Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer

cottageacre

Hello,

I looked at this paper published in "The New England Journal of Medicine on 31.05.2023 with regards to Capivasertib.

https://www.nejm.org/doi/10.1056/NEJMoa2214131

1.

In general Capivasertib is AKT inhibitor for patients with AKT pathway–altered (PIK3CA, AKT1, or PTEN) tumors. It's given with Fulverstrant.

2.

The basis for RCT was as follows:

“In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy”

3.

"The main aim was PFS assessed both in the overall population and among patients with AKT pathway–altered (PIK3CA, AKT1, or PTEN) tumors".

4.

Results:

AKT pathway alterted:

Median progression-free survival was 7.3 months in the capivasertib–fulvestrant group, as compared with 3.1 months in the placebo–fulvestrant group.

Overall population:

7.2 months in the capivasertib–fulvestrant group, as compared with 3.6 months in the placebo–fulvestrant group

5.

I read it few time and can't see the results for nonaltered AKT patients.

It looks as the RCT had either altered or overall.

But Overall gives no indication whatsoever how did the nonlatered AKT group of patients responded to therapy.

It's like saying overall 5 years survival of breast cancer is 91%.

6.

I looked then into Supplementary Appendix S1 to get the idea of the results for non altered population.

My take is as follows:

• There were 400 patients in non altered group (split 50-50 in the RCT arms)
• Figure S2 had these as: Investigator-assessed progression-free survival:
• A) patients with AKT pathway non-altered tumors including unknown NGS result (per protocol)

-- Median PFS 7.2 vs 3.7

• B) patients with AKT pathway non-altered tumors excluding unknown NGS result (exploratory analysis)

-- Median PFS 5.3 vs 3.7

• C) only patients with unknown NGS result (post-hoc exploratory analysis)

-- Median PFS 10 vs 1.9.

Based on this In my it is clear that apivasertib–fulvestrant offer similar or even better PFS in certain nonaltered group than in the altrered group but I don't see this being routinely given?

I certainly did not hear oncologists in UK nor in Poland mentioning it as an option?

Any thoughts? Are you on this or were and if so which line of your treatment it was?

7.

Figure 3 of supplementary appendix.

Investigator-assessed progression-free survival by subgroup in patients with AKT pathway-altered tumors.

It looks as pre-monpausal patients, of Latin America, Eastern Europe, Russia, with prior CDK exposure and chemotherapy had closer or worse results that the placebo arm.

8.

I do not see same comparison for non-altered groups.

I would have thought this is equally important and surely could impact of oncologist chose of treatment?

moderators

You're asking some really thoughtful questions!

Here is a page on Truqap: https://www.breastcancer.org/treatment/targeted-therapy/truqap

Capivasertib (brand name: Truqap) has been approved in the United States for treating advanced breast cancer in patients with hormone receptor-positive (HR+) and HER2-negative tumors. However, as you pointed out, it's only approved for those who have specific genetic changes in their cancer cells.

These genetic changes affect the AKT pathway, which is involved in cancer growth. The mutations that make someone eligible for Capivasertib are found in genes like PIK3CA, AKT1, or PTEN. If a patient's cancer has these mutations, Capivasertib might help slow down the disease.

Capivasertib is typically used after other treatments have stopped working, like hormone therapy (such as aromatase inhibitors) and CDK4/6 inhibitors.

Approval Status:

• In the U.S.: Capivasertib was approved in November 2023 for people whose tumors have these AKT-related mutations. It’s given along with another medication called Fulvestrant.
• In Europe: The approval is still under review but may be available soon.

So, while Capivasertib has shown benefits for people with these specific genetic mutations, it’s only prescribed to those who meet these criteria. If someone doesn’t have these mutations, Capivasertib is not part of their treatment plan right now.

Your Question: What about the AKT non-altered subgroup?

You’re absolutely right to notice that gap in the data. Here’s what’s going on:

The trial mainly looked at:

• The AKT-altered population (n=313)
• The overall population (n=708)

However, the results for the non-altered subgroup aren’t clearly broken out in the main paper. But in the supplementary data, does show some important numbers for non-altered patients.

So, prescribing this comes down to regulatory approval and the study design. The trial wasn’t designed to assess how Capivasertib works in the non-altered subgroup, and the data for these patients is exploratory.

For regulatory approval, drugs are typically only approved for the groups that were clearly studied and shown to benefit. Since the trial didn’t specifically test the non-altered group in a way that would meet approval standards, Capivasertib isn’t being offered routinely to non-altered patients at this point.

You also pointed out the differences in certain subgroups within the AKT-altered population—such as premenopausal patients and those from Latin America or Eastern Europe. Yes, you're right again. Some of these groups seem to have less benefit from Capivasertib. However, the data is preliminary (hypothesis-generating), and the trial wasn’t designed to directly test these smaller subgroups. So, it’s not enough to make decisions based on this alone.

We hope this is helpful.
Your Mods