neratinib (Rx)

Breast Cancer

Early stage breast cancer

• Indicated for the extended adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy
• 240 mg (6 tablets) PO qDay continuously for 1 yr

• Dose escalation regimen to improve tolerability (off-label)

  • Days 1 to 7: 120 mg PO qDay
  • Days 8 to 14: 160 mg PO qDay
  • Day 15 and thereafter: 240 mg PO qDay; continue for up to 1 year
  • Loperamide may be administered PRN in addition to dose escalation (CONTROL trial; Barcenas, et al. Ann Oncol. 2020 Sep;31(9):12223-1230)

Advanced or metastatic breast cancer

• Indicated in combination with capecitabine for advanced or metastatic HER2-positive breast cancer in adults who have received ≥2 prior anti-HER2 based regimens in the metastatic setting
• Each cycle is 21 days
• Days 1-21: 240 mg PO qDay PLUS
• Days 1-14: Capecitabine 750 mg/m² PO BID
• Continue until disease progression or unacceptable toxicities

Dosage Modifications

Dose adjustments for adverse reactions and general toxicities

• Monotherapy

  • First dose reduction: 200 mg/day
  • Second dose reduction: 160 mg/day
  • Third dose reduction: 120 mg/day

• In combination with capecitabine

  • First dose reduction: 160 mg/day
  • Second dose reduction: 120 mg/day
• Additional clinical situations may result in dose adjustments as clinically indicated (eg, intolerable toxicities, persistent grade 2 adverse reactions)
• Discontinue if patient fails to recover to grade 0-1 from treatment-related toxicity, for toxicities that result in a treatment delay >3 weeks, or if unable to tolerate 120 mg/day
• Grade 3: Hold until recovery to Grade ≤1 or baseline within 3 weeks of stopping treatment, then resume at the next lower dose level
• Grade 4: Discontinue permanently

Diarrhea

• Severity

  • Grade 1 diarrhea (increase of <4 stools/day over baseline)
  • Grade 2 diarrhea (increase of 4-6 stools/day over baseline) lasting <5 days
  • Grade 3 diarrhea (increase of ≥7 stools/day over baseline, incontinence, hospitalization indicated, limiting self-care activities of daily living) lasting <2 days
  • Grade 4 diarrhea (life-threatening consequences; urgent intervention indicated)

• Dosage modifications for Grade 1-3 diarrhea

  • Adjust antidiarrheal treatment
  • Diet modifications
  • Maintain fluid intake of ~2 L to avoid dehydration
  • Once resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent administration
  • In combination with capecitabine: Continue at full doses

• Dosage modifications for any grade with complicated features, Grade 2 diarrhea ≥5 days, or Grade 3 diarrhea ≥2 days (monotherapy only)

  • Interrupt treatment
  • Diet modifications
  • Maintain fluid intake of ~2 L to avoid dehydration
  • If diarrhea resolves to Grade ≤1 in <1 week, then resume at the same dose
  • If diarrhea resolves to Grade ≤1 in ≥1 week, then resume at reduced dose
  • Once resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent administration

• Grade 4 diarrhea or Grade ≥2 diarrhea at 120 mg/day (monotherapy only)

  • Permanently discontinue

• Dosage modifications for persisting and intolerable Grade 2 diarrhea ≥5 days, or Grade 3 diarrhea ≥2 days, or Grade 4 diarrhea (in combination with capecitabine)

  • Adjust antidiarrheal treatment
  • Hold neratinib and capecitabine until recovery to Grade ≤1 or baseline
  • Maintain fluid intake of ~2 L/day intravenously, if needed
  • If recovery occurs ≤1 week after withholding, resume same doses of neratinib and capecitabine
  • If recovery occurs within 1-3 weeks after withholding, reduce neratinib dose to 160 mg and maintain the same dose of capecitabine
  • If event occurs a second time and neratinib dose has not already been decreased, reduce dose to 160 mg (maintain the same dose of capecitabine); reduce capecitabine dose to 550 mg/m² BID if neratinib dose was already reduced (maintain the same neratinib dose )
  • If subsequent events occur, reduce neratinib dose or capecitabine to the next lower dose level in an alternate fashion (eg, reduce capecitabine to 375 mg/m² BID if neratinib was previously reduced, or reduce neratinib to 120 mg if capecitabine was previously reduced)
  • Once the event resolved to Grade ≤1 or baseline, start loperamide 4 mg

Hepatoxicity

• Patients who experience Grade ≥3 diarrhea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, should be evaluated for changes in liver function tests; fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation

• Grade 3 ALT (>5-20x ULN) or Grade 3 bilirubin (>3-10x ULN)

  • Hold until recovery to Grade ≤1 and evaluate alternative causes
  • Resume at next lower dose level if recovery Grade ≤1 within 3 wk
  • Permanently discontinue if Grade 3 ALT or bilirubin reoccurs despite 1 dose reduction

• Grade 4 ALT (>20x ULN), OR Grade 4 bilirubin (>10x ULN)

  • Permanently discontinue
  • Evaluate alternative causes

Coadministration with gastric acid reducing agents

• Proton pump inhibitor (PPI): Avoid concomitant use
• H2-antagonists: Avoid concomitant use
• Antacids: Separate dose by 3 hr after antacids

Renal impairment

No clinical significant effect on pharmacokinetics

Hepatic impairment

• Mild-moderate (Child-Pugh A or B): No dose modifications required
• Severe (Child-Pugh C): Reduce starting dose to 80 mg

Breast Cancer with Brain Metastases (Orphan)

Orphan designation for patients with breast cancer who have brain metastases

Orphan sponsor

• Puma Biotechnology Inc; 10880 Wilshire Blvd., Suite 2150; Los Angeles, California 90024

Dosing Considerations

Antidiarrheal prophylaxis

• Recommended during the first 2 cycles (56 days) of treatment and initiated with the first neratinib dose
• Titrate dose to 1-2 bowels/day
• Weeks 1-2 (days 1-14): 4 mg PO TID
• Weeks 3-8 (days 15-56): 4 mg PO BID
• Weeks 9-52 (days 57-365): 4 mg PO PRN; not to exceed 16 mg/day
• May also require dose interruption and reduction, and additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea

Safety and efficacy not established