Cyramza® (ramucirumab): KRAS-Status i RAISE-Studien

Information from Summary of Product Characteristics

Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine.¹

Study Design

The RAISE trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that evaluated FOLFIRI and ramucirumab vs FOLFIRI and placebo in the second-line treatment of patients with mCRC who had progressed on first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomly assigned in a 1:1 ratio (stratified by region, KRAS mutation status, and time to progressive disease after beginning first-line treatment) to receive IV infusions of either FOLFIRI plus ramucirumab 8 mg/kg (n=536) or FOLFIRI plus placebo (n=536) once every 2 weeks.²

The KRAS mutation status (WT vs mutant) of each patient had to be known prior to randomization; however, patients were eligible to enroll irrespective of KRAS mutation status.² The study was not powered to detect differences between subgroups; however, a prespecified data analysis was conducted to determine if KRAS mutational status had an effect on the efficacy of treatment with ramucirumab. Patients were divided into two subgroups: KRAS WT (n=530) and KRAS mutant (n=542).³

Efficacy Results

The efficacy results according to KRAS mutational subgroups are summarized in Table 1

Table 1. Efficacy Outcomes According to KRAS Mutational Status³

Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.

^a The study was not powered for subgroup analysis.

^b Unstratified analysis.

Postdiscontinuation therapy with anti-EGFR therapy was found to be well balanced between treatment groups among KRAS-wild type patients (ramucirumab plus FOLFIRI: 132 patients [49.4%]; FOLFIRI plus placebo: 145 patients [52.7%]).⁴

Safety Results

All-grade TEAEs that occurred in at least 20% of patients in either treatment arm according to KRAS status are summarized below in Table 2.

Table 2. All-Grade TEAEs in ≥20% of Patients in Either Treatment Arm According to KRAS Status⁵

Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; KRAS = Kirsten rat sarcoma viral oncogene; TEAE = treatment-emergent adverse event; WT = wild-type.

^a Consolidated term.

^b p<.05 between treatment group comparison, Fisher's exact test.

Grade ≥3 TEAEs (graded by NCI-CTCAE v4.0) that occurred in at least 5% of patients in either treatment arm according to KRAS status are summarized below in Table 3.

Table 3. Grade ≥3 TEAEs in ≥5% of Patients in Either Treatment Arm According to KRAS Status⁵

Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; KRAS = Kirsten rat sarcoma viral oncogene; TEAEs = treatment-emergent adverse events; WT = wild-type.

^a Consolidated term.

^b p<.05 between treatment group comparison, Fisher’s exact test.

References

1. Cyramza [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508. http://dx.doi.org/10.1016/S1470-2045(15)70127-0

3. Obermannová R, Van Cutsem E, Yoshino T, et al. Subgroup analysis in RAISE: a randomized, double-blind phase 3 study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016;27(11):2082-2090. http://dx.doi.org/10.1093/annonc/mdw402. Accompanied by supplementary appendix available at: http://annonc.oxfordjournals.org/content/suppl/2016/08/28/mdw402.DC1/mdw402supp_table5.docx.

4. Obermannová R, Van Cutsem E, Yoshino T, et al. Subgroup analysis in RAISE: a randomized, double-blind phase 3 study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016;27(11):2082-2090. http://dx.doi.org/10.1093/annonc/mdw402

5. Van Cutsem E, Obermannová R, Bodoky G, et al. Subgroup analysis by KRAS status in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression during or following first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine [abstract and poster]. Eur J Cancer. 2015;51 (suppl 3):S365. http://dx.doi.org/10.1016/S0959-8049(16)31030-9

Glossary

CTCAE = Common Terminology Criteria for Adverse Events

EGFR = epidermal growth factor receptor

FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil 

IV = intravenous

KRAS = Kirsten rat sarcoma viral oncogene

mCRC = metastatic colorectal cancer

NCI = National Cancer Institute

OS = overall survival

TEAE = treatment-emergent adverse event

WT = wild-type