The potent and orally available anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, had successfully demonstrated activity and efficacy against non-small cell lung cancer (NSCLC) in patients who are refractory or could not tolerate crizotinib.1,2 It has also shown to overcome crizotinib resistance mutations, as well as extending disease progression or death, making it a possible candidate for exploration as first-line therapy in ALK+ NSCLC treatment. The findings from the phase 3 trial, ALTA-1L, were presented at the World Conference on Lung Cancer (WCLC).1,3,4
NSCLC makes up of approximately 90% of lung cancers, with 3-5% of NSCLC resulting from the rearrangement of the oncogenic ALK gene.1,2 Development and use of ALK targeted therapies are therefore beneficial to this population of NSCLC patients. Currently there are three ALK inhibitors approved by the US Food and Drug Administration (FDA) for first-line use: crizotinib, ceritinib and alectinib.3
The recent next-generation ALK inhibitor, brigatinib, has shown favorable results from the ALK in Lung Cancer Trial of Brigatinib in 1st Line (ALTA-1L).2,3 This open label, phase 3 trial was conducted to compare the efficacy and safety against crizotinib, a first generation ALK inhibitor, first approved by the FDA in 2011 after proving to have higher response rates and be superior to the standard platinum based/pemetrexed chemotherapy.1 However, the use of crizotinib was limited with the development of resistance within the first 12 months of initiating therapy, as well as disease progression in the central nervous system, which could be due to poor CNS penetration and mutations of ALK.1,2
Brigatinib is currently approved for ALK+ NSCLC in patients treated with crizotinib whom have suffered disease progression or are intolerant.5 Its ability to target a large range of ALK mutations and possession of activity against EGFR mutations makes it the first ALK inhibitor of its kind.2,3 Results from the ALK in Lung Cancer Trial of AP26113 (ALTA) whereby brigatinib was administered to patients with tumor cells unresponsive to crizotinib showed a clinically meaningful and high overall response rate (ORR) with a median progression-free survival (PFS) of 16.7 months.2,5 A direct comparison of efficacy and safety between the two drugs were therefore conducted as the aim of ALTA-1L.2 Dr. Ross Camidge of the University of Colorado Cancer Center, US, lead author of ALTA-1L, suggested from the first interim analysis, the results showed reduced risk of progression and death with brigatinib compared to crizotinib.3 “Interim data shows brigatinib is set to become a first-line treatment option for ALK+ lung cancer,” said Dr. Camidge.4
ALTA-1L was conducted on 275 patients over 20 countries and patient selection criteria included for those tested positive for ALK activity and had not previously received ALK-targeted therapy, with or without baseline brain metastases.2 Patients were randomly assigned in a 1:1 ratio to brigatinib 180mg once-daily (after a 7 day lead in of 90mg once-daily) and crizotinib 250mg twice-daily.2 The treatment continued until patients developed either intolerable side effects, disease progression (assessed by an independent committee not involved in and unaware of the clinical trial) or one of the other discontinuation criterion such as mortality or withdrawal of consent.2 Data collected from February 2018 showed a total of 35 patients from the crizotinib group were accepted to cross over to brigatinib therapy after their disease progression was assessed (again, by an independent reviewer) after a washout period of 10 days.2
During the trial, the patients were assessed every 8 weeks until cycle 14 (28 days per cycle) and then every 12 weeks until treatment end.2 Common (occurring in over 25% of the participants) adverse events included gastrointestinal symptoms and increased blood creatine kinase and alanine aminotransferase levels. Early onset (i.e. taking place within the first 14 days of treatment) pulmonary events, such as pneumonitis, were observed with brigatinib and treatment was discontinued in those patients.2
A 51% lowered risk of disease progression and death (HR=0.49; 95% CI: 0.33-0.74; p<0.001) with brigatinib was shown from the median follow-up of 11 months for brigatinib and 9.3 months with crizotinib.2 The rate of PFS at 12 months was 67% in the brigatinib group (95% CI: 56-75) and 43% in the crizotinib group (95% CI: 32-53).2 A median PFS of 9.8 months was seen with crizotinib, consistent with previous trials, but the median had not been reached for brigatinib.2 In the brigatinib group, a low HR of 0.2 was noted for the risk of disease progression or death in patients with brain metastases at baseline (95% CI: 0.09-0.46), but not significantly lower in the those patients without brain metastases (HR=0.72; 95% CI: 0.44-1.18).2 Dr. Camidge suggested that the effect size from brigatinib may be particularly pronounced in patients with central nervous system (CNS) disease prior to treatment initiation.3
Dr. Fiona Blackhall, clinical senior lecturer and honorary consultant in medical oncology at the Christie Health Service Foundation Trust, UK, suggested that initiating treatment with crizotinib and then switching to a next generation ALK inhibitor on progression is one option physicians may consider.3 She also remarked that with this fourth inhibitor, potentially for first-line use, “which do we choose for our patients? In the absence of direct comparisons of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a best ALK inhibitor.”3
1. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016;8(1)32-47.
2. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018 [Epub ahead of print].
3. Brigatinib: ‘Very Promising’ as First Line for ALK+ Lung Cancer. Medscape. 2018 (Accessed October 6, 2018, at https://www.medscape.com/viewarticle/902575#vp_2).
4. Interim Analysis of ALTA-1L Demonstrates Potential for Brigatinib as First-Line Treatment Option for ALK-Positive Non-Small Cell Lung Cancer. IASLC 19th WCLC Press Release (Accessed October 29, 2018, at https://wclc2018.iaslc.org/media/2018%20WCLC%20Press%20Program%
5. Brigatinib. Approved Drugs. FDA. 2017 (Accessed October 25 2018, at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm555841.htm )