英文原文：Novartis gains FDA approval for Zykadia(TM), first therapy for patients with ALK+ NSCLC previously treated with the ALK inhibitor crizotinib
-Zykadia (ceritinib) demonstrated an overall response rate of 54.6% in patients with ALK+ metastatic NSCLC who have no other treatment option
-Median duration of response to Zykadia was 7.4 months; patients in study started treatment with metastases, including brain (60%), liver (42%) and bone (42%)
-ALK+ NSCLC is driven by a rearrangement of the ALK gene, which is responsible for cancer cell growth in 2-7% of patients with NSCLC
-Approval follows FDA Breakthrough Therapy designation; regulatory application submitted in the EU and filings underway with other health authorities worldwide
Basel, April 29, 2014 - Novartis announced today that the US Food and Drug Administration (FDA) has approved Zykadia(TM) (ceritinib, previously known as LDK378) for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval of Zykadia addresses an unmet medical need for patients with this type of lung cancer who have progressed on prior therapy.
"Zykadia represents an important treatment option for ALK+ NSCLC patients who relapse after starting initial therapy with crizotinib," said lead investigator Alice T. Shaw, MD, PhD, Massachusetts General Hospital Cancer Center, Boston. "This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor."
Lung cancer is the leading cause of cancer death worldwide. The most common type of lung cancer is NSCLC, accounting for 85-90% of all cases. Of those, 2-7% are driven by a rearrangement of the ALK gene, which increases the growth of cancer cells and can be identified by a molecular test of the cancer tumor. Despite significant treatment advances for patients with ALK+ NSCLC, disease progression is often inevitable and more options are needed.
The approval of Zykadia is based on a pivotal trial that included 163 patients with metastatic ALK+ NSCLC who progressed on or were intolerant to treatment with crizotinib. The most common sites of metastases in the patient population studied were brain (60%), liver (42%) and bone (42%).
Among previously-treated patients, Zykadia achieved an overall response rate (ORR) of 54.6% [95% CI, 47-62%] and a median duration of response (DOR) of 7.4 months [95% CI, 5.4-10.1 months]. The most common adverse reactions (incidence of at least 25%) were diarrhea, nausea, elevated transaminases, vomiting, abdominal pain, fatigue, decreased appetite and constipation.
"The approval of Zykadia less than three and a half years after the first patient entered our clinical trial exemplifies what is possible with a highly focused approach to drug development and strong collaboration," said Alessandro Riva, MD, President, Novartis Oncology ad interim and Global Head, Oncology Development and Medical Affairs. "The dedication of clinical investigators, patients, the FDA and others has enabled us to bring this medicine to patients in need as swiftly as possible."
Zykadia is an oral, selective inhibitor of ALK, an important therapeutic target in lung cancer. ALK is a gene that can fuse with other genes to form an aberrant "fusion protein" that promotes the development and growth of cancer cells,. Zykadia is one of the first medicines to be approved following FDA Breakthrough Therapy designation, which was received in March 2013 due to the significance of results observed in the pivotal trial and the serious and life-threatening nature of ALK+ NSCLC. Additional regulatory submissions for Zykadia are underway worldwide, with an application currently filed in the European Union.
About the pivotal trial and Zykadia clinical trial program
The efficacy of Zykadia was established in a multicenter, single-arm, open-label clinical trial. A total of 163 patients with metastatic ALK+ NSCLC who progressed on or were intolerant to treatment with crizotinib were enrolled and treated at a Zykadia dose of 750 mg once daily. The major efficacy outcome measure was ORR according to RECIST v1.0 as evaluated by both investigators and a Blinded Independent Central Review Committee (BIRC). DOR was an additional outcome measure.
The study population characteristics were: median age 52 years, age less than 65 (87%), female (54%), Caucasian (66%), Asian (29%), never or former smoker (97%), ECOG PS 0 or 1 (87%), progression on previous crizotinib (91%), number of prior therapies 2 or more (84%), and adenocarcinoma histology (93%). Sites of extra-thoracic metastasis included brain (60%), liver (42%) and bone (42%). ALK-positivity was verified retrospectively by review of local test results for 99% of patients.
Zykadia achieved an ORR of 54.6% [95% CI, 47-62%] and a median DOR of 7.4 months [95% CI, 5.4-10.1 months] based on investigator assessment. The analysis by the BIRC assessment was similar to the analysis by the investigator assessment with an ORR of 43.6% [95% CI, 36-52%] and a median DOR of 7.1 months [95% CI, 5.6-NE months].
This study is part of the ongoing Novartis clinical trial program in this patient population. Several major studies evaluating treatment with ceritinib are being conducted in more than 300 study centers across more than 30 countries. Two Phase II single-arm clinical trials in previously-treated and treatment-na?ve ALK+ NSCLC patients, (www.clinicaltrials.gov identifiers NCT01685060 and NCT01685138), are fully enrolled and ongoing. In addition, two Phase III clinical trials comparing ceritinib with chemotherapy in treatment-na?ve and in previously-treated patients, (www.clinicaltrials.gov identifiers NCT01828099 and NCT01828112), are ongoing and actively recruiting patients worldwide,,,.
Zykadia (ceritinib) is indicated for the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Zykadia Important Safety Information
Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients treated with Zykadia in Study 1. Dose modification due to diarrhea, nausea, vomiting, or abdominal pain occurred in 38% of patients. Patients should be monitored and managed using standards of care, including anti-diarrheals, anti-emetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold Zykadia with resumption at a reduced dose as described in Table 1 of the package insert.
Drug-induced hepatotoxicity occurred in patients treated with Zykadia. Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 27% of 255 patients in Study 1. One patient (0.4%) required permanent discontinuation due to elevated transaminases and jaundice. Patients should be monitored with liver laboratory tests including ALT, aspartate aminotransferase (AST), and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold Zykadia with