Allosteric Inhibitors Targeting PIK3CA May Reduce Treatment Toxicities in Breast Cancer

A few allosteric inhibitors have arrived that have been developed to reduce toxicities with mutation-specific targeting and build upon the efficacy seen with orthosteric inhibitors such as alpelisib (Piqray) and the recently approved inavolisib (Itovebi) in breast cancer.1,2 Among the select allosteric kinase inhibitors that currently hold indications from the FDA, 2 in the oncology space are trametinib (Mekinist)—which targets MEK1 and MEK2—for patients with melanoma, and asciminib (Scemblix)—a BCR-ABL1 inhibitor—for patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase.3

Many allosteric agents are under evaluation in early-phase trials, which, if proved effective in phase 2 and 3 trials, could fill an unmet need for patients with breast cancer who are experiencing adverse effects (AEs) during treatment with alpelisib, according to investigators. Data from the phase 3 SOLAR-1 trial (NCT02437318), which led to the agent’s approval in combination with fulvestrant (Faslodex) for postmenopausal patients with hormone receptor–positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer, showed that 21% of patients permanently discontinued alpelisib and 4.6% discontinued the combination due to AEs.1,4

“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,” Felipe Batalini, MD, a medical oncologist and assistant professor of oncology at Mayo Clinic College of Medicine in Phoenix, Arizona, said in an interview with OncologyLive.

Alberto Montero, MD, MBA, CPHQ, added that “The field has moved toward a more mutation-specific inhibitor. I believe that is going to open the ability to target this hugely important pathway in cancer and enhance the therapeutic index; [this approach could] block the pathway but have less toxicity at the same time.” Montero is clinical director of the Breast Cancer Medical Oncology Program and the Diana Hyland Chair for Breast Cancer at University Hospitals Seidman Cancer Center in Cleveland, Ohio. He is also an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland.

Targeting PIK3CA With Allosteric Inhibitors

“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 estrogen receptor–positive subtype,” Batalini said. “The issue is that although there are drugs approved—specifically the PI3Kα inhibitor alpelisib in breast cancer—there’s significant toxicity that limits its usefulness in clinic because it also targets the wild-type [enzyme].”

On-target toxicity resulting from treatment with PI3K inhibitors has led to treatment discontinuation in large proportions of patients when hyperglycemia, rash, or gastrointestinal toxicities develop. Research findings published in Cancer Discovery noted that a modest shift in the potency of orthosteric PI3K inhibitors driven by secondary PIK3CA mutations could have a significant effect on clinical efficacy. Allosteric inhibitors have generated excitement as they may be able to overcome resistance driven by acquired PIK3CA alterations and resistance alterations within the catalytic pocket. The effect on insulin signaling can also be minimized with the selective inhibition of the mutant vs wild-type PI3Kα isoform, thus reducing the frequency of hyperglycemia and enabling higher target engagement and a wider therapeutic index.5

“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,” Batalini said. “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.”

STX-478 Shows Promise in Multiple Solid Tumors Including Breast

Initial findings from a first-in-human phase 1/2 study (NCT05768139) were presented at the 2024 European Society for Medical Oncology Congress on the allosteric, central nervous system–penetrant, mutant-selective PI3Kα inhibitor STX-478. The mutant-selective design of the oral agent allows it to selectively target mutant PI3Kα, thus minimizing wild-type toxicities. When investigators gave the agent to efficacy-evaluable patients with advanced solid tumors and PIK3CA helical and kinase domain mutations who received prior standard-of-care therapy (n = 43), the overall response rate (ORR) was 21%. Investigators noted the monotherapy response rate is favorable compared with the monotherapy ORR of 4% to 6% observed with currently approved PI3K pathway inhibitors. Additionally, patients experienced a disease control rate (DCR) of 67%.6

“One of the advantages of STX-478 is it has a very long half-life [of approximately 60 hours],” Montero said. “It’s given once daily, and [data from] the pharmacokinetic studies support that. One of the advantages is that you can get continuous blockade of the pathway because of its long half-life, [and] it doesn’t have toxicities that we’ve seen with the other, [similar drugs].”

When examining responses by tumor type, the ORR was 23% among those with hormone receptor–positive breast cancer (n = 22) and 44% among those with gynecologic tumors (n = 9); respective DCRs were 68% and 67% (Figure).6 Montero noted that the high ORR seen in the gynecologic cohort could be due to the small number of patients enrolled as well as good patient selection, as the trial excluded patients with downstream mutations, where he said one would not expect to see a response to blocking PI3K.

“In uterine cancer, where PIK3CA is a common mutation, [STX-478] showed initial activity although the numbers are small. That by itself is a huge advance, and the company is looking to add more patients [to that cohort] and look at the drug either as a single agent [or in combinations] because my understanding listening to other gynecologic oncologists is that if that held up that would be clinically meaningful, just the activity that we’ve seen as a single agent. But then coming up with rational combinations [is key] because there are a limited number of therapeutic options for uterine cancer,” he added.

Additionally, STX-478 was given at 6 dose levels in the trial, escalating from 20 mg to 160 mg. The maximum tolerated dose was reached at 100 mg; 2 dose-limiting toxicities of grade 3 myalgia and paresthesia occurred in patients who received the agent at 160 mg and resolved rapidly after dose interruption. Notably, no patients discontinued treatment due to an AE and no grade 3 or higher PI3Kα wild-type toxicities were observed.6

“[STX-478] was very well tolerated compared with what we are familiar with for PI3Kα inhibitors,” Montero said. “The 2 important points are [that STX-478 has a] long half-life and it crosses the blood-brain barrier. In the phase 1 trial there weren’t very many patients who had brain metastases. As the trial continues and more patients are enrolled, [we’re] eagerly looking to see [if there’s activity in that population], but at this point we don’t have enough clinical data.”

Furthermore, enrollment in the trial is ongoing in the combination expansion cohort with fulvestrant with or without CDK4/6 inhibitors in patients with hormone receptor–positive, HER2-negative breast cancer. End points of the study include determining the recommended phase 2 dose (RP2D), assessing safety, and examining antitumor activity as well as patient-reported outcomes.

“There’s also a plan to combine it with aromatase inhibitor therapy and CDK4/6 inhibitors. The idea is there’s cross talk between the estrogen pathway and the PI3K pathway, so it’s rational to combine all of them together,” Montero said. “Moving forward with a drug that can be combined with endocrine therapy [that does] not [have] as much potential for toxicity is a big advantage…. I’m enthusiastic for this drug and drugs like [it] that can specifically target a mutated protein and spare the toxicities [of] off-target effects the native, nonmutated protein.”

An Additional Allosteric Inhibitor, RLY-2608, Is Under Development

Another promising allosteric inhibitor is RLY-2608, a panmutant and isoform-selective PI3Kα inhibitor being evaluated in the phase 1 ReDiscover trial (NCT05216432). Interim efficacy data showed that patients (n = 52) with PI3Kα-mutated, hormone receptor–positive, HER2-negative metastatic breast cancer who received the RP2D of the agent and did not have a PTEN or AKT co-mutation experienced a median progression-free survival of 9.2 months. The ORR was 33% among all patients and 53% among those with kinase mutations.7

“It [has also been] demonstrated that allosteric inhibition did [lead 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,” Batalini said.

Pending regulatory discussions, the manufacturer of RLY-2608 noted they plan to initiate a pivotal study of RLY-2608 plus fulvestrant in 2025. Next steps also include reporting primary safety data on the RLY-2608 plus ribociclib (Kisqali) and fulvestrant triplet before 2024 year-end and initiating an expansion cohort in the first half of 2025 with the triplet; a triplet therapy comprising RLY-2608 and atirmociclib plus fulvestrant is also planned. Additionally, data on RLY-2608 will be presented at the San Antonio Breast Cancer Symposium taking place December 10 to 13, 2024.

“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,” Batalini said.

References

1. FDA approves alpelisib for metastatic breast cancer. FDA. Updated May 28, 2019. Accessed October 30, 2024. bit.ly/3AkG323
2. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed October 30, 2024. bit.ly/3C6st33
3. Mingione VR, Paung Y, Outhwaite IR, Seeliger MA. Allosteric regulation and inhibition of protein kinases. Biochem Soc Trans. 2023;51(1):373-385. doi:10.1042/BST20220940
4. Piqray. Prescribing information. Novartis Pharmaceuticals Corporation; 2024. Accessed October 30, 2024. bit.ly/3NJdM8H
5. Varkaris A, Fece de la Cruz F, Martin EE, et al. Allosteric PI3Kα inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations. Cancer Discov. 2024;14(2):227-239. doi:10.1158/2159-8290.CD-23-0704
6. 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
7. Relay Therapeutics announces positive interim data for RLY-2608 demonstrating clinically meaningful progression free survival. News release. Relay Therapeutics Inc. September 9, 2024. Accessed October 30, 2024. bit.ly/3YHgHVC