Patients with estrogen receptor–positive, HER2-negative metastatic breast cancer now have a new medication option that extends survival, according to an ASCO rapid guideline update.1 The update was designed to orient clinicians to outcomes from the CAPItello-291 trial, which led to the U.S. Food and Drug Administration approval of capivasertib, and to provide insight into how the trial’s findings may affect clinical decision-making, particularly for patients whose tumors harbor certain genetic alterations in the AKT pathway.2,3
“One of the really important things that’s evolving in this area of treatment is the use of molecular diagnostics to figure out which tumors, and therefore which patients, require different therapies,” said Expert Panel Co-Chair Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute. “With this particular update, we focused on the molecular testing for PI3 kinase mutations, AKT1 mutations, and PTEN loss mutations, all of which make one a potential candidate for capivasertib.”
Harold J. Burstein, MD, PhD
New Drug Discovery
The phase III CAPItello-291 trial randomly assigned women or men with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer to either capivasertib plus fulvestrant (355 patients) or placebo plus fulvestrant (353 patients).2 Patients underwent next-generation sequencing to assess the presence of tumor mutations involved in the AKT pathway, including PIK3CA, ESR1, AKT1, and PTEN alterations. The AKT pathway has been implicated in treatment failure in breast cancer, and mutations in AKT pathway signaling are prevalent in hormone receptor–positive disease.4
Findings showed median progression-free survival was significantly longer with capivasertib in the overall population (7.2 vs 3.6 months; P < .001) and in a subset of patients whose tumors had AKT pathway alterations (7.3 vs 3.1 months; P < .001). This led the guideline’s Expert Panel to recommend routine testing for AKT pathway alterations and, for patients who exhibit them, consideration of capivasertib.
“The change from the prior rapid update is that we now have to think about more genes than we did before,” said Expert Panel Co-Chair N. Lynn Henry, MD, PhD, FASCO, FACP, of the University of Michigan.
Previously, she said, clinicians typically focused on PI3 kinase or PIK3CA as well as ESR1, because of the availability of two drugs that are targeted toward specific changes in those genes. “With capivasertib, it expands our treatment a little bit because it targets AKT pathway alterations, which include potential changes in three different genes,” Dr. Henry added.
N. Lynn Henry, MD, PhD, FASCO, FACP
Angela DeMichele, MD, MSCE, FASCO
The approval of capivasertib also presents a conundrum for clinicians. Patients whose tumors have activating mutations in PIK3CA now have two drug options—capivasertib or alpelisib. Given the absence of head-to-head trials for these therapies, the guideline update offers clinicians recommendations to support treatment selection, such as consideration of each drug’s slightly different side-effect profile.
“That’s why expert opinion ends up being very important here,” said Expert Panel Co-Chair Angela DeMichele, MD, MSCE, FASCO, of Penn Medicine. “We don’t have data on optimal sequencing in the first, second, and third line, and we don’t have data on head-to-head comparison for drugs that are targeting PIK3CA pathway alterations. That’s where an expert guideline comes in—when you don’t have that kind of feedback.”
Expanding the Treatment Paradigm
Despite the guideline not being able to address questions about treatment selection and sequencing, it serves an important role in potentially increasing the uptake of genomic biomarker testing by clinicians in making treatment decisions—something that Dr. DeMichele noted has been variable. “It’s been an evolution,” she said. “For a long time, we were saying there’s no role for this type of testing because we didn’t have evidence that utilizing the testing to assign therapy would be beneficial. Now we do, so now we need to say, ‘We think it’s okay, and in fact it’s preferable, to embrace this testing.’”
Dr. Burstein added that clinicians treating disease in patients with these types of breast cancer need to perform genomic sequencing on their tumors both early and often to determine whether targetable mutations are present. “Genomic sequencing also needs to occur serially—typically with liquid biopsy—because increasing data suggest that as tumors become treatment-resistant, they acquire novel mutations, and in some cases, those mutations can be targeted,” he added.
However, many questions surround the use of capivasertib in conjunction with biomarker genomic testing. For instance, Dr. Henry noted that data on long-term survival outcomes from CAPItello-291 are needed. It also remains unknown whether the drug influences the activity of tumors other than those that harbor AKT pathway mutations. Additionally, clinical trials are underway, such as CAPItello-292 (ClinicalTrials.gov identifier NCT04862663), to help untangle the effects of combining AKT pathway–inhibitor drugs like capivasertib with CDK4/6 inhibitors.
Nevertheless, the Expert Panel Co-Chairs are hopeful the guideline update will help open the door to more treatment options while expanding clinicians’ approach to treatment decision-making. “The guideline update provides very important information about capivasertib, which is a new drug that most practicing clinicians do not have any experience with. That, in and of itself, will change treatment and ultimately outcomes,” Dr. DeMichele said. “But I think the greater goal here was really to make sure people are thinking about how the treatment paradigm is changing—not just how do you apply this one new drug, but how does this drug fit into an evolving treatment paradigm.”
REFERENCES
1. Burstein HJ, et al: Endocrine and targeted therapy for HR-positive, HER2-negative metastatic breast cancer: Capivasertib-fulvestrant: ASCO Rapid Recommendation Update. J Clin Oncol. March 13, 2024. Available at https://ascopubs.org/doi/10.1200/JCO.24.00248. Accessed March 29, 2024.
2. Turner NC, et al; CAPItello-291 Study Group: Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med 388:2058-2070, 2023.
3. U.S. Food and Drug Administration: FDA approves capivasertib with fulvestrant for breast cancer. November 16, 2023. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer. Accessed March 29, 2024.
4. Cerma K, et al: Targeting PI3K/AKT/mTOR pathway in breast cancer. Biomedicines 11:109, 2023.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, March 15, 2024. All rights reserved.
