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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


April 18, 2018–Osimertinib (Tagrisso®, AstraZeneca Pharmaceuticals LP) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

March 30, 2017–Osimertinib (TAGRISSO®, AstraZeneca Pharmaceuticals, LP) approved for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) (with Pharmacist's Applications to Practice) .

November 13, 2015–Osimertinib (TAGRISSOTM) granted accelerated approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC).


April 18, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf

On April 18, 2018, the Food and Drug Administration approved osimertinib (Tagrisso®, AstraZeneca Pharmaceuticals LP) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Approval was based on a multicenter, international, randomized, double-blind, active-controlled trial (FLAURA, NCT02296125) conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. Patients were randomized (1:1) to receive osimertinib 80 mg orally once daily or “standard-of-care (SOC)” treatment of gefitinib 250 mg or erlotinib 150 mg orally once daily. Of those randomized to SOC, 20% received osimertinib as the next line of antineoplastic therapy.

The estimated median progression-free survival (PFS) was 18.9 months (95% CI: 15.2, 21.4) in the osimertinib arm and 10.2 months (95% CI: 9.6, 11.1) in the SOC arm (hazard ratio 0.46 (95% CI: 0.37, 0.57), p<0.0001). The confirmed overall response rate was 77% for the osimertinib arm and 69% for the SOC arm. The estimated median response durations for the osimertinib and SOC arms were 17.6 and 9.6 months, respectively. At the time of the primary PFS analysis, there were too few deaths to estimate or compare survival outcomes.

The most common adverse reactions (occurring in at least 20% of patients treated with osimertinib) were diarrhea, rash, dry skin, nail toxicity, stomatitis, and decreased appetite. Serious adverse reactions were reported in 4% of patients treated with osimertinib. The most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%).

The recommended dose of osimertinib is 80 mg orally once daily, with or without food.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf

FDA granted this application Priority review and Breakthrough designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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).


March 30, 2017 with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208065s006lbl.pdf

On March 30, 2017, the U.S. Food and Drug Administration granted regular approval to osimertinib (TAGRISSO®, AstraZeneca Pharmaceuticals, LP) for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

In November 2015, osimertinib received accelerated approval for this indication based on an overall response rate (ORR) of 59% among 411 patients in two single-arm clinical trials.

The current approval is based on AURA3 (NCT012151981), a randomized, multicenter open-label, active-controlled trial conducted in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first-line EGFR TKI therapy. All patients were required to have EGFR T790M mutation-positive NSCLC identified by the cobas® EGFR mutation test performed in a central laboratory

AURA3 randomized 419 patients (2:1) to receive osimertinib (n=279) 80 mg orally once daily or platinum-based doublet chemotherapy (n=140). Patients in the chemotherapy arm received either pemetrexed, 500 mg/m2 with carboplatin AUC5, or pemetrexed, 500mg/m2 with cisplatin 75 mg/m2), on day 1 of every 21-day cycle for up to 6 cycles followed by pemetrexed maintenance therapy. Patients on the chemotherapy arm with radiological progression according to both investigator and blinded independent central review were offered osimertinib at progression.

AURA3 demonstrated an improvement in investigator-assessed progression-free survival (PFS), with a hazard ratio of 0.30 (95% CI: 0.23, 0.41; p<0.001). The estimated median PFS was 10.1 months in the osimertinib arm and 4.4 months in the chemotherapy arm. Confirmed ORR, according to investigator assessment, was 65% (95% CI: 59%, 70%) and 29% (95% CI: 21%, 37%) in the osimertinib and chemotherapy arms, respectively (p<0.0001). Estimated median response durations were 11 months (95% CI: 8.6, 12.6) and 4.2 months (95% CI: 3.9, 5.9) in the osimertinib and chemotherapy arms, respectively.

In patients with measurable central nervous system (CNS) lesions on baseline brain scans, the confirmed CNS ORR, assessed by independent central review, was 57% (95% CI: 37%, 75%) and 25% (95% CI: 7%, 52%) in the osimertinib and chemotherapy arms, respectively. The median CNS response duration was not reached in the osimertinib arm (range: 1.4 to 12.5 months) and was 5.7 months (range: 1.4, 5.7 months) in the chemotherapy arm. Overall survival data are immature.

Serious adverse reactions were evaluated in 833 patients receiving osimertinib. The most serious adverse reactions were interstitial lung disease/pneumonitis (3.5%), QTc interval prolongation (0.7%), cardiomyopathy (1.9%), and keratitis (0.7%). The most common adverse reactions (occurring in at least 20% of patients) were diarrhea, rash, dry skin, nail toxicity, and fatigue.

The recommended dose of osimertinib is 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. The presence of an EGFR T790M mutation in a tumor specimen, or plasma specimen (if tumor tissue is unavailable) should be confirmed by an FDA-approved test prior to initiation of treatment

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208065s006lbl.pdf.

FDA previously granted osimertinib Fast Track and Breakthrough Therapy Designation for the current indication, as well as Orphan Drug Designation for the treatment of EGFR mutation-positive NSCLC. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

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

Osimertinib for Metastatic Epidermal Growth Factor (EGFR) T790M Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on or After Treatment with an EGFR Tyrosine Kinase Inhibitor (TKI)

Author: Monique Giordana, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
Regions Hospital
St. Paul, MN

What is the potential role for osimertinib in the treatment of non-small cell lung cancer?1.2

  • Osimertinib is a treatment option for patients with metastatic NSCLC with EGFR T790M mutation who have progressed on a prior EGFR inhibitor.
  • EGFR T790M is a mutation associated with acquired resistance after initial response to EGFR TKI therapy and has been reported to occur in 60% of patients.
  • Studies also suggest that T790M may also occur without prior treatment with EGFR TKI therapy, though this is uncommon.
  • Osimertinib was compared to platinum-pemetrexed chemotherapy in patients with EGFR T790M-positive NSCLC.  The median progression-free survival (PFS) was significantly longer in the osimertinib arm than in the chemotherapy arm (10.1 months vs. 4.4 months).  In addition, the objective response rate was improved in the osimertinib arm (71%, 95% confidence interval [CI] 65-76) compared to the chemotherapy arm (31%, 95% CI 24-40).
    • The improved PFS with osimertinib was also found in the subset population of patients with central nervous system metastases: PFS 8.5 months in the osimertinib arm versus 4.2 months in the chemotherapy arm.
  • A number of third-generation EGFR inhibitors are currently being evaluated in metastatic NSCLC with EGFR T790M mutation: olmutinib, EGF816, AC0010, YH25448, and PF-06747775.

What role can the pharmacist play in the management of patients on osimertinib?2,3

  • Like other TKI therapy, osimertinib is an oral agent that presents opportunities for pharmacists to optimize care through counseling and medication adherence, as well as through the use of pharmacy technicians to assist with access to therapy via prior authorizations and patient assistance programs.
  • To aid in medication adherence, pharmacists can assist with managing drug-related adverse events.  Most adverse events were grade 1 and 2; however, pharmacists can play an important role with supportive care in managing EGFR inhibitor–induced skin rash (all grades, 34%), nausea (all grades, 16%), diarrhea (all grades, 41%), constipation (all grades, 14%), and stomatitis (all grades, 15%).  Pharmacists can also help ensure that patients are monitored for more serious toxicities, including cardiomyopathy, interstitial lung disease or pneumonitis, and arrhythmias.
  • Osimertinib is predominantly metabolized via cytochrome P450 3A4 (CYP3A4) and is a substrate of P-glycoprotein and BCRP; pharmacists therefore play a vital role in evaluating drug-drug interactions and monitoring concomitant medications that prolong the QTc interval.

Clinical Pearls2,3

  • For patients who have difficulty swallowing, the tablet can be dispersed in approximately 60 ml of noncarbonated water and immediately swallowed; the container should then be rinsed with 120-240 ml of water and immediately drunk by the patient. If the medication is administered via nasogastric tube, disperse the tablet in 15 ml of noncarbonated water and use an additional 15 ml of water to transfer the residue to the syringe (about 30 ml fluid).
  • Effective birth control should be recommended for patients while on therapy and for 6 weeks after the final dose of osimertinib in females and for 4 months for males who have female partners of child-bearing potential.
  • Monitoring left ventricular ejection fraction is recommended at baseline and then every 3 months thereafter.
  • Electrocardiogram and electrolyte monitoring is recommended periodically during therapy in patents who have a history or predisposition for QTc prolongation or on concomitant medications known to prolong QTc.

Additional Information4

  • Osimertinib is approved for patients with EGFR T790M mutation positive as detected by a test approved by the U.S. Food and Drug Administration. More information is available at http://www.fda.gov/CompanionDiagnostics.
  • Osimertinib is supplied as a 40 mg and 80 mg beige oval and biconvex tablet.
  • Standard safe handling and precautions related to the disposal of oral TKI should be discussed with the patient and caregivers.
  • Patient assistance is available from AstraZeneca Access 360 program.

References

  1. Mok T, Wu Y, Ahn M, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017; 376:629-40.
  2. Non-Small Cell Lung Cancer. Version 8.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 15, 2017 becomes 2.
  3. Tagrisso (osimertinib) tablets [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals; March 2017.  (This becomes 3)
  4. Osimertinib (Tagrisso). Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm549683.htm. Accessed July 28, 2017.

November 13, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf

On November 13, 2015, the U. S. Food and Drug Administration granted accelerated approval to osimertinib (TAGRISSOTM) once daily tablets, AstraZeneca Pharmaceuticals LP, for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

The approval was based on two multicenter, single-arm, open-label clinical trials in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI (Study 1 and 2). All patients were required to have EGFR T790M mutation-positive NSCLC as detected by the cobas® EGFR mutation test and received osimertinib 80 mg once daily. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by a Blinded Independent Central Review (BICR). Duration of response (DOR) was an additional outcome measure.

Study 1 (n=201) showed an ORR of 57% (95% CI: 50%, 64%). In Study 2 (n=210) the ORR was 61% (95% CI: 54%, 68%). The majority (96%) of patients in both trials had ongoing responses at the time of primary analysis and the median DOR had not been reached with duration of ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months (Study 1) and 4.0 months (Study 2). The dose finding phase of Study 1 (n=63) showed an ORR of 51% and median DOR of 12.4 months.

Safety data was evaluated in 411 patients who received osimertinib at a dose of 80 mg daily. The most common adverse events were diarrhea (42%), rash (41%), dry skin (31%), nail toxicity (25%), eye disorders (18%), nausea (17%), decreased appetite (16%), and constipation (15%). The majority of the above adverse events were grade 1-2. The most common Grade 3-4 adverse reactions were pneumonia and pulmonary embolism (2% each).

The most common nonfatal serious adverse events (SAEs) included pneumonia and pulmonary embolus. Dose reductions due to adverse events occurred in 4.4% of patients. The most frequent adverse reaction leading to dose reductions or interruptions were prolonged QTc and neutropenia (2% each). Adverse events leading to discontinuation included ILD/pneumonitis (2%), and cerebrovascular accident (1%). Fatal adverse events occurred in 3.2% of patients, including 4 cases of pneumonitis attributed to osimertinib.

The recommended dose and schedule for osimertinib is 80 mg given orally once daily.

Osimertinib received Breakthrough Therapy Designation and the current indication was approved under FDA’s accelerated approval program. The application was granted a Priority Review. This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of February 6, 2016. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

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