5-Fluorouracil plus irinotecan or oxaliplatin with target therapy are standard 1st line therapy for metastatic colorectal cancer (mCRC). 5-Fluorouracil plus oxaliplatin are known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that blocks programmed cell death ligand 1 (PD-L1) binding to its receptor (PD-1). Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to FOLFOX increases treatment efficacy.
After a phase I with 9 patients, this phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients (pts) with good performance status pts (ECOG < 2) with untreated, RAS mutational status mCRC. Prior adjuvant therapy is allowed provided recurrence is > 6 months post-completion. Assuming no safety concerns the study will go on to include 39 additional pts. Pts will receive folinic acid/5-fluorouracil (400mg/m2 as bolus followed by 2400mg/m2 as a 46h infusion)/Oxaliplatin (85mg/m2) q14 days with D (750 mg) D1 q 14 days and T (75 mg) D1q 28 days. After 6 cycles of FOLFOX only, D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to PFS; secondary endpoints include overall response rate and quality of life.
9 patients were enrolled in the phase I. Grade 3-4 treatment-related adverse events occurred in 3 of 9 patients. The most common treatment-related grade 3-4 adverse events were neutropenia and diarrhea. No patients discontinued due to a drug-related adverse event. First clinical outcomes have shown 4 patients with partial response, 3 patients with stable disease and 2 patients with progression disease. Ancillary analysis were performed.
FOLFOX/D/T was tolerable with manageable toxicity. Preliminary results have shown encouraging clinical outcome. The results of this phase I study have led to phase II study which are ongoing.
NCT03202758.
Nicolas Isambert.
AstraZeneca.
All authors have declared no conflicts of interest.