STK-478 May Be an Effective, Tolerable Treatment Alternative in PIK3CA-Mutant Breast and Gynecologic Cancers

Alberto Montero, MD, MBA, CPHQ

The next-generation PI3Kα inhibitor STX-478 is associated with reduced metabolic toxicities and a favorable safety profile in PIK3CA-mutant breast and gynecologic cancers, distinguishing it from other available PI3Kα inhibitors and offering a potential new therapeutic option for patients with prior PI3K inhibitor exposure, according to Alberto Montero, MD, MBA, CPHQ.

Results from the phase 1 portion of a first-in-human phase 1/2 trial (NCT05768139) evaluating STX-478 in advanced solid tumors were presented at the 2024 ESMO Congress.¹ Among efficacy-evaluable patients with PIK3CA mutations (n = 43) who had previously received standard therapies, STX-478 produced an overall response rate (ORR) of 21% and a disease control rate (DCR) of 67%. Notably, the ORR with STK-478 monotherapy was higher than historical values for currently approved PI3K inhibitors, which are between 4% and 6%. In subgroup analyses by tumor type, the ORR was 23% for patients with hormone receptor–positive breast cancer (n = 22) and 44% for those with gynecologic tumors (n = 9). The respective DCRs were 68% and 67%.

Based on these data, Montero noted that ongoing and future combination studies aim to expand the application of STK-478 in a variety of gynecologic cancers.

“It’s encouraging, even though [they are] early results, that there’s activity [with STX-478] as a single agent,” Montero said in an interview with OncLive^®. “Because STX-478 [is not associated with] lot of toxicities, it’s going to be easy to build rational combinatorial approaches with it, which will give a meaningful clinical benefit for patients and minimize toxicities for them.”

In the interview, Montero summarized key findings with STX-478 in solid tumors presented at the 2024 ESMO Congress, highlighted the agent’s advantages in safety over its predecessors, and discussed how ongoing efforts to integrate STX-478 into combination regimens could address several unmet needs in breast and gynecologic cancers.

Montero is the 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.

OncLive: What key efficacy findings with STK-478 were presented at the 2024 ESMO Congress?

Montero: Patients with any solid tumor with a kinase or helical domain mutation [were enrolled in the trial]; most had breast cancer. It is important to note from the presentation that the ORR was 21% and that these were heavily pretreated patients. The trial allowed prior PI3K inhibitor treatment, and many patients responded despite having prior exposure to similar drugs.

Looking specifically at breast cancer, the ORR was a bit higher at 23%, so that’s the most important thing [to note] on the efficacy. It seemed that even patients who had a helical domain mutation, which is a little less common than kinase domain mutations, seemed to have a response. We saw responses in non-breast and breast [cancers], and then in helical- and kinase-mutated tumors.

Why might response rates have been higher in the gynecological cancer cohort than the breast cancer and all-tumor cohorts?

The number of patients [in the gynecological cancer cohort was not high, at 9 patients], so part of [the outcome seen] may be [attributed to] the patients who were enrolled. Secondly, the trial excluded patients with downstream mutations, where one would expect no response to blocking PI3K, so part of [this outcome has to do with] good patient selection.

For example, the initial studies of alpelisib [(Piqray) in patients with breast cancer] did not exclude patients who had PTEN mutations. PTEN is downstream [in the] PI3K [pathway], and if a patient has a PTEN mutation, it confers resistance to blocking upstream. Better patient selection—better identification of the patients likely to respond to STX-478—and the small numbers of patients [enrolled may have led to the response rates observed in the gynecologic cancer cohort]. Hopefully [these findings will] still hold up as the trial enrolls to the cohort expansions [for] gynecologic tumors.

​​What early data have been seen so far regarding safety?

The toxicity profile [of STX-478] is favorable compared with alpelisib and some of the other PI3Kα inhibitors. We did not see a significant increase in hyperglycemia, and we even allowed patients who had well-controlled diabetes [to enroll] into the trial—many of these patients are excluded from other PI3K [inhibitor] trials. There were none of the other metabolic toxicities that we typically see; no significant severe diarrhea, mucositis, or rash [were observed].

[The 2] dose-limiting toxicities, which were seen at 160 mg, were myalgia and paresthesia; these went away immediately. [These adverse effects (AEs)] shouldn’t be related to blocking PI3K, but they happened and were reasonably attributed to the drug. However, once the investigators lowered the dose, those toxicities went away in those 2 patients. We haven’t seen [those toxicities] at any other dose levels in other patients. [STX-478] was well tolerated compared with [the AE profiles] we are familiar with for PI3Kα inhibitors.

What STX-478–containing combination regimens are under investigation?

PI3K is important in all solid tumors but particularly in breast cancer and especially in hormone receptor–positive breast cancer. The preclinical data [on] STX-478 showed that although the drug was active as a single agent in preclinical breast cancer animal models, when combined with endocrine therapy and CDK4/6 [inhibitors], there was a synergistic interaction [that produced] and the best preclinical therapeutic response.

As far as clinical development, the goal has been to combine [STX-478] with standard-of-care [agents] once we find its optimal dose as a single agent. In [the phase 2 portion of the phase 1/2 trial], it’s being combined with fulvestrant [Faslodex] and different CDK4/6 inhibitors—palbociclib [Ibrance] and ribociclib [Kisqali]. 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 [inhibitors of both those pathways]. That’s what the current iteration is. There aren’t any other combinations [with STX-478 under investigation] right now, but the company’s interested in planning different combinations for gynecological malignancies, as well as genitourinary malignancies; [these regimens may] end up being combinations with [STX-478 and] chemotherapy or other [agents]; that’s under development at this point.

How could STX-478 fill an unmet need for patients?

This agent meets an unmet need on a variety of levels. In general, because it is a mutation-specific inhibitor of the kinase and helical domains, it shows a proof of principle that we can target this important pathway that’s aberrantly activated in many cancers by using a mutation-specific small molecule inhibitor.

Even though we have other drugs that target PI3Kα that are FDA approved in breast cancer, toxicity limits their use. 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.

[Additionally], 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 investigate the drug either as a single agent [or in combinations]. My understanding from listening to [insights from] other gynecologic oncologists is that if [the data with single-agent STX-478 in uterine cancer] held up [in a larger cohort, they] would be clinically meaningful. However, coming up with rational combinations [is key] because there are a limited number of therapeutic options for uterine cancer.

Those would be the 3 [unmet needs STX-478 could address]: [Showing] a general proof of principle that will help propel the field forward, [having activity] in breast cancer with endocrine therapy, and either [showing efficacy as a] standalone agent or in combination regimens in endometrial cancer.

Reference

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