A phase 1/2 trial of tersolisib (LY4064809/STX-478), a pan-mutant-selective PI3Kα inhibitor (PI3Kαi), in <i>PIK3CA</i> -mutant advanced solid tumors: Updated results from PIKALO-1.

Abstract

1072 Background: PI3Kαi have demonstrated clinical benefit in ~40% of patients (pts) with HR+, HER2- advanced breast cancer (ABC) with PIK3CA mutations ( PIK3CA m). However, broad use is often constrained by toxicities mediated through wild-type PI3Kα inhibition, and exclusion of pts with diabetes (DM) or prediabetes (pDM). Here we report updated results from PIKALO-1 evaluating tersolisib (terso), an oral, allosteric CNS-penetrant, pan-mutant-selective PI3Kαi in pts with PIK3CA m HR+ HER2- ABC. Methods: PIKALO-1 enrolled pts to receive terso (≥1 prior treatment [tx]), terso + fulvestrant (fulv, 1-2 prior txs), or terso + fulv/imlunestrant (imlu) and CDK4/6i (≤2 prior txs). Pts with pDM/DM (HbA1c &lt;8% /FBG &lt;140mg/dL) were eligible. Results: As of 6 Jan 2026, 193 pts with PIK3CA m HR+ HER2- ABC were treated: terso (n=52; 20-160 mg QD); terso (60 mg or 100 mg QD) + fulv (n=45) and terso (20-100 mg QD) + fulv + CDK4/6i (palbociclib, n=70; ribociclib, n=21; abemaciclib, n=5) (n=96). Median age was 62 yrs (Range: 27-84), 54% had pDM/DM. Median prior txs was 2 (0-7) including: CDK4/6i (81%) and SERD (47%). Hyperglycemia (HG) rates (any Grade [G]/G≥3) were 16%/0% in pts without pDM+DM and 37%/1% in pts with pDM+DM. TEAEs (any G/G≥3) ≥25% of all pts; neutropenia (39%/27%), fatigue (35%/4%), diarrhea (34%/&lt;1%), and nausea (31%/1%). Incidence of PI3Ki-class toxicities (rash; 4%/0% and stomatitis; 12%/&lt;1%) were relatively low. TEAEs led to terso dose reduction/discontinuation in 11%/&lt;1%. T. no significant drug-drug interactions. PIK3CA m ctDNA was reduced at all dose levels. Updated data, including dose escalation data with terso + imlu+ abemaciclib, will be presented. Conclusions: Terso, alone or combined with fulv ± CDK4/6i, continues to be well-tolerated, with lower incidence of PI3Ki-class toxicities and no 3 HG in pts with normal baseline glycemic control. Target engagement was robust and clinical benefit continues to mature favorably in heavily pretreated pts with PIK3CAm HR+ HER2- ABC, supporting further study in the Phase 3 PIKALO-2 trial (NCT07174336). Clinical trial information: NCT05768139 . Efficacy summary. Terso Terso + fulv Terso + fulv +CDK4/6i c Efficacy Evaluable Population a , n 48 31 48 Prior Therapies b , n (Range) 3 (1-7) 1 (0-5) 1 (0-6) ORR, n (%) 9 d (19) 11 e (35) 13 f (27) DCR, n (%) 32 d (67) 27 e (87) 38 f (79) a Pts who had measurable disease and ≥1 post baseline response assessment or discontinued prior to first post baseline response assessment. b Locally Advanced/Metastatic Setting, summary based on safety population; all enrolled pts who received ≥1 tx dose. ORR incl. PR, uPR; DCR incl. PR, uPR, SD. c Incl. palbociclib, ribociclib, abemaciclib. Incl. d 1, e 4, f 6 uPR (ongoing, pending confirmation).