Second-Line Irinotecan/Cetuximab/Ramucirumab Combo Ups PFS in Advanced CRC

A combination of irinotecan, cetuximab, and ramucirumab may boost PFS in advanced CRC, when given after failure of oxaliplatin-and-bevacizumab–based therapy.

Combination therapy with irinotecan, cetuximab, and ramucirumab (ICR) may help prolong progression-free survival (PFS) when given as a second-line treatment for advanced colorectal cancer (CRC) following oxaliplatin-and-bevacizumab–based therapy, according to new data (abstract 3504) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago. Investigators found that an anti–vascular endothelial growth factor receptor (VEGFR) antibody combined with anti–epidermal growth factor receptor (EGFR) therapy and irinotecan may help extend PFS in patients with KRAS-selected, wild-type CRC who have undergone prior treatment with oxaliplatin and bevacizumab.

These findings could affect a significant number of patients, because the KRAS oncogene is mutated in approximately 35% to 45% of colorectal cancers. Howard S. Hochster, MD, from Rutgers Cancer Institute, New Brunswick, New Jersey, and colleagues conducted a randomized trial of irinotecan plus cetuximab (IC) vs ICR as second-line therapy following oxaliplatin-and-bevacizumab–based therapy to examine whether ramucirumab improved clinical outcomes in this setting ( identifier: NCT01079780).

There has been controversy over what may be the most appropriate regimen for second-line therapy following oxaliplatin-and-bevacizumab–based therapy. The investigators point out that both anti-VEGF(R) and EGFR antibodies have activity in metastatic KRAS wild-type CRC. However, when they were given together in another study, the combination had a detrimental effect. All patients in the current study had advanced and measurable CRC (by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and were progressing at the time of randomization. All had previously received FOLFOX or CAPOX (capecitabine and oxaliplatin) with bevacizumab as first-line therapy.

Patients were randomized to IC (I, 180 mg/m2; C, 500 mg/m2) or ICR (with R given at 8 mg/kg) every 2 weeks. However, a planned interim analysis showed excess grade 3 to 5 toxicity for the ICR arm after 35 patients were randomized. The trial was then altered, and the ICR arm was modified (I, 150 mg/m2; C, 400 mg/m2; and R, 6 mg/kg), and 102 patients were then randomized to IC or modified ICR between June 2014 and July 2017.

Among the 102 patients, 65% were male, 9% were black, and 8% were Hispanic. The median age was 60 years. Twenty-four percent had progressed while on oxaliplatin, and 15% of patients progressed more than 6 months after completion of treatment. The researchers found that the grade 3/4 overall toxicity for IC was 47% vs 54% for the modified ICR. The most common side effects were diarrhea (10% for patients treated with IC vs 15% for those treated with modified ICR), rash (13% for IC vs 8% for modified ICR) and neutropenia (9% for IC vs 10% for modified ICR).

Hochster and coinvestigators conducted a stratified log-rank analysis that showed a HR of 0.65 for PFS with modified ICR, compared with IC (overall median PFS, 5.8 months; P = .068), which met the primary endpoint of the study (of P < .15). They reported that overall survival appeared to be equal (median, 20.5 months). The researchers concluded that the antibodies against VEGFR and EGFR in this regimen may provide additional benefit in the appropriate patient population.       

Mehmet Sitki Copur, MD, of Saint Francis Cancer Center, Grand Island, Nebraska, commented on the trial results, saying, "In this randomized phase II study, the addition of anti-VEGFR2 antibody ramucirumab to irinotecan and cetuximab improved progression-free survival with some increased but manageable toxicities. Stratification factors of progression on FOLFOX and time since last treatment had enhanced effects, suggesting that prior negative results of this combination may have been due to use of this combination in unselected populations."