EMERYVILLE, Calif., May 6, 2026
Totus Medicines announced encouraging interim Phase 1b clinical data for its investigational therapy TOS-358 in combination with Fulvestrant for patients with heavily pre-treated HR-positive/HER2-negative metastatic breast cancer during the ESMO Breast Cancer Annual Congress 2026 in Berlin, Germany. The study results demonstrated a remarkable 100% disease control rate (DCR) and an 89% clinical benefit rate (CBR) among evaluable women receiving the combination therapy, including patients previously treated with PI3K/AKT/mTOR pathway therapies. The data positions TOS-358 as a potentially differentiated next-generation PI3Kα inhibitor capable of overcoming many of the efficacy and safety limitations associated with earlier drugs targeting the PI3K pathway. Investigators also highlighted the therapy’s favorable safety profile, durable responses, and prolonged patient benefit, which together reinforce the growing clinical interest surrounding Totus Medicines’ precision oncology platform.
TOS-358 Combination Therapy Shows Durable Clinical Activity
The interim data were presented from the ongoing TOS-358-001, a global, open-label, multi-center Phase 1 clinical trial evaluating TOS-358 both as monotherapy and in combination treatment settings. The latest analysis focused on ten evaluable women with metastatic HR+/HER2− breast cancer who received TOS-358 combined with Fulvestrant. Patients enrolled in the study were heavily pre-treated, with a median of 3.5 prior lines of therapy and some patients having already received earlier PI3K/AKT/mTOR-directed treatments. Despite the advanced disease setting, the study achieved a 100% disease control rate, while 89% of women experienced measurable clinical benefit.
Researchers observed that responses deepened over time, with several patients converting from stable disease to confirmed partial responses during continued therapy. More than 60% of patients remained on treatment beyond 24 weeks, demonstrating sustained disease control and prolonged therapeutic activity. One particularly notable case involved a 72-year-old patient carrying dual PI3Kα mutations who achieved an approximate 68% confirmed partial response alongside near-complete PET-CT resolution of bone metastases. These findings suggest TOS-358 may provide meaningful anti-tumor activity even in patients with resistant disease biology and multiple prior treatment exposures.
Favorable Safety Profile Differentiates TOS-358 from Existing PI3K Therapies
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A major challenge for currently available PI3K inhibitors has been their toxicity profile, which often limits dosing intensity and long-term treatment continuation. According to Totus Medicines, TOS-358 demonstrated a highly differentiated safety and tolerability profile across the broader study population of 56 patients treated to date. Investigators reported zero cases of bone marrow toxicity, hepatic toxicity, renal toxicity, ocular toxicity, rash, stomatitis, or grade 3 diarrhea, toxicities that have historically impacted the clinical utility of earlier PI3K-targeted therapies.
Hyperglycemia, another well-known complication associated with PI3K inhibition, appeared manageable in the study. Only two patients required ongoing insulin support, representing approximately 3.6% of the treated population, and both patients had obesity-related risk factors. Importantly, no patients discontinued treatment because of intolerance to TOS-358. The encouraging safety profile is believed to result from the drug’s covalent and highly selective mechanism, which allows continuous target engagement without excessive systemic drug exposure that can trigger off-target adverse effects.
Covalent PI3Kα Inhibition Strategy Expands Future Clinical Potential
TOS-358 is described as the first and only clinical-stage covalent pan-mutant PI3Kα inhibitor, designed to inhibit a broad range of PI3Kα mutations, including resistance-associated variants frequently seen after earlier therapies. Unlike mutation-selective or non-covalent PI3K inhibitors, TOS-358 achieves more than 95% continuous target engagement through covalent binding while maintaining strong selectivity for PI3Kα. This mechanism enables sustained suppression of oncogenic signaling pathways believed to drive tumor growth across several solid tumors.
PI3Kα mutations are highly prevalent in oncology, occurring in approximately 40% of ER-positive/HER2-negative breast cancers, nearly half of endometrial adenocarcinomas, and a meaningful subset of head and neck cancers. Totus Medicines is continuing enrollment in expansion cohorts evaluating both doublet and triplet combination strategies, including TOS-358 combined with Fulvestrant and CDK4/6 inhibitors. The company believes the therapy could emerge as a potential best-in-class precision oncology treatment capable of addressing major unmet needs in multiple cancer settings.
The program also highlights the growing role of AI-powered drug discovery platforms in oncology innovation. Totus Medicines’ proprietary OmniDEL platform leverages DNA-encoded covalent library technology to identify difficult-to-drug molecular targets and accelerate the development of novel precision medicines. As additional clinical data mature, TOS-358 may become an important competitor in the rapidly evolving PI3K-targeted cancer therapy market.
Source: Totus Medicines press release
