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Cyramza ® (ramucirumab)
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Cyramza® (ramucirumab): The RELAY study
Cyramza in combination with erlotinib is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutations.
Study Design
The RELAY trial was a phase 3, global, multicenter, randomized, double-blind, placebo-controlled trial in patients (N=449) with previously untreated EGFR mutation-positive, metastatic NSCLC. All patients had an EGFR mutation of exon 19 deletion or exon 21 L858R and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by sex, region, EGFR mutation type, and EGFR testing method) to receive treatment with erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks; n=224) or placebo (every 2 weeks; n=225) until disease progression or unacceptable toxicity.1
Efficacy Results
Patients treated with ramucirumab plus erlotinib had a significantly longer median PFS (investigator-assessed) than patients treated with placebo plus erlotinib (19.4 months vs 12.4 months; HR=0.59; 95% CI: 0.46-0.76; p<.0001). A consistent PFS benefit was also observed in an independent, blinded central review (HR=0.671; 95% CI: 0.518-0.869; p=.0022) as well as in both EGFR mutation types (exon 19 deletion [HR=0.65; 95% CI: 0.47-0.90; p=.0098] and exon 21 L858R [HR=0.62; 95% CI: 0.44-0.87; p=.0060]).1
The median interim OS and PFS2 have not yet been reached for either treatment group.1
Efficacy endpoint results are summarized in Table 1.
Table 1. Efficacy Endpoint Results1
Endpoint |
RAM
+ ERL |
PBO
+ ERL |
Median PFSa, mo (95% CI) |
19.4 |
12.4 |
HR (95% CI); p value |
0.59 (0.46-0.76); p<.0001 |
|
1-yr PFS, % (95% CI) |
71.9 (65.1-77.6) |
50.7 (43.7-57.3) |
ORRb (CR + PRc), % (95% CI) |
76 (71-82) |
75 (69-80) |
CR, n (%) |
3 (1) |
2 (1) |
PR, n (%) |
168 (75) |
166 (74) |
SD, n (%) |
42 (19) |
47 (21) |
DCR (CR + PR + SD), % (95% CI) |
95 (92-98) |
96 (93-98) |
Median DOR, mo (95% CI) |
18.0 (13.9-19.8) |
11.1 (9.7-12.3) |
HR (95% CI); p valued |
0.62 (0.48-0.81); p=.0003 |
Abbreviations: CR = completed response; DCR = disease control rate; DOR = duration of response; ERL = erlotinib; HR = hazard ratio; ORR = objective response rate; PBO = placebo; PD = progressive disease; PFS = progression-free survival; PR = partial response; RAM = ramucirumab; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.
a Investigator-assessed. A consistent PFS benefit was observed in the sensitivity analysis of PFS by independent, blinded central review (HR=0.671; 95% CI: 0.518-0.869; p=.0022).
b Response rate assessed using RECIST 1.1 at baseline, every 6 weeks for the first 72 weeks, and then every 12 weeks thereafter.
c Treatment difference, CR or PR, was estimated with the stratified method of Miettinen and Nurminen.
Safety Results
In the ramucirumab plus erlotinib group compared to the placebo plus erlotinib group
grade ≥3 TEAEs were reported in 72% of patients vs 54% of patients, and
any grade TE-SAE were reported in 29% of patients vs 21% of patients.1
Treatment-emergent adverse events that occurred in ≥20% of patients are summarized in Table 2.
Table 2. Treatment-Emergent Adverse Events Occurring in ≥20% of Patients1,2
TEAE |
Any
Gradea |
Grade ≥3 |
Any
Gradea |
Grade ≥3 |
RAM
+ ERL |
PBO
+ ERL |
|||
Diarrhea |
155 (70) |
16 (7) |
160 (71) |
3 (1) |
Dermatitis acneiform |
149 (67) |
33 (15) |
153 (68) |
20 (9) |
Paronychia |
118 (53) |
9 (4) |
114 (51) |
7 (3) |
Hypertension |
100 (45) |
52 (24) |
27 (12) |
12 (5) |
Increased ALT |
94 (43) |
19 (9)b |
70 (31) |
17 (8)c |
Stomatitis |
92 (42) |
4 (2) |
82 (36) |
3 (1) |
Increased AST |
92 (42) |
11 (5) |
58 (26) |
10 (4)d |
Dry skin |
83 (38) |
1 (<1) |
91 (40) |
5 (2) |
Alopecia |
75 (34) |
0 |
44 (20) |
0 |
Proteinuria |
75 (34) |
6 (3) |
19 (8) |
0 |
Epistaxis |
74 (33) |
0 |
27 (12) |
0 |
Blood bilirubin increased |
68 (31) |
3 (1) |
70 (31) |
2 (1) |
Decreased appetite |
57 (26) |
6 (3) |
47 (21) |
4 (2) |
Nausea |
57 (26) |
2 (1) |
44 (20) |
2 (1) |
Pruritus |
51 (23) |
2 (1) |
66 (29) |
2 (1) |
Peripheral edema |
50 (23) |
2 (1) |
10 (4) |
0 |
Cough |
48 (22) |
1 (<1) |
35 (16) |
0 |
Pyrexia |
47 (21) |
0 |
28 (12) |
1 (<1) |
Rash |
39 (18) |
2 (1) |
54 (24) |
5 (2) |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ERL = erlotinib; ILD = interstitial lung disease; PBO = placebo; RAM = ramucirumab; TEAE = treatment-emergent adverse event.
a No deaths were reported due to TEAEs occurring in at least 20% of participants; 1 death occurred on study and was because of a pulmonary hemorrhage event of hemothorax; 1 patient in the placebo group had a fatal event of ILD more than 30 days after treatment discontinuation.
b Includes 2 patients (1%) with grade 4 events.
c Includes 3 patients (1%) with grade 4 events.
d Includes 1 patient (<1%) with a grade 4 event.
1. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. https://doi.org/10.1016/S1470-2045(19)30634-5
2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Glossary
ECOG = Eastern Cooperative Oncology Group
EGFR = epidermal growth factor receptor
HR = hazard ratio
NSCLC = non-small cell lung cancer
OS = overall survival
PFS = progression-free survival
PFS2 = time from randomization to 2nd disease progression (defined as objective radiological or symptomatic progression after start of additional systematic anticancer treatment), or death from any cause, whichever comes first
PS = performance status
TEAE = treatment-emergent adverse event
TE-SAE = treatment-emergent serious adverse events
Datum fӧr senaste ӧversyn 2019 M11 11