More Support for a Higher Dose of Brigatinib in Advanced ALK-Positive NSCLC

The benefit of dose escalation of brigatinib, a next-generation oral ALK inhibitor — as well as the robust extracranial and intracranial efficacy of this agent — in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) with disease progression following treatment with crizotinib, were supported by 2-year follow-up results of an ongoing phase 2 clinical trial evaluating 2 dosing regimens of brigatinib in these patients. These findings were published in the Journal of Thoracic Oncology.¹

Crizotinib is a first-generation ALK inhibitor that has been shown to be effective in the treatment of approximately 5% of patients with advanced NSCLC with disease characterized by an ALK rearrangement (ie, ALK-positive disease). Nevertheless, most patients develop resistance to crizotinib due to the presence of ALK resistance mutations or other driver alterations, or insufficient CNS penetrance.

Furthermore, only a limited progression-free survival (PFS) benefit of 1 year or less has been observed in studies investigating subsequent treatment with second-line ALK inhibitors, such as ceritinib and alectinib, and the third-line ALK inhibitor, loratinib, in this patient population.

In the open-label ALTA study (ClinicalTrials.gov Identifier: NCT02094573), patients with crizotinib-refractory, ALK-positive advanced NSCLC were randomly assigned in a 1:1 ratio to receive brigatinib at a dose of 90 mg once daily or 90 mg once daily for 7 days followed by 180 mg once daily.

The 2 study arms were balanced with respect to sex, best response to crizotinib, prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status, and the presence of brain metastases. The primary study endpoint was investigator-assessed confirmed objective response rate (ORR), with secondary study endpoints including independently assessed intracranial ORR, PFS, intracranial PFS, duration of response, and overall survival.

In 2017, the higher-dose regimen of brigatinib received accelerated approval by the US Food and Drug Administration (FDA) in patients with ALK-positive NSCLC refractory to crizotinib on the basis of earlier results of the ALTA study reported at a median follow-up of 8 months.³

Of the 222 patients enrolled in the study, 112 received brigatinib at the 90 mg once daily dose and 109 were treated with brigatinib at a dose of 180 mg following the lower 7-day lead-in dose.  At baseline, brain metastases were present in 69% of patients, and 74% had been previously treated with chemotherapy.³

At 8-month follow-up, the ORR was 45% and 54% in the lower and higher brigatinib dosing arms, respectively, with 42% and 67% of patients achieving an intracranial ORR in these respective arms.  Furthermore, median PFS was 9.2 months for those receiving the 90-mg dose and 12.9 months for those treated with a daily dose of brigatinib of 180 mg following the 7-day lead-in, and toxicity was considered manageable in both arms.³

In this article, which reported findings from the ALTA study at a median follow-up of approximately 2 years, results were consistent with earlier study findings and provided additional support for the higher brigatinib dose.For example, the investigator-assessed ORR rate was 46% and 56% in the lower and higher dose study arms, respectively, similar to previously reported results. Notably, median PFS and median OS was 9.2 months and 29.5 months in the lower-dose arm, respectively, compared with 16.7 months and 34.1 months, respectively, for those receiving higher-dose brigatinib.¹

“Why brigatinib is associated with the longest recorded median PFS to date of any second- or third-generation ALK inhibitor in the post-crizotinib setting is only partially understood,” the study authors commented.¹

They also noted that “preclinically, [brigatinib] has a broader spectrum of activity against the ALK resistance mutations that arise after crizotinib use than that of either ceritinib or alectinib, but not that of lorlatinib. Whether this reflects either some aspect of clinical anti-ALK activity missed by preclinical modeling or some clinically relevant non–ALK-related activity inherent in brigatinib but not in the other drugs has to be considered.”¹

The benefit of the higher-dose regimen was also seen in study endpoints specifically focusing on the subgroup of patients with brain metastases. For example, the intracranial ORR was 50% and 67% in those receiving lower- and higher-dose brigatinib, respectively, with corresponding median intracranial PFS times of 12.8 months and 18.4 months. In addition, the duration of intracranial response was nearly 2 times longer in the higher- compared with the lower-dose arm (9.4 months vs 16.6 months, respectively).

Exploratory multivariate analyses showed that the depth of investigator-assessed target lesion response was independently associated with PFS and OS. For example, median PFS and median OS for those with best target lesion shrinkage of 0% was 3.6 months and 19.5 months, respectively. In contrast, for those with best target lesion shrinkage of 76% to 100%, median PFS was 8.3 months (hazard ratio [HR], 0.26 compared with no shrinkage; 95% CI, 0.13-0.51) and median OS was not reached (HR, 0.27 compared with no shrinkage; 95% CI, 0.12-0.60).¹

Another finding was that response to crizotinib was a predictor of response to brigatinib. No new safety signals were observed with longer follow-up.¹

“Intracranial versus extracranial efficacy and depth of response may be important endpoints to capture in future targeted therapy trials, and response to previous crizotinib may be important to consider when comparing data between trials,” the study authors concluded.

Disclosure: The corresponding author, as well as some of the other authors, reported the receipt of personal fees from pharmaceutical and/or medical device companies. For a full list of disclosures, please refer to the original study.

References

1. Huber RM, Hansen KH, Paz-Ares Rodriguez L, et al. Brigatinib in crizotinib-refractory ALK+ NSCLC: 2-year follow-up on systemic and intracranial outcomes in the phase 2 ALTA trial. J Thorac Oncol. 2020;15:404-415.
2. Brigatinib (Alunbrig^®) [package insert]. Cambridge, MA: Takeda Pharmaceutical Co. Ltd.; 2018.  
3. Kim D-W, Tiseo, Ahn M-J, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A randomized, multicenter phase II trial. J Clin Oncol. 2017;35:2490-2498.