CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 27, 2023
Expiration: July 26, 2024
Combining Targeted and Antiestrogen Therapies to Overcome Resistance in HR+ Advanced 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—and perhaps the most important—pathway that leads to resistance not only to endocrine therapy (ET), but also to targeted therapies and chemotherapy.1 Mutations in PIK3CA and AKT1 and loss of PTEN can activate this pathway in breast cancer.2
In HR-positive breast cancer, the PI3K/AKT pathway also directly phosphorylates the estrogen receptor (ER) and can enhance transcription involving the ER.3,4 Therefore, dual blockade of both the ER and the PI3K/AKT pathway is essential for shutting down these 2 collaborating and driving mechanisms of breast cancer growth and metastasis, as well as treatment resistance. If you block only the ER or the PI3K/AKT pathway, it is very clear preclinically that the cancer cells can rewire and use the alternative pathway—ER or PI3K/AKT—to escape blockade of the other.
Frequency of PI3K/AKT/mTOR Pathway Alterations in Breast Cancer
This pathway is very commonly altered in breast cancer, both in primary breast cancers and in the metastatic setting. Searching for genomic alterations in circulating tumor DNA (ctDNA) in patients with metastatic disease under the selective pressure of prior therapies can lead to the emergence of PTEN loss, whereas PIK3CA and AKT mutations are generally foundational mutations present early in breast carcinogenesis. PIK3CA mutations are the most common—up to 45% in some series in HR-positive breast cancer.5 In triple-negative breast cancer (TNBC), PIK3CA mutations occur in approximately 10% to 15% of patients and tend to be part of the luminal androgen receptor–positive subtype.6-9 They tend to be relatively stable.
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.6 These are very important activating mutations that drive resistance to therapy and promote growth and proliferation.2 AKT mutations can be acquired in the metastatic setting but are generally present in primary breast cancer.
PTEN is a very important phosphatase. It is a tumor suppressor that dampens signaling throughout the PI3K/AKT/mTOR pathway,2 and when that very important phosphatase is lost, you have enhanced activation of the PI3K/AKT pathway.
PTEN loss is identified in approximately 5% of primary HR-positive/HER2-negative breast cancers.6 It can be acquired, and it is enriched more in metastatic breast cancer. It can be found in ctDNA, although genomic deletions and loss of heterozygosity can be more challenging to ascertain on ctDNA.10 PTEN loss is the most common mechanism of activation of the PI3K/AKT pathway in TNBC, occurring in at least 25% of patients.5 So, this is a very common alteration leading to activation of the PI3K/AKT pathway.
Although these alterations can be found in the primary breast cancer setting, they also can be acquired or at least come to clinical fruition in the metastatic setting.6 Even if not found on next-generation sequencing (NGS) of primary breast cancer, they can be identified in metastatic tissue or on ctDNA.
Select Investigational ATP-Competitive AKT Inhibitors
Two AKT inhibitors—capivasertib and ipatasertib—have been in clinical development. These are ATP-competitive AKT inhibitors that inhibit AKT1, AKT2, and AKT3.5 The IC50 for these agents is in the low nanomolar range, and they are both oral agents with different schedules. Ipatasertib is given as ≥200 mg once daily for 21 days of a 28-day cycle, and capivasertib is given as 400 mg twice daily for 4 days on and 3 days off.11,12 The 3 days off with capivasertib is to allow for recovery from toxicity, which will be discussed.
Approach to Therapy for HR+/HER2- Metastatic Breast Cancer: Move to Personalization
We are looking forward to FDA approval of fulvestrant and capivasertib in patients with HR-positive/HER2-negative metastatic breast cancer that has progressed on first-line AI plus CDK4/6 inhibitor therapy. As we will discuss, the CAPItello-291 trial has shown substantial improvement in PFS with the addition of capivasertib to fulvestrant in patients with progression on AI plus CDK4/6 inhibitor therapy.13 We are hopeful that this is going to soon become an important second-line option for patients post progression on a CDK4/6 inhibitor.
NCI-MATCH EAY131-Y Trial: Capivasertib in AKT1 E17K‒Mutated Tumors
Among AKT1 mutations, E17K is the most common activating mutation in breast cancer and numerous other malignancies. The oral AKT inhibitor capivasertib has been evaluated as a single agent in AKT1 E17K‒mutant breast and gynecologic cancers, among others, in an early basket trial and has considerable activity as a single agent. This waterfall plot shows capivasertib reducing cancer burden in breast, endometrial, and other cancers.14 Again, however, in HR-positive breast cancer, to prevent breast cancer from being able to escape through the ER, it is important to pursue dual inhibition of both ER and the AKT1-activating mutation.
FAKTION: Capivasertib + FULV vs Placebo + FULV in AI-Resistant, HR+/HER2- Advanced Breast Cancer
Let's review some of the data that support the anticipated FDA approval of capivasertib. The FAKTION trial was a randomized, proof-of-concept phase II trial including patients who were resistant to AI but who had not received a previous CDK4/6 inhibitor.15 They were randomized to receive fulvestrant plus placebo or fulvestrant plus capivasertib at 400 mg twice daily for 4 days on and 3 days off. This was an all-comers trial in patients with HR-positive/HER2-negative disease after progression on AI therapy. The primary endpoint was investigator-assessed PFS in the intention-to-treat (ITT) population.
FAKTION: Updated PFS and Mature OS in ITT Population
The primary endpoint was met in the ITT population, with the PFS more than doubling with the addition of capivasertib to fulvestrant—from 4.8 to 10.3 months—and very highly significant with a hazard ratio of 0.56. There was also a significant improvement of approximately 6 months in overall survival (OS) with capivasertib—29.3 vs 23.4 months—with a hazard ratio of 0.66.15
FAKTION: PFS in Pathway-Altered vs Nonaltered Subgroups
Looking at PFS in patients in the PI3K/AKT/PTEN pathway‒altered vs nonaltered subgroups, the hazard ratio for PFS was 0.44, which was highly significant in patients in the pathway-altered subgroup. With regard to the nonaltered subgroup, there was a trend toward improvement in PFS, but this was not statistically significant.15
FAKTION: OS in Pathway-Altered vs Nonaltered Subgroups
Likewise, we see a very nice improvement in OS in the pathway-altered vs nonaltered subgroups with wild-type PI3K/AKT/PTEN, with a hazard ratio of 0.46, with the addition of capivasertib to fulvestrant. We see no difference, however, in OS in the nonaltered population.15 So, these are very intriguing data pointing us toward benefit with capivasertib in the pathway-altered subgroup.
CAPItello-291: Capivasertib + FULV vs Placebo + FULV in AI-Resistant, HR+/HER2- Advanced Breast Cancer
The FAKTION trial led to the randomized, definitive phase III study CAPItello-291, 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. Patients’ A1C had to be less than 8.0%. Patients could not have insulin-dependent diabetes, and they had to have tissue available for NGS from either the primary or the metastatic cancer. Again, there are dual primary endpoints of investigator-assessed PFS in the overall population and in those with an AKT pathway–altered breast cancer.13
CAPItello-291: Investigator-Assessed PFS
The primary endpoint of PFS in the overall population was highly significant, with a doubling from 3.6 to 7.2 months with the addition of capivasertib to fulvestrant, with a hazard ratio of 0.60, which was highly statistically significant. If we look at the other coprimary endpoint—PFS in the pathway-altered subgroup—we also see more than a doubling of PFS from 3.1 to 7.3 months, with a hazard ratio of 0.5, with the addition of capivasertib.13 These results are very impressive.
Looking at the curves, you can see a dramatic fall in the first couple of months, with approximately 50% of patients having rapid disease progression with fulvestrant alone. That decreased to fewer than 20% of patients having progression at their first scan with the addition of capivasertib, which is overcoming the resistance to ET and to CDK4/6 inhibitor therapy.13
CAPItello-291: OS
Overall survival was encouraging both in the overall population and in the AKT pathway–altered population, as you can see here.
However, these data are immature, with only 28% of the survival events having occurred to date.13
CAPItello-291: AEs in >10% of Overall Population
With regard to overall safety, capivasertib is administered for 4 days on, followed by 3 days off, which allows for recovery from toxicity. So, 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. The main toxicities included diarrhea, with 72.4% of patients having any-grade diarrhea. Fortunately, grade 3 diarrhea occurred in fewer than 10% of patients. Nausea and vomiting also were more common toxicities, occurring in approximately 20% to 34% of patients. Rash occurred in 38% of patients and was treatment limiting in some, although the incidence of grade 3 or higher rash was low at 12.1%. Hyperglycemia occurred in only 16.3% of patients, with only 2% with grade 3 or higher.13 Patients with obesity or a history of diabetes at baseline tended to have more issues with toxicity related to hyperglycemia.16 However, it was very much less than what we see with the inhibition of PI3K with alpelisib.
CAPItello-291: Characterization and Management of AEs
We now have more information about these key treatment-limiting toxicities, including diarrhea, rash, and hyperglycemia, from the 2023 American Society of Clinical Oncology Annual Meeting, with regard to the number of patients who required intervention and the management of these toxicities with supportive medications. So, for diarrhea, which occurred at any grade in 72.4% of patients receiving capivasertib, 42.5% did require therapy to manage, mostly with loperamide (38.0%).16
Rash occurred in 38% of patients, and only 7.9% required a systemic corticosteroid, 18% a topical corticosteroid, and 21.1% an antihistamine. So, it was the minority of patients who required actual supportive medication management. Hyperglycemia of any grade again occurred in 16.3% of patients, and only 5.1% of patients required metformin and 2.8% insulin.16 Again, it was only a minority of patients who required supportive therapy to manage AEs, and this is because the 3 days off leads to pretty rapid improvement in these toxicities. The AEs were really quite manageable. We look forward to the anticipated FDA approval of capivasertib in combination with fulvestrant for our patients with HR-positive/HER2-negative metastatic breast cancer whose disease progressed on a CDK4/6 inhibitor.
We do not know whether the approval will be in the ITT population of all-comers, as seen in CAPItello-291, or whether it will be in the approximately 40% of patients on CAPItello-291 with an activating mutation in PIK3CA/AKT1 or genomic loss of PTEN.13 Regardless, we look forward to deploying this very important agent in practice.
IPATunity130 Cohort B: Ipatasertib + Paclitaxel for PIK3CA/AKT1/PTEN-Altered HR+/HER2- Advanced Breast Cancer
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 weekly paclitaxel with ipatasertib 400 mg once daily for 21 days of a 28-day cycle, with a primary endpoint of PFS.17
IPATunity130 Cohort B: PFS and Safety
Unfortunately, cohort B of the IPATunity130 trial was a negative study with ipatasertib, with no difference in the primary endpoint of PFS,17 and it is unclear as to why this was found in this AKT pathway–altered population. There has been speculation 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 cancer to escape via the ER. So, that potentially could have contributed to the resulting negative trial.
Select Ongoing Trials in HR+/HER2- Metastatic Breast Cancer
Several other important trials of AKT inhibitors in HR-positive/HER2-negative metastatic breast cancer are ongoing. There is an important signal-seeking, randomized phase II study (NCT05720260) evaluating a control arm of goserelin and fulvestrant in premenopausal patients with metastatic breast cancer whose disease has progressed on prior ET compared with goserelin, fulvestrant, and capivasertib vs goserelin, fulvestrant, capivasertib, and durvalumab vs goserelin, fulvestrant, and durvalumab. This is an important signal-finding trial.
The phase III CAPItello-292 trial (NCT04862663) is currently enrolling. This trial includes patients who have had prior ET with tamoxifen or an AI, who are randomized to receive fulvestrant and palbociclib plus placebo or fulvestrant and palbociclib plus capivasertib. So, this trial is evaluating a triplet regimen in patients whose breast cancer has recurred on adjuvant AI therapy or progressed in the metastatic setting on AI therapy.
We await results of the IPATunity150 trial (NCT04060862), which has completed enrollment. This trial is evaluating fulvestrant and palbociclib plus placebo vs fulvestrant and palbociclib plus ipatasertib, which is very similar to CAPItello-292. These patients will have had no previous treatment with fulvestrant, any inhibitor of the PI3K pathway, or a CDK4/6 inhibitor.
Lastly, the phase III FINER trial (NCT04650581) is evaluating fulvestrant alone vs fulvestrant plus ipatasertib following progression on first-line CDK4/6 inhibitor plus AI therapy.
Phase II Trials of AKT Inhibitors Combined With Paclitaxel for First-line Metastatic TNBC
There were 2 randomized phase II trials of AKT inhibitors in TNBC—capivasertib was evaluated in the PACT trial18 and ipatasertib in the LOTUS trial.19 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. Shown here is the subset of patients with a genomic alteration of PI3K/AKT or loss of PTEN, hence the small numbers.
As you can see in both studies, there was a very impressive signal of activity with the addition of the AKT inhibitors to paclitaxel regarding PFS in the pathway-altered populations.18,19 Very, very intriguing. So, these data led to the conduct of the IPATunity130 trial.
IPATunity130 Cohort A: Ipatasertib + Paclitaxel for First-line Advanced TNBC
Cohort A of the phase III IPATunity130 trial randomized patients with metastatic TNBC in the first-line setting to receive paclitaxel plus placebo or paclitaxel plus ipatasertib. This trial included only patients with a known activating alteration in PIK3CA/AKT1/PTEN.20
IPATunity130 Cohort A: PFS and Safety
Unfortunately, this was a negative study.20 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.
CAPItello-290: Capivasertib + Paclitaxel vs Placebo + Paclitaxel for First-line Metastatic TNBC
We await results of the CAPItello-290 trial (NCT03997123), which is evaluating paclitaxel plus placebo vs paclitaxel plus capivasertib in the first-line setting for metastatic TNBC. We are very much looking forward to the results of this trial in metastatic TNBC, both in the ITT and AKT pathway–altered populations, because there is a great unmet need in TNBC to overcome resistance to chemotherapy, as well as, potentially, resistance to immune checkpoint inhibitor therapy.
Summary
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. The question remains whether an approval will be in unselected patients or limited to those with PI3K/AKT/mTOR pathway alterations. If the approval is only for patients with pathway alterations, then we will need to determine how best to identify these alterations. Do we evaluate tissue or ctDNA? If we use tissue, do we use primary 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 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 mutation 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.
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