First line setting
The evidence supporting the use of brigatinib in the treatment of locally advanced or metastatic ALK-positive non small cell lung cancer (NSCLC) is provided by a phase III open-label multicentre randomised trial ALTA-1L. ALK inhibitor naive patients were treated with either brigatinib or crizotinib.r
Between April 2016 and August 2017, 275 patients underwent randomisation to receive oral treatment with either brigatinib 180 mg once daily with a 7 day lead-in at 90 mg (n=137) or crizotinib 250 mg twice daily (n=138).
The primary end point was progression free survival (PFS) and secondary end points included objective response rate (ORR) and intracranial response.
In patients who had not previously been treated with an ALK inhibitor treatment with brigatinib resulted in significantly longer PFS than crizotinib.
Second line setting
The evidence supporting the second line use of brigatinib in the treatment of locally advanced or metastatic ALK-positive non small cell lung cancer (NSCLC) is provided by a phase II open-label multicentre randomised trial - ALTA. Patients who had progressed whilst receiving crizotinib were treated with brigatinib Between June 2014 and September 2015, 222 patients were randomised 112 to receive 90 mg brigatinib once daily (arm A) and 110 to receive 180 mg brigatinib once daily with a seven-day lead in dose of 90 mg brigatinib once daily (arm B) until disease progression or unacceptable toxicity.r
The primary end point was investigator assessed confirmed objective response rate (cORR). Secondary end points included duration of response, overall survival (OS), independent review committee (IRC) assessed cORR, PFS, CNS response and intercranial PFS, safety and tolerability.r
Efficacy
First line setting
After a median follow up of 11.0 months in the brigatinib group and 9.3 months in the crizotinib group, the median 12-month estimated PFS was 67% (95% confidence interval [CI], 56 to 75) in the brigatinib group compared with 43% (95% CI, 32 to 53) in the crizotinib group. Hazard ratio (HR) for progression or death was 0.49 (95% CI, 0.33 to 0.74; p<0.001). Subgroup analysis also favoured brigatinib.r
The cORR was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib.
PFS (A), subgroup analysis (B), best target lesion responses (C), survival without intracranial disease progression among patients with brain metastases at baseline (D) r
© N Engl J Med 2018
Second line setting
After a median follow up of 19.6 months in arm A and 24.3 months in arm B the investigator assessed cORR (97.5% CI) was 46% (35 to 57%) in arm A and 56% (45 to 67%) in arm B, median duration or response was respectively 12.0 months (95% CI: 9.2 to 17.7) and 13.8 months (95% CI: 10.2 to 19.3). In arm A the IRC-assessed cORR was 51% (95% CI: 41% to 61%) compared with 56% (95% CI: 47% to 66%) in arm B. Median IRC-assessed PFS was 9.2 months (95% CI: 7.4 to 12.8) in arm A and 16.7 months (95% CI: 11.6 to 21.4) in arm B. Median OS was 29.5 months (95% CI: 18.2 to not reached [NR]) in arm A and 34.1 months (27.7 to NR) in arm B.r
Kaplan-Meier estimates of IRC-assessed PFS (A) and OS (B)r
© J Thorac Oncol 2020
Toxicity
The most common adverse events with brigatinib were diarrhoea, increased blood creatine kinase, nausea, cough, hypertension, elevated liver aminotransferase and lipase level, vomiting, constipation, pruritis and rash.r
Grade 3 or 4 events occurred with similar incidence in both the brigatinib and crizotinib groups (61% and 55% respectively). Permanent discontinuation secondary to adverse events occurred in 12% of those receiving brigatinib, and 9% of those receiving crizotinib. There were no treatment related deaths.
Adverse eventsr
© N Engl J Med 2018