Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab as first-line treatment in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial (GOIRC-03-2018).
Authors: Damato Angela , Bergamo Francesca , Antonuzzo Lorenzo , Nasti Guglielmo , Pietrantonio Filippo , Tonini Giuseppe , Maiello Evaristo , Bordonaro Roberto , Rosati Gerardo , Romagnani Alessandra , Iachetta Francesco , Larocca Mario , Maglietta Giuseppe , Normanno Nicola , Pinto Carmine 
Published: June 2022

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Background: FOLFOXIRI plus bevacizumab (BEV) represents standard chemotherapy in first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). The NIVACOR study evaluates the addition of nivolumab (NIV) to FOLFOXIRI/BEV as first-line therapy in mCRC RAS/BRAF mut pts regardless of MSS/MSI status. Methods: This is a single-arm, multicenter, open-label, phase II trial in first-line treatment of pts with mCRC RAS/BRAF mut. Pts received NIV at a flat dose of 240 mg q14 days, FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil CI 3,200 mg/m2 for 48 hours) in combination with BEV at the dose of 5 mg/kg IV q14 days for eight cycles and then, the maintenance with BEV/NIV until PD or unacceptable toxicities. The primary endpoint was the ORR according to RECIST 1.1 Criteria. All images are reviewed by Independent Data Monitoring Committee. According to Fleming’s design with alpha and beta levels of 0.05 and 0.2 respectively, in a sample size of 73 pts (comprehensive of a 10% drop-out rate), at least 56 responses were necessary to not reject the alternative hypothesis of an ORR=0.80. Results: From October 2019 to March 2021, 73 pts were enrolled in 9 Italian centers. The median age was 60 (51-65) years and 50.7% were male; the main primary tumor side was right (50.7%). The molecular characterization was: 87.7% RAS mut, 16.2% BRAF mut, and 4.5% both RAS and BRAF mut; 10/62 were MSI (16.1%), 52/62 (83.9%) MSS, and 11 pts not assessed. Liver metastases were present in 56.2% pts. The median follow-up was 14.3 (IQR 11.5-16.5) months on December 31, 2021. The median (m) duration of treatment was 12 (8-17) cycles. The ORR was 76.7%, with 7(9.6%) CR and 49(67.1%) PR. SD were 15(20.6%) with a DCR of 97.3%; 2(2.7%) pts were not evaluable. The mDOR was 8.4 (95%CI, 7-NE) months. The mPFS was 10.1 months (95%CI, 9.4-NE) and 12-months PFS was 53.4%. At data cut-off, 65 (89.1%) pts are still alive. In subgroups analysis of MSS pts the ORR was 78.9% with a mDOR of 7.59 (95% CI 6.21 -11.43) months, DCR of 96.2%, and mPFS of 9.8 (95%CI 8.18-15.24) months. The surgery of the primary tumor, metastases, or both was performed in 6(8.2%), 9(9.6%), and 5(6.9%) of pts, respectively. 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%). Conclusions: The primary endpoint ORR was met. These results show the preliminary efficacy and safety of NIV in combination with FOLOXIRI/BEV as first-line therapy in pts with mCRC RAS/BRAF mut. Also, promising activity was observed in MSS subgroup pts. These data support the conduction of phase III randomized-controlled study. Research Sponsor: Bayer, Bristol Myers-Squibb. Clinical trial information: NCT04072198.