A study published in ESMO Open evaluated the efficacy of ramucirumab plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) in second-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with an anti-vascular epidermal growth factor receptor (EGFR) antibody.
The study was a nonrandomized phase 2 trial that enrolled 92 patients with RAS wild-type mCRC. Enrolled patients had received a first-line anti-EGFR antibody in combination with a doublet or triplet chemotherapy regimen. Patients were eligible if they did not obtain early tumor shrinkage (ETS) after first-line treatment. The primary end point was 6-month progression-free survival (PFS), and secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of ETS, and safety.
Treatment was administered on a 2-week cycle, where on day 1 patients received intravenous (IV) RAM (8 mg/kg) followed by the FOLFIRI regimen (IV irinotecan 150 mg/m2, followed by or concurrent with IV levofolinate 200 mg/m2, followed by IV bolus fluorouracil 400 mg/m2, and then 2400 mg/m2 given as a continuous infusion over 48 hours). Treatment continued until radiographic confirmation of disease progression.
At data cutoff, the median number of treatment cycles was 11. Sixty-three patients (70.0%) discontinued treatment due to disease progression; 13 (14.4%) discontinued due to delayed administration (>28 days) due to adverse events; 6 (6.7%) discontinued due to adverse events; 4 (4.4%) discontinued due to withdrawal of patient consent; and 4 (4.4%) discontinued due to other reasons.
The 6-month PFS rate was 58.2% (90% CI, 49.3-66.2). Median PFS was 7.0 months (95% CI, 5.7-7.6), and median OS was 23.6 months (95% CI, 16.5-26.3). Six-month PFS was 58.3% and 57.9% in patients who had received doublet and triplet regimens in the first line, respectively. Median PFS was significantly longer for patients who had received a doublet regimen compared with a triplet regimen (7.4 vs 6.4 months; P=.036).
Regarding treatment response, 1 patient (1.2%) achieved a complete response and 8 (9.5%) achieved a partial response. The confirmed ORR was 10.7% (95% CI, 4.1-17.3). For the remaining 64 patients, the disease control rate was 86.9% (95% CI, 79.7-94.1). Fourteen patients achieved ETS at the final assessment. In a subgroup analysis of patients with and without ETS, the median PFS in patients with ETS was 10.5 months (95% CI, 5.7-18.4) and in patients without ETS, median PFS was 6.4 months (95% CI, 5.3-7.4 months; P=.057).
No treatment-related deaths occurred. The most common adverse event was grade 3 or 4 neutropenia, which occurred in 47.8% of patients. Three patients (3.3%) had grade 3 febrile neutropenia. The most common grade 3 or 4 nonhematological toxicities were hypertension (27.2%), hypoalbuminemia (13.1%), anorexia (2.2%), and pneumonitis (2.2%). All-grade proteinuria and thromboembolism, which the authors noted were considered adverse events related to ramucirumab, occurred in 33.7% and 1.1%, respectively, and no grade 3 or 4 cases occurred.
The authors concluded, “This study is the first prospective trial to demonstrate the efficacy of anti-VEGF antibody combination chemotherapy as second-line therapy after first-line combination chemotherapy with anti-EGFR antibody in patients with RAS wild-type mCRC. Our results indicate that anti-VEGF antibody, including ramucirumab plus FOLFIRI, is a clinically useful second-line treatment for patients with RAS wild-type, left-sided primary mCRC and is the first treatment regimen to demonstrate efficacy and safety, specifically after first-line anti-EGFR antibody combination therapy.”