The Phase II study single-centre study, evaluating the triplet combination of FOLFOXIRI + bevacizumab + nivolumab in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial.
Nivolumab Mechanism of Action: Antibody-dependent cell cytotoxicity; Programmed cell death-1 receptor antagonists; T lymphocyte stimulants
In 2017, USFDA gave accelerated approval to OPDIVO drug to treat patients with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed following treatment with FOLFOXIRI. Currently, nivolumab is being evaluated with chemotherapy and bevacizumab to treat first-line patients with RAS/BRAF mutation, where bevacizumab + chemotherapy is the current standard of care (SOC).
At the data cutoff in December 2021, 73 patients were enrolled in 9 Italian centres. The mDOR was 8.4 months. The mPFS was 10.1 months, and 12-months PFS was 53.4%.
In subgroups analysis of MSS patients, the ORR was 78.9% with an mDOR of 7.59 months, DCR of 96.2%, and mPFS of 9.8 months. The ORR has been achieved in 100% patients dMMR patients and in only 29% of the pMMR patients. The main grade (G) 3 -4 toxicities were: neutropenia (G3 21.9%, G4 15.1%), diarrhea (G3 17.8%, G4 1.4%), hypertension G3 (6.8%), fatigue G3 (6.8%), and febrile neutropenia G4 (4.1%).
“The safety run-in results of the NIVACOR trial do not raise concerns regarding the co-administration of chemotherapy (FOLFOXIRI) / bevacizumab), and nivolumab.”–Expert Opinion.
Despite recent advancements in cancer management, colorectal cancer (CRC) remains the top cause of cancer-related deaths in the United States and globally. Like many other cancers, CRC is a diverse illness with many subtypes defined by genetic differences. The BRAF gene is mutated frequently in CRC (most commonly V600E substitution). Despite a rapidly increasing therapeutic arsenal, the overall survival (OS) for metastatic colorectal cancer (mCRC) patients did not routinely exceed 18–20 months until a few years ago. These outcomes have been transformed by targeted medicines, which have resulted in a significant rise in response rate (RR), progression-free survival (PFS), and overall survival (OS).
The FDA has only approved anti-PD-1 monoclonal antibodies for DNA mismatch repair-deficient/microsatellite instability-high (MMRd/MSI-H) mCRC, accounting for a small percentage of all mCRC. The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab and FOLFOXIRI + bevacizumab in patients with good performance status. The current trial is evaluating the efficacy of anti-PD1 therapy with current SOC proven to be beneficial and efficacious for first-line RAS/BRAF patients who previously had an unmet need of lack of any targeted therapy. Further evaluation of this regimen, if proved efficacious, can become a new SOC.
The primary endpoint Overall response rate (ORR) was met in the ITT population (BRAF and RAS mutated), and the response rate endpoint was met in the MSS group.