Leon-Ferre Explores Targeting of PIK3CA Alterations in ER+ Breast Cancer

Roberto A. Leon-Ferre, MD

Assistant Professor of Oncology

Consultant, Division of Medical Oncology, Department of Oncology

Mayo Clinic

Rochester, MN

PEERS & PERSPECTIVES IN ONCOLOGY: What impact does the HER2-low subtype of breast cancer have in the ER+ metastatic setting?

LEON-FERRE: The lines are getting blurrier in terms of subtypes of breast cancer. We don’t think HER2-low breast cancer is necessarily a distinct biological entity. By that, I mean it doesn’t necessarily have a distinct clinical behavior. It is a therapeutic entity because now we have these drugs that are approved… in the HER2-low setting and…if we look at the distribution of HER2-low expression—IHC 1+ or 2+ with FISH negative—across breast cancers, it is higher in the ER+ subtype. Up to 60% of all ER+, HER2-negative breast cancers would fit the HER2-low description, and approximately 40% of ER-negative, HER2-negative breast cancers would fit that HER2-low description. So, this is a substantial proportion of patients, as the HER2-negative category represents the vast majority of the overall breast cancer population—up to 70% of patients.¹

We’re also going to be looking at some of the targeted therapeutic options beyond HER2; particularly, we focus on PIK3CA alterations. In ER+ breast cancer particularly, these alterations are quite common. Depending on the series you look at, it can [reach] two-thirds of all patients in this particular setting.² When you look at the spectrum of all the alterations beyond PIK3CA, there’s also the AKT- and the PTEN-inactivating alterations, which are smaller slices of the pie but expand that proportion of patients with a PIK3CA alteration per the traditional definition.

What is important to know about the available targeted drugs for PIK3CA alterations?

Essentially, we have 2 drugs: alpelisib [Piqray] and capivasertib [Truqap]. These are both category 1 by the National Comprehensive Cancer Network guidelines,³ but there are some differences in the tolerability. I want to point out [that because capivasertib] is a newer drug, it has a bit of a different schedule—4 days on, 3 days off—so they get a longer weekend without the fever, but it’s given twice daily.⁴ Also remember that for alpelisib, the FDA approval is for PIK3CA-activating mutations, whereas capivasertib has the PTEN losses and the AKT1 alterations.⁵ [Almost] 15% of all those patients could benefit from it.²

What data support the use of capivasertib in patients with hormone receptor– positive, HER2-negative advanced breast cancer?

This is the phase 3 CAPItello study [NCT04305496] that enrolled patients with ER+ disease with 2 or fewer lines of endocrine therapy and 1 or fewer lines of chemotherapy for metastatic breast cancer. They allowed prior CDK4/6 inhibitors and required that the majority had received a CDK4/6 inhibitor. None of these patients received a prior selective [ER] degrader, mTOR inhibitor, or a PI3K inhibitor. There was a hemoglobin A1C requirement [of less than 8.0%], and patients were randomly assigned to capivasertib with fulvestrant [Faslodex] or placebo with fulvestrant.

[The dual primary end point was] progression-free survival [PFS] in the AKT pathway-altered population, patients who had an alteration in 1 of those 3 major molecular features. Capivasertib [had a median PFS of] 7.3 months and fulvestrant alone [had a median PFS of] 3.1 months [adjusted HR, 0.50; 95% CI, 0.38-0.65; 2-sided P < .001].⁶ The overall survival data are still trending for capivasertib, and the CI was approaching but not quite touching 1.0 in the overall population [adjusted HR, 0.74; 95% CI, 0.56-0.98]. Then if you look at the AKT-altered population, the numbers are smaller, so it didn’t quite meet statistical significance, but it’s still trending in favor of capivasertib compared with fulvestrant alone [adjusted HR, 0.69; 95% CI, 0.45-1.05].

What tolerability concerns are there with capivasertib?

Notably, if you look at hyperglycemia, there was only 16% all-grade hyperglycemia, which is a lot less than with alpelisib.^6,7 It has less hyperglycemia, but it has a bit more diarrhea—72% any grade, [although] most of them are grade 1 [Table⁶]. There were similar rates of rash and fatigue as well [38.0% and 20.8%, respectively, for capivasertib], but the main [benefit] here is the hyperglycemia that’s substantially less.

Can you summarize the outcomes of the phase 3 SOLAR-1 study (NCT02437318)?

The SOLAR-1 study is with alpelisib. Here, they [tested for] the PIK3CA alteration. The other alterations were not specifically called out; they just needed to have the PIK3CA status determined. They had 2 cohorts: 1 for the PIKC3A mutated and 1 for the nonmutant PIK3CA. All patients were randomly assigned to alpelisib or not, along with fulvestrant.

In this study, we saw a particularly [favorable PFS] benefit in the PIK3CA-altered tumors [HR, 0.65; 95% CI, 0.50-0.85; P < .001], but not so much in the PIK3CA wild-type population [HR, 0.85; 95% CI, 0.58-1.25; posterior probability of HR < 1.00; 79.4%].⁷

[In terms of adverse events], any-grade hyperglycemia occurred in 63.7% vs less than 20% with capivasertib. The rate of diarrhea was 60%, nausea was 45%, and then rash in 36%. I don’t think SOLAR-1 required an antihistamine, but rash is still a problem with both drugs.

Why was the FDA approval for capivasertib limited to patients with 1 or more PIK3CA/AKT1/PTEN alterations, though PFS benefit was observed in the overall population?^5,6

They concluded that most of the benefit was driven by the AKT-altered population based on the HR and the CI,⁵ but this was interesting because for other drugs, they’ve taken the approach of going to the intention-to-treat population unless they required the biomarker [to enroll in the study]. It’s a bit of an interesting decision.

How would you give capivasertib to a patient who received prior fulvestrant? Could it be given with an AI?

For this patient, we don’t have data—at least with capivasertib that I’m aware of—with an AI or post fulvestrant. There are data with alpelisib⁸ and some real-world data suggesting that you could combine it with an AI, but that’s a bit of an unknown, let alone with ESR1 alterations [and combining with] elacestrant [Orserdu]. If you have both, you go after the PIK3CA alteration. At least as of now, we can’t combine elacestrant with a targeted therapy. We don’t have data on that yet, but there are going to be some emerging.

REFERENCES:

1. Cancer stat facts: female breast cancer subtypes. National Cancer Institute. Accessed June 14, 2024. https://tinyurl.com/2jkrsstf

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. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2024. Accessed June 14, 2024. https://tinyurl.com/2khn5xtm

4. Truqap. Prescribing information. AstraZeneca; 2023. Accessed June 14, 2024. https://tinyurl.com/7uwrmm6c

5. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed June 14, 2024. https://tinyurl.com/bdfmyap2

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

7. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904

8. Jacobson A. Alpelisib plus fulvestrant or letrozole demonstrates sustained benefits across subgroups of patients with PIK3CA-mutated HR+/ HER2- advanced breast cancer. Oncologist. 2022;27(suppl 1):S13-S14. doi:10.1093/oncolo/oyac011