Anti-MEK and Anti-EGFR mAbs in RAS-Mutant Metastatic Colorectal Cancer: Case Series and Rationale.

KRAS (Kirsten rat sarcoma viral oncogene) or BRAF (v-raf murine sarcoma viral oncogene homolog B1) constitutive activation leads to anti-EGFR (epidermal growth factor receptor) therapy resistance of metastatic colorectal cancer patients. In this article we investigate the effects of anti-MEK (mitogen-activated protein kinase) antibody (trametinib) combined with anti-EGFR (cetuximab) on colon cancer cell lines with different RAS statuses. Even though cetuximab has no effect on RAS cell viability and ERK (extracellular-signal-regulated kinase) phosphorylation (one of the last kinases of the EGFR pathway), trametinib can induce cell death and inhibit the activation of ERK alone or in combination with cetuximab. In a more pathologic context, we observed that KRAS colon cancer patient biopsies treated ex vivo with trametinib and cetuximab also present less ERK phosphorylation. Finally, nine ovarian, endometrial and colon cancer patients with different KRAS statuses were treated with anti-EGFR/anti-MEK combination off label after molecular tumor board decision. KRAS exon 2 patients have significantly longer PFS (progression-free survival) than with previous lines of treatments. We believe that such observations provide a rationale for designing a clinical trial to test this association in RAS exon 2 mutated cancers.

Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer.

BACKGROUND: 5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. 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 oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy. METHODS: This phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six 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 progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, ß=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.