Clinical Trials

Date: 2016-12-07

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer (WCLC) in Vienna

Company: Ariad Pharmaceuticals (USA - MA)

Product: brigatinib (AP26113)

Action mechanism: kinase inhibitor/tyrosine kinase inhibitor. Brigatinib (AP26113) is an investigational, targeted cancer medicine discovered internally at ARIAD Pharmaceuticals, Inc. It is in development for the treatment of patients with ALK+ NSCLC that is resistant to crizotinib. Brigatinib received Breakthrough Therapy designation from the FDA in October 2014 on the basis of an ongoing Phase 1/2 trial.  

Disease: non-small cell lung cancer (NSCLC)

Therapeutic area: Cancer - Oncology

Country: Australia, Austria, Belgium, Canada, Denmark, France, Germany, Hong Kong, Italy, Republic of Korea, The Netherlands, Norway, Singapore, Spain, Sweden, Switzerland, UK, USA

Trial details: The ALTA (ALK in Lung Cancer Trial of AP26113) trial is designed to determine the safety and efficacy of brigatinib (previously known as AP26113) in refractory non-small cell lung cancer (NSCLC) patients who test positive for the ALK oncogene (ALK+) and who have been treated with and progressed on their most recent crizotinib therapy. The trial enrolled 222 patients with ALK+ NSCLC who had been treated with and experienced disease progression on their most recent crizotinib therapy. Patients were randomized one-to-one to receive either 90 mg of brigatinib once per day (QD) (Arm A), or 180 mg QD, preceded by a lead-in dose of 90 mg QD for seven days (Arm B). In addition, patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib therapy. The primary endpoint of the trial is objective response rate (ORR) as measured by RECIST criteria.  The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of AP26113 in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib. Key secondary endpoints include PFS, confirmed ORR assessed by an IRC, overall survival (OS), CNS response and PFS, duration of response, safety and tolerability. (NCT02094573)

Latest news:

• • On December 7, 2016, Ariad Pharmaceuticals announced clinical data on brigatinib from the pivotal ALTA trial in ALK-positive (ALK+) non-small cell lung cancer patients who had experienced disease progression on crizotinib therapy. As of May 31, 2016, the data show that of patients on the 180-mg regimen with a median follow-up of 11 months, 55 percent achieved confirmed objective response as assessed by the investigator. In this arm, the median progression-free survival (PFS) was 15.6 months in this post-crizotinib setting, by both investigator and independent review committee (IRC) assessment. Additionally, in this arm, 67 percent of patients with measurable brain metastases achieved a confirmed intracranial objective response, and intracranial PFS was 18.4 months among patients with any brain metastases at baseline. These data have been presented at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer (WCLC) being held in Vienna.
• Clinical Data as of May 31, 2016 with IRC Data as of July 13, 2016: A total of 222 patients with ALK+ NSCLC treated with prior crizotinib therapy were randomized in the study (110 patients in Arm B at the 180-mg dose level with a seven-day lead-in at 90 mg and 112 patients in Arm A at the 90-mg dose level). The last patient was enrolled in the study in September 2015. The median follow-up was 11 months in Arm B and 10.2 months in Arm A. ALTA trial data presented at the 2016 American Society of Clinical Oncology (ASCO) meeting, as of February 29, 2016, had median follow-up of 8.3 months in Arm B and 7.8 months in Arm A. Investigator-assessed confirmed ORR in Arm B was 55 percent. IRC-assessed confirmed ORR in Arm B was 54 percent. Investigator-assessed confirmed ORR in Arm A was 45 percent. IRC-assessed confirmed ORR in Arm A was 49 percent. In a subgroup analysis of confirmed ORR by baseline characteristics, there was no difference in confirmed ORR based on prior chemotherapy versus no prior chemotherapy. The subgroup analysis by best response to prior crizotinib (partial or complete response versus other) suggests that patients who had achieved partial or complete responses on prior crizotinib treatment had a significantly higher confirmed ORR, compared with patients who did not achieve these responses. Responses in Arm B included a confirmed partial response in a patient with the ALK kinase domain G1202R mutation at baseline, which is associated with resistance to all approved tyrosine kinase inhibitors (TKIs). Median PFS was 15.6 months by both investigator assessment and IRC assessment in Arm B. Median PFS was 8.8 months by investigator assessment and 9.2 months by IRC assessment in Arm A. Probability of OS at one year was 82 percent and 71 percent in Arm B and Arm A, respectively. The median OS had not been reached in either arm. Of the 44 patients with measurable intracranial brain metastases at baseline, the IRC-assessed intracranial ORR was 67 percent (12/18) in Arm B and 46 percent (12/26) in Arm A. The median IRC-assessed intracranial PFS was 18.4 months in Arm B and 15.6 months in Arm A. The most common treatment-emergent adverse events (TEAEs; ? 30% of all patients, [Arm B/A]), regardless of relationship to treatment, were nausea (43%/36%), diarrhea (39%/21%), cough (36%/23%), headache (30%/28%) and increased blood creatine phosphokinase (CPK) (33%/11%). TEAEs, grade ?3, occurring in ?4 percent of all patients (excluding neoplasm progression; Arm B/A), were increased CPK (10%/3%), hypertension (6%/6%), pneumonia (5%/3%) and increased lipase (3%/5%). A subset of pulmonary adverse events (AEs) with early onset (median: Day 2; range: Day 1-9) occurred in six percent of all patients (grade ?3 in 3% of patients); no such events with early onset occurred after dose escalation to 180 mg QD in Arm B. Discontinuations and dose reductions due to AEs (Arm B/A) were 10 percent/three percent and 23 percent/eight percent, respectively. Discontinuations due to documented progressive disease (Arm B/A) were 23 percent and 30 percent.
• • On September 15, 2015, Ariad Pharmaceuticals announced that it has achieved full enrollment in the pivotal Phase 2 ALTA trial of its investigational anaplastic lymphoma kinase (ALK) inhibitor, brigatinib. This registration study enrolled approximately 220 patients at approximately 75 sites in North America , Europe and Asia . Median time on treatment for patients in the ALTA trial is less than 4 months, and follow-up data are limited at this time. As a result, ARIAD now expects that first data from the trial will be submitted for presentation at the American Society of Clinical Oncology ( ASCO ) annual meeting in 2016. Presenting data at ASCO will also align more closely with the anticipated filing for marketing approval of brigatinib in the U.S. in the third quarter of 2016.
• A randomized front-line clinical trial of brigatinib is expected begin in early 2016. This Phase 3 trial will compare brigatinib to crizotinib in approximately 300 patients with ALK+ NSCLC, who have not received prior ALK inhibitors.

Is general: Yes