Sara Hurvitz, MD: The majority of patients won’t have a PI3 kinase pathway mutation. So let’s assume this particular patient has progressed on a frontline CDK4/6 inhibitor and has no mutation on analysis. Sara, can you take us through what sort of patient-related and tumor-related factors influence your treatment recommendation? What do we know about the use of other PI3 kinase pathway inhibitors in this situation?

Sara Tolaney, MD: If this patient fell into that 60% cohort without a PI3 kinase mutation who progressed on a CDK4/6 inhibitor, I think our choices here would be whether we feel comfortable using endocrine therapy alone, so for example, fulvestrant, or if we have a preference for adding a targeted agent to that fulvestrant, such as mTOR inhibition with everolimus? I think the third option, although it’s not one that I would utilize, but a question that arises would be, is there any benefit to continuation of CDK4/6 inhibition beyond progression? I think those are the 3 things that are often crossing people’s mind when they’re trying to figure out what to do.

How does one decide? Our data for adding mTOR inhibition to endocrine therapy predominantly come from the BOLERO-2 and PrECOG studies. BOLERO-2 looked at adding everolimus to exemestane, suggesting dramatic improvements in progression-free survival with a hazard ratio of around 0.4. Then we also have data from the PrECOG study showing very similar benefit for adding everolimus to a fulvestrant backbone. Obviously, the challenge here is these are data that came out prior to CDK4/6 inhibition being a standard first-line treatment option.

I think my general sense is that benefits from endocrine monotherapy, post-CDK4/6 progression, seem much more modest than they had been in patients who were CDK4/6 naїve. And given that, I have tended toward wanting to add additional targeted therapy to that endocrine backbone for my patients who may be wild type for PI3 kinase. So in this case my preference generally has been to add everolimus to fulvestrant in this type of a patient.

One could do fulvestrant alone as an alternative, and so when trying to decide that, I think the thing many of us are keeping in the back of our minds is, well, how well did that patient really do on endocrine therapy? Were they on their AI [aromatase inhibitor] CDK4/6 for 5 years and seemed very endocrine sensitive, or were they someone on it for 6 months where they progressed really quickly and I’m not feeling so comfortable about my endocrine treatment? I think these are factors that play into our decision-making about how comfortable we would feel with endocrine monotherapy in a patient, based on how well they’ve previously done with endocrine treatment.

In this particular case, again I think there are some who would give fulvestrant alone. I would probably give fulvestrant/everolimus. I typically have not utilized continuation of CDK4/6 beyond progression, and we do not yet have data for that from a randomized trial. There are trials ongoing, such as MAINTAIN and PACE, that will answer this question. But for now, what we have are case series, and I think they’re challenging to interpret because there’s a lot of selection that goes into a patient for whom you may continue beyond progression that’s going to bias your analyses. And these aren’t randomized studies. So we can’t really conclude from these series if CDK4/6 inhibition beyond progression is working. I think we need more work in that area, and again, hopefully in the near future we’ll get those answers.

Sara Hurvitz, MD: I think you bring up really good points. The preclinical evidence that we have does not suggest that inhibition of CDK4/6 will benefit tumors beyond progression on one. I think some people are interested in seeing whether abemaciclib may have activity given it’s a more promiscuous inhibitor, perhaps hitting other targets and maybe would have differential activity. But I agree wholeheartedly with you that we need to see these clinical trials read out. I think we’ve gotten really good in the HER2-positive realm at switching out chemotherapy partners or HER2-targeted agents one after the other, but this is a situation where HER2 is the driver. So I think it’s important to distinguish that. That was a really nice review, and of course, we have the TRINITI study, which we’ve seen results from, but again not randomized, unfortunately, looking at ribociclib, everolimus, and exemestane altogether. So I think we do need the randomized data to come out.

Transcript Edited for Clarity