Atezolizumab and motixafortide, cobimetinib or simlukafusp alfa in pretreated advanced pancreatic cancer: phase I/IIb MORPHEUS-PDAC umbrella study

BACKGROUND: The MORPHEUS platform comprised multiple open-label, randomized, phase Ib/II trials to identify early signals with different treatment combinations across multiple cancers. MORPHEUS-PDAC (NCT03193190) evaluated atezolizumab combinations in pancreatic ductal adenocarcinoma (PDAC). We describe outcomes with atezolizumab plus either motixafortide, cobimetinib, or two simlukafusp alfa regimens. METHODS: Eligible patients with advanced, pretreated PDAC were randomized to receive second-line (2 L) atezolizumab plus either motixafortide (BL8040; n = 15), cobimetinib (n = 14), simlukafusp alfa every 2 weeks (q2w; n = 15), or simlukafusp alfa every 3 weeks (q3w; n = 16); or control (mFOLFOX6 [n = 25] or gemcitabine plus nab-paclitaxel [n = 25]). Patients experiencing disease progression or toxicity who met eligibility criteria were enrolled to receive third-line (3 L) atezolizumab plus cobimetinib (n = 14), or atezolizumab plus simlukafusp alfa q2w (n = 1) or q3w (n = 6). Primary endpoints were objective response rates (ORRs) per RECIST 1.1 and safety. RESULTS: ORRs were 7.1% with atezolizumab-simlukafusp alfa q2w, 8.7% with mFOLFOX6 (both 2 L; 0% in other arms), 14.3% with atezolizumab-cobimetinib, and 16.7% with atezolizumab-simlukafusp alfa q3w (both 3 L). Grade 3-5 adverse event rates were 53.3% (2 L atezolizumab-motixafortide), 64.3% (2 L atezolizumab-cobimetinib), 57.1% (2 L atezolizumab-simlukafusp alfa q2w), 53.3% (2 L atezolizumab-simlukafusp alfa q3w), 63.0% (2 L mFOLFOX6 or gemcitabine-nab-paclitaxel), 50.0% (3 L atezolizumab-cobimetinib), and 100% (3 L atezolizumab-simlukafusp alfa q3w). CONCLUSIONS: The overall safety of atezolizumab combinations was manageable and consistent with each agent's known safety profile. This novel trial design enabled rapid evaluations of 3 atezolizumab combinations; all had limited efficacy as 2 L or 3 L treatment for metastatic PDAC. New treatments are needed to improve outcomes in previously treated PDAC.