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Published on: August 21, 2019
The role of brigatinib in crizotinib-resistant non-small cell lung cancer
Laura Mezquita1, David Planchard1
1Medical Oncology Department, Gustave Roussy, Villejuif, France.
Abstract:
Despite the advances in new targeted therapies in ALK positive population, most patients progress under ALK inhibitors within first 2 years; being the brain the most frequent site of relapse. ALK mutations, in ~30% of patients, are the main known mechanism of resistance. Classically, second-generation ALK inhibitors have been the standard of care in the crizotinib-resistant population; however, each ALK inhibitor has a different spectrum of sensitivity to ALK mutations, complicating the optimal treatment strategy for the resistant population. Brigatinib (AP26113) is a novel highly selective and potent inhibitor of ALK and ROS1 with a high degree of selectivity. In vitro, brigatinib not only inhibited ALK with 12-fold higher potency compared to crizotinib, but also inhibited IGF-1R, FLT3 and EGFR mutants, with some activity against the EGFRT790M resistance mutation. In xenograft models, brigatinib overcomes resistance to ALK inhibitors, including the ALK G1202R mutation, which is resistant to first- and second-generation inhibitors. The efficacy of brigatinib in crizotinib-resistant, ALK-positive patients has been demonstrated in two early studies, which led to its approval in this setting, and it is currently being investigated as the first-line therapy versus crizotinib in tyrosine kinase inhibitor-naïve patients. Brigatinib demonstrates not only promising whole-body activity, but also an impressive improvement of intracranial outcomes in terms of both objective response rate and progression-free survival in the crizotinib-resistant population, with optimal efficacy at 180 mg (following a 90 mg run-in for 7 days) and good tolerance. These data confirm brigatinib as an excellent therapeutic strategy after crizotinib failure, particularly in the setting of central nervous system involvement. In this review, we summarize the two main clinical studies reported to date with brigatinib in ALK-positive advanced NSCLC patients, in particular, in the crizotinib-resistant population. We also address the mechanism of action for development of resistance and the challenging issues of optimal implementation for sequences of administration for ALK inhibitors.
Insights
Brigatinib shows significant efficacy in ALK-positive non-small cell lung cancer patients resistant to crizotinib, particularly those with brain metastases. This targeted therapy offers improved intracranial outcomes and good tolerance after crizotinib failure.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Most ALK-positive non-small cell lung cancer (NSCLC) patients develop resistance to ALK inhibitors within two years, with the brain being a common site of relapse.
- ALK mutations are the primary mechanism of resistance, complicating treatment strategies as different inhibitors have varying sensitivities to these mutations.
- Brigatinib is a potent, selective inhibitor of ALK and ROS1, also targeting other kinases like IGF-1R, FLT3, and EGFR mutants.
Purpose of the Study:
- To evaluate the efficacy and safety of brigatinib in ALK-positive NSCLC patients who have progressed on crizotinib.
- To assess brigatinib's activity against specific ALK resistance mutations, including those conferring resistance to earlier generation inhibitors.
- To review clinical data on brigatinib's whole-body and intracranial activity, particularly in the context of central nervous system involvement.
Main Methods:
- Review of two key clinical studies investigating brigatinib in crizotinib-resistant, ALK-positive advanced NSCLC patients.
- In vitro and xenograft studies assessing brigatinib's potency and ability to overcome resistance mechanisms, including the ALK G1202R mutation.
- Analysis of brigatinib's efficacy, including objective response rate (ORR) and progression-free survival (PFS), especially in patients with brain metastases.
Main Results:
- Brigatinib demonstrated significant whole-body and intracranial activity in crizotinib-resistant patients.
- Optimal efficacy was observed at a dose of 180 mg daily (following a 90 mg run-in for 7 days), with good tolerability.
- Brigatinib overcomes resistance to first- and second-generation ALK inhibitors, including the challenging ALK G1202R mutation.
Conclusions:
- Brigatinib is an effective therapeutic option for ALK-positive advanced NSCLC patients who have failed crizotinib, especially those with central nervous system metastases.
- The drug's ability to overcome resistance mechanisms and its favorable intracranial efficacy profile support its role in managing advanced disease.
- Ongoing investigations are exploring brigatinib as a first-line treatment option against crizotinib in tyrosine kinase inhibitor-naïve patients.
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