Brigatinib has intracranial activity in patients with ALK-rearranged NSCLC
medwireNews: Patients with anaplastic lymphoma kinase (ALK) translocation-positive non-small-cell lung cancer (NSCLC) that has metastasized to the central nervous system (CNS) derive benefit from treatment with brigatinib, suggests an analysis of two trials.
One was a phase I/II study in which the next-generation ALK inhibitor was administered at doses ranging from 90 to 240 mg/day and the other was the phase II ALTA trial, which involved random assignment to receive one of two daily doses – 90 mg or 180 mg, where the latter included a 7-day lead-in period at the 90 mg dose. Altogether the trials included 301 patients with locally advanced or metastatic ALK-positive disease, only four of whom had not received prior crizotinib.
The majority of participants in the phase I/II trial (66% of 79) and each arm of the ALTA trial (71% of 112 and 66% of 110 in the 90 and 180 mg/day groups, respectively) had brain metastases at baseline. Of these, 46 patients in the phase I/II trial and all of the ALTA participants with CNS disease had available scans and were included in the current exploratory analysis.
As reported in the Journal of Clinical Oncology, a confirmed CNS objective response as assessed by independent review was achieved by 53% of the 15 patients with measurable disease (CNS lesions ≥10 mm) in the phase I/II study, and by 46% of 26 patients who received the 90 mg dose in ALTA and 67% of 18 given the 180 mg dose.
For patients with nonmeasurable disease at baseline, only complete responses – defined as the disappearance of all CNS lesions – could be recorded and the corresponding rates were 35%, 7%, and 18%.
Across all patients with brain metastases, CNS responses lasted for a median of 11.4 months in the phase I/II trial, while the median was unreached in either group of the ALTA trial.
And independent review-assessed median CNS progression-free survival (PFS) was 14.6 months for the participants of the phase I/II study, and 15.6 and 18.4 months for the 90 and 180 mg groups of the ALTA trial, respectively.
In light of these results and the previously reported findings for the overall populations of the trials, lead author D Ross Camidge (University of Colorado Cancer Center, Aurora, USA) and team speculate that “[b]rigatinib has broad preclinical activity against ALK mutations, which likely contributes to prolonged PFS systemically and potentially in the brain.”
Commenting on the results in a linked editorial, Jeffrey Zweig and Joel Neal, both from Stanford University School of Medicine in California, USA, say that “[f]or patients with ALK-positive NSCLC, the CNS has transitioned from a sanctuary site of disease to a penetrable space.”
They continue: “[W]ith the explosion of therapeutic options for patients with ALK-positive NSCLC over the last few years, including those with brain metastases, there is renewed optimism for achieving long-term control of this disease.”
Speaking to medwireNews, Camidge noted that two key questions remain regarding the future role of brigatinib in patients with ALK-rearranged NSCLC.
First, given the results of the ALEX trial pitting alectinib against crizotinib in the first-line, whether brigatinib is “going to have relevant activity” if it is given after alectinib remains unknown, and second, will brigatinib – and indeed lorlatinib or ensartinib – make the transition to the first-line setting just as alectinib has done, he asked.
All three of these next-generation ALK inhibitors – brigatinib, lorlatinib, and ensartinib – are being compared with crizotinib in treatment-naïve patients with ALK-positive disease, and we will have to see whether these agents extend PFS to the same degree in the first-line as they do in the second-line, continued Camidge.
He believes that the “one good problem” for the investigators is that the first-line median PFS durations are predicted to be in years.
Thus, “while we may know that each of these drugs can beat crizotinib, we won’t know which one has the longest PFS until the data are mature, and that may take a long time. While we await that first-line decision making may well have to be based on more basic issues such as dosing convenience, tolerability, and cost,” Camidge concluded.
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