The primary endpoint of the phase III ALTA-1L trial has been met, as brigatinib was found to reduce the risk of disease progression or death versus crizotinib in adult patients with locally advanced or metastatic <em>ALK</em>-positive non–small cell lung cancer who had not received a prior ALK inhibitor, Takeda Pharmaceutical Company, the manufacturer of brigatinib, has announced.
Jesus Gomez Navarro, MD
The primary endpoint of the phase III ALTA-1L trial has been met, as brigatinib (Alunbrig) was found to reduce the risk of disease progression or death versus crizotinib (Xalkori) in adult patients with locally advanced or metastaticALK-positive nonsmall cell lung cancer (NSCLC) who had not received a prior ALK inhibitor, Takeda Pharmaceutical Company, the manufacturer of brigatinib, has announced.
According to a press release from Takeda, the findings from this interim analysis will be presented at a future medical conference. The company also noted that no new safety issues emerged with brigatinib in the trial.
“This represents a major milestone for the Alunbrig program. Our goal with Alunbrig is to improve the lives of patients withALK-positive NSCLC by furthering the available therapeutic options,” Jesús Gomez-Navarro, MD, vice president, head of Oncology Clinical Research and Development, Takeda, said in a statement.
“We are encouraged by the data, which demonstrated a statistically significant improvement in progression-free survival versus crizotinib in patients withALK-positive advanced NSCLC, and look forward to beginning discussions with regulatory authorities as we seek to expand Alunbrig’s indication into the frontline setting,” added Gomez-Navarro.
The FDA granted brigatinib an accelerated approval in April 2017 for the treatment of patients with metastaticALK-positive NSCLC who are resistant to prior crizotinib. Accelerated approvals are contingent upon results from subsequent confirmatory trials.
The accelerated approval was based on findings from the phase II ALTA trial, in which the confirmed ORR for brigatinib at 180 mg daily was 53% (95% CI, 43-62) and the median PFS was 13.8 months.
The ALTA trial enrolled 222 patients withALK-positive NSCLC following progression on crizotinib. Patients were randomized to receive brigatinib at either 90 mg daily (n = 112) or 180 mg daily with a 7-day lead in period at 90 mg per day (n = 110). Sixty-nine percent of patients had brain metastases at the time of enrollment.
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.
The confirmed ORR was 48% (95% CI, 39-58) in the 90-mg arm. In those who had not received prior chemotherapy, the ORR was 52%. In the 180-mg dose group, those who had not received chemotherapy had an ORR of 52%. There were 4 confirmed complete responses in the 180-mg arm and 1 in the 90-mg group. The median duration of response was 13.8 months in both arms.
The median PFS in the 90-mg arm was 9.2 months. 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 rate was 39% with the 90-mg dose and 54% in the 180-mg arm.
The 1-year OS rate was 71% with the 90-mg dose versus 80% with the larger 180 mg dose, representing a nonstatistically significant 43% reduction in the risk of death with the larger dose (HR, 0.57; 95% CI, 0.31-1.05). The median OS had not yet been reached in both arms.
In those with measurable, active brain metastases treated with the 180-mg dose (n = 18), the intracranial ORR was 67%. In those with brain metastases treated with the 90-mg dose (n = 26), the intracranial ORR was 42% (95% CI, 23-63).
The median intracranial duration of response was not estimable in the 90-mg arm and was 5.6 months among patients receiving 180 mg. In the group achieving an intracranial response, the response lasted for at least 4 months in 78% and 68% of patients in the 90- and 180-mg arms, respectively.
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).
There was a subset of patients (6%) who experienced early onset pulmonary AEs, which occurred within a median of 2 days (range, 1-9). These events occurred prior to dose escalation in the 180-mg arm. Overall, 8% and 3% of patients discontinued treatment due to AEs in the 180 mg and 90 mg arms, respectively.
In October 2017, the FDA approved a supplemental new drug application for the use of 180-mg tablets of brigatinib for the treatment of patients with NSCLC. Previously, brigatinib was only available in 30- and 90-mg tablets.
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).
The multicenter, open-label phase III ALTA-1L trial (NCT02737501) randomized 275 patients to brigatinib at a lead-in dose of 90 mg once daily for 7 days followed by 180 mg once daily, or crizotinib at 250 mg twice daily. Treatments were administered until disease progression, unacceptable toxicity, or withdrawal of consent. Beyond the primary endpoint of progression-free survival (PFS), secondary outcome measures included objective response rate (ORR), intracranial ORR, intracranial PFS, overall survival (OS), safety, and tolerability.