PI3K Inhibitors for HR+ Metastatic Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: One last thing, before we move on from this topic of hormone therapy and targeted therapies, is the PI3-kinase inhibitors. As we all know, PI3-kinase mutations are the most common mutations in breast cancer, and obviously, we want to try something because it’s the most common mutation. But to me, it has just been a little bit on the disappointing side so far. Any comments? Let me start with José and then Debu.

José Baselga, MD, PhD: My comment would be to keep the faith. We had the first few years of PIK3 inhibitors. Buparlisib was one of them. Remember, for buparlisib, the study was positive. It made a difference, but the toxicity was very significant, so it was not doable. Patients only stayed on for less than 2 months, and yet you saw the outcome was different. Now we have 2 alpha-specific inhibitors that are far less toxic. You have alpelisib, and then you have taselisib. You have 2 phase III clinical trials that are enrolling incredibly well. You have the SANDPIPER trial on one side, and then you have the SOLAR trials on the other. Those are going to be out by the beginning of next year or the end of this year. Based on the single-agent data that we have, we just published a paper in Cancer Discovery with the phase I data—a 36% response rate in patients with a PI3-kinase mutant tumor.

Adam M. Brufsky, MD, PhD: Across all tumor types?

José Baselga, MD, PhD: No, no, this is in breast cancer. So they’re active. It could be an issue on how tolerable they are, but these are alpha inhibitors. So, I have to say, I am very optimistic.

Debu Tripathy, MD: I agree. I think that we have to know whom to treat. Even with the BELLE study, which was with a pan-PI3-kinase inhibitor, there was clearly a signal that those with activating PIK3CA mutations responded. I think it’s a matter of selecting the patients. The other thing that we have to understand as time goes on—we have to really pay attention to the correlative studies.

You all had a very nice paper come out in Science looking at epigenetic modifications as a clue to at least 1 mechanism of resistance. I think that these drugs will probably be used in combinations as we start to understand the mechanisms of resistance and develop rational combinations.

Adam M. Brufsky, MD, PhD: But it’s going to be tough. All these people, at least with the PI3-kinase trials to date, are CDK4-naïve, right?

José Baselga, MD, PhD: Yes. It’s probably going to be neutral because one of the things that are interesting is that the CDK4/6 inhibitors are working independently of PI3-kinase mutation status. And that could be indirect evidence that they are working through non-overlapping mechanisms of actions, I would hope.

Adam M. Brufsky, MD, PhD: Good point.

Carlos L. Arteaga, MD: The other point to make about the SOLAR-1 and SANDPIPER trials is that those studies are powered to answer the question of whether or not these drugs are better in the mutant population or in the whole population.

Adam M. Brufsky, MD, PhD: Right. And it gives us yet another reason to do circulating tumor DNA testing in people.

Carlos L. Arteaga, MD: In fact, I know that the SOLAR-1 trial is using plasma tumor DNA in all patients, so this could be perhaps, as suggested by the BELLE-2 trial, the first targeted therapy that may be associated with a plasma tumor in the DNA.

Adam M. Brufsky, MD, PhD: As long as you’re testing them for 1, you might as well test them for a couple, right? You’re already testing for PI3-kinase mutation. Do ESR1 mutation testing and maybe HER2 mutation testing at the tyrosine kinase domain. And suddenly, we’ll be like the lung guys—we’ll actually have genomics that we could use.

Denise A. Yardley, MD: I think also about the FERGI trial, which was a negative trial, but I think much of what Carlos was saying—they were measuring the PI3 in the primary tumors. And now that we’re able to really measure real-time circulating tumor DNA, I think we may see some differences and see that signal now emerge a lot stronger.

Carlos L. Arteaga, MD: But the other lesson from these trials is that we have to really try to use target specific inhibitors, PI3-kinase-alpha inhibitors. Think about it. I think there will be a time when we will have a PI3-kinase mutant-specific inhibitor. There is an inhibitor from Genentech that seems to look that way. So, think about that. An inhibitor that will not give you rash or hypoglycemia raises the question: What would you use as your biomarker in the phase I? But we’ll get there one day, I think.

Adam M. Brufsky, MD, PhD: That’s great. That’s really neat.

Transcript Edited for Clarity