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AKT Inhibitors in MBC
My Thoughts on the Potential of AKT Inhibitors in Metastatic Breast Cancer

Released: August 15, 2023

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Key Takeaways
  • AKT inhibitors target a key pathway involved in breast cancer growth and metastasis, as well as resistance to multiple treatments, including endocrine therapy.
  • The approval of the investigational AKT inhibitor, capivasertib, in combination with fulvestrant, is anticipated in patients with hormone receptor–positive metastatic breast cancer after progression on an aromatase inhibitor plus a CDK4/6 inhibitor.

What is the rationale for targeting AKT in metastatic breast cancer?

The PI3K/AKT/mTOR pathway is a key pathway to target in breast cancer, particularly in the metastatic setting, because it is a very common pathway that leads to resistance not only to endocrine therapy (ET), but also to targeted therapies and chemotherapy. Mutations in PIK3CA and AKT1 and loss of PTEN can activate this pathway in breast cancer. In hormone receptor (HR)–positive breast cancer, the PI3K/AKT pathway also directly phosphorylates the estrogen receptor (ER) and can enhance ER-driven transcription. Therefore, dual blockade of both the ER and the PI3K/AKT pathway is essential for inhibiting these 2 collaborating and dominant mechanisms of breast cancer growth and metastasis, as well as treatment resistance. If you block only one of these pathways, it is clear from preclinical studies that the cancer cells can rewire to then use the alternative pathway—ER or PI3K/AKT—to escape blockade of the other.

This pathway is very commonly altered in breast cancer, both in primary breast cancers and in the metastatic setting. PIK3CA mutations are the most common—up to 45% in some series in HR-positive breast cancer. AKT mutations are less common, with some series reporting AKT1 mutations in approximately 3% of primary and 7% of metastatic HR-positive/HER2-negative breast cancers. These are very important activating mutations that drive resistance to therapy and promote growth and proliferation. The phosphatase PTEN is a tumor suppressor protein that dampens signaling through the PI3K/AKT/mTOR pathway, and when this important phosphatase is lost, it leads to enhanced activation of the pathway. PTEN loss is identified in approximately 5% of primary HR-positive/HER2-negative breast cancers, and it is the most common mechanism of activation of the PI3K/AKT pathway in triple-negative breast cancer (TNBC), occurring in at least 25% of patients.

What are the current data on the use of investigational AKT inhibitors in metastatic breast cancer?

Two oral AKT inhibitors, capivasertib and ipatasertib, have been in clinical development. These are ATP-competitive AKT inhibitors that inhibit AKT1, AKT2, and AKT3.

The AKT inhibitor capivasertib has shown the most promise to date in patients with HR-positive/HER2-negative metastatic breast cancer. The phase II FAKTION trial randomized patients who were resistant to an aromatase inhibitor (AI) but who had not received a previous CDK4/6 inhibitor to fulvestrant plus placebo or fulvestrant plus capivasertib at 400 mg twice daily for 4 days on and 3 days off. The primary endpoint of investigator-assessed progression-free survival (PFS) in the intention-to-treat population was met, with the median PFS more than doubling with the addition of capivasertib to fulvestrant—from 4.8 to 10.3 months. There was also a significant improvement of approximately 6 months in median overall survival (OS) with capivasertib—29.3 vs 23.4 months. Looking at the PFS in patients in the PI3K/AKT/PTEN pathway‒altered vs nonaltered subgroups, there was a highly significant improvement in the pathway-altered patients, and a nonsignificant trend toward improved PFS with capivasertib in the nonaltered subgroup. The same was observed for the OS, with a significant benefit with capivasertib in the pathway-altered cohort, and no difference in the nonaltered subgroup. So, these are very intriguing data pointing us toward benefit with capivasertib in the AKT pathway-altered subgroup.

The FAKTION trial led to the randomized, definitive phase III CAPItello-291 study, which included patients who could have received previous CDK4/6 inhibitor therapy. In fact, 70% of the patients coming onto this trial had had disease progression on an AI plus CDK4/6 inhibitor. The coprimary endpoint of PFS in the overall population was statistically significantly positive, with a doubling of median PFS from 3.6 to 7.2 months with the addition of capivasertib to fulvestrant, with a hazard ratio of 0.60. If we look at the other coprimary endpoint—PFS in the pathway-altered subgroup—we also see more than a doubling of median PFS with the addition of capivasertib from 3.1 to 7.3 months, with a hazard ratio of 0.5. These results are very impressive. Overall survival was encouraging both in the overall population and in the AKT pathway–altered population. However, these data are immature, with only 28% of the survival events having occurred to date.

What about AKT inhibitors in combination with chemotherapy in HR-positive/HER2-negative metastatic breast cancer? Cohort B of the IPATunity130 trial included patients with HR-positive/HER2-negative metastatic breast cancer with PIK3CA/AKT1/PTEN alterations whose disease had become resistant to ET or who were in visceral crisis. Previous treatment with CDK4/6 and PI3K/mTOR inhibitors was permitted. Patients were randomized to receive weekly paclitaxel plus placebo or ipatasertib 400 mg once daily for 21 days of a 28-day cycle, with a primary endpoint of PFS. Unfortunately, the results in the cohort B population of IPATunity130 were negative, with no difference in the primary endpoint of PFS with the addition of ipatasertib to paclitaxel. This was a surprising result in this AKT pathway–altered population. One hypothesis is that perhaps because the ER was not inhibited, it was an opportunity for the cancer to upregulate and signal through ER, which can happen when you block the PI3K/AKT pathway, allowing the growth and survival escape via the ER.

Ongoing phase III trials of AKT inhibitors in HR-positive metastatic breast cancer include CAPItello-292 (NCT04862663), which randomizes to fulvestrant and palbociclib plus capivasertib vs fulvestrant and palbociclib plus placebo in patients who have had prior ET with tamoxifen or an AI; IPATunity150 (NCT04060862), which evaluates fulvestrant and palbociclib plus ipatasertib vs fulvestrant and palbociclib plus placebo (completed enrollment and we await results); and FINER (NCT04650581), which is evaluating fulvestrant alone vs fulvestrant plus ipatasertib following progression on first-line CDK4/6 inhibitor plus AI therapy.

In TNBC, there were 2 randomized phase II trials of AKT inhibitors—capivasertib was evaluated in the PACT trial and ipatasertib in the LOTUS trial. In these trials in first-line metastatic TNBC, paclitaxel plus placebo was compared with paclitaxel plus the AKT inhibitor. Both studies included all-comers, regardless of the presence of an alteration in the PI3K/AKT pathway. In both studies, there was a very impressive signal of activity with the addition of the AKT inhibitor to paclitaxel regarding PFS in the pathway-altered populations. These data led to the conduct of the phase III IPATunity130 trial.

Cohort A of IPATunity130 randomized patients with metastatic TNBC in the first-line setting to receive paclitaxel plus placebo or ipatasertib. This trial included only patients with a known activating alteration in PIK3CA/AKT1/PTEN. Unfortunately, this was a negative study. Metastatic TNBC is a very heterogeneous population, and although this group of patients was selected for activation of the PI3K/AKT pathway, this is a very genomically complex breast cancer, with potential heterogeneity around activation of other pathways, as well. So unfortunately, it was a negative trial in patients with TNBC.

We are very much looking forward to the results of CAPItello-290 (NCT03997123), which is evaluating paclitaxel plus capivasertib in the first-line setting for metastatic TNBC patients. There is a great unmet need in TNBC to overcome resistance to chemotherapy as well as, potentially, resistance to immune checkpoint inhibitor therapy.

What adverse events (AEs) are expected with AKT inhibitors and how are they managed?

Neither AKT inhibitor is given continuously—capivasertib is administered for 4 days on, followed by 3 days off, and ipatasertib for 21 days on, followed by 7 days off—which allows for recovery from toxicity. In CAPItello-291, only 19.7% of patients required a dose reduction, and 13.0% of patients discontinued capivasertib because of AEs, which is not very high in this metastatic population.

Regarding toxicity, diarrhea is the most commonly observed AE with the addition of AKT inhibitors. Diarrhea was the main toxicity observed with capivasertib in CAPItello-291, with diarrhea of any grade occurring in 72.4%; fortunately, grade 3 diarrhea occurred in fewer than 10% of patients. Nausea and vomiting also were common toxicities, occurring in approximately 20% to 34% of patients. Rash occurred in 38.0% of patients and was treatment-limiting in some, with the incidence of grade 3 or higher rash at 12.1%. Hyperglycemia occurred in only 16.3% of patients, 2.0% grade 3 or higher. Patients with obesity or a history of diabetes at baseline tended to have a greater likelihood of developing hyperglycemia. However, it was considerably less than what we see with the inhibition of PI3K with alpelisib.

We now have more information about these key treatment-limiting toxicities—including diarrhea, rash, and hyperglycemia—from an update at the American Society of Clinical Oncology 2023 Annual Meeting, regarding the number of patients who required intervention and the management of these toxicities with supportive medications. For diarrhea with capivasertib, 42.5% did require therapy to manage it, mostly with loperamide (38.0%). For the management of rash, only 7.9% required a systemic corticosteroid, 18.0% a topical corticosteroid, and 21.1% an antihistamine. For the management of hyperglycemia, only 5.1% of patients required metformin and 2.8% insulin. So, it was the minority of patients who required actual supportive medication management, and this is because the 3 days off generally leads to rapid improvement in these toxicities. The AEs were overall quite manageable.

How would the approval of an AKT inhibitor impact your current clinical practice?

We anticipate the FDA approval of capivasertib plus fulvestrant in patients with HR-positive/HER2-negative metastatic breast cancer following progression on AI plus CDK4/6 inhibitor therapy. We are hopeful that this is going to soon become an important second-line option for patients post-progression on a CDK4/6 inhibitor. The question remains whether an approval will be in unselected patients or limited to those whose cancers contain an alteration in the PI3K/AKT/mTOR pathway. If the approval is focused on patients with pathway alterations, then we will need to determine how best to identify these alterations. Do we evaluate tissue or circulating tumor DNA (ctDNA)? If we use tissue, do we use primary or metastatic tissue? PIK3CA and AKT mutations are foundational; that is, they are found in the primary breast cancer and occur early in carcinogenesis. So, you can perform next-generation sequencing (NGS) on the primary cancer, but loss of PTEN is more commonly acquired in the metastatic setting. Having said that, I think it is important to perform NGS on the primary breast cancer, as well as a metastatic biopsy, and on ctDNA post-progression on first-line CDK4/6 inhibitor therapy, to get the most comprehensive picture of the targetable mutations in the patient’s cancer. This is potentially an area for further discussion, depending on the FDA labeling associated with the pending approval of capivasertib. Regardless, we look forward to deploying this very important agent in practice.

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