Brigatinib demonstrated sustained long-term responses and survival in patients with crizotinib-refractory ALK-positive non–small cell lung cancer.
Brigatinib (Alunbrig) demonstrated sustained long-term responses and survival in patients with crizotinib (Xalkori)-refractory ALK-positive non–small cell lung cancer (NSCLC), according to long-term efficacy and safety results from the phase 1/2 (NCT01449461) and phase 2 ALTA (NCT02094573) trials that were presented virtually during the 2021 ASCO Annual Meeting.
At a median follow-up of 27.7 months, the confirmed investigator-assessed objective response rate (ORR) was 67% (95% CI, 56%-77%), with a median duration of response (DOR) of 14.9 months (95% CI, 9.9-29.5) in patients with ALK-positive NSCLC enrolled in the phase 1/2 trial (n = 79). The median investigator-assessed progression-free survival (PFS) was 14.5 months (95% CI, 10.8-21.2) in all patients and 34.2 months (95% CI, 7.4-63.9) in crizotinib-naïve patients. The median overall survival (OS) was 47.6 months (95% CI, 28.6-not reached [NR]) in all patients, with an estimated 5-year OS rate of 42% (95% CI, 23%-61%). A total of 10 patients were still receiving brigatinib up to the study end.
At a median follow-up of 28.3 months, the approved dosing regimen for brigatinib led to an ORR of 56% (95% CI, 47%-66%) by independent review, with a median DOR of 15.7 months (95% CI, 13.6-22.1) in crizotinib-refractory patients with ALK+ NSCLC enrolled in arm B of the phase 2 trial (n = 110). The median PFS by independent review was 16.7 months (95% CI, 11.6-21.4). The median OS was 40.6 months (95% CI, 32.5-NR), with an estimated 5-year OS rate of 43% (95% CI, 33%-53%). A total of 10 patients in arm A and 17 patients in arm B were still on brigatinib up to study end.
“Brigatinib showed sustained long-term activity and PFS in the final analyses of the phase 1/2 and phase 2 ALTA trials,” Scott N. Gettinger, MD, professor of Internal Medicine (Medical Oncology), and chief of Thoracic Medical Oncology at Yale School of Medicine, and co-authors wrote in the study poster.
In 2017, brigatinib was approved by the FDA for the treatment of patients with ALK-positive NSCLC who experienced disease progression on crizotinib or intolerance to tolerate the agent. The approval was based on findings from the phase 1/2 and phase 2 ALTA trials, in which brigatinib led to an ORR of 56% and an intracranial ORR of 67% in patients with measurable baseline brain metastases, with an acceptable safety profile.
In the phase 1/2 trial, patients with advanced malignancies (n = 137) received brigatinib at one of the following doses: 60 mg once daily (n = 1), 90 mg once daily (n = 14), 120 mg daily (n = 6), 90 mg followed by 180 mg once daily (n = 28), 180 mg daily (n = 25), or 240 mg daily or 300 mg once daily (n = 5).
In the phase 2 trial, patients with locally advanced or metastatic ALK-positive NSCLC with disease progression on crizotinib who had not received any other ALK-directed therapy were randomized 1:1 to 90 mg of brigatinib once daily (arm A; n = 112) or 90 mg once daily for a 7-day lead-in followed by 180 mg once daily (arm B; n = 110).
Regarding baseline characteristics, patients were a median age of 54, 51, and 57 years in the phase 1/2 trial, and arm A and arm B of the phase 2 ALTA trial, respectively. Brain metastases at baseline were reported in 63%, 71%, and 67% of patients, respectively. The majority of patients across each of the 3 arms had an ECOG performance status of 1, adenocarcinoma histology, and received prior chemotherapy and crizotinib.
Additional findings from the phase 2 trial indicated that the intracranial ORR by independent review was 67% (95% CI, 41%-87%) in patients with measurable central nervous system lesions, with a median intracranial DOR of 16.6 months (95% CI, 3.7-NR).
Notably, the approved dosing regimen that was administered in arm B of the phase 2 trial was associated with a numerically higher ORR, PFS, and OS compared with the 90-mg daily dose that was administered in arm A of the trial.
The median intracranial PFS by independent review in patients with any baseline brain metastases was 18.4 months (95% CI, 12.6-23.9), with an estimated 4-year intracranial PFS rate of 8% (95% CI, 2%-23%).
Moreover, the safety profile of brigatinib was consistent with prior reports, with no new safety concerns.
In the phase 1/2 trial, grade 3 or greater treatment-related adverse effects (TRAEs) included increased lipase (18%), hypertension (8%), increased amylase (5%), hypophosphatemia (5%), increased blood creatine phosphokinase (5%), fatigue (3%), increased aspartate aminotransferase (AST; 3%), increased alanine aminotransferase (ALT; 3%), dyspnea (3%), diarrhea (1%), nausea (1%), and cough (1%).
In arm B of the phase 2 trial, grade 3 or greater TRAEs included increased blood creatine phosphokinase (14%), increased lipase (8%), hypertension (6%), increased ALT (4%), increased AST (3%), increased amylase (2%), nausea (1%), and hypophosphatemia (1%).
Treatment discontinuation because of any AE occurred in 10%, 4%, and 13% of patients in the phase 1/2 trial, and arm A and arm B of the phase 2 ALTA trial, respectively. Dose interruptions because of any AE occurred in 59%, 49%, and 61% of patients, respectively. Dose reductions because of any AE occurred in 13%, 8%, and 33% of patients, respectively.
On May 22, 2020, the FDA approved brigatinib for the frontline treatment of patients with ALK-positive metastatic NSCLC, as detected by an FDA-approved test.