Data from the Phase III ALTA-1L trial (ALK in Lung Cancer Trial of BrigAtinib in 1st Line; NCT02737501) showed improved intracranial progression-free survival (PFS) and intracranial objective response rate (ORR) with brigatinib (Alunbrig?; Takeda Oncology) compared to crizotinib (Xalkori?; Pfizer/EMD Serono) among anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients.
Data for these secondary endpoints was presented in a poster discussion at the Annual Congress of the European Society for Medical Oncology – ESMO 2018 Congress on Friday, October 19, in Munich, Germany. These results further support brigatinib as a potential treatment for adults with ALK+ locally advanced or metastatic NSCLC who had not received a prior ALK inhibitor.
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.
Brigatinib is currently not approved as first-line therapy for advanced ALK+ NSCLC.
The ALTA-1L trial showed that treatment with brigatinib significantly delayed progression of disease in the brain compared to crizotinib…
Clinical trial
The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial of brigatinib in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor. Patients received either brigatinib, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival (OS), safety and tolerability.
A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstrate a minimum of six months PFS improvement over crizotinib. The trial is designed with two pre-specified interim analyses for the primary endpoint ? one at approximately 50% of planned PFS events and one at approximately 75% of planned PFS events.
Brain
?ALK+ NSCLC often spreads to the brain, so having options that can clearly demonstrate efficacy both in the brain and systemically is important for physicians and their patients,? said Sanjay Popat, PhD, FRCP, Medical Oncologist, Royal Marsden Hospital.
?The ALTA-1L trial showed that treatment with brigatinib significantly delayed progression of disease in the brain compared to crizotinib,? Popat added.
In the first interim analysis of the ALTA-1L trial, intracranial PFS was significantly improved with brigatinib compared to crizotinib in the Intention to Treat population (ITT) (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.24?0.70; log-rank P=0.0006) and the population with baseline brain metastases (HR: 0.27, 95% CI: 0.13?0.54; log-rank P<0.0001). Among patients with brain metastases at baseline, brigatinib reduced the risk of progression in the brain or death by 73%. Intracranial PFS in patients without brain metastases at baseline is not yet mature as of this first interim analysis.
Treatment with brigatinib also demonstrated an improved intracranial ORR compared to crizotinib. For patients with measurable brain metastases at baseline, 78% achieved confirmed intracranial OR in the brigatinib arm versus 29% in the crizotinib arm. For patients with non-measurable brain metastases at baseline, 67% achieved confirmed intracranial OR in the brigatinib arm versus 17% in the crizotinib arm.
Delayed progression
In addition, brigatinib significantly delayed both central nervous system (CNS) progression (without prior systemic progression) and systemic progression (without prior CNS progression) compared to crizotinib. Baseline factors related to the CNS, such as the proportion of patients with baseline brain metastases, mean number of brain metastases, and prior brain radiotherapy, including type, were balanced among patients in the two study arms. The safety profile associated with brigatinib in the ALTA-1L trial was generally consistent with the existing U.S. prescribing information.
?CNS disease presents a significant burden for patients with ALK+ NSCLC,? said David Kerstein, MD, Global Clinical Lead for Brigatinib and Lung Cancer Clinical Portfolio Strategy Lead, Takeda.
?These additional intracranial efficacy results from the ALTA-1L trial build upon activity previously reported with brigatinib in patients with brain metastases in the post-crizotinib setting and demonstrate Takeda?s dedication to research that aims to improve outcomes for those living with this serious disease.?
Superior PFS
These data build on results recently presented during the Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer (WCLC), which showed that treatment with brigatinib resulted in superior PFS compared to crizotinib as assessed by a blinded independent review committee, corresponding to a 51% reduction in the risk of disease progression or death (HR: 0.49, 95% CI: 0.33?0.74]; log-rank P=0.0007).
Grade 3 to 5 treatment-emergent adverse events occurred in 61% of the patients in the brigatinib arm and 55% of the patients in the crizotinib arm. Most common grade 3 or greater treatment-emergent adverse events for brigatinib were increased blood creatine phosphokinase (16%), increased lipase (13%), hypertension (10%), and increased amylase (5%); and for crizotinib were increased alanine aminotransferase (9%), increased aspartate aminotransferase (6%), and increased lipase (5%).
Development
Brigatinib is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, brigatinib received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ metastatic NSCLC patients 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
In July 2018, Health Canada approved brigatinib for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The FDA and Health Canada approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.
Brigatinib received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.
Clinical trial
ALTA-1L Study: A Phase 3 Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-small Cell Lung Cancer (NSCLC) Participants (ALTA-1L) – NCT02737501
Last Editorial Review: October 21, 2018
Featured Image: ESMO 2018 Congress. Courtesy: ? 2018 European Society for medical Oncology. Used with permission.
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