RECIST criteria have been developed. What’s really, I think, comforting is to know that regardless of which approach you use—the RECIST 1.1 or the immune-modified—we still saw the same overall benefit associated with the PD-L1–positive tumors, overall for the population in favor of the combination over sunitinib but even more so in the PD-L1–positive tumors. So, I think it justifies that whatever means we use to judge these tumors, we’re going to be able to translate these study results into our real-world practice.

Transcript Edited for Clarity 
 
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