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

Efficacy Outcomea	FOLFIRI + Ramucirumab (n=267)	FOLFIRI + Placebo (n=275)	FOLFIRI + Ramucirumab (n=269)	FOLFIRI + Placebo (n=261)
	KRAS Wild-Type		KRAS Mutant
Median OS, months (95% CI)	14.4 (12.7-16.1)	11.9 (10.8-13.3)	12.7 (11.6-14.0)	11.3 (10.6-12.9)
HR (95% CI); p valueb	0.82 (0.67-1.0); .049		0.89 (0.73-1.09); not significant
Interaction p value	Not significant
Median PFS, months (95% CI)	5.7 (5.5-6.2)	4.7 (4.2-5.6)	5.6 (5.1-6.8)	4.3 (4.1-5.4)
HR (95% CI); p valueb	0.77 (0.65-0.92); .004		0.84 (0.70-1.00); not significant
Interaction p value	Not significant

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

Preferred Term	KRAS WT (n=263) n (%)	KRAS Mutant (n=266) n (%)	KRAS WT (n=269) n (%)	KRAS Mutant (n=259) n (%)
	FOLFIRI + Ramucirumab		FOLFIRI + Placebo
Neutropeniaa	155 (58.9)b	156 (58.6)b	131 (48.7)	110 (42.5)
Fatigue	144 (54.8)	161 (60.5)b	143 (53.2)	132 (51.0)
Diarrhea	155 (58.9)b	161 (60.5)	132 (49.1)	139 (53.7)
Hypertension	64 (24.3)b	72 (27.1)b	18 (6.7)	27 (10.4)
Stomatitis	85 (32.3)b	78 (29.3)	45 (16.7)	65 (25.1)
Abdominal paina	66 (25.1)	74 (27.8)	70 (26.0)	69 (26.6)
Thrombocytopeniaa	75 (28.5)b	75 (28.2)b	39 (14.5)	33 (12.7)
Vomiting	80 (30.4)	74 (27.8)	71 (26.4)	73 (28.2)
Nausea	125 (47.5)	137 (51.5)	128 (47.6)	143 (55.2)
Decreased appetite	95 (36.1)	103 (38.7)b	80 (29.7)	64 (24.7)
Anemiaa	38 (14.4)	48 (18.0)	48 (17.8)	62 (23.9)
Constipation	64 (24.3)	87 (32.7)	56 (20.8)	64 (24.7)
Peripheral edema	51 (19.4)b	57 (21.4)b	25 (9.3)	23 (8.9)
Epistaxis	81 (30.8)b	96 (36.1)b	36 (13.4)	43 (16.6)
Alopecia	70 (26.6)	85 (32.0)	86 (32.0)	79 (30.5)

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

Preferred Term	KRAS WT (n=263) n (%)	KRAS Mutant (n=266) n (%)	KRAS WT (n=269) n (%)	KRAS Mutant (n=259) n (%)
	FOLFIRI + Ramucirumab		FOLFIRI + Placebo
Neutropeniaa	96 (36.5)b	107 (40.2)b	65 (24.2)	58 (22.4)
Fatigue	30 (11.4)	31 (11.7)b	24 (8.9)	17 (6.6)
Diarrhea	28 (10.6)	29 (10.9)	26 (9.7)	25 (9.7)
Hypertension	25 (9.5)b	32 (12.0)b	5 (1.9)	10 (3.9)
Stomatitis	13 (4.9)	7 (2.6)	7 (2.6)	5 (1.9)
Abdominal paina	8 (3.0)	10 (3.8)	11 (4.1)	8 (3.1)
Thrombocytopeniaa	10 (3.8)b	6 (2.3)	2 (0.7)	2 (0.8)
Vomiting	6 (2.3)	9 (3.4)	6 (2.2)	7 (2.7)
Nausea	7 (2.7)	6 (2.3)	4 (1.5)	10 (3.9)
Decreased appetite	6 (2.3)	7 (2.6)	6 (2.2)	4 (1.5)
Anemiaa	2 (0.8)b	6 (2.3)	13 (4.8)	6 (2.3)

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