What question did this study set out to answer?

The research aims to assess the safety and efficacy of tersolisib in patients with PIK3CA-mutant advanced breast cancer.

May 29, 2026

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

Key Points

The research aims to assess the safety and efficacy of tersolisib in patients with PIK3CA-mutant advanced breast cancer.
PIKALO-1 trial enrolled patients to receive tersolisib alone or in combination with fulvestrant and CDK4/6 inhibitors.
Patients had a history of prior treatments and included those with and without diabetes who met specific glycemic criteria.
The updated trial involved 193 patients, monitoring treatment effects and adverse events.
Overall response rates (ORR) were 19% for tersolisib, 35% for tersolisib + fulvestrant, and 27% for tersolisib + fulvestrant + CDK4/6i.
Disease control rates (DCR) were 67% for tersolisib, 87% for tersolisib + fulvestrant, and 79% for tersolisib + fulvestrant + CDK4/6i.
Adverse events were manageable, with a reduction in hyperglycemia rates in patients maintaining normal glycemic control.

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 <8% /FBG <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%/<1%), and nausea (31%/1%). Incidence of PI3Ki-class toxicities (rash; 4%/0% and stomatitis; 12%/<1%) were relatively low. TEAEs led to terso dose reduction/discontinuation in 11%/<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).

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