On October 10, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reportedupdated clinical data on its investigational tyrosine kinase inhibitor (TKI), brigatinib, in patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial (Press release, Ariad, OCT 10, 2016, View Source;p=RssLanding&cat=news&id=2210388 [SID:SID1234515707]).

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The updated Phase 1/2 results were included in a poster presentation on Sunday, October 9 at the 41st Annual Congress of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) held in Copenhagen, Denmark.

Phase 1/2 Study

The data presented at ESMO (Free ESMO Whitepaper) include safety analyses on all patients in the trial (N=137) and efficacy analyses on all patients with ALK+ NSCLC (n=79). Of the 79 ALK+ NSCLC patients, all but eight had failed prior crizotinib therapy. The presentation is based on patient data as of May 2016 with a median time on brigatinib treatment for ALK+ NSCLC patients of 20.0 months (range, 0.03 – 47.4 months, ongoing). Patient enrollment in the trial is complete, with the last patient enrolled in July 2014.

"The long-term follow up on this clinical trial of brigatinib continues to show anti-tumor activity with a confirmed overall objective response rate of 62 percent in crizotinib-resistant ALK-positive NSCLC patients at all doses evaluated, and 76 percent among those patients who received the 180 mg dose regimen with a seven-day lead-in at 90 mg once daily," stated Lyudmila A. Bazhenova, M.D., a clinical professor of medicine at the University of California San Diego Moores Cancer Center. "The median progression-free survival in this post-crizotinib ALK+ NSCLC patient group continues to exceed one year."

Key data from the study include:

Anti-tumor Activity of Brigatinib in ALK+ NSCLC Patients
Data as of May 31, 2016

Of the 71 ALK+ NSCLC patients with prior crizotinib therapy, 44 (62%) achieved a confirmed objective response to brigatinib.
Of the 25 patients treated with the 180 mg dose regimen (with 90 mg lead-in), 19 (76%) achieved a confirmed objective response.
Of the eight crizotinib-naive ALK+ NSCLC patients treated with brigatinib, all achieved an objective response (100%), including three complete responses (CR). All responses were confirmed.
The "waterfall plot" analysis demonstrated 100 percent tumor shrinkage of target lesions in 24 (33%) of 72 evaluable ALK+ NSCLC patients.
The median duration of response in confirmed responders was 14.5 months in ALK+ NSCLC patients treated with prior crizotinib therapy and was not yet reached in ALK+ NSCLC patients who were crizotinib-naive.
Median progression-free survival (PFS) was 12.9 months in ALK+ NSCLC patients with prior crizotinib therapy and was not yet reached in ALK+ NSCLC patients who were crizotinib-naive. The longest time on treatment for a patient who was crizotinib-naive was 47.4 months.
The probability of overall survival (OS) at one year was 77 percent in ALK+ NSCLC patients who received prior crizotinib therapy (projected two-year OS was 61%) and 100 percent in patients who were crizotinib-naive (projected two-year OS was 100%).
CNS Anti-tumor Activity of Brigatinib in ALK+ NSCLC Patients
Data as of October 8, 2015

An evaluation of the efficacy of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also included in the poster. In an independent central review of brain magnetic resonance imaging (MRI) scans, 46 ALK+ NSCLC patients were evaluable for intracranial response, including 15 who had measurable intracranial CNS metastases at baseline, and 31 patients who had only non-measurable intracranial CNS metastases.
10 of 15 (67%) patients with measurable intracranial CNS metastases had an intracranial objective response, and 13 of 31 (42%) with only non-measurable intracranial CNS metastases had complete disappearance of intracranial lesions.
Median intracranial PFS for ALK+ NSCLC patients with intracranial CNS metastases at baseline was 14.6 months. Median duration of intracranial response in confirmed responders was 11.4 months.
Safety and Tolerability – All Patients Enrolled
Data as of May 31, 2016

The most common treatment-emergent adverse events (AEs; ≥ 30%), regardless of relationship to treatment, were nausea (53%), fatigue (45%), diarrhea (42%), headache (35%), and cough (33%).
Treatment-emergent AEs, regardless of relationship to treatment, grade 3 or higher, occurring in ≥4 percent of patients (excluding disease progression) were increased lipase (12%), pneumonia (7%), dyspnea (6%), hypoxia (6%), hypertension (5%), increased amylase (4%), fatigue (4%), hypophosphatemia (4%), and hyponatremia (4%).
Serious treatment-emergent AEs, regardless of relationship to treatment, occurring in ≥2 percent of patients (excluding disease progression) were pneumonia (7%), dyspnea (6%), hypoxia (5%), pneumonitis (3%), pulmonary embolism (3%), confusional state (2%), malignant pericardial effusion (2%), and seizure (2%).
A subset of pulmonary AEs (including dyspnea, hypoxia, pneumonia and/or pneumonitis) was observed to occur within seven days of treatment initiation or treatment re-initiation following a prolonged dose interruption. Most events occurred within 48 hours of dosing and were generally managed with dose interruption or discontinuation and empiric treatment (steroids and/or antibiotics).
Rates of these AEs were numerically lower with lower starting doses (11/137 (8%), overall)
6/44 (14%) in patients started at 180 mg qd
1/50 (2%) in patients started at 90 mg qd
Among 32 patients treated with 90 mg qd for seven days followed by 180 mg qd, no such events were reported after dose escalation.
Administration of brigatinib at 180 mg with a seven-day lead-in at 90 mg appears not to be associated with an increased risk of additional early pulmonary AEs, when compared with continuous administration of brigatinib at 90 mg.
About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell cancer (NSCLC). The global Phase 2 ALTA trial, designed to determine the safety and efficacy of brigatinib in refractory ALK+ NSCLC patients who have been treated with and progressed on their most recent crizotinib therapy, is the basis for brigatinib’s initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor.