On May 6, 2026 Totus Medicines, a clinical-stage, precision medicines company leveraging AI-powered small molecule drug discovery to advance a differentiated pipeline of therapeutics against high-value, historically difficult-to-drug targets, reported the presentation of interim Phase 1b clinical data from its ongoing study of TOS-358, a next-generation pan-mutant, covalent, alpha-selective PI3Ka inhibitor, in combination with Fulvestrant, in heavily pre-treated metastatic HR+/HER2− breast cancer patients. The data were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Breast Cancer Annual Congress, taking place in Berlin, Germany, May 5–8, 2026.

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Presentation Details:

Conference: ESMO (Free ESMO Whitepaper) Breast Cancer 2026

Session: Poster Presentation

Abstract Number: 492P

Date / Time: 13:15, Thursday, May 7, 2026

"These initial combination data with TOS-358 and Fulvestrant are highly encouraging and reinforce our confidence in TOS-358’s differentiated profile as a covalent, pan-mutant PI3Ka inhibitor," said Zelanna Goldberg, M.D., Chief Medical Officer of Totus Medicines. "Achieving 100% disease control and an 89% clinical benefit rate in women, including patients with prior PI3K/AKT/mTOR pathway therapy, alongside a class-leading tolerability profile, underscores the potential of TOS-358 to address a critical unmet need in HR+/HER2− metastatic breast cancer. The durability of responses, with more than 60% of patients remaining on therapy beyond 24 weeks, further validates our approach of near-total, sustained PI3Ka pathway suppression."

First Combination Data: TOS-358 + Fulvestrant Efficacy and Durability

The poster (Abstract 492P) presents the early clinical data from the doublet cohort of TOS-358-001, the ongoing open-label, global, multi-center Phase 1 study. Ten evaluable HR+/HER2− breast cancer patients were treated with TOS-358 in combination with Fulvestrant (median 3.5 prior lines of therapy; range 1–5), with a data cutoff of March 31, 2026. Key efficacy and durability findings include:

100% Disease Control Rate (DCR) in women treated with TOS-358 + Fulvestrant
89% Clinical Benefit Rate (CBR) in women, including patients who had received prior PI3K/AKT/mTOR (PAM)-directed therapy and patients in the 4th line and beyond
Responses continued to deepen over time, including conversions from stable disease (SD) to partial responses (PR), consistent with TOS-358’s near-total inhibition of PI3Ka signaling
60% of patients on TOS-358 + Fulvestrant remained on therapy beyond 24 weeks, with an additional 20% of patients ongoing at less than 24 weeks on trial; median time on therapy exceeds 24 weeks for the overall Phase 1 population
A 72-year-old heavily pre-treated patient with an H1047K/G106V dual PI3Ka mutation achieved a confirmed RECIST partial response of ~68%, with near complete PET-CT resolution of bone metastases
Class-Leading Safety and Tolerability

Across the overall TOS-358 safety population to date (N=56, including monotherapy and doublet patients), TOS-358 demonstrated a class-leading tolerability profile with an absence of toxicities that have limited other PI3Ka inhibitors:

0% bone marrow toxicity
0% hepatic toxicity
0% renal toxicity
0% ocular symptoms
0% rash
0% stomatitis/mucositis
0% grade 3 diarrhea
Hyperglycemia was manageable: only 3.6% of patients (2/56) required ongoing insulin, and all patients who received insulin were obese (BMI >30)
No treatment discontinuations due to intolerance to TOS-358
Maturing Overall Phase 1 Experience

The overall Phase 1 cohort currently demonstrates a 78% DCR and 57% CBR, with data continuing to mature. Among the overall population treated with TOS-358, median time on therapy now exceeds 24 weeks, with 50% of patients maintaining disease control beyond this landmark. The ongoing Phase 1b expansion cohort is currently enrolling across doublet (TOS-358 + Fulvestrant) and triplet (TOS-358 + Fulvestrant + CDK4/6 inhibitor) arms.

TOS-358: A Differentiated Approach to PI3Ka Inhibition

TOS-358 is the first and only clinical-stage covalent PI3Ka inhibitor. As a pan-mutant, a-selective oral small molecule, TOS-358 achieves >95% continuous target engagement at clinically relevant doses through covalent binding to a cysteine residue equally accessible in helical, kinase-domain, and other mutants of PI3Ka while avoiding high plasma concentrations that can potentially lead to off-target effects. This broad mutant coverage – extending to acquired resistance mutations – differentiates TOS-358 from non-covalent and mutation-selective PI3Ka inhibitors currently approved or in development. The near-total, sustained suppression of oncogenic signaling enabled by this mechanism is reflected in the depth and durability of responses observed clinically, as well as the absence of many of the class-effect toxicities that have limited other agents.

PI3Ka driver mutations are present in approximately 40% of ER-positive/HER2-negative breast cancer, 50% of endometrial adenocarcinoma, and a meaningful subset of head and neck squamous cell carcinoma (HNSCC) patients. Totus Medicines is advancing TOS-358 as a potential best-in-class PI3Ka inhibitor across selected solid tumor indications. TOS-358-001 (EU CT 2023-505346-26-01; NCT#05683418) is an ongoing open-label, global, multi-center Phase 1 study evaluating the safety and efficacy of TOS-358 alone and in combination.

(Press release, Totus Medicines, MAY 6, 2026, View Source [SID1234665229])