Cyramza® (ramucirumab): Effektivitet enligt EGFR-mutationsstatus i RELAY

Detailed Information

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 n=224	PBO + ERL n=225
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)	0.591 (0.461-0.760); p<.0001
ERL + PBO (n=225)	12.4 (11.0-13.5)
Exon 19 deletion
RAM + ERL (n=123)	19.6 (15.1-22.2)	0.651 (0.469-0.903)
ERL + PBO (n=120)	12.5 (11.1-15.3)
Exon 21 (L858R) mutation
RAM + ERL (n=99)	19.4 (14.1-21.9)	0.618 (0.437-0.874)
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 n (%)	Grade ≥3 n (%)	Any Gradea n (%)	Grade ≥3 n (%)
	RAM + ERL n=221		PBO + ERL n=225
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.

References

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