EU Panel Grants Positive Opinion to Brigatinib for ALK+ NSCLC

Enriqueta Felip, MD, PhD

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended full approval of brigatinib (Alunbrig) as a treatment for patients with advanced ALK-positive non—small cell lung cancer (NSCLC) who are previously treated with crizotinib (Xalkori).¹

The recommendation is based on data from the phase II ALTA trial, which showed that the objective response rate (ORR) was 56% for those who received brigatinib.2 Moreover, the median progression-free survival (PFS) as assessed by an independent review committee (IRC) was 16.7 months, and the median investigator-assessed overall survival was 34.1 months.

"The ALTA trial has established [brigatinib] as a potential second-line treatment option for ALK-positive NSCLC, by demonstrating significant efficacy with a manageable safety profile," said Jesús Gómez-Navarro, MD, vice president and head of Oncology Clinical Research and Development at Takeda Pharmaceutical Company, the manufacturer of brigatinib.

"With 16.7 months median progression-free survival, the longest of any ALK inhibitor to be reported in this setting, [brigatinib] offers great potential for patients who progressed on crizotinib. Today's positive opinion brings us closer toward the ultimate goal of advancing the treatment paradigm for the considerable number of crizotinib-treated ALK-positive NSCLC patients living in Europe. We look forward to the European Commission's review of the CHMP positive opinion and introducing [brigatinib] to patients and healthcare professionals in the European Union if approved."

As part of the submission, the CHMP also reviewed data from the first interim analysis of the international, randomized, open-label, multicenter, comparative, ongoing phase III ALTA-1L trial (NCT02737501), which is comparing brigatinib with crizotinib in the frontline setting of ALK-positive NSCLC. Takeda previously announced that brigatinib demonstrated a statistically and clinically significant improvement in PFS versus crizotinib as assessed by a blinded IRC; the company is planning to present the interim findings at an upcoming medical meeting. Tolerability with the ALK inhibitor was also reported to be consistent with prior studies.

ALTA-1L 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.

ALTA was a randomized, global phase II study that investigated the efficacy and safety of brigatinib in 222 patients with locally advanced or metastatic ALK-positive NSCLC who progressed on crizotinib. Patients 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 ECOG performance status (PS) was primarily 0 and 1 (93%), with 7% having an ECOG PS of 2. Sixty percent 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.

Results demonstrated that of the patients who received the 180-mg dose, 56% achieved an ORR as assessed by investigator and 56% as assessed by IRC. Moreover, the median duration of response was 13.8 months as assessed by investigator and 15.7 months by IRC assessment.

Additionally, of those with measurable brain metastases at baseline (n = 18), 67% achieved an intracranial ORR by IRC assessment; median duration of intracranial response was 16.6 months by IRC assessment.

In the 90-mg arm, the median PFS was 9.2 months. Moreover, 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.

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).

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).

If approved, brigatinib will be the sole ALK inhibitor available for use in the European Union as a one tablet daily that can be taken with or without food.

"While ALK inhibitors have demonstrated tremendous growth in this treatment space over the past decade, having an additional targeted therapy option available for the treatment of ALK-positive NSCLC has been eagerly anticipated," said Enriqueta Felip, MD, PhD, head of the Thoracic Oncology Unit in the Oncology Department at Vall d'Hebron University Hospital in Barcelona, Spain. "With a median progression-free survival of 16.7 months and overall survival of 34.1 months, [brigatinib] has shown impressive results, representing new progress for ALK-positive NSCLC treatment in this setting."

The positive opinion will now be reviewed by the European Commission. if approved, it will be available for use in the 28 countries of the European Union, as well as in Iceland, Liechtenstein and Norway. The FDA granted an accelerated approval to brigatinib for the treatment of patients with metastatic ALK-positive NSCLC who are resistant to prior crizotinib in April 2017.

References

1. Takeda receives positive CHMP opinion recommending ALUNBRIG® (brigatinib) for the treatment of ALK+ non-small cell lung cancer in patients previously treated with crizotinib [press release]. Cambridge, MA: Takeda; September 21, 2018.investor.takedaoncology.com/phoenix.zhtml?c=80159&p=irol-newsarticle&ID=2368417. Accessed September 21, 2018.
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).