Cyramza® (Ramucirumab)

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Ramucirumab: Exposure-Response Analysis in the RELAY Study

In RELAY, no statistically nor clinically significant relationship was observed between exposure and efficacy or safety.

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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

Exposure-Response Analysis

Methods for Exposure-Response Analysis

Pharmacokinetic samples to determine ramucirumab concentration in serum were collected predose and 1 hour postinfusion on day 1 of selected cycles.1,2 Ramucirumab-treated patients were divided into 4 quartiles defined as

  • Q1: Cmin,1 <25%
  • Q2: Cmin,1 25% to <50%
  • Q3: Cmin,1 50% to <75%, and
  • Q4: Cmin,1 ≥75%.1,2

A 2-compartment disposition PK model following a zero order infusion input rate was used to 

  • predict Cmin,1 and Cmin,ss 
  • evaluate the correlation between ramucirumab exposure and 
    • efficacy (PFS analyzed using multivariate Cox regression by Cmin,1 quartiles and case-matched controls) and 
    • safety (incidence rates for safety parameters by quartiles).2

Exposure-Efficacy Analysis

No statistically nor clinically significant relationship was observed between exposure and efficacy for the 10 mg/kg every 2 week dosing in the RELAY study.2 Progression-free survival according to quartile is summarized in Progression-Free Survival According to Cmin,1 Exposure Quartile.

Progression-Free Survival According to Cmin,1 Exposure Quartile2

Outcome

PBO + ERL
(n=225)

RAM + ERL
(n=224)

RAM + ERL Q1
(n=54)a

RAM + ERL Q2
(n=54)a

RAM + ERL Q3
(n=54)a

RAM + ERL Q4
(n=54)a

Median PFS, months

12.4

19.4

18.0

15.8

19.6

21.9

HR (95% CI)

0.591b (0.461-0.760); p<.0001c

0.671 (0.452-0.994)d

0.769 (0.528-1.120)d

0.566 (0.381-0.843)d

0.504 (0.334-0.759)d

Abbreviations: ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; ERL = erlotinib; HR = hazard ratio; PBO = placebo; PFS = progression-free survival; PS = performance status; RAM = ramucirumab.

aPatients with missing baseline covariate factors were omitted from the analysis. Adjusted for ECOG PS (0 vs 1).

bStratified by the randomization strata (EGFR mutation type, gender, region, and EGFR testing method).

cTreatment effect/difference/p values were computed based on comparator placebo plus erlotinib.

dMulitvariate Cox regression analysis. 

Exposure-Safety Analysis

Dose Intensity and Dose Adjustments

The relative dose intensity of ramucirumab or erlotinib was generally similar across the 4 exposure quartiles.2 No apparent relationship was observed between ramucirumab exposure and dose adjustments of 

  • ramucirumab (dose reduction, omission or delays) or
  • erlotinib (dose reduction and dose omission).2

The percentage of patients with dose adjustments of

  • ramucirumab in all 4 ramucirumab plus erlotinib quartiles was generally higher in the ramucirumab plus erlotinib arm (76%) compared with the placebo plus erlotinib arm (59%)
  • erlotinib was generally similar between the placebo plus erlotinib arm and all 4 ramucirumab plus erlotinib quartiles.2

Adverse Events According to Exposure 

No statistically nor clinically significant relationship was observed between exposure and safety for the 10 mg/kg every 2 week dosing in the RELAY study.2 Grade ≥3 TEAE and AESI according to quartile is summarized in Grade ≥3 TEAE and AESI According to Cmin,ss Exposure Quartile.

Grade ≥3 TEAE and AESI According to Cmin,ss Exposure Quartile2

PBO + ERL
(n=225)

RAM + ERL ITT
(n=225)

RAM + ERL Q1
(n=54)

RAM + ERL Q2
(n=54)

RAM + ERL Q3
(n=54)

RAM + ERL Q4
(n=54)

RAM concentration range, mcg/mL

NA

10.1-208.0

10.1-74.9

75.1-89.6

89.8-108.0

109.0-208.0

Grade ≥3 TEAE, n (%)

Diarrheaa

3 (1.3)

16 (7.4)

4 (7.4)

4 (7.4)

3 (5.6)

5 (9.3)

Dermatitis acneiforma

20 (8.9)

33 (15.3)

10 (18.5)

6 (11.1)

7 (13.0)

10 (18.5)

AESI, n (%)

Any Grade

Hypertensiona

27 (12.0)

99 (45.8)

25 (46.3)

25 (46.3)

23 (42.6)

26 (48.1)

Proteinuriab

19 (8.4)

76 (35.2)

18 (33.3)

20 (37.0)

18 (33.3)

20 (37.0)

ALT increasedc

70 (31.1)

93 (43.1)

21 (38.9)

27 (50.0)

17 (31.5)

28 (51.9)

AST increasedc

58 (25.8)

91 (41.2)

21 (38.9)

24 (44.4)

19 (35.2)

27 (50.0)

Grade ≥3

Hypertension

12 (5.3)

52 (24.1)

17 (31.5)

11 (20.4)

15 (27.8)

9 (16.7)

Proteinuriab

0 (0)

6 (2.8)

3 (5.6)

0 (0)

1 (1.9)

2 (3.7)

Abbreviations: AESI = adverse event of special interest; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ERL = erlotinib; NA = not applicable; PBO = placebo; RAM = ramucirumab; TEAE = treatment-emergent adverse event.

aPreferred term.

bConsolidated term.

cAnalysis on grade ≥3 ALT and AST was not performed as there was <2% difference in incidence between the RAM and PBO groups.

References

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, Garon E, Gao L, et al. RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small cell lung cancer: exposure-response relationship. Poster presented at: Annual Meeting of the European Society for Medical Oncology (ESMO Virtual); September 19-21, 2020. Accessed September 17, 2020. https://cslide.ctimeetingtech.com/esmo2020/attendee/confcal_2/presentation/list?q=1298P

Glossary

AESI = adverse event of special interest

Cmin,1 = minimum concentration after first dose administration

Cmin,ss = minimum concentration at steady state

ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

NSCLC = non-small cell lung cancer

PFS = progression-free survival

PK = pharmacokinetic(s)

PS = performance status

TEAE = treatment-emergent adverse event

Fecha de la última revisión: 2020 M09 01


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