Insilico Medicine reports a 40% response rate with ISM6331 at 130 mg in mesothelioma, based on 2 of 5 evaluable patients in Phase 1 dose-escalation data.
Written By: Charvi Kalal, PharmD
Reviewed By: Pharmacally Editorial Team
Insilico Medicine reported preliminary first-in-human results for ISM6331, its investigational oral pan-TEAD inhibitor, at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid. As of the August 14, 2026, data cutoff, the objective response rate (ORR) among response-evaluable patients with mesothelioma was 40% at 130 mg once daily. Across the 30–130 mg dose range, ORR was 18.2% and the disease control rate (DCR) was 68.2% at the first tumour assessment.
Presented by Melina E. Marmarelis, MD, of the University of Pennsylvania’s Abramson Cancer Center, the findings provide an early clinical signal for a candidate designed using Insilico’s Chemistry42 generative AI platform. However, the small response-evaluable populations and ongoing dose escalation limit conclusions about efficacy and the optimal dose.
ISM6331 and the clinical study
ISM6331 is an investigational, non-covalent inhibitor of TEAD1–4, transcription factors downstream of the Hippo signalling pathway. It is designed to inhibit TEAD-dependent transcription and has been optimised for once-daily dosing. The candidate received US Food and Drug Administration (FDA) Orphan Drug Designation in June 2024 and Fast Track Designation in July 2026 for mesothelioma. It is not approved for clinical use.
The ongoing first-in-human study (NCT06566079) evaluates ISM6331 in patients with advanced or metastatic mesothelioma and other advanced solid tumours. The current report covers dose-escalation findings from 36 participants treated across doses of 15–130 mg. Participants had received a median of two previous lines of therapy, with a range of one to 12. Dose escalation was continuing at the data cutoff.
Responses observed across dose cohorts
At 130 mg once daily, two of five response-evaluable patients with mesothelioma achieved an objective response, corresponding to an ORR of 40%. Their target lesions decreased by 58% and 36%.
Across the 30–130 mg dose range, four of 22 response-evaluable patients achieved an objective response, giving an ORR of 18.2%. The DCR was 68.2% at the first tumour assessment, conducted at Week 8. Responses occurred at 30, 50 and 130 mg, indicating preliminary activity across multiple dose levels without establishing a clear dose-response relationship.
Three of the four responders showed a response at the first Week 8 assessment. Three of the four partial responses remained ongoing at the cutoff, including one lasting approximately a year. These observations suggest that responses may be durable in some patients, although the available data do not establish the overall duration of response or the proportion of patients likely to benefit.
Preliminary activity signals were also reported in other tumour types. These included target-lesion shrinkage in heavily pretreated non-small cell lung cancer and head and neck squamous cell carcinoma, as well as stable disease lasting more than four months in individual patients with epithelioid hemangioendothelioma and colorectal cancer. These observations remain exploratory and do not establish efficacy in these cancers.
Safety and pharmacological findings
No dose-limiting toxicities were reported from 15 to 130 mg, and no treatment-related adverse events (TRAEs) led to treatment discontinuation. Most TRAEs were Grade 1 or 2. Grade 3 TRAEs occurred in 8.3% of participants and included asymptomatic increases in amylase and lipase, fatigue and drug dermatitis. Treatment-related proteinuria, identified as an adverse event of special interest, occurred in 11.1% of participants and was reported as low-grade and reversible.
Sustained reductions in circulating CCN2, a pharmacodynamic marker reported by the company, support engagement of the TEAD pathway. A terminal half-life of approximately 18–32 hours are consistent with once-daily dosing. Neither finding independently establishes clinical benefit or identifies the optimal dose.
Clinical interpretation
The results provide an early signal of antitumour activity for TEAD inhibition in heavily pretreated mesothelioma, but the 40% ORR at 130 mg is based on only two responses among five evaluable patients. The broader 18.2% ORR is based on 22 evaluable patients across several dose levels. These figures should therefore be interpreted as preliminary rather than definitive estimates of treatment activity.
Important uncertainties remain, including whether responses were confirmed, the maturity of response-duration data and the relationship between dose, efficacy and toxicity. The small safety dataset also limits assessment of uncommon or delayed adverse effects. The reported findings do not establish a survival benefit or demonstrate superiority over existing treatments.
Insilico plans to complete dose selection and, subject to emerging data, initiate a randomised Phase 2a dose-optimisation study in mesothelioma. That study should help clarify dose selection and provide a more informative assessment of antitumour activity and safety. Until further data become available, ISM6331 remains investigational, and its clinical benefit is not yet established.
Reference
Insilico Medicine Reports 40% ORR at 130 mg for Pan-TEAD Inhibitor ISM6331 Designed Using Generative AI in Heavily Pretreated Mesothelioma at ESMO 2026, Insilico Medicine, October 25, 2026.
Study of ISM6331 in Participants with Advanced/Metastatic Mesothelioma or Other Advanced Solid Tumors, ClinicalTrials.gov ID NCT06566079
About the Writer
Charvi Kalal (LinkedIn) is a Pharm.D intern and aspiring medical writer with hands-on experience in medical writing, clinical research, pharmacovigilance, and clinical pharmacy. She has experience in medical content writing through CliMed, along with exposure to ADR monitoring, prescription analysis, patient counselling, literature review, and research documentation. Her research focuses on ADR monitoring and reporting in breast cancer patients receiving targeted therapy. With certifications in GCP, biomedical research, scientific writing, and clinical research, she is passionate about transforming scientific evidence into accurate, engaging, and accessible healthcare content.