Examining the Evolution of Treatment With Targeted Agents in Metastatic Breast Cancer

The AKT inhibitor capivasertib (Truqap), studied in the phase 3 CAPItello-291 trial (NCT04305496) in combination with fulvestrant (Faslodex), is one of the more recent targeted agents to have been granted regulatory approval by the FDA for the treatment of hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN mutations, adding to the growing arsenal of treatment options for this patient population.¹

In addition to capivasertib, other inhibitors that are currently FDA approved for the treatment of metastatic breast cancer following progression on endocrine therapy include elacestrant (Orserdu) for the treatment of estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated disease and alpelisib (Piqray) plus fulvestrant for HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic disease. Because of this continually growing treatment landscape, combination therapies are at the forefront of clinical investigations.^2,3

“It’s an interesting space right now in breast cancer where there are a lot of new agents in the ER-positive/HER2-negative metastatic setting, starting with CDK4/6 inhibitors that were all approved around 2017. However, with newer agents that are coming to market, [there are] questions on how to best sequence them,” Anne Favret, MD, said following an OncLive State of the Science Summit™ on breast and lung cancer, which she cochaired with Samantha DiBenedetto, MD. “Overall, [combination therapies] are an exciting area for breast cancer [research] and, as always, look to a clinical trial for patient treatment.”

Inavolisib plus palbociclib (Ibrance) and fulvestrant is a triplet therapy that has shown promise in the first-line treatment of patients with advanced HR-positive, HER2-negative breast cancer and a PIK3CA mutation. Inavolisib’s manufacturer, Genentech, announced in a December 2023 press release that treatment with the triplet significantly improved progression-free survival vs palbociclib and fulvestrant alone in the phase 3 INAVO120 trial (NCT04191499). Overall survival data were immature, and Genentech reported that data will be shared at an upcoming medical meeting.⁴

In an interview with OncLive, Favret expanded on the evolution of treatment with endocrine-based combination therapies in HR-positive/HER2-negative metastatic breast cancer, highlighted how she typically approaches combination treatments within this landscape, and discussed notable ongoing trials regarding combination treatments. Favret is a medical oncologist at Virginia Cancer Specialists, The US Oncology Network.

OncLive: What combinations do you commonly use to treat patients in this population?

Favret: I start with a CDK4/6 inhibitor and there are 3 that are currently in the market: palbociclib, ribociclib [Kisqali], and abemaciclib [Verzenio]. They are paired with an endocrine backbone, either an aromatase inhibitor or fulvestrant. Which one you pick has to do with the adverse effect profile. Abemaciclib is often associated with diarrhea, and palbociclib is often [associated with] cytopenias, [so] we pick based on that. Overall, a CDK4/6 inhibitor is almost definitely going to be the first-line treatment.

Are there any other combinations under evaluation in clinical trials that are showing promise in this space?

After the use of a first-line CDK4/6 inhibitor, it’s now standard of care to receive next-generation sequencing. Elacestrant is currently FDA approved for individuals with an ESR1 mutation, and alpelisib is for patients whose [disease] is PIK3CA mutated.

However, capivasertib is new to the market [and was evaluated in] the phase 3 CAPItello-291 trial for individuals who have AKT1, PTEN, or PIK3CA mutations. That’s a new and exciting drug. In addition, there’s a first-line trial looking at inavolisib, which is an oral drug, being paired with a CDK4/6 inhibitor. This has shown a lot of promise and a recent clinical trial. We’re [also] looking at oral selective ER degraders as an area of interest.

What next steps are needed for combination regimens in this setting to improve outcomes for patients?

We’re seeing [triplet therapies, and] the [INAVO120 trial] is [examining] a triplet. I believe that the arena we’re going into is more targeted [therapy focused], using mutational status to help guide better treatment and looking for drugs that are more tolerable. The combination [should be] promoting efficacy and also be well tolerated. In the metastatic setting, it’s a marathon, not a sprint, and a lot of individuals will be on these drugs for years. We want to make sure their quality of life is excellent. [Safety] does differ from regimen to regimen, and the toxicity profile is part of how we try to decide the next move.

What are some notable advancements in the HER2-positive breast cancer space?

Some of the notable advancements are drugs that are crossing the blood-brain barrier. The old stalwart trastuzumab [Herceptin] did not cross the blood-brain barrier particularly well. Now, we have the antibody-drug conjugate [ADC] fam-trastuzumab deruxtecan-nxki [Enhertu] that does. Tucatinib [Tukysa], which is an oral drug, also crosses the blood-brain barrier. That’s an exciting new space but [is] also something which could use more exploration.

Are there any research initiatives in the metastatic breast cancer space that are important to highlight?

At [my institution], we have a whole plethora of clinical trials. We have some ADC trials, including a sacituzumab govitecan-hziy [Trodelvy] trial. We also have a new ADC in ER-positive/HER2-low breast cancer that’s a brand-new drug vs investigator’s choice of therapy; the trial is run out of the Sarah Cannon Research Institute. We have a host [of trials], and I was just looking for a trial for a patient who progressed on a CDK4/6 inhibitor, [which made me think] we almost have too many options.

References

1. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer
2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer
3. FDA approves alpelisib for metastatic breast cancer. FDA. Updated May 28, 2019. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer
4. Genentech announces positive phase III results for inavolisib combination in people with advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. News release. December 4, 2023. Accessed April 10, 2024. https://www.gene.com/media/press-releases/15011/2023-12-04/genentech-announces-positive-phase-iii-r