Other Treatment Modalities for HR+ Metastatic Breast Cancer

Transcript:

Aditya Bardia, MD, MPH:We reviewed CDK46 endocrine-based therapy and endocrine-based combination: PI3 kinase, AKT, and mTOR inhibitors like everolimus. Sara, you were involved with development of some of these agents. Could you review the data behind these 3 classes of agents—PIK3CA, AKT, and mTOR—and the adverse effect [AE] profile that could help decide which agent to choose?

Sara A. Hurvitz, MD: Our first inhibitor of this pathway was an mTOR inhibitor, everolimus, which was approved about a decade ago. It held that position for some time, until alpelisib came along. A PI3 kinase inhibitor with activity was restricted to those patients with a PIK3CA mutation, whereas everolimus seems to have benefits compared with single-agent endocrine therapy regardless of PIK3CA mutation status. Both alpelisib and everolimus improve progression-free survival [PFS] when added to endocrine therapy compared with single-agent endocrine therapy, and neither improve overall survival.

In the beginning, everolimus was challenging for us to utilize because stomatitis was a real problem. Now we use prophylactic steroid mouthwash, and it’s much easier for patients. Alpelisib has been challenging due to the diarrhea, rash, and hyperglycemia we see with this agent, requiring patients to have antidiarrheals on hand at home, use prophylactic antihistamines, and closely monitor their glucose…. It’s not a user-friendly agent. In my practice, I’m very careful with patient selection.

There was an interesting poster presented as a discussion for the METALLICA clinical trial, looking at the use of metformin concurrently with alpelisib in patients who are going to be starting it and who had tumor PIK3CA mutations. It met its primary end point in this trial, showing that fewer patients who used prophylactic metformin developed hyperglycemia. In cohort A, 2% of patients had grade 3/4 hyperglycemia; in cohort B, only 15% of patients. Cohort A was patients who had normal fasting glycemia and an HbA1C [glycosylated hemoglobin] of less than 5.7%; cohort B was higher-risk patients. The AE profile seemed to be reasonable when using metformin prophylactically. This provides us an agent, prophylactically, to help us reduce the risk of hyperglycemia in patients starting alpelisib.

One of the most exciting presentations at San Antonio [Breast Cancer Symposium] was the CAPItello-291 clinical trial. It was a phase 3 clinical trial in which patients who had up to 2 prior lines of endocrine therapy in the advanced-disease setting and up to a line of chemotherapy were enrolled. They received capivasertib and a pan-AKT inhibitor in combination with fulvestrant or fulvestrant with placebo. Patients were allowed if they had an HbA1C of less than 8%, so they had a lower risk of hyperglycemia. The study met its primary end point, both in the overall population, demonstrating a significantly improved progression-free survival on the order of almost 4 months in the overall population and in patients who had an AKT pathway alteration. As an exploratory end point, patients who had no AKT pathway alteration also appeared to have a very similar benefit in terms of PFS. Looking at subgroups, even patients who have liver metastases or who previously used a CDK46 inhibitor appeared to benefit. Overall survival was not mature but was trending in the right direction.

One of the most notable things about this drug is the adverse effect profile, which compares quite favorably with alpelisib and even everolimus, with pretty low rates of grade 3/4 diarrhea or hyperglycemia. This agent may be available to us soon. The data were quite impressive, even more so because the outcomes were improved regardless of whether the tumor had an AKT pathway alteration.

Aditya Bardia, MD, MPH: Great point. Whenever we talk to a patient with metastatic breast cancer, it’s both efficacy and the adverse effect profile, the impact on quality of life.

In terms of alpelisib, we saw data from SOLAR-1, which led to the approval of alpelisib. But that trial didn’t include several patients with prior CDK4/6 inhibitor, which is what we use in the first-line setting. Sara, can you review any data, particularly related to the use of alpelisib in the post–CDK4/6 setting?

Sara A. Hurvitz, MD: This was an interesting study because it gave us evidence to support combining alpelisib with an aromatase inhibitor or fulvestrant, because SOLAR-1 was only with fulvestrant. As you said, it provided us data in the post–CDK4/6 inhibitor setting. An interesting analysis was presented at San Antonio looking at the proportion of patients…who had long-term disease control, which was defined as a 12-month or greater progression-free survival or very long-term disease control of at least 18 months’ progression-free survival. Cohort A showed that a quarter of patients achieved long-term disease control with alpelisib and endocrine therapy with the median PFS just over 2 years. That’s about 16% of patients or so who had very long-term disease control at least 18 months. That’s a sizable proportion of patients who did well for a fairly long time with alpelisib-based therapy.

Interestingly, they showed that patients who had long-term or very long-term disease control tended to have a better performance status—not at all surprising—and a lower BMI [body mass index], which may play into the hyperglycemia, the ability to stay on therapy, and maybe factors indicative of better long-term outcomes. They also had a longer time from their initial diagnosis to recurrence or relapse. Patients who have good prognostic indicators were the ones who seem to benefit longer term, which reflects or coincides a bit with the EMERALD data that Virginia presented, showing that patients who had good prognostic features and did well on a CDK4/6 inhibitor previously tend to do better long term. It was an interesting analysis.

Aditya Bardia, MD, MPH: It looks like we might have multiple agents in the second- and third-line space: novel ER [estrogen receptor] blockers, PROTAC, SERDs [selective estrogen receptor degraders], combination therapy with PIK3 kinase, AKT, and mTOR, and the option of continuing CDK46 blockade. Virginia, how do we select these different agents? In the patient example we’re talking about in the second-line setting, should we consider single-agent therapy or combination with these pathway inhibitors vs continuing CDK46? How do you envision we’ll be using these agents in the next year or 2?

Virginia Kaklamani, MD: This used to be a very simple question to answer, but now it’s complicated. Based on the data we have available, here’s what I would do. If a patient has been on a CDK46 inhibitor for at least 12 months, then I’d check ESR1 mutation status. If they have a tumor with ESR1 mutation, then I’d give them our SERD with elacestrant. If they don’t have an ESR1 mutation, then the question is what combination therapy should we be giving? Based on the CAPItello data—I’m assuming capivasertib is going to make it to market pretty soon—I’d favor capivasertib. The interesting part of the data is that you don’t need a PIK3CA mutation to get a benefit. I don’t even know if we need to do PIK3CA testing anymore. If a patient’s cancer progresses within those 12 months, this looks like it’s endocrine resistant. We have to make a decision to give doublet again with capivasertib or move on to chemotherapy.

Aditya Bardia, MD, MPH: It needs to be the right drug for the right patient. If it’s completely endocrine resistant, there’s no point in giving endocrine therapy. Maybe we should look at other options.

Transcript edited for clarity.