Cyramza ® (ramucirumab)

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Cyramza® (ramucirumab): Adverse Events Leading to Treatment Discontinuation in RELAY

In RELAY, overall incidence of TEAEs leading to the discontinuation of study treatment was similar in the ramucirumab plus erlotinib arm and the placebo plus erlotinib arm.

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 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

Treatment Discontinuation Due to Adverse Event

In RELAY, the overall incidence of TEAEs leading to the discontinuation of study treatment was similar in the ramucirumab plus erlotinib arm and the placebo plus erlotinib arm (12.7% vs 10.7%, respectively).1

Patients were required to discontinue from ramucirumab or placebo if they experienced

  • grade 3 or 4

    • IRR

    • ATE

    • VTE

    • bleeding or hemorrhage events, or

    • CHF

  • uncontrolled hypertension, hypertensive crisis, or hypertensive encephalopathy (grade 4)

  • proteinuria >3 g/24 h or in the setting of nephrotic syndrome

  • GI perforation

  • fistula

  • RPLS, or

  • hepatic encephalopathy and/or hepatorenal syndrome.2

Patients were required to discontinue erlotinib treatment if they experienced

  • ILD

  • severe abnormal laboratory results

  • GI perforation

  • severe bullous

  • blistering or exfoliation skin conditions

  • corneal perforation, or

  • severe ulcerations.2

The TEAEs leading to discontinuation of study treatment are summarized in Table 1.

Table 1. Treatment-Emergent Adverse Events Leading to Discontinuation of All Study Treatment Occurring in ≥1 Patients in the Ramucirumab Plus Erlotinib Arm Safety Population in RELAY2

TEAE, n (%)

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Ramucirumab + Erlotinib
(N=221)

Placebo + Erlotinib
(N=225)

Patients discontinued study treatment due to TEAE

28 (12.7)

15 (6.8)

24 (10.7)

13 (5.8)

ALT increased

3 (1.4)

3 (1.4)

4 (1.8)

3 (1.3)

Paronychia

3 (1.4)

0

0

0

Dermatitis acneiform

2 (0.9)

2 (0.9)

0

0

Proteinuria

2 (0.9)

0

0

0

Acute kidney injury

1 (0.5)

0

0

0

Anemia

1 (0.5)

1 (0.5)

0

0

Anxiety

1 (0.5)

1 (0.5)

0

0

AST increased

1 (0.5)

1 (0.5)

1 (0.4)

0

Blood creatine phosphokinase increased

1 (0.5)

0

0

0

Diarrhea

1 (0.5)

0

0

0

Encephalitis influenza

1 (0.5)

1 (0.5)

0

0

Gamma-glutamyltransferase increased

1 (0.5)

0

0

0

Gastritis erosive

1 (0.5)

0

0

0

Hemothorax

1 (0.5)

1 (0.5)

0

0

Hepatic function abnormal

1 (0.5)

1 (0.5)

3 (1.3)

3 (1.3)

Hepatitis

1 (0.5)

1 (0.5)

0

0

Herpes zoster

1 (0.5)

1 (0.5)

0

0

Platelet count decreased

1 (0.5)

0

0

0

Pleural effusion

1 (0.5)

0

0

0

Septic shock

1 (0.5)

1 (0.5)

0

0

Small intestinal hemorrhage

1 (0.5)

1 (0.5)

0

0

Stomatitis

1 (0.5)

0

0

0

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TEAE = treatment-emergent adverse event. 

Treatment Discontinuation Due to Death

The incidence of deaths that occurred while on treatment and up to 30 days after discontinuation from study treatment were reported only in the ramucirumab plus erlotinib arm (2.7%) and none reported in the placebo plus erlotinib arm.1 Majority of the deaths reported by the investigator are due to AEs (encephalitis influenza, hemothorax, lymphoma, pneumonia, pneumonia bacterial, and renal failure).2 Only 1 event (hemothorax) was assessed by the investigator as related to study drug treatment.2 Deaths on therapy and within 30 days of treatment discontinuation are summarized in Table 2.

Table 2. Deaths on Therapy or Within 30 Days of Treatment Discontinuation in RELAY2

 

Ramucirumab + Erlotinib
N=221
n (%)

Placebo + Erlotinib
N=224
n (%)

Deaths on therapy or within 30 days of treatment discontinuation

8 (3.6)

2 (0.9)

Adverse events

6 (2.7)

0

Adverse events related to study treatment

1 (0.5)

0

Study disease

2 (0.9)

2 (0.9)

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

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AE = adverse event

ATE = arterial thromboembolic event

CHF = congestive heart failure

ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

GI = gastrointestinal

ILD = interstitial lung disease

IRR = infusion-related reaction

NSCLC = non-small cell lung cancer

PS = performance status

RPLS = reversible posterior leukoencephalopathy syndrome

TEAE = treatment-emergent adverse event

VTE = venous thromboembolic event

Date of Last Review: October 23, 2019

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