On March 18, 2026 Totus Medicines, a clinical stage, precision medicine company leveraging a novel covalent DNA-encoded library + AI-powered small molecule drug discovery platform to advance a differentiated pipeline of therapeutics against high-value, historically difficult to drug targets in multiple therapeutic areas, reported the presentation by Dr. Antonio Giordano of Dana Farber Cancer Center of new clinical data for TOS-358, its lead oral covalent PI3Ka inhibitor, in an oral presentation at the European Society for Medical Oncology Targeted Anticancer Therapies (ESMO TAT) Congress in Paris, France.

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"TOS-358 was designed to overcome the limitations of currently available PI3Ka inhibitors by delivering sustained and specific, >90% covalent inhibition of the target combined with a best-in-class safety profile," said Zelanna Goldberg, M.D., Chief Medical Officer of Totus Medicines. "We are very encouraged by the early clinical efficacy data, which demonstrate durable tumor control and class-leading tolerability in heavily pretreated patients, including those who had previously progressed on other PI3K pathway therapies.

"TOS-358 is amongst the most interesting agents in this class to emerge. It appears to be a well-tolerated and straightforward drug to give for PI3Ka mutant disease with early data suggesting the potential for meaningfully durable tumor control. This may help inhibit tumor growth and maintain quality of life, which is a promising combination for our patients" said Dr. Antonio Giordano.

TOS-358 is an oral, highly selective, pan-mutant, covalent PI3Ka inhibitor that achieves >95% continuous target engagement for deep and durable inhibition of PI3K-AKT signaling which is required for optimal efficacy and durability.

Phase 1a Key Clinical Findings:

Clinical results from the efficacy cohort demonstrated encouraging anti-tumor activity and durability of response:

Overall efficacy profile:

CBR: 50%
DCR: 75%
ORR: 15%
≥20% tumor shrinkage: 40%
Patients on therapy for ≥24 weeks: 45%

Clinically meaningful disease control in heavily pre-treated patients:

DCR in PAM-resistant patients: 67%
DCR in PAM-intolerant patients: 100%

Class-leading Safety & Tolerability Profile:

TOS-358 demonstrated a favorable and differentiated safety profile, with minimal gastrointestinal or epithelial toxicities.

Key observations included:

No bone marrow toxicity
No hepatic toxicity
No renal toxicity
No ocular symptoms
No rash
No stomatitis or mucositis
<5% of patients required medication for nausea or diarrhea

Hyperglycemia, an expected on-target effect of PI3Ka inhibition, was primarily low grade and manageable with oral medications. Only 3.6% (2/54 pts) required ongoing insulin, which is similar to, or lower than, other PI3Ka inhibitors in development including mutant selective and/or allosteric compounds.

Phase 1b study design:

TOS-358 is currently being evaluated in an ongoing Ph1b study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of TOS-358 in combination with fulvestrant and in combination with fulvestrant and CDK inhibitors in patients with PI3Ka-mutated, HR+/HER2- metastatic breast cancer. Initial data from these combination cohorts are expected to be presented at future medical and scientific conferences.

(Press release, Totus Medicines, MAR 18, 2026, View Source [SID1234663728])