Brown-Glaberman Reviews Data for PIK3CA-Altered Metastatic Breast Cancer

Ursa Brown-Glaberman, MD

Associate Professor

Department of Internal Medicine

Division of Hematology/Oncology

University of New Mexico School of Medicine Albuquerque, NM

Peers & Perspectives in Oncology: What therapeutic options could be considered for this patient?

Brown-Glaberman: I think that those are all reasonable things to consider…. The National Comprehensive Cancer Network guidelines for targeted therapies and associated biomarker testing show that with PIK3CA activating mutations, there would be category 1 recommendation for fulvestrant plus alpelisib [Piqray] and fulvestrant plus capivasertib [Truqap].¹ The difference with capivasertib is that you can have the PIK3CA activating mutation but also AKT activating mutations or a mutation in PTEN. The vast majority are going to be PIK3CA mutations. If you have a patient with an alteration in this pathway, about 87% are going to have a PIK3CA mutation, 6% will have a PTEN inactivating alteration, and about 7% will have an AKT activating mutation.² I know we’re all testing for this.

Capivasertib…is the newer PIK3CA inhibitor. [The phase 3 CAPItello-291 trial (NCT04305496)] was for patients with metastatic breast cancer; they had to have had progression on [or after] the first line of endocrine therapy. They could have 2 or fewer lines of prior endocrine therapy and 1 or fewer lines of chemotherapy. They could have had capecitabine. This was not biomarker selected; this was for all comers, and then they were randomly assigned to capivasertib [or placebo]. I think the dosing schedule is important; [it was] 4 days on, 3 days off with fulvestrant vs placebo plus fulvestrant. The co–primary end points were progression-free survival [PFS] in the overall population, and then looking at PFS in patients with PIK3CA or AKT activations or PTEN alterations.

Is the on-off schedule of capivasertib challenging to use in practice?

I do worry about that. [Using a pill box organizer] is critical, and I think we can ask [the drug company] representatives [because] I know that they often put effort into marketing these with pill boxes so that people can set it up…. It is complicated, but [you can think of it as] Monday through Thursday. I’m sure that some pharmacokinetics data support this dosing.

Right now, we’re using Pillsy [smart pill] bottles where it records every time they take it. We all think our patients are way better [at adherence] than they are with all drugs. If you look at how many times they opened that bottle, it’s not as many times as we hope.

What were the outcomes of this trial, and how did it compare to the data for alpelisib?

In the overall population, the median PFS with capivasertib plus fulvestrant was 7.2 months vs 3.6 months with just fulvestrant [HR, 0.60; 95% CI, 0.51-0.71; 2-sided P < .001].3 In [patients with] an AKT-altered pathway, it was similar, 7.3 months vs 3.1 months, respectively [HR, 0.50; 95% CI, 0.38-0.65; 2-sided P < .001]. Looking at OS [overall survival], at the time of this analysis, it’s still pretty immature, but we are seeing a trend toward improved OS with the addition of capivasertib in this population [Table³].

The alternative PIK3CA inhibitor that we are all most familiar with is alpelisib. We participated in and had…the [phase 2] BYLieve trial [NCT03056755] open. The landscape was a little different then because CDK4/6 inhibitors were not standard care when these studies started. This is the closest comparison. [The phase 3 trial] SOLAR-1 [NCT02437318] was before patients got CDK4/6 inhibitors routinely. For [BYLieve], there were 3 cohorts, but cohort C is comparable to [CAPItello-291]; those patients got AI [aromatase inhibitors], CDK4/6, and then they got 1 line of chemotherapy. Cohort A is also patients who got CDK4/6 plus AI and then switched to alpelisib plus fulvestrant. Cohorts A and C are the most comparable. CAPItello-291 and SOLAR-1 are not comparable. The median PFS was 7.2 months with capivasertib, and then if you look at BYLieve cohort A, which is without chemotherapy, and then cohort C, who got 1 line of chemotherapy, they had 7.3 months and 5.6 months in terms of PFS, respectively.^4,5 We can’t make cross-trial comparisons, but this is just to show [similar populations].

Anyone who has used alpelisib knows that the hyperglycemia can be challenging. In terms of grade 3 hyperglycemia, it ranges between 23% and 36% with alpelisib vs 2.3% with capivasertib.^6,7 Rash, diarrhea, nausea, and fatigue were more comparable. It was grade 3 hyperglycemia that was clearly lower. Also, to compare these 2 drugs in terms of dosing schedule, alpelisib is every day vs 4 days on, 3 days off [with capivasertib]. You do need to watch for hyperglycemia with capivasertib plus fulvestrant, but you don’t see the severity that we have all seen with alpelisib. There are dose modification regimens for both drugs. I know these are not easy drugs to use.

If a patient had a partial response on one of the targeted drugs, would you use the other next?

I would not do that without some data. It’s the toxicity that would worry me; I think you might have a hard time [getting] the patient to tolerate that. In my practice, I was a believer in alpelisib, and I used it for a long time. If you get the person on the right dose and they do well, they could be on it for a very long time. I think it’s worth a try. I think that capivasertib is easier to use because the hyperglycemia is much less of an issue and I think that every patient is going to get hyperglycemia. In New Mexico, where a lot of our patients are prediabetic or diabetic to begin with, I do think it’s a much easier drug to use.

I generally tend to start people on an antihistamine because it really can prevent rash, and they’re very well tolerated. I usually start those at the same time for both drugs. I don’t use any other prophylaxis medicines. It’s important to see patients frequently until they stabilize and…do well.

People are gun-shy because a lot of people had [negative] experiences with alpelisib. If you have a PIK3CA mutation, you can give it a try. I think that you should; I agree with that practice. I think it’s not for everybody, but if you can get a patient on it, you can get a lot of mileage out of that. I try to maximize people’s time on [targeted] therapy. At times, they are effective, but you start to run out of options.

The other hard [question] is, what if they have PIK3CA and ESR1 mutation? Would you try elacestrant [Orserdu] vs capivasertib? I think there are data for both. I would tend to try to use the PIK3CA inhibitor at this point because the performance status is better, and this is a more toxic drug than elacestrant. A lot of us participated in [the phase 3 trial] EMERALD [NCT03778931], and that was a very late-line trial. I like that drug, and it’s well tolerated, so I tend to use it second because [when they have] a better performance status I’d like to try it earlier [PIK3CA inhibitor].

I don’t think there [are] wrong data either way. There are some data looking at patients still responding to elacestrant with a PIK3CA mutation.⁸

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2024. Accessed September 24, 2024. https://tinyurl.com/2khn5xtm

2. Cerma K, Piacentini F, Moscetti L, et al. Targeting PI3K/AKT/mTOR pathway in breast cancer: from biology to clinical challenges. Biomedicines. 2023;11(1):109. doi:10.3390/biomedicines11010109

3. Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Study Group. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131

4. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22(4):489-498. doi:10.1016/S1470-2045(21)00034-6

5. Chia S, Neven P, Ciruelos EM, et al. Alpelisib + endocrine therapy in patients with PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2–negative, advanced breast cancer: Analysis of all 3 cohorts of the BYLieve study. J Clin Oncol. 2023;41(suppl 16):1078.

6. Truqap. Prescribing information. AstraZeneca; 2023. Accessed September 24, 2024. https://tinyurl.com/7uwrmm6c

7. Piqray. Prescribing information. Novartis; 2023. Accessed September 24, 2024. https://tinyurl.com/mpndkb8y

8. Bardia A, O’Shaughnessy J, Bidard FC, et al. Elacestrant vs standard-of-care in ER+/HER2– advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract PS17-02.