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September 27, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf

On Sept. 27, 2018, the Food and Drug Administration approved dacomitinib tablets (VIZIMPRO, Pfizer Pharmaceutical Company) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

Approval was based on a randomized, multicenter, open-label, active controlled trial (ARCHER 1050; NCT01774721) comparing the safety and efficacy of dacomitinib to gefitinib in 452 patients with unresectable, metastatic NSCLC. Patients were required to have no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic non-EGFR TKI-containing therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and EGFR exon 19 deletion or exon 21 L858R substitution mutations. Patients were randomized (1:1) to receive either dacomitinib 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity.

The trial demonstrated a significant improvement in progression-free survival; no improvement in overall response rate or overall survival were demonstrated. The median progression-free survival, as determined by an independent review committee. was 14.7 and 9.2 months in the dacomitinib and gefitinib arms, respectively (hazard ratio 0.59; 95% CI: 0.47, 0.74; p<0.0001).

The prescribing information contains warnings and precautions for interstitial lung disease (ILD), diarrhea, and dermatologic adverse reactions. Of 394 patients who received dacomitinib, serious adverse reactions occurred in 27%. The most common adverse reactions resulting in discontinuation in of dacomitinib were diarrhea and ILD. The most common (>20%) adverse reactions of dacomitinib were diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus).

The recommended dacomitinib dose is 45 mg orally once daily with or without food.

View full prescribing Information for Vizimpro.

FDA granted this application priority review, and orphan drug designation.FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Dacomitinib for Metastatic Non-Small-Cell Lung Cancer

Author: Amanda S. Cass, PharmD BCPS
Clinical Pharmacist, Thoracic Oncology
Vanderbilt University Medical Center
Nashville, TN

What is the potential role for dacomitinib in the treatment of non-small-cell lung cancer NSCLC?1-6

  • Dacomitinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in the front-line setting for patients with metastatic NSCLC with an EGFR exon 19 deletion or exon 21 L858R substitution.
    • EGFR mutations such as exon 19 deletions or exon 21 L858R substitutions are sensitizing mutations that are associated with responsiveness to EGFR TKI therapy.
    • Sensitizing EGFR mutations are found in approximately 10% of Caucasian patients and in up to 50% of Asian patients with NSCLC, primarily adenocarcinoma.
  • First-generation EGFR TKIs erlotinib and gefitinib have shown improvements only in response rates and progression-free survival (PFS) but no improvement in overall survival (OS) when compared to chemotherapy.
    • No significant differences in OS were seen in a direct comparison of erlotinib and gefitinib.
  • When afatinib, the first second-generation EGFR TKI, was compared to chemotherapy, afatinib did not show any improvement in OS.
    • When afatinib was compared to gefitinib, a statistically significant improvement in PFS was seen with afatinib; however, no significant difference in OS was seen.
  • Osimertinib, a third-generation EGFR TKI, was initially approved for patients whose disease had progressed on a first- or second-generation EGFR TKI and who had developed a EFGR T790M resistance mutation on the basis of the AURA trial, which showed improved PFS for osimertinib compared to carboplatin and pemetrexed.
  • On the basis of the FLAURA trial, osimertinib is now approved in the first-line setting in patients with untreated metastatic NSCLC with a sensitizing EGFR mutation.
    • Osimertinib showed increased PFS of 18.9 months when compared to either erlotinib or gefitinib, with a PFS of 10.2 months (p < .001).
    • Fewer grade 3/4 adverse events occurred with osimertinib when compared to erlotinib or gefitinib.
    • FLAURA does not yet have OS data; however, the investigators have reported a trend toward OS improvement with osimertinib (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.45–0.88; p = .0068).
  • Dacomitinib was approved by the U.S. Food and Drug Administration on the basis of the ARCHER 1050 trial, which showed an increase in PFS with dacomitinib versus gefitinib when used in the first-line setting in patients with metastatic NSCLC and sensitizing EGFR mutations (14.7 months vs. 9.2 months, p < .0001).
    • Although OS was not mature at the time of initial publication, it has now been reported that the estimated HR for OS was 0.76 (p = .044).
    • Median OS for dacomitinib was 34.1 months, compared to 26.8 months with gefitinib.
    • Dacomitinib had more grade 3/4 skin and gastrointestinal (GI) adverse events compared to gefitinib.
  • Although treatment with dacomitinib is a National Comprehensive Cancer Network (NCCN) category-1 recommendation for the treatment of metastatic NSCLC with a sensitizing EGFR mutation, osimertinib is a category-1 recommendation and NCCN’s preferred treatment in the first-line setting on the basis of the phase 3 FLAURA trial, which showed a longer PFS than was seen in the ARCHER 1050 trial.

What role can the pharmacist play in the management of patients on dacomitinib?1,7,8

  • To be considered for treatment with dacomitinib, patients must exhibit an EGFR exon 19 deletion or an exon 20 L858R mutation.
  • Dosage is 45 mg once daily, with or without food.
  • There is no recommended dosage adjustment for those with a creatinine clearance less than 30 mL/min or severe hepatic impairment.
  • Concomitant use of proton pump inhibitors should be avoided.
    • If dacomitinib is administered with an H2 blocker or an antacid, administer the dacomitinib at least 6 hours before or 10 hours after the H2 blocker or antacid.
  • Concomitant use of CYP2D6 substrates should be avoided.
  • The pharmacist should monitor for adverse events associated with dacomitinib and recommend the dose adjustments below. Dose adjustments are recommended for grade 3/4 dermatologic toxicity, grade 3/4 GI toxicity, and any grade 3/4 adverse event.
    • Initial dose: 45 mg once daily
    • First dose reduction: 30 mg once daily
    • Second dose reduction: 15 mg once daily.
  • Adverse events (all grades) occurring in more than 20% of patients who were on dacomitinib in the clinical trial included diarrhea (87%), paronychia (64%), dermatitis acneiform (49%), stomatitis (45%), decreased appetite (31%), dry skin (30%), weight decrease (26%), alopecia (23%), cough (21%), pruritus (21%), and increased alanine aminotransferase (ALT) (20%).
  • Dacomitinib should be discontinued in any patient who develops interstitial lung disease (3%).
  • Females of reproductive potential should use effective contraception during therapy and for at least 17 days after the final dose.
  • Pfizer provides a patient assistance program to those who qualify regardless of insurance coverage and provides a co-pay card to those with commercial insurance.

Clinical Pearls1,7,8

  • Dacomitinib is considered a hazardous drug. Patients and healthcare providers should use caution when handling this medication.
  • Dacomitinib is available as 15-mg, 30-mg, and 45-mg tablets.
  • Patients with central nervous system metastases were ineligible for the trial with dacomitinib because of the unknown capacity of dacomitinib to cross the blood-brain barrier.

References

  1. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454-1466.
  2. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36:2244-2250.
  3. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376: 629-640.
  4. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378: 113-125.
  5. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Annals of Oncology (2017) 28 (suppl_5): v605-v649. 10.1093/annoc/mdx440
  6. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. Version 3.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 25, 2019.
  7. Vizimpro (dacomitinib) tablets [package insert]. New York, NY. Pfizer Inc.; September 2018.
  8. Dacomitinib (Vizimpro). Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. Accessed October 31, 2018.
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