Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

Background: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC).
Patients and Methods: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m ² then 250 mg/m ² weekly) plus FOLFIRI [irinotecan 180 mg/m ² , leucovorin 400 mg/m ² , 5-fluorouracil 400 mg/m ² (bolus) then 2400 mg/m ² (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory.
Results: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups.
Conclusions: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.
Competing Interests: Disclosure JS has done speaking honoraria for Ipsen, Lilly, Merck, MSD, Pfizer, Roche, Shire and Servier, advisory roles for Amgen, Bayer, Bristol-Myers Squibb, Celgene, Ipsen, Merck, Roche, Sanofi and Servier, and received travelling and accommodation support from Ipsen and Merck. JMV reports grants, personal fees, non-financial support and other from Roche, non-financial support and other from Amgen, and non-financial support from Servier, Bristol-Myers Squibb, BTG and Sanofi outside the submitted work. JJR-Z has done consulting or advisory roles for Amgen, Archimedes, Bayer, Ipsen, Merck, Novartis, Pfizer, Prostrakan, Roche, Sanofi and Servier, and received travel, accommodation and expenses from Amgen, Bayer, Ipsen, Merck, Novartis, Prostrakan, Roche, Sanofi and Servier. MJS has done consulting or advisory roles for Amgen, Merck, Roche, Sanofi and Servier, and received travel, accommodation and expenses from Amgen, Merck and Roche. ALC has received travel, accommodation and expenses from Amgen. EP has done speaking honoraria for Amgen, Ipsen, Servier, Roche, Merck, Sanofi and received travel and accommodation from Merck, Roche, Ipsen, Novartis and Amgen. EAM has done advisory roles for Amgen, Roche, Merck, Bayer and Servier, speaking honoraria for Lilly, Roche and Amgen, and travel and accommodation from Roche, Amgen, Merck, Lilly and Servier. BGP reports personal fees and non-financial support from Sanofi, personal fees from Amgen, Advanced Accelerator Applications, Ipsen Pharma and Merck Serono, personal fees and non-financial support from Servier, Roche and Novartis outside the submitted work. RLL has stock and other ownership interests in MTrap and Nasasbiotech SL, has done consulting or advisory roles for Bayer, Bristol-Myers Squibb, Janssen, Lilly, MSD and Roche, done speakers' bureaus for Novartis and Roche, received institutional research funding from Lilly, Merck and Roche, and received travel, accommodation and expenses from Pierre Fabre, Roche and Tesaro. EA has done consulting or advisory roles for Amgen, Bayer, Celgene, Merck, Roche and Sanofi. EDR has done consulting or advisory roles for Amgen, Bayer, Genomica, Merck Serono and Servier, speakers' bureaus for MSD and Servier, and received research funding from Amgen, AstraZeneca, Merck Serono, Roche and Sysmex. PGA, MTC, FR, AS, GQ, LRD, SG, MG and MVA declare no competing interests. Data sharing The study data (i.e. de-identified participant data and datasets analysed for the present manuscript) are available from the corresponding author, Dr J. Sastre (e-mail: jsastrev@salud.madrid.org), on reasonable request and subject to approval from the lead investigators. Additional, related documents will also be available (study protocol, statistical analysis plan, informed consent form).
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