Background: AKT1/2/3 point mutations are found in ~1% of all solid tumors, with varying prevalence across different tumor types. Ipatasertib is an inhibitor of the AKT kinase, but its antitumor activity as monotherapy in patients with AKTmut tumors is unknown. We present efficacy and safety data of ipatasertib in patients with advanced/metastatic AKTmut solid tumors from Cohort E of the TAPISTRY trial (NCT04589845). Methods: TAPISTRY is a phase II, global, open-label, multi-cohort trial evaluating the efficacy and safety of different therapies in patients with advanced/metastatic solid tumors. Patients in Cohort E were aged ≥12 years and had solid tumors harboring an AKT1/2/3mutation identified by next-generation sequencing and measurable disease by RECIST v1.1. Oral ipatasertib 400 mg was administered once daily. Tumor assessments were performed at screening, every eight weeks from Day 1/Cycle 1 for one year, and every 12 weeks after that. The primary endpoint was objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints included ORR by investigator, duration of response, progression-free survival, overall survival and safety. Results: At data cut-off (16 Jul 2023), 50 patients were safety evaluable and 48 were efficacy evaluable. In the safety-evaluable population, median age was 59 years (range, 30–79); 98% of patients (n/N = 49/50) had an AKT1 mutation (AKT1E17K, n=47) and 2% (n/N = 1/50) had an AKT2E17K mutation; 41/50 patients (82%) had received ≥2 prior lines of treatment. Efficacy-evaluable patients had 10 different tumor types, the most common being breast cancer (n/N = 21/48; 44%). Key outcomes are summarized in the Table. After a median follow-up of 11.3 months, ORR by IRC in efficacy-evaluable patients was 31.3% (n/N = 15/48; 95% CI 18.7–46.3), driven by responses in three tumor types: breast (n/N = 7/21; 33%), endometrial (n/N = 7/7; 100%), and head and neck (n/N = 1/2; 50%). The most frequent adverse event was diarrhea (n/N = 39/50; 78%). Safety was consistent with the known profile of ipatasertib; no new safety signals were identified. Conclusions: Treatment with ipatasertib led to a marked and durable antitumor activity in some tumor types such as endometrial cancer, but not in the overall tumor-agnostic cohort. Further studies are needed to understand the relevance of AKT inhibition in these tumor types. Clinical trial information: NCT04589845.