SIZE XSSIZE SMSIZE MDSIZE LG

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.


November 6, 2017–Alectinib (ALECENSA, Hoffmann-La Roche, Inc./Genentech, Inc.) for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test (with Pharmacist's Applications to Practice.)

December 11, 2015–Alectinib (ALECENSA® capsules) approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib


November 6, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208434s003lbl.pdf

On November 6, 2017, the Food and Drug Administration granted regular approval to alectinib (ALECENSA, Hoffmann-La Roche, Inc./Genentech, Inc.) for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.

In December 2015, alectinib received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed on or who were intolerant of crizotinib based on an independent review committee (IRC)-assessed overall response rate (ORR) of 38% and 44% among 87 and 138 patients, respectively, in two single arm trials.

This current approval is based on data from ALEX (NCT02075840), a randomized, multi-center, open-label, active-controlled trial conducted in 303 patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) CDx Assay performed through central laboratory testing. Patients were randomized 1:1 to receive alectinib 600 mg orally twice daily (n=152) or crizotinib 250 mg orally twice daily (n=151).

ALEX demonstrated an improvement in progression-free survival (PFS) as assessed by blinded IRC (BIRC), with a hazard ratio (HR) of 0.53 (95% CI: 0.38, 0.73; p<0.0001). The estimated median PFS for patients randomized to alectinib was 25.7 months (95% CI: 19.9, not estimable [NE]) compared with 10.4 months (95% CI: 7.7, 14.6) for those randomized to crizotinib. The time to cause-specific central nervous system (CNS) progression as assessed by IRC was also significantly improved; there was a lower incidence of progression in the CNS as first site of disease progression, alone or concurrent with systemic progression, in the alectinib arm (12%) compared to the crizotinib arm (45%). Confirmed ORR was 79% (95% CI: 72, 85) and 72% (95% CI: 64, 79) in the alectinib and crizotinib arms, respectively. Among the 120 responders in the alectinib arm and the 109 responders in the crizotinib arm, the proportion of patients with response duration of ≥12 months was 64% and 36%, respectively.

CNS involvement was assessed in all patients. Among the 43 patients with measurable CNS lesions on baseline brain scans, the CNS ORR, assessed by BIRC neuro-radiologist, was 81% (95% CI: 58, 95) in the alectinib arm and 50% (95% CI: 28, 72) in the crizotinib arm. Among patients with measurable CNS lesions and a CNS response, the proportion of patients with a CNS response duration of ≥12 months was 59% in the alectinib arm and 36% in the crizotinib arm.

The most common adverse reactions (occurring in ≥20% of patients taking alectinib in ALEX) were fatigue, constipation, edema, myalgia, and anemia. Serious adverse reactions occurred in 28% of patients treated with alectinib. Adverse reactions leading to alectinib discontinuation occurred in 11%. Adverse reactions that led to alectinib discontinuation in 1% or more of patients were renal impairment, hyperbilirubinemia, increased alanine aminotransferase, and increased aspartate aminotransferase. Dose interruption due to adverse reactions occurred in 19% of alectinib-treated patients, while dose reductions were required in 16%.

The recommended dose of alectinib is 600 mg orally twice daily with food.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208434s003lbl.pdf

FDA granted breakthrough therapy designation to alectinib for this indication in September 2016. 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

Alectinib (Alecensa) for Anaplastic Lymphoma Kinase–Positive Metastatic Non-Small-Cell Lung Cancer, as Detected by an FDA-Approved Test

Authors: Jessie Lawton, PharmD BCOP
Aurora BayCare Medical Center
Green Bay, WI

Megan Beak, PharmD candidate
Concordia University School of Pharmacy
Mequon, WI

What is the potential role for alectinib in the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small-cell lung cancer (NSCLC)?1-6

  • Alectinib is a tyrosine kinase receptor inhibitor (TKI) targeting ALK and RET approved as first-line therapy in ALK-positive metastatic NSCLC (about 5% of NSCLC), as detected by a test approved by the U.S. Food and Drug Administration (FDA).
  • In December 2015, the FDA provided accelerated approval for alectinib to treat patients with advanced ALK-positive NSCLC whose disease had progressed or who could not tolerate treatment with crizotinib.
  • First-line approval was based on the phase 3 ALEX study, in which alectinib showed a significant improvement in progression-free survival (PFS) with a reduction in risk of disease progression or death in patients with untreated ALK-positive NSCLC (hazard ratio for disease progression or death, .50; 95% confidence interval (CI), .36 to .70; p < .001). The median PFS for patients in the alectinib treatment group was 25.7 months compared to 10.4 months in the crizotinib treatment group. The study also found that the incidence of brain metastases was lower with alectinib than with crizotinib (9% vs. 41%) at 12 months.
  • Alectinib is the fourth TKI to be approved by the FDA for ALK-positive advanced NSCLC. Other second-generation ALK inhibitors include ceritinib and brigatinib. No head-to-head trials comparing these agents currently exist.
  • According to National Comprehensive Cancer Network (NCCN) guidelines, alectinib is considered a first-line therapy for ALK rearrangement–positive NSCLC. Alectinib can be used when the ALK rearrangement is discovered prior to initiation of first-line chemotherapy (category 1, preferred recommendation), or it can be used after the completion of planned chemotherapy, including maintenance therapy. The planned chemotherapy can also be interrupted, and alectinib can be used if ALK rearrangement is found after first-line chemotherapy has been initiated. Alectinib is also another treatment option in patients whose disease has progressed on crizotinib or who are unable to tolerate crizotinib.
  • Brigatinib is another recently approved ALK inhibitor with a broader spectrum of inhibition, but it has been associated with high-grade early pulmonary toxicity. Interstitial lung disease or pneumonitis was seen in 9.1% of patients, with 2.7% being grade 3 or 4. For alectinib, the rate was .4%.

What role can the pharmacist play in the management of patients on alectinib?1,5-6

  • Alectinib is supplied as 150 mg capsules, and the recommended dosing is 600 mg (4 capsules) orally twice a day with food.
  • Alectinib can be administered until the disease progresses or an unacceptable level of toxicity is reached.
  • These points should be covered in patient education:
    • The capsules should be taken with food and should be swallowed whole.
    • If vomiting occurs after taking a dose, the patient should not take an extra dose; the next dose should be taken at the regularly scheduled time.
    • Photosensitivity occurred in 9.9% of patients in clinical trials, so the patient should be made aware of the signs and symptoms associated with photosensitivity and the importance of using sunscreen and proper protection from the sun.
    • Alectinib can cause fetal toxicity, so effective contraception should be used.
  • Information about the Alectinib Patient Assistance and co-pay card for nongovernment medication insurance plans is available at Genentech-access.com.
  • Monitor liver function (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] and bilirubin) every 2 weeks for the first 3 months, then once per month and as clinically indicated.
  • Monitor creatine phosphokinase (CPK) every 2 weeks for the first month of treatment and in patients who report muscle pain, tenderness, or weakness.
  • Monitor heart rate and blood pressure regularly because bradycardia has been seen in patients receiving alectinib.
  • Monitor for signs and symptoms of interstitial lung disease (ILD), pneumonitis, and myalgia.
  • Because of the potential for bradycardia, concomitant antihypersensitive medications should be evaluated.
  • Common adverse effects (all grades greater than 15%): anemia (56%), increased AST (51%), increased alkaline phosphatase (47%), increased CPK (43%), fatigue (41%), increased bilirubin (39%), hyperglycemia (36%), increased ALT (34%), constipation (34%), hypocalcemia (32%), edema (30%), hypokalemia (29%), increased creatinine (28%), hypophosphatemia (21%), hyponatremia (20%), nausea (18%), bradycardia (8%–20%), skin rash (18%), diarrhea (16%), and dyspnea (16%).
    • Reasons for potential dose reductions or discontinuations: ILD/pneumonitis, bradycardia, and elevated ALT, AST, bilirubin, or CPK. See package insert for exact criteria and dose modification schedule.
    • Dose reduction schedule and dose level
      • Starting dose: 600 mg taken orally twice daily
      • First dose reduction: 450 mg taken orally twice daily
      • Second dose reduction: 300 mg taken orally twice daily
    • Discontinue alectinib if patients are unable to tolerate the 300-mg twice-daily dose.

Clinical Pearls7

  • VENTANA ALK (D5F3) CDx Assay by Roche is the only approved FDA test for ALK for alectinib (also a Roche product).
    • This test is a qualitative detection of the ALK protein in formalin-fixed paraffin-embedded NSCLC tissue stained with the BenchMark XT or BenchMark ULTRA automated staining instrument.
    • This assay is approved to assess eligibility for crizotinib, ceritinib, and (more recently) alectinib.
    • Medicare and most private insurance will cover ALK testing as needed for initiating alectinib.

References

  1. Alecensa (alectinib). [Package insert]. South San Francisco, CA: Genentech, Inc.; revised November 2017.
  2. 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;377:829-838.
  3. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 4.2018). www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.
  4. Alubbrig (brigatinib}. [Package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd; revised April 2017.
  5. Alectinib. LexiComp, Lexi-Drugs [online database]. St. Louis, MO: Wolters Kluwer Health, Inc.: 2005. Accessed December 12, 2017.
  6. Alectinib. Micromedex [online database]. Greenwood Village, CO: Truven Health Analytics. Accessed December 12, 2017.
  7. VENTANA ALK (D5F3) CDx Assay. 2016. Ventana Medical Systems, Inc. www.ventana.com/product/1816?type=2326

December 11, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf

On December 11, 2015, the U. S. Food and Drug Administration granted accelerated approval to alectinib (ALECENSA® capsules, Hoffmann-La Roche Inc.) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

The approval was based on two multicenter, single arm, open-label clinical trials in patients with metastatic ALK rearrangement-positive NSCLC who had progressed on or were intolerant to the ALK inhibitor crizotinib (Study 1 and 2) and the majority also received previous systemic chemotherapy. All patients received alectinib 600 mg twice daily. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by an independent review committee (IRC) and by Investigator. Additional outcome measures included duration of response (DOR), central nervous system (CNS) ORR according to RECIST v1.1 in patients with baseline measurable lesions in the CNS, and CNS DOR.

Study 1 (n=87) showed an ORR of 38% (95% CI: 28%, 49%) by IRC and 46% (95% CI: 35%, 57%) by Investigator. In Study 2 (n=138) the ORR was 44% (95% CI: 36%, 53%) by IRC and 48% (95% CI: 39%, 57%) by Investigator. The median DOR was 7.5 months in Study 1 and 11.2 months in Study 2 after a median duration of follow-up of 4.8 months and 10.9 months, respectively. In a pooled analysis of patients from Study 1 and Study 2 with baseline measurable lesions in the CNS, the CNS ORR was 61% (95% CI: 46%, 74%) and the median CNS DOR was 9.1 months.

Safety data was evaluated in 253 patients who received alectinib at a dose of 600 mg twice daily. The most common adverse reactions were fatigue, constipation, edema, and myalgia. The majority of these adverse reactions were grade 1-2. The most common grade 3-4 adverse reaction was dyspnea. The most common laboratory abnormalities were anemia, elevations in aspartate aminotransferase (AST), elevations in alkaline phosphatase, and elevations in creatine phosphokinase (CPK). The majority of the above laboratory abnormalities were grade 1-2. The most common grade 3-4 laboratory abnormalities were elevations in alanine aminotransferase (ALT), lymphopenia, and elevations in CPK.

Serious adverse events (SAEs) were reported in 19% of patients. The most common SAEs (reported in 3 patients each) included dyspnea, pulmonary embolism, and elevations in bilirubin. The most frequent adverse reactions leading to dose reductions or interruptions were elevations in bilirubin, CPK, ALT, AST, and vomiting. The most common adverse events leading to discontinuation included ALT elevations (1.6%), and bilirubin elevations (1.6%). Fatal adverse events occurred in 2.8% of patients, including 1 case each of hemorrhage and intestinal perforation attributed to alectinib.

The recommended dose and schedule for alectinib is 600 mg orally with food twice daily.

This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of March 4, 2016. Alectinib received Breakthrough Therapy Designation, and the current indication was approved under FDA’s accelerated approval program. The application was granted Priority Review. 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.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.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).

 

xs
sm
md
lg