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                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
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          FDA D.I.S.C.O.: Two approvals for ALK-positive non-small cell lung cancerResources for Information | Approved Drugs FDA D.I.S.C.O.: Two approvals for ALK-positive non-small cell lung cancer
  
  	
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*FDA medical oncologists discuss the FDA approvals of brigatinib and ceritinib for ALK-positive non-small cell lung cancer.*

*Transcript:*

Sanjeeve Bala: Welcome back to the DISCO. Today’s Drug Information Soundcast in Clinical Oncology from FDA’s Oncology Center of Excellence discusses two recent approvals: brigatinib, marketed as ALUNBRIGTM, and ceritinib marketed as ZYKADIA®. I’m Sanjeeve Bala, a medical oncologist and acting clinical team leader at FDA.

Abhi Nair: Hi, I am Abhi Nair, also a medical oncologist here at the FDA. Non-small cell lung cancer is no longer considered a single disease. With the identification of EGFR and ALK alterations, treatment has been evolving to include more targeted approaches. The past couple of years have witnessed many approvals for patients with the ALK-positive subset of non-small cell lung cancers.

SB: Today our focus is on brigatinib for the treatment of patients with ALK-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We will also briefly discuss the regular approval of ceritinib for patients with metastatic non-small cell lung cancer whose tumors are ALK-positive as detected by an FDA-approved test.

AN: Sanjeeve, give us a little background on ALK-positive non-small cell lung cancer.

SB: Sure, Abhi. Tumors from approximately 3 to 7% of patients with non-small cell lung cancer have a specific type of DNA abnormality, a rearrangement in the anaplastic lymphoma kinase or ALK gene. ALK rearrangements have been reported to occur more frequently in younger patients and in light or never smokers.

AN: And what FDA approved drugs do we have so far for the treatment of these patients?

SB: Crizotinib, a “first generation” ALK inhibitor, received regular FDA approval in 2013 for metastatic ALK-positive NSCLC. Crizotinib was compared to standard cytotoxic chemotherapy. However, most patients progress on crizotinib within about a year, which is generally better than that which we see for conventional cytotoxic therapy. For these patients, two other ALK-inhibitors are FDA approved. Ceritinib received accelerated approval in 2014 and regular approval that we’ll discuss shortly. Also, alectinib received accelerated approval in 2015.

AN: Since you’re distinguishing accelerated and regular approval, let me recap this for our listeners. Accelerated approval is based on surrogates, like response rates, which are likely to predict clinical benefit. Regular approval is based on a direct measure of clinical benefit, such as overall survival or a clinically meaningful effect on progression-free survival.

SB: Right, and accelerated approval is contingent upon demonstration of additional supportive clinical evidence after the accelerated approval. When these requirements are met, this allows the accelerated approval to formally switch to regular approval.

AN: Thanks, Sanjeeve. So now let’s get back to brigatinib. Tell us about its mechanism of action.

SB: Brigatinib is another oral tyrosine kinase inhibitor. It has demonstrated in vitro activity against multiple kinases including ALK, ROS1, and IGF-1.

AN: Give us some insight into the FDA considerations in the approval of brigatinib.

SB: The accelerated approval was based on a non-comparative, open-label, multicenter clinical trial randomizing 222 patients to one of two different dosing regimens of brigatinib. They had locally advanced or metastatic ALK-positive non-small cell lung cancer. All patients had progressed on crizotinib. This interesting trial design randomized patients to receive brigatinib 90 mg once daily or to 180 mg once daily following a seven-day lead-in at 90 mg once daily.

Overall, about half the patients in this study had an objective response. At the recommended dosing regimen of 90 mg once daily for seven days, with escalation to 180 mg once daily, if tolerated, 53% had a confirmed objective response as measured by an independent review committee. The median duration of response was approximately 14 months.

AN: Sanjeeve, you haven’t said how these patients were selected for this trial. Was there a specific test used?

SB: All patients in this trial had tumors with a documented ALK rearrangement. Testing was based on an FDA-approved test such as the Vysis® ALK Break-Apart fluorescence in situ hybridization, or FISH, Probe Kit test. Some patients had a different test with adequate archival tissue to confirm ALK rearrangement by the Vysis test.

AN: Going back to the accelerated regulatory pathway requirements, how will the clinical benefit of brigatinib be confirmed?

SB: Brigatinib is being assessed in an ongoing randomized clinical trial versus crizotinib in patients who have not yet received an ALK TKI. The primary endpoint will be PFS.

AN: There is an important subgroup of patients that might benefit greatly from brigatinib that we should discuss. Can you elaborate on that?

SB: Sure, Abhi. Neurologically stable patients with central nervous system metastases were also enrolled in the pivotal trial. This was also included as a stratification factor. Twelve of the 18 patients with measurable brain metastases at baseline who received brigatinib at the recommended dosing regimen had a CNS response. Because duration of follow-up in these patients was limited, the sponsor has agreed to provide additional data regarding the duration of response in these patients.

AN: I noticed that the dosing strategy is unusual for brigatinib. Can you explain how patients should be dosed?

SB: The recommended dosing regimen is 90 mg orally once daily for the first seven days and if tolerated, the dose is increased to 180 mg orally once daily.

AN: What about the safety profile? Is it as expected for a tyrosine kinase inhibitor?

SB: One unique toxicity that is important is the early onset of interstitial lung disease or pneumonitis. This has often occurred within 48 hours of starting the drug, and is the rationale for the seven-day lead-in dosing strategy.

AN: So if the seven-day lead-in is tolerated, the dose can be more safely escalated to 180 mg daily.

SB: With brigatinib, an increase in blood pressure was seen, which is not typical for other ALK-inhibitors, although it is seen with other types of tyrosine kinase inhibitors. Otherwise, for the most part the toxicities of brigatinib are similar to other approved ALK tyrosine kinase inhibitors. At the recommended dosing regimen, the most common adverse reactions, occurring in at least 25% of patients taking brigatinib, were nausea, diarrhea, fatigue, cough, and headache. The most common serious adverse reactions were pneumonia and interstitial lung disease or pneumonitis. The package insert has more detailed toxicity information.

AN: When I start a patient on brigatinib, what are the toxicities I should watch out for?

SB: Patients should be monitored for new or worsening respiratory symptoms, hypertension, bradycardia, visual symptoms, and elevations in amylase, lipase, blood glucose, and creatine phosphokinase.

AN: Now let’s discuss the regular approval of ceritinib. Sanjeeve, as you might recall, ceritinib received accelerated approval in 2014 for patients with ALK-positive metastatic non-small cell lung cancer whose disease had progressed on or who were intolerant of crizotinib. This approval was based on a single-arm trial of 163 patients in which an overall response rate of 44% was reported as assessed by a blinded independent review committee. So what’s the latest with the ceritinib story?

SB: Abhi, the key change here is the approval in previously-untreated patients. Now, ceritinib has regular approval in untreated ALK-positive non-small cell lung cancer.

AN: What was the evidence for this change?

SB: Abhi, the confirmation of clinical benefit was demonstrated in an open label, multicenter trial in 376 patients called ASCEND-4. They were randomized to receive either ceritinib 750 mg orally once daily or platinum-pemetrexed doublet chemotherapy for four cycles followed by pemetrexed as a single agent until disease progression. The median PFS was 16.6 months for patients on the ceritinib arm and 8.1 months on the chemotherapy arm. The overall response rate was 73% for ceritinib vs. 27% in the chemotherapy arm as assessed by a blinded independent review committee.

AN: And there was an interesting aspect to the responses. Tell us more about that.

SB: Responses were also observed in patients with CNS lesions on baseline brain scans. The confirmed overall intracranial response rate in patients with measurable CNS lesions was 57% in the ceritinib arm and 22% in the chemotherapy arm.

AN: So this is a change, since now ceritinib can be used in patients who have not received prior crizotinib or any other systemic treatment such as chemotherapy. Sanjeeve, can you summarize the three take-home points from this D.I.S.C.O.?

SB: Sure, Abhi. First, brigatinib is an ALK inhibitor that represents an additional option for ALK-positive patients with non-small cell lung cancer who have progressed on crizotinib. Second, CNS responses were observed in the pivotal trial and this is important for this high-risk subset of patients, though we have limited data regarding the durability of these responses. Finally, the regular approval of ceritinib in untreated ALK-positive non-small cell lung cancer patients presents a new first-line option for these patients.

Detailed prescribing and safety information may be found in the package inserts, available on the web at Drugs@FDA.

For a transcript with links to the FDA analysis, and the multidisciplinary review team of FDA experts who conducted the review, visit our website at www.fda.gov/DISCO.

AN: Thank you Sanjeeve. What other FDA oncology drug approvals would you like to hear about on D.I.S.C.O.? Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback. I’m Abhi Nair, thank you for tuning in to D.I.S.C.O. today.

SB: And until next time at the D.I.S.C.O., I’m Sanjeeve Bala.

Acknowledgements:

*This Drug Information Soundcast in Clinical Oncology was developed by Abhilasha Nair, Sanjeeve Bala, M. Naomi Horiba, Erin Larkins, Steven Lemery, Martha Donoghue, Gideon Blumenthal, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.*

*The FDA review documents for these product approvals are available on**Drugs@FDA**.*

*Members of the Multi-Disciplinary Review and Evaluation teams for these product applications were:*

Brigatinib

Regulatory Project Manager: Leah S. Her
Nonclinical Reviewers: M. Anwar Goheer, Emily F. Wearne
Nonclinical Team Leader: Whitney S. Helms
Office of Clinical Pharmacology Reviewers: Ruby Leong, Hongshan Li
Office of Clinical Pharmacology Team Leaders: Hong Zhao, Jiang Liu
Clinical Reviewer: M. Naomi Horiba
Clinical Team Leader and Cross-Disciplinary Team Leader: Steven Lemery
Statistical Reviewer: Thomas Ly
Statistical Team Leader: Kun He
Division Director (DHOT): John K. Leighton
Division Director (OCP): NAM Atiqur Rahman
Division Director (OB): Rajeshwari Sridhara
Acting Associate Division Director (OHOP): Martha Donoghue
Office Director: Richard Pazdur

Ceritinib

Regulatory Project Manager: Ingrid Fan
Clinical Reviewer: Barbara Scepura
Medical Officer: Denise Casey
Clinical Team Leader: Erin Larkins
Statistical Reviewer: Umaporn Siangphoe
Pharmacology Toxicology Review: Emily F. Wearne
Clinical Pharmacology Review: Yuan Xu, Ruby Leong
Clinical Outcomes Assessment Review: Nikun J.B. Patel
Office of Prescription Drug Promotion Review: Nazia Fatima
Office of Scientific Investigations: Lauren C. Iacono-Conors
Maternal Health Review: Tamara N. Johnson
Patient Labeling Review: Morgan A. Walker
Division Director (DOP2): Patricia Keegan

                                                                                  Content current as of:
      07/28/2017
              
              
Regulated Product(s)
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						  OncologyResources for Information | Approved Drugs

          
                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
          Ongoing | Cancer Accelerated Approvals
          Verified Clinical Benefit | Cancer Accelerated Approvals
          Withdrawn | Cancer Accelerated Approvals
          Other | Cancer Accelerated Approvals


                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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