AstraZeneca AKT inhibitor for HR-positive breast cancer phase 3 clinical trial reached the primary endpoint!

Breast cancer is the most common cancer in the world, of which more than 70% are HR-positive breast cancer, and endocrine therapy is an important treatment for
this part of the patient.
However, many patients with advanced disease develop resistance to CDK4/6 inhibitors and existing endocrine therapies, resulting in limited
treatment options.
At present, the five-year survival rate for patients with HR-positive/HER2-negative metastatic disease is still only 30%.

On October 26, AstraZeneca announced that its Phase III CAPItello-291 study of its Akt inhibitor capivasertib combined with fulvestrant in breast cancer patients has reached the primary endpoint or become a powerful "sniper"
for endocrine-resistant breast cancer.

Capivasertib plus fulvestrant (Faslodex) produced statistically and clinically significant improvements in progression-free survival (PFS) after recurrence or progression in patients with hormone receptor (HR)-positive, low or negative HER2, locally advanced, or metastatic breast cancer or with or without CDK4/6 inhibitors after endocrine therapy, preliminary results from the Phase 3 CAPItello-291 trial (NCT04305496) showed that The combination met the two primary endpoints
of PFS compared to fulvestrant alone, both in the general population and in a prespecified biomarker subgroup of patients whose tumors had PIK3CA, AKT1, or PTEN modifications.
Notably, patients with changes in PIK3CA, AKT1, or PTEN account for about 40% of
the total population.
While early data are encouraging, data for the key secondary endpoint of overall survival are premature
.

Potential "first-in-class"! A new option for endocrine-resistant breast cancer

The CAPItello-291 study is a global, multicenter, double-blind, randomized phase III clinical trial to evaluate the efficacy and safety of capivasertib plus fulvestrant in patients with HR-positive, HER2-low-expressing or negative breast cancer who have relapsed or progressed during or after aromatase inhibitor therapy, with or without CDK4/6 inhibitors, and who have received only up to 1 line of chemotherapy
for advanced disease.

The primary endpoint of the trial was progression-free survival (PFS) overall and in patients with mutations in the PIK3CA/AKT1/PTEN gene, while other secondary endpoints included time to secondary progression, overall response rate, duration of response, and clinical benefit, and safety
.

Preliminary results suggest that the combination regimen with capivasertib resulted in statistically significant and clinically significant improvements
in PFS in both overall and specific biomarker subgroups with changes in PIK3CA, AKT1, or PTEN compared with fulvestrant alone.
Overall survival data for key secondary endpoints are still immature, but early results are encouraging
.

"These encouraging data show that capivasertib has the potential to be a new potential
'first-in-class' therapy for the treatment of patients with hormone receptor-positive breast cancer.
" Dr Susan Galbraith, AstraZeneca's executive vice president of cancer research and development, said: "These patients often face tumor progression or resistance to existing hormone therapies, and there is an urgent
need for new treatment options that extend the efficacy.
”

About PI3K/AKT/PTEN and Capivasertib

PI3K/AKT/PTEN signaling pathway, as one of the important intracellular conduction pathways, plays a role in inhibiting apoptosis and promoting cell proliferation in cells, and is closely related to
the occurrence and development of human tumors.

About 40% of patients with estrogen receptor-positive advanced breast cancer carry mutations
in the PIK3CA gene.
In addition, 5-10% of patients with advanced breast cancer carry an activating mutation in the AKT1 gene, and 5-10% carry an inactivated mutation
in PTEN.

For AKT at the center node of PI3K/AKT/mTOR key signaling pathway, PTEN deletion, AKT/PIK3CA mutation or amplification will cause excessive activation of AKT signaling pathway, resulting in tumor occurrence and progression.
Recent studies have found that AKT activation is associated
with drug resistance in tumor treatment.
As a result, AKT has become a research hotspot in anti-tumor therapy, and it is also a promising new treatment strategy
for HR-positive and HER2-negative breast cancer.

Capivasertib is a highly selective oral small molecule AKT inhibitor that efficiently and selectively inhibits three AKT subtypes (AKT1/2/3).

It is also the world's first AKT inhibitor
to "enter" clinical phase III development and reach the primary endpoint.

Previously, data from the Phase II FAKTION study updated in Lancet Oncol showed that fulvestrant combined with capivasertib significantly prolonged PFS (10.
3 vs 4.
8 months, HR=0.
56, 95% CI: 0.
38-0.
81; p=0.
0023) and OS (29.
3 vs 23.
4 months, HR=0.
66,95%) in patients with ER+/HER2-advanced breast cancer after AI progression.
CI：0.
45-0.
97；p=0.
035）
。 Biomarker analysis showed that Capivasertib combination therapy was effective
in patients with mutations in the PIK3CA-AKT-PTEN signaling pathway.

What will be the final surprise of the CAPItello-291 study, a phase III trial based on the FAKTION study? Let's wait and see!

References

Capivasertib plus Faslodex significantly improved progression-free survival vs.
Faslodex in CAPItello-291 phase III trial in advanced HR-positive breast cancer.
News release.
AstraZeneca.
October 26, 2022.
Accessed October 26, 2022.

Capivasertib+fulvestrant vs placebo+fulvestrant as treatment for locally advanced (inoperable) or metastatic HR+/HER2- breast cancer (CAPItello-291).
ClinicalTrials.
gov.
Updated October 4, 2022.
Accessed October 26, 2022.
 https://clinicaltrials.
gov/ct2/show/NCT04305496