Brigatinib in patients with crizotinib-refractory ALK-positive non-small-cell lung cancer: a randomized, multicenter phase II trial (ALTA)
The primary report of ALTA: after crizotinib, brigatinib shrank tumours in about half of patients, more so at the 180 mg dose after a week at 90 mg, and held the disease for around a year.
Overview
Randomised phase 2 trial of two brigatinib regimens in 222 patients with ALK-positive non-small-cell lung cancer that had progressed on crizotinib, stratified by brain metastases and best response to crizotinib: 90 mg once daily (arm A) or 180 mg once daily after a 7-day 90 mg lead-in (arm B). The primary endpoint was investigator-assessed confirmed objective response rate.
At 8.0 months median follow-up the confirmed response rate was 45 percent in arm A and 54 percent in arm B; median progression-free survival was 9.2 and 12.9 months. Intracranial response by independent review in patients with measurable brain metastases was 42 percent (11 of 26) and 67 percent (12 of 18). Early-onset pulmonary adverse events occurred in 14 of 219 treated patients, none after escalation to 180 mg in arm B.
- Confirmed objective response rate 45% (97.5% CI 34 to 56) with 90 mg and 54% (97.5% CI 43 to 65) with 180 mg after lead-in.
- Median progression-free survival 9.2 months (95% CI 7.4 to 15.6) and 12.9 months (95% CI 11.1 to not reached).
- Intracranial response 11 of 26 (42%) and 12 of 18 (67%) among patients with measurable brain metastases; early pulmonary events in 6% of treated patients, grade 3 or higher in 3%.
This is the trial behind brigatinib's first approval, after crizotinib, and it set the 180 mg dose with a 90 mg lead-in that the label uses. For a patient it shows a drug with strong activity in the brain and an unusual early lung side effect that the lead-in week was designed to soften.
- No control arm: both arms received brigatinib, so the trial compares doses, not brigatinib against another treatment.
- Median follow-up was only 8.0 months at the primary report.
- The 97.5% confidence intervals reflect the two-arm design and are wider than the usual 95%.
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