In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On April 29, 2014, ceritinib (Zykadia) was granted accelerated approval for treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non–small cell lung cancer (NSCLC) with disease progression on or intolerance to crizotinib (Xalkori).1-3 Accelerated approval was based on tumor response rate and duration of response. No improvement in survival or disease-related symptoms has yet been established. Continued approval may be contingent on verification of clinical benefit in confirmatory trials.
Pivotal Study
Approval was based on findings in a multicenter, single-arm, open-label trial in 163 patients with metastatic ALK-positive NSCLC who had shown disease progression on or were intolerant of crizotinib. All patients received ceritinib at a dose of 750 mg once daily.
The primary endpoint supporting approval was objective response rate according to RECIST v1.0 criteria as evaluated by both investigator and blinded independent central review committee. Duration of response was also assessed.
Patients had a median age of 52 years, 54% were female, 66% were white, 97% were never or former smokers, 87% had Eastern Cooperative Oncology Group performance status of 0 or 1, 93% had adenocarcinoma histology, 91% had disease progression on crizotinib, 84% had received at least two prior therapies for metastatic disease, and sites of extrathoracic metastasis included the brain in 60%, liver in 42%, and bone in 42%.
The objective response rate was 44% (95% confidence interval [CI] = 36%–52%), and median duration of response was 7.1 months based on independent central review and 55% (95% CI = 47%–62%) and 7.4 months based on investigator assessment.
Editor’s note: Data were updated in abstract 8003 presented at the ASCO Annual Meeting, where after a median of 7 months of follow-up, patients treated with ceritinib achieved an overall response rate of 58.5% and median progression-free survival of 8.2 months. See the next issue of The ASCO Post for a full report on the ASCO presentation by Dong-Wan Kim, MD, PhD, of Seoul National University Hospital or visit ASCOPost.com.
How It Works
Ceritinib is an inhibitor of ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1 kinases, with greatest activity against ALK. It has been shown to inhibit autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
The drug inhibits proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and exhibits dose-dependent inhibition of EML4-ALK–positive NSCLC xenograft growth in mice and rats. It also has exhibited dose-dependent antitumor activity at clinically relevant concentrations in mice with EML4-ALK–positive NSCLC xenografts with demonstrated resistance to crizotinib.
How It Is Given
The recommended dose of ceritinib is 750 mg once daily until disease progression or unacceptable toxicity. A recommended dose has not been determined for patients with moderate to severe hepatic impairment. Approximately 60% of patients starting treatment at this dose required at least one dose reduction, and the median time to first dose reduction was 7 weeks. Ceritinib should be discontinued in patients unable to tolerate 300 mg daily.
Dose interruption or reduction is recommended for alanine transaminase or aspartate transaminase elevation more than five times the upper limit of normal with bilirubin elevation less than or equal to two times the upper limit of normal, QTc interval > 500 msec on two separate measurements, severe or intolerable nausea, vomiting, or diarrhea, persistent hyperglycemia > 250 mg/dL, and symptomatic bradycardia.
Permanent discontinuation of ceritinib is recommended for alanine transaminase or aspartate transaminase elevation more than three times the upper limit of normal with bilirubin elevation more than two times the upper limit of normal in the absence of cholestasis or hemolysis, QTc interval prolongation with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, and life-threatening bradycardia in patients not taking medication known to cause bradycardia or hypotension.
Concurrent use of strong CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole) should be avoided; if such use is unavoidable, the ceritinib dose should be reduced by approximately one-third (rounding to nearest 150 mg) and can be resumed at the former dose after discontinuation of the CYP3A inhibitor.
Safety Profile
The median duration of exposure to ceritinib in the clinical trial was 6 months. The most common clinical adverse events of any grade were diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%), and fatigue (52%); the most common grade 3 or 4 adverse events were diarrhea (6%), fatigue (5%), nausea (4%), and vomiting (4%).
The most common grade 3 or 4 laboratory abnormalities were increased alanine transaminase (27%), increased aspartate transaminase (13%), increased glucose (13%), increased lipase (10%), decreased phosphate (7%), and decreased hemoglobin (5%). Additional clinically significant adverse events included neuropathy (17%), vision disorder (9%), interstitial lung disease/pneumonitis (4%), prolonged QT interval (4%), and bradycardia (3%).
Adverse events led to dose reduction in 59% of patients, with the most common causes of dose reduction or interruption being increased alanine transaminase (29%), nausea (20%), increased aspartate transaminase (16%), diarrhea (16%), and vomiting (16%); overall, gastrointestinal toxicity resulted in dose modification in 38% of patients. Adverse events led to discontinuation of treatment in 10%.
Serious adverse events in ≥ 2% consisted of convulsion, pneumonia, interstitial lung disease/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse events occurred in 5% of patients, consisting of pneumonia in four patients and respiratory failure, interstitial lung disease/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis in one patient each.
Ceritinib carries warnings/precautions for severe or persistent gastrointestinal toxicity, hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, and embryofetal toxicity.
Liver tests should be performed at least monthly. Electrocardiograms and electrolytes should be monitored in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and those who are taking medications that are known to prolong the QTc interval.
Cost
The wholesale cost of ceritinib is estimated at $13,500 per month. ■
References
1. U.S. Food and Drug Administration: Ceritinib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm395386.htm.
2. ZYKADIA™ (ceritinib) capsules prescribing information, Novartis Pharmaceuticals Corporation, April 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/205755lbl.pdf.
3. Shaw AT, Kim D-W, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med 370:1189-1197, 2014.
