SO-4 phase Ib/II, open-label, randomised evaluation of atezolizumab plus RO6874281 vs control in MORPHEUS–pancreatic ductal adenocarcinoma

The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. RO6874281, also known as fibroblast activation protein-α–targeted interleukin-2 variant (FAP-IL2v), is an engineered immunoglobulin-cytokine fusion protein that binds to tumour stroma with high affinity and targets IL-2v in the tumour microenvironment. IL-2v is designed to activate and expand immune effector cells in the absence of regulatory T-cell activation. In pancreatic ductal adenocarcinoma (PDAC), FAP is highly expressed in the stroma. Because preclinical studies demonstrated that RO6874281 combined with an anti–PD-L1 antibody resulted in enhanced survival, the combination of atezolizumab plus RO6874281 was evaluated in second-line (2L) patients with metastatic (m) PDAC. In MORPHEUS-PDAC (NCT03193190), eligible 2L patients with mPDAC were enrolled. Patients in the atezolizumab plus RO6874281 arms received either atezolizumab (1200 mg intravenous [IV]) plus RO6874281 (10 mg IV) Q3W or atezolizumab (840 mg IV) plus RO6874281 (15 mg IV) Q2W. Control treatment was mFOLFOX6 or gemcitabine plus nab-paclitaxel (Gem/nab-pac). Primary endpoints were objective response rate (ORR; investigator-assessed RECIST 1.1) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Patients randomised to a 2L treatment arm without RO6874281 could receive atezolizumab plus RO6874281 as third-line (3L) treatment after disease progression or loss of clinical benefit while on previous treatment. The interim analysis data cutoff date was 14 October 2019. Fifteen patients received atezolizumab plus RO6874281 Q3W, and 14 received atezolizumab plus RO6874281 Q2W. In the control arm, 23 patients received mFOLFOX6, and 23 received Gem/nab-pac. The best overall response was 2 patients with stable disease (SD; ORR, 0%) in the Q3W arm, and 1 partial response (PR) and 2 SD (ORR, 7.1%) in the Q2W arm. In comparison, 1 PR and 19 SD (ORR, 2.2%) occurred in the control arm. Median PFS was 1.4 mo (95% CI: 1.4, 2.7) in the Q3W arm, 1.5 mo (95% CI: 1.3, 1.6) in the Q2W arm and 2.5 mo (95% CI: 1.6, 4.1) in the control arm. OS is not yet mature and will be provided. Treatment-related adverse events (AEs, grade 1-4) occurred in 13 Q3W patients (86.7%), 13 Q2W patients (92.9%) and 39 control patients (84.8%). No grade 5 AEs occurred in either of the atezolizumab plus RO6874281 treatment arms, and 1 (2.2%) grade 5 AE occurred in the control arm. Three patients (21.4%) in the Q2W arm and 29 (63.0%) in the control arm had dose modifications or interruptions due to treatment-related AEs of any grade. One patient (2.2%) in the control arm withdrew from treatment due to a treatment-related AE. Biomarker, PK and 3L data will also be presented. Atezolizumab plus RO6874281 resulted in limited responses in mPDAC and was not able to significantly overcome barriers to response; similar to other checkpoint inhibition studies in pancreatic cancer. The observed AEs from atezolizumab plus RO6874281 were consistent with the current known risks of both study drugs.