Brigatinib Approved in Europe for ALK+ NSCLC

The European Commission has approved brigatinib (Alunbrig) for the treatment of adult patients with ALK-positive non–small cell lung cancer who were previously treated with crizotinib (Xalkori).

Enriqueta Felip, MD, PhD

The European Commission has approved brigatinib (Alunbrig) for the treatment of adult patients with ALK-positive non—small cell lung cancer (NSCLC) who were previously treated with crizotinib (Xalkori), according to Takeda Pharmaceutical Company, the developer of the ALK inhibitor.1

The approval follows a positive opinion granted by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in September 2018. The decision was based on findings from the phase II ALTA trial, in which the overall response rate (ORR) was 56% for patients with pretreated ALK-positive NSCLC treated with the recommended 180-mg dose of brigatinib.2 Additionally, the median overall survival with this dose was 34.1 months.

“The introduction of targeted therapies has greatly improved the treatment of ALK-positive NSCLC, yet for the approximately 70% of patients who progress on crizotinib with brain metastases, additional therapeutic options are needed,” Enriqueta Felip, MD, PhD, head of the Thoracic Oncology Unit, Oncology Department at Vall d’Hebron University Hospital in Barcelona, Spain, said in a statement.

“Data from the ALTA trial investigating Alunbrig showed sustained systemic and intracranial efficacy results and a manageable safety profile, leading to the longest progression-free survival and overall survival reported in this setting. This approval gives physicians in the European Union another choice in addressing ALK-positive NSCLC patients previously treated with crizotinib,” added Felip.

In the international, randomized ALTA trial, 222 patients with locally advanced or metastatic ALK-positive NSCLC who progressed on crizotinib were randomized to receive 1 of 2 doses—90 mg once daily (n = 112) or 180 mg once daily with a 7-day lead-in at 90 mg once daily (n = 110).

The median age of patients across the study was 54 years, and the ECOG performance status (PS) was primarily 0 and 1 (93%), with 7% having an ECOG PS of 2. Moreover, 60% of patients did not have a smoking history prior to entering the trial and 74% had received prior chemotherapy. Sixty-five percent of patients had experienced a complete or partial response to crizotinib.

Findings showed that of the patients who received the 180-mg dose, 56% achieved an ORR as assessed by investigator and 56% as assessed by an independent review committee (IRC). Moreover, the median duration of response was 13.8 months as assessed by investigator and 15.7 months by IRC assessment. Of those with measurable brain metastases at baseline (n = 18), 67% achieved an intracranial ORR by IRC assessment; the median duration of intracranial response was 16.6 months by IRC assessment.

The median progression-free survival (PFS) with those who received the 180-mg dose was 16.7 months via IRC assessment and was 9.2 months in the 90-mg arm. Data showed that there was a 45% reduction in the risk of progression or death with the 180-mg dose of brigatinib versus the 90-mg dose (HR, 0.55; 95% CI, 0.35-0.86). The 1-year PFS rates were 39% and 54% in the 90-mg and 180-mg arms, respectively.

The median OS in the 180-mg arm was 34.1 months. Additionally, the 1-year OS rate was 71% with the 90-mg dose versus 80% with the 180-mg dose, which represented a nonstatistically significant 43% reduction in the risk of death with the larger dose (HR, 0.57; 95% CI, 0.31-1.05).

Regarding safety, the most common all-grade treatment-emergent adverse events (AEs) in the 90-mg and 180-mg arms, respectively, were nausea (40% and 33%), diarrhea (38% and 19%), cough (34% and 18%), and headache (27% and 28%). The most common grade ≥3 treatment-emergent AEs in the 90-mg and 180-mg arms, respectively, were increased blood creatinine phosphokinase (3% and 9%) and hypertension (6% each).

The FDA granted an accelerated approval to brigatinib in April 2017 for the treatment of patients with metastatic ALK-positive NSCLC who are resistant to prior crizotinib. With the European approval, brigatinib is now indicated in the 28 member states of the European Union, as well as Norway, Liechtenstein, and Iceland. The recommended starting dose of brigatinib is 90 mg once daily for the first 7 days, followed by 180 mg once daily.

“The European Commission’s decision to approve [Alunbrig] for patients with ALK-positive NSCLC is a significant advancement for European patients impacted by this life-threatening disease,” said Jesús Gómez-Navarro, MD, vice president, Head of Oncology Clinical Research and Development, Takeda. “This is the first time a median progression-free survival of over 16 months as assessed by an independent review committee and median overall survival of 34 months have been reported in the post-crizotinib setting, which highlights the strength of the ALTA trial data.”

As part of the submission, the CHMP also reviewed data from the first interim analysis of the international, open-label, multicenter, randomized phase III ALTA-1L trial (NCT02737501), which enrolled 275 patients with ALK-positive locally advanced or metastatic NSCLC who had not received prior treatment with an ALK inhibitor. Patients received either 180 mg once daily with a 7-day lead-in at 90 mg once daily or crizotinib at 250 mg twice daily. The primary endpoint was IRC-assessed PFS, and secondary endpoints included ORR per RECIST v1.1, intracranial ORR, intracranial PFS, OS, safety, and tolerability.

Takeda previously reported in a press release that results from the first interim analysis of ALTA-1L showed as significant improvement in intracranial PFS with brigatinib versus crizotinib in the ITT population (HR, 0.42; 95% CI, 0.24−0.70; P = .0006) and in the subgroup of patients with baseline brain metastases (HR, 0.27, 95% CI, 0.13-0.54; P <.0001). Additionally, for patients with measurable brain metastases at baseline, the confirmed intracranial response rate was 78% versus 29% with brigatinib versus crizotinib, respectively. The rates were 67% versus 17%, respectively, in patients with nonmeasurable brain metastases at baseline.


  1. European Commission Approves ALUNBRIG® (brigatinib) for ALK+ Non-Small Cell Lung Cancer in Patients Previously
  2. Kim D-W, Tiseo M, Ahn M-J, et al. Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): first report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA). J Clin Oncol. 2016;34 (suppl; abstr 9007).