HR+/HER2- Breast Cancer: Inhibiting the PI3K/AKT/mTOR Pathway


Dr Vidal expands on use of PI3K/AKT/mTOR pathway inhibitors following frontline progression, focusing on the PI3K inhibitor alpelisib for patients with PIK3CA mutations, as well as capivasertib, an AKT inhibitor in development.


Komal Jhaveri, MD, FACP: Greg, maybe you can address this as well. What has your experience been with alpelisib? How do you use it? And where do you use it? In what setting for HR-positive disease? And let’s say CAPItello tomorrow is going to be approved and you have that scenario, how are you thinking about both these trials, both these medications? What are you offering your patients and why?

Gregory Vidal, MD, PhD: So to answer the first question, I’m using it in the second [and] third line, depending on my CDK4/6 anti-estrogen partner in the first line and having PI3K [phosphoinositide 3-kinase] mutation. Toxicity is an issue in my neck of the hood where I treat patients. A lot of my patients come in who are diabetic [and] on numerous anti-diabetes medication, and it’s difficult for that population with the hypoglycemia. The rash is also the other thing. Premedication with antihistamine is usually very helpful in that situation and in the nausea. It is a challenging drug for some patients. Now with CAPItello and utilizing an AKT inhibitor ahead of it, we don’t really have data. It’s in the same sort of pathway. Is [the] PI3K mutation mutant inhibitor going to be active after failure for AKT inhibitor? We don’t know for sure. For some patients, again, if that’s what we have in the setting of no data, we use what we have. We have a conversation with the patient and make a decision about how the disease is progressing, which is very important. So a more indolent, slow progressing disease, I’m more likely to take a chance and say, “Let’s try this,” rather than something that is flourishing and growing rather rapidly. But again, confusion [with the] lack of data and [how] it’s changing so rapidly.

Komal Jhaveri, MD, FACP: Between the 2 drugs, remind me, what would you offer for the PI3K-altered patient?

Gregory Vidal, MD, PhD: Which one I would use first?

Komal Jhaveri, MD, FACP: Yes.

Gregory Vidal, MD, PhD: For the PI3K patient I would use CAPItello. Why? Because I don’t really have to test. It is active in the mutant and the nonmutant population, and it seemed like it’s a much better tolerated drug. Although, again, caution [because] this was in a very sterile, very well-controlled study environment, but it does appear to be better tolerated and the fact that it works in mutant and nonmutant, that would probably be my choice.

Komal Jhaveri, MD, FACP: Aditya, would you do anything differently or think about it differently?

Aditya Bardia, MD, MPH: No. I agree. I think it’s a discussion with a patient talking about both these options, alpelisib and CAPItello. You have lower incidence of rash and hyperglycemia with the AKT inhibitor, which is an advantage.

Komal Jhaveri, MD, FACP: Do you ever think about, or is there rationale to combining PI3K inhibitors with CDK4/6 inhibitors? Maybe tell us if there are any efforts, and do you think that approach or that rationale makes sense to you?

Aditya Bardia, MD, MPH: From a scientific perspective? Yes. There’s a lot of evidence to suggest that if you block PI3K plus CDK4/6, that would be synergistic. There are ongoing trials investigating these approaches. There are 2 trials. The first is a trial called VIKTORIA-1 [NCT05501886], which is looking at a dual PI3K mTOR inhibitor gedatolisib in combination with fulvestrant/palbociclib. So asking this triplet question. And there’s also a trial with PI3K inhibitor called GDC-0077 or Inavolisib, which is a first-line therapy looking at fulvestrant/palbociclib plus the PI3K inhibitor. The challenge is going to be the toxicity. We are talking about toxicity with 2 agents and now we have 3 agents. That’ll increase toxicity. We’ll have to see if the results look good, even if they meet their primary end point. What’s the delta? How significant are the results? And whether that’s worth the additional toxicity with the triplet agent.

Gregory Vidal, MD, PhD: Does the CDK4/6 matter?

Aditya Bardia, MD, MPH: In [both of] these trials? Palbociclib has been used and that’s a great question in terms of whether that’s the best option.

Komal Jhaveri, MD, FACP: Yeah. I think it’s such an important question, Greg, that you bring up. When we think about endocrine therapy comparisons with endocrine therapy, the hazard ratios are 0.8, 0.9, and then when you add a CDK4/6 inhibitor, we saw that the PARSIFAL study [NCT02491983] was negative. When you’re making combinations, you’re not able to tease out the impact of an individual contribution of a drug. So when you have triplet, I think it’s going to get even more complicated. Assuming that they are safe, we will be able to hopefully improve outcomes for our patients. At least there are efforts in place, scientifically, making sense that when you do this dual vertical blockades, maybe you can have a better impact and, maybe potentially, may I say the word cure in some patients and improve the outcomes very durably for a very long time for these patients. Time will tell how this will impact.

Transcript edited for clarity.

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