Cyramza® (Ramucirumab)

Para consultar la información para prescribir completa de Cyramza® (Ramucirumab) de clic en el siguiente enlace: Información para prescribir

La información es proporcionada en respuesta a su solicitud, y puede contener datos relacionados a dosis, usos, formulaciones y poblaciones diferentes a la Información para Prescribir del producto. Consulte la Información para Prescribir en la liga que aparece arriba.

Ramucirumab: Efficacy and Safety According to EGFR Mutation Status in RELAY

A PFS benefit was observed in both EGFR mutation types.

MX_cFAQ_RAM122_RELAY_EFFICACY_SAFETY_ EGFR_MUTATION
MX_cFAQ_RAM122_RELAY_EFFICACY_SAFETY_ EGFR_MUTATION
es-MX

The information contained in this letter may not completely match the current local labeling for RAMUCIRUMAB. Please see local labeling approved in your country. 

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

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 EGFR mutation type and EGFR testing methods are summarized in Baseline EGFR Mutation Type and Testing Method Utilized in the RELAY Study.

Baseline EGFR Mutation Type and Testing Method Utilized in the RELAY Study1
Characteristic
RAM + ERL
(n=224)
PBO + ERL
(n=225)

EGFR mutation typea, n (%)

Exon 19 deletion

123 (55)

120 (53)

Exon 21 (L858R) mutation

99 (44)

105 (47)

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.

aDetermined by local testing. In the ramucirumab plus erlotinib arm, there was 1 patient (<1%) with a result of "missing" and 1 patient with a result of "other".

Patient Demographics and Baseline Characteristics According to EGFR Mutation Status

Baseline characteristics were generally balanced between the EGFR mutation subgroups, with the exception that the exon 21 mutation group had a higher proportion of

  • females (67% vs 60%)
  • people of Asian race (83% vs 72%), and
  • people with bone metastases (34% vs 26%).2

Patient demographics and baseline characteristics according to EGFR mutation status are summarized in Patient Demographics and Baseline Characteristics According to EGFR Mutation Status in the RELAY Study.

Patient Demographics and Baseline Characteristics According to EGFR Mutation Status in the RELAY Study2

Characteristica


RAM + ERL
(n=123)

PBO + ERL
(n=120)

RAM + ERL
(n=99)

PBO + ERL
(n=105)

Exon 19 Deletion

Exon 21 (L858R) Mutation

Female

74 (60)

72 (60)

66 (67)

70 (67)

Median age, year (range)

64 (27-84)

63 (23-83)

67 (44-86)

66 (41-89)

Raceb

Asian

89 (72)

85 (71)

81 (82)

89 (85)

White

34 (28)

33 (28)

18 (18)

15 (14)

Smoking history never

71 (58)

73 (61)

61 (62)

66 (63)

ECOG PS 0

65 (53)

66 (55)

50 (51)

53 (51)

Disease classification

Primary metastatic

103 (84)

104 (87)

91 (92)

87 (83)

Recurrent metastatic

20 (16)

16 (13)

8 (8)

18 (17)

Metastatic sites

Lung

112 (91)

112 (93)

93 (94)

95 (91)

Lymph

78 (63)

74 (62)

64 (65)

63 (60)

Bone

35 (29)

28 (23)

33 (33)

36 (34)

Liver

11 (9)

15 (13)

10 (10)

9 (9)

Other

70 (57)

76 (63)

48 (49)

56 (53)

Number of metastatic sites

1

12 (10)

17 (14)

9 (9)

14 (13)

2

50 (41)

40 (33)

46 (47)

40 (38)

3

50 (41)

49 (41)

32 (32)

42 (40)

4

11 (9)

9 (8)

9 (9)

6 (6)

≥5

0

5 (4)

3 (3)

3 (3)

Abbreviations: ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; ERL = erlotinib; PBO = placebo; PS = performance status; RAM = ramucirumab.

aData are presented as n (%) unless otherwise indicated.

bThe PBO + ERL arm included 3 other: 1 Black or African American, 1 missing (Ex19del group), and 1 American Indian or Alaska Native (Ex21L858R group).

Efficacy According to EGFR Mutation Status

The median (range) follow-up time was 20.7 (0.1-35.4) months. The improvement in PFS for the group of patients who received ramucirumab plus erlotinib was similar between patients with exon 19 deletion and patients with exon 21 (L858R) mutation.2

The 1-year PFS rate for exon 19 deletion patients was

  • 74% for ramucirumab plus erlotinib, and
  • 54% for placebo plus erlotinib.2

The 1-year PFS rate for exon 21 (L858R) mutation patients was

  • 70% for ramucirumab plus erlotinib, and
  • 47% for placebo plus erlotinib.2

Compared with placebo plus erlotinib, the improvement in median PFS for patients who received ramucirumab plus erlotinib was

  • 7.1 months for exon 19 deletion patients, and
  • 8.2 months for exon 21 (L858R) mutation patients.2

Efficacy results according to EGFR mutation status are summarized in Efficacy Results According to EGFR Mutation Status in the RELAY Study. At the time of interim analysis, OS data were immature as censoring rates were high (overall censoring rate was 82%).1 The final OS analysis will be conducted when a total of 300 events have occurred.3

Efficacy Results According to EGFR Mutation Status in the RELAY Study1-3

Outcome

RAM + ERL
(n=123)

PBO + ERL
(n=120)

RAM + ERL
(n=99)

PBO + ERL
(n=105)

Exon 19 Deletion

Exon 21 (L858R) Mutation

Median PFS, months (95% CI)

19.6 (15.1-22.2)

12.5 (11.1-15.3)

19.4 (14.1-21.9)

11.2 (9.6-13.8)

Unstratified HR (95% CI)

0.65 (0.47-0.90); p=.0098

0.62 (0.44-0.87); p=.0060

1-year PFS rate, % (95% CI)

74 (64.1-80.8)

54 (43.9-62.2)

70 (58.9-77.9)

47 (37.0-57.1)

ORR, % (95% CI)

79 (72-86)

83 (76-89)

74 (65-82)

66 (57-75)

DCR, % (95% CI)

96 (92-99)

96 (92-99)

95 (91-99)

95 (91-99)

Interim OS

1-year OS rate, % (95% CI)

94 (88-97)

94 (88-97)

92 (84-96)

93 (86-97)

2-year OS rate, % (95% CI)

83 (74-89)

87 (78-93)

84 (74-90)

71 (58-80)

Median TTRa, months (95% CI)

1.4 (1.3-2.6)

1.4 (1.3-1.7)

1.5 (1.4-1.7)

1.4 (1.3-1.6)

Median DORa, months (95% CI)

18.2 (13.8-20.9)

11.0 (9.7-12.3)

16.2 (12.5-20.1)

11.1 (9.7-12.7)

Unstratified HR (95% CI)

0.54 (0.38-0.77)

0.73 (0.49-1.08)

Response at 12 months, %

69

42

63

45

Response at 18 months, %

50

23

47

26

Median PFS2b, months (95% CI)

33.1 (28.1-NR)

NR

NR (26.6-NR)

26.3 (22.4-NR)

Unstratified HR (95% CI)

0.926 (0.577-1.485)

0.600 (0.371-0.969)

Median TTCTc, months (95% CI)

28.6 (26.2-33.7)

NR (25.3-NR)

NR (26.0-NR)

26.3 (18.7-30.7)

Unstratified HR (95% CI)

1.034 (0.682-1.567)d

0.554 (0.352-0.872)e

Rate of deathf, % (n)

17 (21)

13 (15)

16 (16)

26 (27)

Abbreviations: DCR = disease control rate; DOR = duration of response; EGFR = epidermal growth factor receptor; ERL = erlotinib; HR = hazard ratio; NR = not reached; ORR = overall response rate; PBO = placebo; PFS = progression-free survival; PFS2 = progression-free survival from randomization to progression (or death) on second-line systemic therapy; RAM = ramucirumab; TTCT = time-to-chemotherapy; TTR = time-to-response.

aFor TTR and DOR, in the exon 19 deletion subgroup: RAM + ERL, n=97 and ERL + PBO, n=99; in the exon 21 mutation subgroup: RAM + ERL, n=73 and ERL + PBO, n=69.

bPFS2 data were immature (overall censoring rate was 69%).

cGiven that exon 19 deletion is more common in Western patients, who were underrepresented in RELAY (only 28% of exon 19 deletion patients were white/Caucasian), results should be interpreted with caution.

dCensoring rate was 63%.

eCensoring rate was 61%.

fInterim data.

Kaplan Meier estimates of PFS according to EGFR mutation types are displayed in Kaplan-Meier Curve of PFS for Patients With Exon 19 Deletion and Kaplan-Meier Curve of PFS for Patients With Exon 21 Mutation.

Kaplan-Meier Curve of PFS for Patients With Exon 19 Deletion1

Abbreviations: ERL = erlotinib; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.

Kaplan-Meier Curve of PFS for Patients With Exon 21 Mutation1

Abbreviations: ERL = erlotinib; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.

Safety Results According to EGFR Mutation Status

All patients experienced at least 1 any-grade TEAE.2 Additional safety results according to EGFR mutation status are summarized in Safety Results According to EGFR Mutation Status.

Safety Results According to EGFR Mutation Status2,3

Outcome, n (%)

RAM + ERL
(n=122)

PBO + ERL
(n=120)

RAM + ERL
(n=97)

PBO + ERL
(n=105)

Exon 19 Deletion

Exon 21 (L858R) Mutation

Patients with at least 1 grade ≥3 TEAE

86 (71)

62 (52)

72 (74)

59 (56)

Patients with ≥1 SAE

38 (31)

19 (16)

26 (27)

28 (27)

Patients who discontinued study treatment due to AE

16 (13)

9 (8)

13 (13)

15 (14)

Patients who discontinued study treatment due to SAE

4 (3)

5 (4)

6 (6)

4 (4)

Deaths on study treatment due to AEa

0

0

2 (2)b

0

Abbreviations: AE = adverse event; EGFR = epidermal growth factor receptor; ERL = erlotinib; PBO = placebo; RAM = ramucirumab; SAE = serious adverse event; TEAE = treatment-emergent adverse events.

aDeaths are also included as SAEs and discontinuations due to AEs.

bOne death (hemothorax after a thoracic drainage for pleural empyema)​ was considered related to study treatment by the investigator.

Co-Occurring Genetic Variations According to EGFR Mutation Status

Genetic Variations at Baseline

The frequencies of altered genes co-occurring with exon 19 deletion and exon 21 mutation at baseline were

  • TP53 (43%)
  • additional EGFR variants (25%)
  • PIK3CA (10%)
  • NF1 (8%)
  • APC (7%)
  • BRAF (6%)
  • CDK6 (5%), and
  • MET (5%).4

No EGFR T790M mutations were present at baseline.4

The additional EGFR variants included

  • amplifications in 17% of patients
  • one splice-acceptor variant, and
  • 40 single-nucleotide variant alterations.4

Of the 40 single-nucleotide variant alterations,16 occurred in the tyrosine kinase domain (EGFR SNV Alterations in the Tyrosine Kinase Domain Co-occurring with Exon 19 Deletion or Exon 21 Mutation in the RELAY Study).4

EGFR SNV Alterations in the Tyrosine Kinase Domain Co-occurring with Exon 19 Deletion or Exon 21 Mutation in the RELAY Study4

Exon 18

Exon 19

Exon 20

Exon 21

E709G, G719S, F723F, V689M

E734K, E746G, L747P, V742I

I780L, I780M, I821I, R776H, S768I, S811F (n=2)

L861Q, V834L

Abbreviation: EGFR = epidermal growth factor receptor; SNV = single nucleotide variant.

The prevalence of TP53 and other EGFR co-mutations was similar at baseline regardless of the patients' EGFR-activating mutation type. The only genes with co-occurring variants having differential prevalence by EGFR-activating mutation subgroup were PIK3CA (12.7% for exon 19 deletion vs 7.2% for exon 21 mutation) and ERBB2 (1.5% for exon 19 deletion vs 6.1% for exon 21 mutation).2,3

Baseline alterations in TP53, PIK3CA, and other EGFR alterations co-occurring with exon 19 deletion or exon 21 mutation were prognostic markers for worse PFS.4

Patients with TP53 mutations who received ramucirumab plus erlotinib had improved PFS compared with patients who received placebo plus erlotinib for both EGFR mutation subgroups (Exon 19 deletion: 17.97 vs 9.86 months, HR=0.50; 95% CI: 0.29-0.85; Exon 21 mutation: 14.65 vs 10.84 months, HR=0.56; 95% CI: 0.34-0.95).3

In patients with wild type TP53, the benefits of treatment with ramucirumab plus erlotinib compared with ramucirumab plus placebo appear to be greater among patients with exon 21 mutations compared with patients with exon 19 deletions (median PFS, months—Exon 19 deletion: 20.57 vs 19.35, HR=1.00; 95% CI: 0.62-1.61; Exon 21 mutation: 20.76 vs 13.83, HR=0.60; 95% CI: 0.35-1.02).3

Treatment-Emergent Gene Alterations

The distribution of treatment-emergent gene alterations identified in post-study treatment discontinuation samples was similar among patients who received ramucirumab plus erlotinib and patients who received placebo plus erlotinib.4

The most frequently-occurring treatment-emergent alterations were EGFR, especially T790M, and TP53 (Treatment-emergent Gene Alterations in the RELAY Study).4

The frequency of treatment-emergent EGFR T790M alterations was higher in patients with baseline TP53 alterations (30%) than in patients without baseline TP53 alterations (16%).4

Treatment-emergent Gene Alterations in the RELAY Study4

Gene Alteration, % (95% CI)

Population 1a

Population 2b

RAM + ERL
(N=36)

PBO + ERL
(N=60)

RAM + ERL
(N=98)

PBO + ERL
(N=129)

EGFR

44 (30-60)

55 (43-67)

28 (20-37)

36 (29-45)

T790M

42 (27-58)

50 (38-62)

19 (13-28)

25 (18-33)

Amplification

6 (2-18)

13 (7-24)

3 (1-9)

8 (4-14)

Others

0

5 (2-14)

9 (5-17)

12 (7-18)

TP53

22 (12-38)

12 (6-22)

17 (11-26)

12 (8-19)

NF1

14 (6-29)

2 (<1-9)

7 (4-14)

2 (1-7)

APC

11 (4-25)

2 (<1-9)

5 (2-11)

2 (1-7)

MET

8 (3-22)

8 (4-18)

6 (3-13)

5 (3-11)

BRAF

3 (1-14)

10 (5-20)

3 (1-9)

5 (2-10)

Abbreviations: EGFR = epidermal growth factor receptor; ERL = erlotinib; PBO = placebo; RAM = ramucirumab.

Note: Includes gene alterations present in ≥6% of patients in the pooled arms for population 1.

aIncludes patients with disease progression in the post-study treatment discontinuation samples and detectable EGFR exon 19 deletion or exon 21 mutation at baseline and at post-study treatment discontinuation.

bIncludes patients who stopped study treatment for any reason by the post-study treatment discontinuation visit and had ≥1 gene alteration at baseline and at post-study treatment discontinuation.

Exon 20 Mutations

The safety and efficacy of ramucirumab in patients with exon 20 mutations alone or co-occurring with exon 19 deletion or exon 21 mutation have not been evaluated.

Reference

1Nakagawa 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

2Nakagawa K, Nadal E, Garon EB, et al. RELAY subgroup analyses by EGFR Ex19del and Ex21L858R mutations for ramucirumab plus erlotinib in metastatic non-small cell lung cancer. Clin Cancer Res. Published online July 22, 2021. https://dx.doi.org/10.1158/1078-0432.CCR-21-0273

3Nakagawa K, Nadal E, Garon EB, et al. RELAY, erlotinib plus ramucirumab in previously untreated, EGFR-mutated, metastatic NSCLC: Outcomes by EGFR mutation type. Poster presented at: Annual Meeting of the European Society for Medical Oncology (ESMO Virtual); September 19-21, 2020.

4Garon EB, Reck M, Nishio K, et al. RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation positive metastatic NSCLC: next generation sequencing (NGS) results. Poster presented at: American Association for Cancer Research (AACR 2020 Virtual); June 22-24, 2020.

Glossary

ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

ERBB2 = erb-b2 receptor tyrosine kinase 2

HR = hazard ratio

NSCLC = non-small cell lung cancer

OS = overall survival

PFS = progression-free survival

PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PS = performance status

T790M = Thr790Met

TEAE = treatment-emergent adverse event

TP53 = gene encoding tumor protein 53

Fecha de la última revisión: 2021 M07 26


Contáctenos para saber más de la información Médica de Lilly

Contacto vía correo electrónico

Correo electrónico: infomed@lilly.com

Envíe su consulta

Escriba su consulta