What is the first-line therapy for metastatic colorectal cancer (CRC)?

From the Guidelines

First-line therapy for metastatic colorectal cancer typically involves combination chemotherapy regimens with targeted agents based on the patient's molecular profile, with the most recent guidelines from 2024 1 supporting the use of FOLFOX or FOLFIRI with a biologic agent. The standard backbone consists of either FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan), often combined with a biologic agent. Some key points to consider when selecting a first-line therapy include:

• For RAS wild-type tumors, an anti-EGFR antibody like cetuximab (initial dose 400 mg/m² followed by 250 mg/m² weekly) or panitumumab (6 mg/kg every 2 weeks) may be added, as supported by studies such as the PRIME trial 1.
• For RAS-mutated tumors, bevacizumab (5 mg/kg every 2 weeks) is typically preferred, as indicated in the 2021 NCCN guidelines 1.
• Treatment is usually administered in 2-week cycles and continued until disease progression or unacceptable toxicity.
• Before starting treatment, patients should undergo molecular testing for RAS, BRAF mutations, and microsatellite instability status to guide therapy selection, as recommended in the 2024 NCCN guidelines 1.
• The choice between FOLFOX and FOLFIRI is often based on side effect profiles, with FOLFOX causing neuropathy and FOLFIRI causing more diarrhea and alopecia. These regimens improve survival by targeting both rapidly dividing cancer cells (chemotherapy) and tumor blood supply or growth signaling pathways (biologics), with the goal of reducing morbidity, mortality, and improving quality of life.

From the FDA Drug Label

1. 1 Metastatic Colorectal Cancer First-Line Therapy in Combination with 5-FU/LV: Studies 1 and 2 Two phase 3, randomized, controlled, multinational clinical trials support the use of irinotecan hydrochloride injection as first-line treatment of patients with metastatic carcinoma of the colon or rectum.

In each study, combinations of irinotecan with 5-FU and LV were compared with 5-FU and LV alone

Study 1 compared combination irinotecan/bolus 5-FU/LV therapy given weekly with a standard bolus regimen of 5-FU/LV alone given daily for 5 days every 4 weeks;

Study 2 evaluated two different methods of administering infusional 5-FU/LV, with or without irinotecan

The first line therapy for metastatic colorectal cancer is irinotecan in combination with 5-FU/LV 2.

• The combination of irinotecan with 5-FU and LV has been shown to result in significant improvements in objective tumor response rates, time to tumor progression, and survival when compared with 5-FU/LV alone.
• This combination can be administered using different schedules, including weekly bolus or every-2-week infusional regimens.
• The use of irinotecan as a first-line treatment for metastatic colorectal cancer is supported by two phase 3, randomized, controlled clinical trials.

From the Research

First-Line Therapy for Metastatic Colorectal Cancer

• The first-line therapy for metastatic colorectal cancer (mCRC) relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile 3.
• Chemotherapy doublets or triplets, and the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents are commonly used in the treatment of mCRC 3, 4, 5.
• The standard first-line regimen for mCRC is a combination of chemotherapy plus a biological agent either targeting the main angiogenic growth factor vascular endothelial growth factor (VEGF) via Bevacizumab or by antibodies targeting the epidermal growth factor receptor (EGFR) via Panitumumab or Cetuximab 6.

Targeted Therapies

• The use of anti-VEGF and anti-EGFR antibodies in combination with doublet and triplet chemotherapy has shown improved progression-free survival (PFS) and overall response rates (ORR) in patients with mCRC 4, 5, 7.
• The efficacy of EGFR-antibodies is restricted to patients whose tumors are RAS wild-type (WT), and their use is recommended for patients with left-sided tumors 5, 6.
• The RAS-mutation status is not predictive for VEGF-inhibitors, and anti-VEGF antibodies have shown improved PFS in combination with chemotherapy doublets or triplets 5, 6.

Treatment Options

• FOLFOX-4 (oxaliplatin, leucovorin, and fluorouracil) with or without cetuximab is a commonly used first-line treatment for mCRC 4, 7.
• The addition of cetuximab to FOLFOX-4 has shown a clinically significant increased chance of response and a lower risk of disease progression in patients with KRAS wild-type tumors 4.
• Intensified regimens, such as FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), can be offered initially to unresectable patients to achieve resectability, but at a higher price of toxicity 5.