Role of PI3K Inhibitors in HR+ Metastatic Breast Cancer

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Sara Hurvitz, MD: The SANDPIPER results are eagerly awaited. We’re really interested in seeing whether patients who had endocrine-resistant breast cancer that’s hormone receptor—positive benefit from a selected PI3-kinase inhibitor, taselisib. In this study, taselisib was combined with fulvestrant and compared with fulvestrant alone in patients with AI-resistant metastatic breast cancer.

And what the study actually showed was a 2-month improvement in median progression-free survival, which is statistically significant. However, the disappointing part of the study, in my own opinion, was the side effect profile. About 17% of patients actually came off this trial due to toxicity. There’s a fair amount of GI toxicity as well as hyperglycemia, which has been reported in this study and is not unexpected with PI3-kinase inhibitors. So, I think overall, we’re all very excited about seeing the successful development of PI3-kinase inhibitors. But the toxicity and the results so far haven’t been clinic changing, in my own opinion, outside of the data we saw with the mTOR inhibitor, everolimus. We really have to overcome these challenges in order to widen the therapeutic index. I’m hopeful that future studies that are evaluating PI3-kinase inhibitors will find or will show that inhibiting this pathway, especially in patients with upregulation of that pathway in their tumor, is going to be beneficial.

Hatem Soliman, MD: The BELLE-3 trial looked at the benefit of a pan-PI3K inhibitor, buparlisib, in combination with fulvestrant in women with hormone receptor—positive, HER2-negative metastatic breast cancer. And so, it was studying, in essence, the combination of the 2 agents compared with fulvestrant with a placebo alone, and specifically also looking at it in the entire population that was treated, and also in the PI3K-mutated subset of patients as well, to look to see if there was a differential benefit. And what the trial demonstrated was that there was a benefit to the addition of buparlisib to fulvestrant in the treatment of those patients with an absolute difference of close to 2 months and progression-free survival.

However, one of the main issues with this class of drugs and has, in essence, affected the development of these agents over time is that there has been a concern over the toxicities of these agents, given their modest benefits that they’ve imparted to patients. And so, the therapy that was used in this one was a pan-PI3K inhibitor that led to some additional side effects such as psychiatric issues, in addition to some of the class effects that we see with hyperglycemia and rash.

So, the development of this agent, unfortunately, is no longer moving forward due to those concerns. And now the development is focusing on how we can better optimize the targeting of the pathway with more selective PI3K isoform inhibitors that are potent, have less off-target effects, and potentially can deliver larger gains in progression-free survival for patients who do harbor those selective mutations, and maximizing the risk-benefit ratio for those individuals going forward.

Transcript Edited for Clarity