Moreover, we show that in the H1047R mutant, the cavity, where the allosteric ligands STX-478 and RLY-2608 bind, is more accessible contrary to the WT. This study provides insights into the molecular mechanisms underlying activation of oncogenic PI3Kα by C-terminal mutations and represents a valuable resource for continued efforts in the development of mutant selective inhibitors as therapeutics.

P1, N=193, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting | N=400 --> 193

P1, N=16, Completed, Eli Lilly and Company | Not yet recruiting --> Completed

P1, N=42, Completed, Eli Lilly and Company | Recruiting --> Completed

P1/2, N=400, Recruiting, Scorpion Therapeutics, Inc. | Trial completion date: Apr 2028 --> Feb 2029 | Trial primary completion date: Apr 2026 --> Feb 2027

P1/2, N=400, Recruiting, Scorpion Therapeutics, Inc. | N=220 --> 400 | Trial completion date: Jun 2026 --> Apr 2028

P1, N=150, Recruiting, OnKure, Inc. | Not yet recruiting --> Recruiting

P1, N=150, Not yet recruiting, OnKure, Inc.

However, in contrast to the FDA-approved PI3Kα isoform-selective inhibitor alpelisib, STX-478 does not induce hyperglycemia or other metabolic dysfunctions. See related article by Buckbinder et al., p. 2432 (7).

Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme...Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate that OKI-219 offers improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. OKI-219 is advancing into clinical trials.

In a panel of PI3Kα mutant CDX and PDX models, STX-478 provided efficacy that was similar or superior to higher than clinically achievable doses of alpelisib...In a representative PDX model, STX-478 combined with the ER degrader fulvestrant and palbociclib was well tolerated for > 90 days of dosing in mice and resulted in durable tumor regressions that were superior to STX-478 alone...These properties combined with the potential for CNS penetration and excellent pharmacokinetic profile in higher species make STX-478 a potentially best-in-class mutant-selective PI3Kα inhibitor. STX-478 is currently being evaluated in a Phase I clinical trial (NCT05768139).

The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme...Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models...STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.

P1, N=16, Not yet recruiting, Eli Lilly and Company

P1, N=400, Recruiting, Eli Lilly and Company | N=300 --> 400

Table. Dose Expansion (Phase 1b)

Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R- mutant T47D model...Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib...Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo...LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705).

When combined with fulvestrant, lapatinib, or abemaciclib, STX-478 demonstrated synergistic anti-proliferative activity in cell lines with relevant ER/HER2 status...In the T47D (PI3Kα H1047R) breast cancer model, STX-478 (100 mg/kg) monotherapy caused tumor regression whereas alpelisib caused only stasis...In an ER+/HER2+ PDX model (PI3Kα H1047R/R108H), palbociclib and STX-478 (100 mg/kg) monotherapy resulted in similar efficacy while the combination was well tolerated and yielded tumor regression...The significant CNS exposure of STX-478 is expected to enable this treatment for patients with brain tumors and brain metastases not afforded by existing options. STX-478 is currently in IND enabling studies and is expected to enter human clinical trials in 2023.

Alpelisib is a PI3Kα isoform-selective, orthosteric kinase inhibitor, having equivalent activity on wild-type (wt) and mutant (mt) forms and was approved to treat PI3Kα mt, HR+/HER2- breast cancer in combination with fulvestrant, nearly doubling progression-free survival (Andre 2019)...ST-814 has robust anti-tumor activity in PI3KαH1047X in xenografts, with efficacy similar or superior to alpelisib dosed at 50 mg/kg (Table 1)...A clinical candidate from this program is currently in IND enabling studies. >