Targeting PIK3CA With Allosteric Inhibitors Is Promising New Approach in Breast Cancer

Allosteric inhibitors targeting PIK3CA under development represent a new wave of agents looking to improve upon the safety of already approved orthosteric inhibitors targeting PIK3CA, according to Felipe Batalini, MD.

Data from a first-in-human phase 1/2 study (NCT05768139) revealed that the allosteric, central nervous system–penetrant, mutant-selective PI3Kα inhibitor STX-478 led to a disease control rate of 67% in patients with advanced solid tumors and PIK3CA helical and kinase domain mutations who received prior standard-of-care therapy (n = 43). No grade 3 or higher PI3Kα wild-type toxicities were observed in the trial and no patients discontinued STX-478 due to an adverse effect (AE).1

“The power of allosteric inhibition of the PIK3CA enzyme or gene is [that] it allows for a more focused, selective targeting of the mutant type of PIK3CA and therefore [offers] a better safety and tolerability profile,” Batalini said in an interview with OncLive®.

Additional findings showed that treatment with the allosteric inhibitor RLY-2608 led to an objective response rate (ORR) of 33% among all patients with PI3Kα-mutated, hormone receptor–positive, HER2-negative metastatic breast cancer (n = 52) treated in the phase 1 ReDiscover trial (NCT05216432). The ORR among those with kinase mutations who received the panmutant and isoform-selective PI3Kα inhibitor was 53%.2

In the interview, Batalini detailed how targeting PIK3CA is evolving in breast cancer and highlighted allosteric inhibitors that are currently under evaluation in early phase trials. Batalini is a medical oncologist and assistant professor of oncology at Mayo Clinic College of Medicine in Phoenix, Arizona.

OncLive: How key is targeting PIK3CA in breast cancer?

Batalini: PI3K is a very important pathway [that is] now targetable for patients with estrogen receptor [ER]–positive breast cancer, but it’s important across breast cancers. It’s very classically activated in an ER, but it’s also downstream of HER2 so it is important in those groups of patients [with HER2 mutations]. It is also commonly mutated in patients with triple-negative disease.

PIK3CA encodes for the p110 subunit of the PI3K enzyme, and specifically PI3Kα. PIK3CA is the most commonly mutated oncogene across [breast] cancer and can be mutated in as [much] as 40% of breast cancers for the ER-positive subtype. In triple-negative disease, [the mutations are] a little less frequent, but still responsible for a fair number of mutations at approximately 10% to 15% in that population.

How do allosteric inhibitors targeting PIK3CA differ from orthosteric inhibitors targeting PIK3CA?

The issue is that although there are drugs approved—specifically the PI3Kα inhibitor alpelisib [Piqray] in breast cancer—there’s significant toxicity that limits its usefulness in the clinic because it also targets the wild-type [enzyme]. [Treatment with alpelisib results in a] significant amount of hyperglycemia, rash, and diarrhea, but hyperglycemia is one of the most important AEs seen.

The target itself is [not] new, but the way we are targeting PIK3CA using an allosteric inhibitor is unique because [we’re not] targeting the catalytic domain with small molecule inhibitors, which is the typical way of targeting the ATP binding site, [where] it’s harder to be specific. We often see these AEs because this targeting of the catalytic domain may not be very selective to the mutant [enzyme]. Using the whole protein surface and identifying a pocket that is much more specific to the mutant PIK3CA is a very interesting approach.

What allosteric inhibitors are currently under evaluation?

[There are] a few allosteric inhibitors [to note]. LOXO-783 was evaluated in the phase 1 PIKASSO-01 trial [NCT05307705] that unfortunately was closed early due to toxicities. RLY-2608 and STX-478 are 2 [additional] drugs. RLY-2608 is being evaluated in the ReDiscover trial and the initial paper published looking at the mechanisms of resistance to PI3K inhibition demonstrated that half of [39] patients [with advanced breast cancer] developed another mutation in the same pathway, either in the PIK3CA gene itself or in downstream genes like AKT1 or even upstream at PTEN. [This] showed that biologically these tumors are dependent on the pathway, so [they are] developing or selecting clones with mutations in this pathway.

In that work, it was also demonstrated that allosteric inhibition [led to] response in patients who had progressed on prior orthosteric PI3K inhibition, showing that there’s potential for these drugs [to] act on resistance to orthosteric inhibition. There’s a lot of excitement with the allosteric inhibition of PIK3CA. These data from phase 1 trials are preliminary, but the hyperglycemia AE was not noticed [frequently at a grade above 1].

Data [on] RLY-2608 combined with fulvestrant [Faslodex] showed an overall response rate of 33% with significant tumor reduction [observed] in some patients. A presentation at the 2024 ESMO Congress [was also given] on STX-478, and differently from RLY-2608 which was given in combination with fulvestrant, STX-478 showed responses in patients as a monotherapy. The ORR across all tumors was 21%, which is comparable with the [23%] response rate seen in breast cancer.

It is certainly a very exciting approach, and we are hopeful that the confirmation of these phase 1 results happens in phase 2 and then phase 3 trials because it’s a very commonly altered pathway for patients with breast cancer, so it would be great to have better-tolerated options.

References

1. Montero AJ, Giordano A, Jhaveri K, et al. First-in-human results of STX-478, a mutant-selective PI3Kα inhibitor, in advanced solid tumor patients. Ann Oncol. 2024;35(suppl 2):S1220. doi:10.1016/j.annonc.2024.08.2266
2. Relay Therapeutics announces positive interim data for RLY-2608 demonstrating clinically meaningful progression free survival. News release. Relay Therapeutics Inc. September 9, 2024. Accessed December 6, 2024. https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-positive-interim-data-rly-2608