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Cyramza ® (ramucirumab)
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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 status, and EGFR testing method) to receive treatment with erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks; n=224) or placebo (10 mg/kg every 2 weeks; n=225) until disease progression or unacceptable toxicity.1
Assessment of EGFR Mutation Status
All patients were assessed for EGFR mutation status prior to study enrollment and all patients were required to have an EGFR mutation of exon 19 deletion or exon 21 L858R.1 Baseline patient characteristics related to EGFR status are summarized in Table 1.
Table 1. Patient Demographics and Baseline Characteristics Related to EGFR Status1
Characteristic |
RAM
+ ERL |
PBO
+ ERL |
EGFR mutation typea, n (%) |
||
Exon 19 deletion |
123 (55) |
121 (54) |
Exon 21 (L858R) mutation |
101 (45) |
104 (46) |
EGFR testing methoda, n (%) |
||
Therascreen® (Qiagen) and Cobas® (Roche) |
96 (43) |
101 (45) |
Other PCR and sequencing-based methods |
127 (57) |
124 (55) |
Abbreviations: EGFR = epidermal growth factor receptor; ERL = erlotinib; PBO = placebo; PCR = polymerase chain reaction; RAM = ramucirumab.
a Determined by local testing.
Efficacy According to EGFR Mutation Status
Efficacy results according to EGFR mutation status are summarized in Table 2
Table 2. Efficacy Results According to EGFR Mutation Status1
Endpoint |
Median PFS, mo (95% CI) |
HR (95% CI) |
ITT Populationa |
||
RAM + ERL (n=224) |
19.4 (15.4-21.6) |
|
ERL + PBO (n=225) |
12.4 (11.0-13.5) |
|
Exon 19 deletion |
||
RAM + ERL (n=123) |
19.6 (15.1-22.2) |
|
ERL + PBO (n=120) |
12.5 (11.1-15.3) |
|
Exon 21 (L858R) mutation |
||
RAM + ERL (n=99) |
19.4 (14.1-21.9) |
|
ERL + PBO (n=105) |
11.2 (9.6-13.8) |
Abbreviations: EGFR = epidermal growth factor receptor; HR = hazard ratio; ITT = intent-to-treat; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.
a Investigator-assessed PFS was the primary endpoint. 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=.002).
Kaplan Meier estimates of PFS according to EGFR mutation types are displayed in Figure 1 and Figure 2.
Figure 1. Kaplan-Meier Curve of PFS for Patients With Exon 19 Deletion1
Abbreviation: ERL = erlotinib; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.
Figure 2. Kaplan-Meier Curve of PFS for Patients With Exon 21 Mutation1
Abbreviation: ERL = erlotinib; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.
Safety Results
Safety results according to EGFR mutation status are not available; however, RELAY demonstrated that the safety profile of ramucirumab when used in combination with erlotinib was largely consistent with the known safety profiles of each of the individual treatment components in the disease setting of metastatic EGFR-mutated NSCLC. The percentage of patients discontinuing all study treatment due to an AE or an SAE was similar between treatment arms.1
Grade ≥3 TEAEs were reported in 72% of patients in the ramucirumab plus erlotinib group and 54% patients in the placebo plus erlotinib group.1 Treatment-emergent adverse events that occurred in ≥40% of patients are summarized in Table 3.
Table 3. Most Common (≥40%) TEAEs in Safety Population1
TEAE |
Any
Gradea |
Grade ≥3 |
Any
Gradea |
Grade ≥3 |
RAM
+ ERL |
PBO
+ ERL |
|||
Diarrhea |
155 (70) |
16 (7) |
160 (71) |
3 (1) |
Acneiform dermatitis |
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 (7)c |
Increased AST |
92 (42) |
11 (5) |
58 (26) |
10 (4)d |
Stomatitis |
92 (42) |
4 (2) |
82 (36) |
3 (1) |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ERL = erlotinib; PBO = placebo; RAM = ramucirumab; TEAE = treatment-emergent adverse event.
a No grade 5 events.
b Includes 2 patients (1%) with grade 4 events.
c Includes 3 patients (1%) with grade 4 events.
d Includes 1 patient (0.4%) 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
Glossary
AE = adverse event
ECOG = Eastern Cooperative Oncology Group
EGFR = epidermal growth factor receptor
NSCLC = non-small cell lung cancer
PFS = progression-free survival
PS = performance status
SAE = serious adverse event
TEAE = treatment-emergent adverse event
Datum fӧr senaste ӧversyn 2019 M06 03