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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.


May 26, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205755s009lbl.pdf

On May 26, 2017, the U.S. Food and Drug Administration granted regular approval to ceritinib (ZYKADIA®, Novartis Pharmaceuticals Corp.) for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

In April 2014, ceritinib received accelerated approval for patients with ALK-positive metastatic NSCLC whose disease has progressed or who are intolerant to crizotinib based on a blinded independent review committee (BIRC)-assessed overall response rate (ORR) of 44% among 163 patients in a single-arm trial.

The current approval is based on data from ASCEND-4 (NCT01828099), a randomized, multicenter, open-label, active-controlled trial conducted in patients with untreated ALK-positive NSCLC. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) test performed through central laboratory testing.

ASCEND-4 randomized 376 patients (1:1) to receive either ceritinib (n=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (n=187). Patients in the chemotherapy arm received pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC 5-6) on day 1 of every 21-day cycle for up to 4 cycles, followed by pemetrexed maintenance therapy.

ASCEND-4 demonstrated an improvement in progression-free survival (PFS) as assessed by BIRC, with a hazard ratio (HR) of 0.55 (95% CI: 0.42, 0.73, p-value <0.0001). The estimated median PFS was 16.6 months (95% CI: 12.6, 27.2) in the ceritinib arm and 8.1 months (95% CI: 5.8, 11.1) in the chemotherapy arm. Confirmed ORR, was 73% (95% CI: 66%, 79%) and 27% (95% CI: 21%, 34%) in the ceritinib and chemotherapy arms, respectively. Estimated median response durations were 23.9 months (95% CI: 16.6, not estimable [NE]) and 11.1 months (95% CI: 7.8, 16.4) in the ceritinib and chemotherapy arms, respectively. Overall survival data are immature.

In patients with measurable central nervous system (CNS) lesions on baseline brain scans, the confirmed overall intracranial response rate (OIRR), assessed by BIRC neuro-radiologist, was 57% (95% CI: 37%, 76%) in the ceritinib arm and 22% (95% CI 9%, 42% in the chemotherapy arm. The median CNS response duration was 16.6 months (95% CI: 8.1, NE) and not estimable (95% CI: 1.5, NE) in the ceritinib and chemotherapy arms, respectively.

The most common adverse reactions (occurring in at least 25% of ceritinib-treated patients in ASCEND-4) were diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and cough. Serious adverse reactions occurred in 38% of patients treated with ceritinib. Adverse reactions leading to ceritinib discontinuation occurred in 12%. Adverse reactions that led to ceritinib discontinuation in 1% or more of patients were increased creatinine, increased amylase, and increased lipase. Dose interruption due to adverse reactions occurred in 77% of ceritinib-treated patients, while dose reductions were required in 66%.

The recommended ceritinib dose is 750 mg orally once daily, to be taken at least 1 hour before or at least 2 hours after a meal.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205755s009lbl.pdf.

FDA previously granted ceritinib Breakthrough Therapy Designation for the first-line treatment of ALK-positive metastatic NSCLC with metastases to the brain. The application was granted Priority Review. 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

Ceritinib (Zykadia) for the Treatment of Metastatic Non-Small Cell Lung Cancer in Patients Whose Tumors Are Anaplastic Lymphoma Kinase Positive

Author: Claymore Cuny, PharmD BCPS
PGY-2 Oncology Resident
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Aurora, CO

What is the potential role for ceritinib in the treatment of anaplastic lymphoma kinase (ALK)–positive non-small cell lung cancer NSCLC?1-11

  • Ceritinib is a second-generation ALK tyrosine kinase inhibitor (TKI) that was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in April 2014 for the treatment of ALK-positive NSCLC in patients whose disease has progressed or who are intolerant to crizotinib.
  • On the basis of the results of the ASCEND-4 trial, which included 376 patients, ceritinib received its updated approval. Whereas previous data from a single-arm trial had demonstrated an overall response rate (ORR) of 44% in 163 patients, ceritinib had a statistically significant and clinically meaningful increase in median progression-free survival (PFS) as first-line treatment, compared to platinum-based chemotherapy(16.6 months vs. 8.1 months). Previously, crizotinib was the only ALK-directed TKI with first-line indication in ALK-positive NSCLC, with a reported PFS of 10.9 months versus 7 months in treatment-naive patients.
  • Crizotinib is highly active in patients with ALK-positive NSCLC; however, most patients will develop resistance to crizotinib during the first year of treatment. Ceritinib has been shown to improve PFS (5.4 vs. 1.6 months) in patients who have developed resistance to crizotinib compared to chemotherapy and is an appropriate second-line treatment in patients who have failed initial treatment with crizotinib.  
  • The central nervous system (CNS) is a common site of disease progression in newly diagnosed patients and in patients who have failed initial treatment with an ALK-directed TKI. Crizotinib has poor CNS penetration, and although ceritinib achieves higher CNS concentrations than crizotinib, alectinib, another second-generation ALK inhibitor, may be a preferred option in patients with CNS involvement. At this time no comparative studies between ceritinib and alectinib exist; however, retrospective comparisons of phase 2 data associate alectinib with higher intracranial ORRs than ceritinib (83% vs. 45%). Also, a phase 3 trial comparing alectinib versus crizotinib as first-line therapy showed that patients receiving alectinib had a significant increase in PFS (68.4% vs. 48.7%) and a decrease in disease progression in CNS (12% vs. 45%). On the basis of these results, the National Comprehensive Cancer Network (NCCN) now recommends alectinib as preferred first-line therapy in metastatic ALK-positive NSCLC.

What role can the pharmacist play in the management of patients on ceritinib?1

  • Treatment with ceritinib is generally well tolerated, but it has been associated with some significant adverse effects that may require dose adjustments. These adverse effects include gastrointestinal (GI) side effects, pneumonitis, cardiac toxicity, and liver function test abnormalities.
    • Over one-third of patients treated with ceritinib in study required dose modifications because of nausea, vomiting, or diarrhea.
    • For severe or intolerable nausea, vomiting, or diarrhea despite optimal antiemetic or antidiarrheal therapy, treatment should be withheld until symptoms improve, and ceritinib dose should be reduced by 150 mg.
  • Ceritinib is metabolized through cytochrome p450 CYP3A4, and strong CYP3A4 inducers and inhibitors may affect systemic exposure. If ceritinib is administered with a strong CYP3A4 inhibitor, ceritinib should be dose reduced by one-third. Strong CYP3A4 inducers should be avoided because they decrease systemic exposure of ceritinib.
  • Hepatotoxicity can develop, and liver function tests should be monitored every 2 weeks for the first 8 weeks of therapy. Liver function abnormalities may require treatment interruption and dose reductions.
  • In clinical trials, grade 3-4 hyperglycemia occurred in 13% of patients treated with ceritinib. Fasting blood glucose monitoring should be done prior to starting treatment and periodically afterward. Elevated blood glucose levels should be managed using hyperglycemic medications. A dose adjustment may be indicated for patients with persistent hyperglycemia.
  • QTc prolongation occurred in 6% of patients across clinical trials. Electrocardiogram monitoring should be conducted at baseline and throughout treatment. Concurrent use of other medications that may prolong QTc should be avoided. Ceritinib should be withheld from patients who develop a QTc interval greater than 500 msec on at least two separate EKGs, and treatment should not be restarted until the QTc interval is less than 481 msec or recovery to baseline QTc interval. At that time, a 150-mg dose reduction should be made. Ceritinib should be permanently discontinued in patients who develop Torsades de pointes, polymorphic ventricular tachycardia, or serious arrhythmia.

Clinical Pearls1,12

  • Ceritinib 750 mg received approval with the directions to take at least 1 hour before or at least 2 hours after a meal. Part 1 of the ASCEND-8 study was designed to assess whether doses of ceritinib at 450 mg or 600 mg taken with a low-fat meal versus 750 mg fasted improved GI tolerability while maintaining comparative drug pharmacokinetic (PK) parameters.
    • Compared to the 750-mg dose, the 450-mg dose had similar Cmax and AUC0-24h, while the 600-mg dose had an increased Cmax and AUC0-24h.
    • The 450-mg dose given with a low-fat meal had fewer GI adverse effects compared to the 750-mg fasted dose.
  • Ceritinib 450 mg with a low-fat meal had a similar PK profile, with more tolerable GI effects compared to the traditional 750-mg fasted dose.

References

  1. Zykadia (Ceritinib) capsules, for oral use [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Co.; June 2017.
  2. Shaw AT, Dong-Wan K, Ranee M, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014; 370:1189-1197.
  3. Soria JC, Tan DS, Chiari R, Wu YL, et al. First line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study. Lancet 2017 Mar 4;389(10072):917-929.
  4. Solomon BJ, Mok T, Kim DW, Wu YL, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec; 371(23):2167-2177.
  5. Johung KL, Yeh N, Desai NB, et al. Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol. 2016 Jan 10;34(2):123-129.
  6. Kim DW, Mehra R, Tan DSW, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicenter, open-label, phase 1 trial. Lancet Oncol. 2016 April 17;4:452-463.
  7. Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase ii global study. J Clin Oncol. 2016 Mar 1;34(7):661-668.
  8. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Guidelines Version 8.2017. July 14. National Comprehensive Cancer Network.
  9. Ou SI, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol 2016;34:661-668.
  10. Crino L, Ahn MJ, De Marinis F, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol. 2016;34:2866-2873.
  11. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017. Aug 31;377(9):829-838.
  12. Cho BC, Kim DW, Bearz A, et al. ASCEND-8: A randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017 Sept;12(9):1357-1367. Epub 2017 Jul 17.
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