FDA approves Portrazza(Necitumumab) to treat advanced squamous non-small cell lung cancer

November 24, 2015

The U.S. Food and Drug Administration today approved Portrazza (necitumumab) in combination with two forms of chemotherapy to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) who have not previously received medication specifically for treating their advanced lung cancer.

DESCRIPTION

  • Necitumumab is an anti-EGFR recombinant human monoclonal antibody of the IgG1 kappa isotype.
  • It specifically binds to the ligand binding site of the human EGFR.
  • Necitumumab has an approximate molecular weight of 144.8 kDa.
  • Necitumumab is produced in genetically engineered mammalian NS0 cells.

CLINICAL PHARMACOLOGY

Mechanism of Action

  • Necitumumab is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands.
  • Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis.
  • Binding of necitumumab induces EGFR internalization and degradation in vitro.
  • In vitro, binding of necitumumab also led to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-expressing cells.
  • In in vivo studies using xenograft models of human cancer, including non-small cell lung carcinoma, administration of necitumumab to implanted mice resulted in increased antitumor activity in combination with gemcitabine and cisplatin as compared to mice receiving gemcitabine and cisplatin alone.

INDICATIONS AND USAGE

PORTRAZZA™ is an epidermal growth factor receptor (EGFR) antagonist indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.

Limitation of Use: PORTRAZZA is not indicated for treatment of non-squamous non-small cell lung cancer.

DOSAGE AND ADMINISTRATION

Recommended dose of PORTRAZZA is 800 mg (absolute dose) as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle.

Premedication

For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent PORTRAZZA infusions [see Dosage and Administration

For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each PORTRAZZA infusion

DOSAGE FORMS AND STRENGTHS

Injection: 800 mg/50 mL (16 mg/mL) solution in a single-dose vial.

Safety & Efficacy

prtazza

The safety and efficacy of Portrazza were evaluated in a multicenter, randomized, open-label clinical study of 1,093 participants with advanced squamous NSCLC who received the chemotherapies gemcitabine and cisplatin with or without Portrazza. Those taking Portrazza plus gemcitabine and cisplatin lived longer on average (11.5 months) compared to those only taking gemcitabine and cisplatin (9.9 months). Portrazza was not found to be an effective treatment in patients with non-squamous NSCLC.

WARNINGS AND PRECAUTIONS

  • Cardiopulmonary Arrest: Closely monitor serum electrolytes during and after PORTRAZZA.
  • Hypomagnesemia: Monitor prior to each infusion and for at least 8 weeks following the completion of PORTRAZZA. Withhold PORTRAZZA for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of PORTRAZZA may be administered in these patients once electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as necessary.
  • Venous and Arterial Thromboembolic Events (VTE and ATE): Discontinue PORTRAZZA for severe VTE or ATE.
  • Dermatologic Toxicities: Monitor for dermatologic toxicities and withhold or discontinue PORTRAZZA for severe toxicity.
  • Limit sun exposure.
  • Infusion-Related Reactions: Monitor for signs and symptoms during and following infusion. Discontinue PORTRAZZA for severe reactions.
  • Increased Toxicity: Non-Squamous NSCLC – Increased toxicity and increased mortality.
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

Dose Modifications

Infusion-Related Reactions (IRR)

  •  Reduce the infusion rate of PORTRAZZA by 50% for Grade 1 IRR
  • Stop the infusion for Grade 2 IRR until signs and symptoms have resolved to Grade 0 or 1; resume PORTRAZZA at 50% reduced rate for all subsequent infusions
  • Permanently discontinue PORTRAZZA for Grade 3 or 4 IRR

Dermatologic Toxicity

  • Withhold PORTRAZZA for Grade 3 rash or acneiform rash until symptoms resolve to Grade ≤2, then resume PORTRAZZA at reduced dose of 400 mg for at least 1 treatment cycle.
  • If symptoms do not worsen, may increase dose to 600 mg and 800 mg in subsequent cycles.
  • Permanently discontinue PORTRAZZA if: – Grade 3 rash or acneiform rash do not resolve to Grade ≤2 within 6 weeks, – Reactions worsen or become intolerable at a dose of 400 mg.

ADVERSE REACTIONS

The most common adverse reactions (all grades) observed in PORTRAZZA-treated patients at a rate of ≥30% and ≥2% higher than gemcitabine and cisplatin alone arm were rash and hypomagnesemia.

The most common side effects of Portrazza are skin rash and magnesium deficiency (hypomagnesemia), which can cause muscular weakness, seizure, irregular heartbeats and can be fatal.

Portrazza includes a boxed warning to alert health care providers of serious risks of treatment with Portrazza, including cardiac arrest and sudden death, as well as hypomagnesemia.

Portrazza is marketed by Eli Lilly and Company, based in Indianapolis, Indiana.

Reference:

FDA News.

Prescribing information