Background: Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM) however the factors that determine sensitivity are unknown. Combined inhibition of vascular endothelial growth factor (VEGF) may potentiate efficacy through remodelling of the tumour microenvironment and inhibition of angiogenesis. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis and to uncover cellular and molecular determinants of efficacy as arm 4 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST4). Methods: Patients with any histological subtype or site of MM (pleural or peritoneal) were enrolled. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1^st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Atezolizumab 1200mg iv q3w with bevacizumab 15mg/kg iv q3w (AtzBev). Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Baseline BAP1, p16ink4a, PD-L1 (DAKO22C3), gut microbiome 16s RNA metagenomics, multiplex immunofluorescence, and whole exome and RNA transcriptome sequencing was conducted to explore cellular and molecular correlates of sensitivity. Results: Between January 2020 and February 2021, 26 patients with MM started treatment and received at least one dose of AtzBev. The median age of pts was 68 (range, 44-80) years, 69% were male, 77% epithelioid, 85% ECOG PS1, > 1 prior systemic therapy 54%. The median cycles of Atz dosing was 4.5 (IQR, 2-8) and Bev dosing was 4.5 (IQR, 2-7). DCR12w: 53.8% (95% confidence limit (CI), 33.4% – 73.4%), DCR24w: 23.1% (95%CI, 9.0% – 43.6%). Best responses (evaluable within 24w): partial – 3.8% (95%CI, 0.1- 19.6%); stable disease – 69.2% (48.2 – 85.7%); progression – 15.4% (4.4 – 34.9%). Adverse events (any cause): ≥ grade 3 toxicities affected 35% of pts. Conclusions: MiST4 met its primary endpoint however responses were heterogeneous. Analysis of cellular and molecular correlates are ongoing and will be presented. Clinical trial information: NCT03654833.