PI3K Inhibitors for PIK3CA-Mutated HR+ MBC


Considerations for treating patients with HR+/HER2- metastatic breast cancer with alpelisib, a PI3K inhibitor, following frontline treatment with a CDK4/6 inhibitor.

Joyce O’Shaughnessy, MD: We know it’s a really important target, the PIK3CA. We’ll come to everolimus too when we talk about what do we do after progression on CDK4/6 inhibitors. Neil, what are the big picture data that you carry around in your own head for alpelisib for these patients with PIK3CA mutations?

Neil M. Iyengar, MD: I agree that the rate of PIK3CA mutations is about 40%, and it’s a relatively stable mutation. I think one of the things that’s fascinating is we’re starting to see global reports of PIK3CA mutations in various populations, and it’s relatively consistent across the world. I think that is one interesting observation. The other interesting piece is that the PI3 kinase or the PIK3CA story is not new, but the specificity of targeting specific isoforms of PI3 kinase is what’s fairly new. We have gone down this path of PI3 kinase inhibition that hasn’t been terribly successful, and that may largely be due to the nonspecificity of PI3 kinase inhibition. Now with alpelisib we see an alpha-specific inhibitor. I think that does 2 things. One is it may be contributing to the efficacy of the drug, and 2, the reduced toxicity of the drug. I think that’s actually the major piece of it because these broad PI3 kinase inhibitors can be fairly toxic and difficult to adhere to. Whereas an alpha-specific inhibitor like alpelisib certainly has its own toxicities, but these toxicities are manageable. That allows for adherence and the drug to do its job.

Gabriel Hortobagyi, MD, MACP, FASCO: It’s interesting that when we ran the BOLERO-2 trial, we found about a 38% mutation rate from PI3 kinase. Digging deeper in that, some of those were activating mutations, some were not, but we have never pursued that line of reasoning. Theoretically, you would expect that the only place where these PI3 kinase mutations should work is in the case of activating mutations. That’s not the case, or at least we have not generated enough data for that. Just pathway activation is not sufficient, as showed in the BELLE-2 and BELLE-3 trials. There’s a whole lot more to this than what we have seen, and perhaps that’s why we only see a benefit in the SOLAR-1 trial in little bit less than half of the patients treated.

Joyce O’Shaughnessy, MD: Yes, and only in those with the PIK3CA mutation. We have to give alpelisib only to those who have the PIK3CA mutation. SOLAR-1 was pretty persuasive, fulvestrant plus/minus alpelisib. If you didn’t have a PIK3CA mutation, there was no benefit at all basically. Very interesting, but we’re used to this. I think the lung cancer doctors are very used to going after very targeted agents, those specific activating mutations, so it makes a lot of sense that that should be the case. It got the median progression-free survival up to 11 months. It’s very good after second-line endocrine therapy. The caveat being that it was only a small subset of patients who had a prior CDK4/6 inhibitor. I think it was 26 patients, so we didn’t have a lot of data coming out of SOLAR-1 about how alpelisib works after a CDK4/6 inhibitor. The point estimate for that subset was just as good as the overall population. Then we had the BYLieve trial data. Neil, tell us about the BYLieve, what was that about?

Neil M. Iyengar, MD: Yes. That’s an important point, Joyce. What is the efficacy of PI3 kinase inhibition after prior CDK4/6 inhibition? BYLieve tested this. Essentially, patients who had been previously exposed to CDK4/6 inhibitors derived benefit from alpelisib in the next line. I think those are really reassuring data because functionally that’s essentially how we’re using PI3 kinase inhibitors in the clinic.

Joyce O’Shaughnessy, MD: Yes. It was single-arm, patients progressing on a CDK inhibitor, PIK3CA mutation, they got the fulvestrant and alpelisib. I carry around a little over 50% clinical benefit rate, which is reasonable. For patients who had already had fulvestrant, they could get letrozole plus alpelisib after their CDK4/6. It was maybe a little bit shy of 50%, is what I carry around in terms of a clinical benefit rate. Right around 50% of patients is what I carry around in my head, for who benefited with alpelisib with the PIK3CA following the CDK4/6. That’s what I remember.

Transcript edited for clarity.

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