Background: AXL receptor tyrosine kinase is a key facilitator of immune escape and drug resistance, conferring a more aggressive phenotype. Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM), however, responses are only observed in a fraction of patients. Preclinical studies suggest that dual PD1 and AXL inhibition is synergistic. We developed a multi-centre, molecularly stratified phase IIa trial to evaluate the efficacy of AXL/PD-1 inhibition with bemcentinib (Bem)/pembrolizumab (Pem) and to uncover cellular and molecular determinants of efficacy as arm 3 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST3). Methods: Patients with pleural mesothelioma were enrolled. Key inclusion factors were ECOG performance status (PS) 0-1, prior platinum-based chemotherapy (maximum of 2 prior lines allowed), evidence of disease progression with measurable disease by CT (Modified RECIST 1.1), and adequate haematological/organ function. All patients received 200mg Pem IV q3W in combination with Bem, loading dose 400mg PO for the first 3 days and then 200mg od q3w. Primary endpoint was disease control rate at 12 weeks (DCR12w). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate (ORR) and toxicity (NCI CTCAE 4.03). Pre-treatment fresh biopsy was required to enable multiplex immunofluorescence, whole exome and RNA transcriptome sequencing. Gut microbiome 16s RNA sequencing also was undertaken at baseline (n=21). Results: Between September 2020 and March 2022, 26 patients with MM started treatment and received at least one dose of Pem Bem. Median age was 72.5 (range, 55-85) years, 88% were male 12% were female, Histology: 88% epithelioid, 8% Biphasic, 4% Sarcomatoid, ECOG PS1 77%, > 1 prior systemic therapy 35%. The median cycles of Pem Bem was 4 (IQR, 2-11). The DCR12w was 46.2% (12/26) (90% confidence limit (CI), 29.2% –63.4 %;), ORR was 15.4% (95%CI, 4.4- 34.9%; all PR)) with stable disease in 57.7% (36.9 – 76.6%); DCR24w was 38.5% (10/26) (95%CI, 20.2% – 59.4%). Adverse events (any cause): ≥ grade 3 toxicities affected 38% of pts and there were no treatment-related deaths. The most frequent adverse events recorded were fatigue in 12/26 (46%) patients and nausea in 11/26 (42%) patients. Conclusions: MiST3 met its primary endpoint and warrants further evaluation. Analysis of the cellular and molecular correlates of response are ongoing and will be presented. Clinical trial information: NCT03654833.