Results from the randomized phase 2 ALTA trial in patients with crizotinib-refractory, metastatic anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) paved the way for the FDA approval of brigatinib in April 2017, and subsequently, its approval of brigatinib 180-mg tablets. A post hoc analysis of these results evaluated the clinical benefit of continuing brigatinib after disease progression (PD).
For ALTA, 222 patients with ALK-positive NSCLC who had developed resistance to previous crizotinib treatment were randomized to receive brigatinib 90 mg once daily (n = 112) or 180 mg once daily with a 7-day lead-in at 90 mg (n = 110). Patients in the 90-mg arm could escalate their dose to 180 mg once daily after PD, as determined by Response Evaluation Criteria in Solid Tumors. The post hoc analysis evaluated 107 patients who experienced PD with brigatinib, did not have PD as their best response, and survived ≥21 days after PD.
As of February 21, 2017, 84 patients continued brigatinib and 23 discontinued brigatinib after PD. The investigators used a Kaplan-Meier estimate from the time of first PD to determine 1-year overall survival (OS) after PD. Of the patients who continued brigatinib after PD, 1-year OS after PD was 66% (95% confidence interval [CI], 53-99), compared with 31% among those who discontinued brigatinib (95% CI, 13-100). The highest proportion of 1-year OS after PD was seen in patients in the 90-mg arm who escalated their dose of brigatinib to 180 mg after PD, at 70% (95% CI, 44-99).
Unadjusted hazard ratios (HRs) showed significantly longer OS in patients who continued brigatinib compared with those who discontinued brigatinib (HR, 0.32 [95% CI, 0.17-0.62]). This was especially true in patients who continued brigatinib at the 180-mg dose. Numerically longer OS was seen in patients who continued brigatinib, through HRs adjusted for duration of previous crizotinib treatment, number of previous treatment regimens (1, 2, or ≥3), time to investigator-assessed PD, whether PD was due to new lesions only, and Eastern Cooperative Oncology Group (ECOG) performance status at the time of PD (0, 1, or ≥2; HR, 0.53 [95% CI, 0.26-1.08]).
Heavily pretreated patients, as well as those who received brigatinib treatment for longer durations before PD, whose PD was not attributed to new lesions, had confirmed objective response, and had better ECOG performance status at the time of PD, had a greater likelihood of continuing brigatinib after PD. Several factors were independently associated with worse OS (P <.05)—2 previous treatment regimens versus ≥3, shorter time to investigator-assessed PD, PD attributed to new lesions only, and ECOG performance status ≥2 versus 0.
The investigators concluded that patients who continued brigatinib after PD experienced greater survival benefit. “Continuing brigatinib, especially at 180 mg, could be one of many factors associated with longer OS after PD in these patients,” they wrote.
Langer C, Huang H, Reichmann W, et al. Overall survival (OS) after disease progression (PD) on brigatinib in patients with crizotinib-refractory ALK+ NSCLC in ALTA. J Thorac Oncol. 2017;12(11 Suppl 2):S1893-S1894.