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Garon EB et al. Lancet. 2014;384:665-673

FDA and EMA prescribing information and miscellaneous sources

 

Prophylaxis for infusion-related reaction from ramucirumab:

Diphenhydramine 25–50 mg; administer intravenously, 30–60 minutes before starting ramucirumab, plus

Acetaminophen 650–1000 mg; administer orally, 30–60 minutes before starting ramucirumab (only if history of grade 1/2 infusion reaction), plus

Dexamethasone 8 mg; administer orally or intravenously, 30–60 minutes before starting ramucirumab (only if history of grade 1/2 infusion reaction; note dexamethasone is also indicated for prophylaxis with docetaxel, as described below)

 

Ramucirumab 10 mg/kg; administer intravenously in 250 mL of 0.9% sodium chloride injection (0.9% NS) over 1 hour on day 1 before docetaxel, every 3 weeks (total dosage/cycle = 10 mg/kg)

 

Prophylaxis for fluid retention and hypersensitivity reactions from docetaxel:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days, starting the day before docetaxel is administered (total dose/cycle = 48 mg)

Docetaxel 75 mg/m2; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection, USP, sufficient to produce a solution with concentration within the range of 0.3–0.74 mg/mL over 1 hour on day 1, every 3 weeks (total dosage/cycle = 75 mg/m2)

Notes:

  • Consider a starting docetaxel dose of 60 mg/m2 rather than 75 mg/m2 in East Asian patients based on findings of higher rates of neutropenia in this group in the REVEL study

  • Some formulations of docetaxel contain alcohol; use caution or consider using a non-alcohol-containing formulation in patients who are sensitive to alcohol

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis MAY be indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is MODERATE

  • Antimicrobial primary prophylaxis to be CONSIDERED:

    • Antibacterial—not indicated

    • Antifungal—not indicated

    • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

 

Patient Population Studied

A multicenter, double-blind, randomized, phase 3 study of 1253 patients with pathologically confirmed, squamous or non-squamous, stage IV NSCLC who had progressed during or after a first-line platinum-based chemotherapy. Eligible patients were aged ≥18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. Patients were not eligible if their only previous therapy for advanced or metastatic disease was EGFR tyrosine kinase inhibitor monotherapy. Patients received docetaxel with (1:1) ramucirumab or placebo

 

Efficacy (N = 1253)

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Median overall survival

10.5 months with docetaxel + ramucirumab

9.1 months with docetaxel + placebo

HR 0.86, 95% CI 0.75–0.98, P = 0.023

Median progression-free survival

4.5 months with docetaxel + ramucirumab

3.0 months with docetaxel + placebo

HR 0.76, 95% CI 0.68–0.86, P <0.0001

Objective response rate

23% with docetaxel + ramucirumab

14% with docetaxel + placebo

OR 1.89, 95% CI 1.41–2.54, P <0.0001

Overall response rate is the percentage of patients who experienced a confirmed partial or complete response to the study drug

 

Therapy Monitoring

  1. Draw serum bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle

  2. Obtain CBC with differential at a minimum once per cycle, but initially also at days 10–14

  3. Observe closely for hypersensitivity reactions, especially during the first and second ramucirumab infusions

  4. Monitor patients with preexisting effusions closely for possible exacerbation of effusions

  5. Monitor all patients for fluid retention. Median cumulative dose to onset of moderate/severe fluid retention was 819 mg/m2 of docetaxel

  6. Check blood pressure every 2 weeks or more frequently as indicated during treatment.

  7. Assess proteinuria by urine dipstick and/or urinary protein creatinine ratio at baseline and every 2 cycles. If protein ≥ 2+, then collect a 24-hour urine for protein measurement

  8. Assess thyroid function at outset and every 3 months while on therapy

 

Treatment Modifications

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RAMUCIRUMAB DOSE MODIFICATIONS
Starting dose 10 mg/kg (starting ramucirumab dose for lung cancer)
Dose level −1 8 mg/kg
Dose level −2 6 mg/kg
G1/2 infusion-related Stop ramucirumab. Administer dexamethasone intravenously at commonly used antiemetic doses of 8–20 mg (or equivalent) and acetaminophen, then resume infusion at 50% of previous rate. Use the 50% infusion rate for all subsequent administrations
Prior G1/2 infusion-related reaction Premedicate with dexamethasone intravenously at commonly used antiemetic doses of 8–20 mg (or equivalent) and acetaminophen prior to each ramucirumab infusion. Continue diphenhydramine 25–50 mg intravenously
G3/4 infusion-related reaction Permanently discontinue ramucirumab
G3/4 hypertension Interrupt ramucirumab until symptoms controlled with medical management; if unable to control with medical management, discontinue ramucirumab
PRES Permanently discontinue ramucirumab
Urine protein ≥2 g/24 hours Interrupt ramucirumab. Reinitiate treatment at a reduced dose once the urine protein level returns to <2 g/24 hours
Reoccurrence of urine protein ≥2 g/24 hours Interrupt ramucirumab and reduce the dose once the urine protein level returns to <2 g/24 hours
Urine protein >3 g/24 hours or nephrotic syndrome Permanently discontinue ramucirumab
Anticipated wound healing Stop ramucirumab ≥4 weeks prior to a scheduled surgery and until wound is fully healed; discontinue ramucirumab if patient develops wound healing complications
G3/4 bleeding, arterial thromboembolic event, gastrointestinal perforation Permanently discontinue ramucirumab
G3/4 Fatigue/asthenia Interrupt ramucirumab. Reinstitute treatment at a reduced dose once toxicity is G1
G3/4 Stomatitis/mucosal inflammation
DOCETAXEL DOSE MODIFICATIONS
Starting docetaxel dose 75 mg/m2 (recommended starting dose in East Asian patients = 60 mg/m2)
Dose level −1* 65 mg/m2
Dose level −2* 50 mg/m2
Serum bilirubin > ULN Do not administer docetaxel
AST and/or ALT >1.5× ULN with concomitant with alkaline phosphatase >2.5× ULN Do not administer docetaxel
ANC <1500/mm3; platelet count <100,000/mm3 Withhold docetaxel until ANC >1500/mm3 and platelet count <100,000/mm3
ANC nadir <500 cells/mm3 for >1 week Reduce dose by 1 level in subsequent cycle
Platelet nadir <25,000 cells/mm3
Febrile neutropenia
Severe or cumulative cutaneous reactions from docetaxel Withhold treatment until toxicity improves, then resume with dose reduced by 1 level
G3/4 nonhematologic toxicities Withhold treatment until toxicity improves to G1, then resume with dose reduced by 1 level
Severe hypersensitivity reaction Immediately discontinue docetaxel infusion and administer dexamethasone intravenously at commonly used antiemetic doses 8–20 mg
History of severe hypersensitivity to docetaxel or other drugs formulated with polysorbate 80 Do not administer docetaxel
Minor flushing or localized skin reactions Interruption of therapy is not required
≥G3 peripheral neuropathy Discontinue docetaxel
Fluid retention Treat with salt restriction and oral diuretics; reduce dose by 1 level
Mild peripheral edema Treat with salt restriction and oral diuretics

Abbreviations: ALT, alanine transaminase; ANC, absolute neutrophil count; AST, aspartate transaminase; PRES, Posterior reversible leukoencephalopathy syndrome; ULN, upper limit of normal

*The U.S. FDA-approved package insert for docetaxel recommends only 1 dose reduction of docetaxel to 55 mg/m2 in patients with NSCLC after platinum failure; the dose levels listed above were included to allow for greater physician discretion.

Notes:

  • Patients who are pregnant or who becomes pregnant should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant during therapy

  • No dose adjustments for docetaxel or ramucirumab are recommended for patients with renal impairment

  • Dose adjustments for hepatic impairment:

    • Ramucirumab: No dose adjustment is recommended for patients with mild (total bilirubin within ULN and AST >ULN, or total bilirubin >1.0–1.5× ULN and any AST or moderate (total bilirubin >1.5-3.0× ULN and any AST) hepatic impairment

    • Docetaxel: Use is not recommended for patients with total bilirubin > ULN, or AST and/or ALT >1.5× ULN concomitant with alkaline phosphatase >2.5× ULN

 

Adverse Events (N = 1245)

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Docetaxel + Ramucirumab Docetaxel + Placebo
Grade (%) Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
Nonhematologic Adverse Events
Fatigue 41 14 39 10
Diarrhea 27 5 25 3
Decreased appetite 27 2 24 1
Nausea 26 1 26 1
Alopecia 26 26
Stomatitis 19 4 11 2
Neuropathy 20 3 19 2
Dyspnea 18 4 16 8
Cough 21 <1 20 1
Pyrexia 16 <1 13 <1
Peripheral edema 16 0 8 <1
Mucosal inflammation 13 3 6 <1
Constipation 16 <1 17 1
Vomiting 13 1 12 2
Lacrimation increased 13 <1 4 0
Myalgia 12 1 10 1
Arthralgia 10 1 7 1
Back pain 10 1 8 <1
Abdominal pain 10 1 9 1
Insomnia 10 <1 8 <1
Dysgeusia 11 7
Headache 10 <1 10 1
Hypertension 5 6 3 2
Infusion-related reaction 3 1 4 1
Proteinuria 3 <1 1 0
Renal failure 2 <1 2 <1
Congestive heart failure <1 1 <1 <1
Gastrointestinal perforation <1 1 0 <1
Hematologic Adverse Events
Neutropenia 6 49 6 39
Febrile neutropenia 0 16 0 10
Bleeding or hemorrhage 26 2 13 2
Leucopenia 8 14 6 12
Anemia 18 3 22 6
Epistaxis 18 <1 6 <1
Thrombocytopenia 11 3 5 1
Pulmonary hemorrhage 7 1 6 1
Hemoptysis 5 1 5 1
Gastrointestinal hemorrhage 2 1 1 <1
Venous thromboembolic <1 2 3 3
Arterial thromboembolic <1 1 <1 1

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

Denotes those events of special interest

Notes: Toxicities are included in the table if all-grade events occurred in ≥10% of patients or were of special interest. Events are included regardless of whether they were caused by the study treatment.

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