- Changes in the Anaplastic lymphoma kinase (ALK) gene could result in ALK-positive lung cancer.
- FDA approved Brigatinib drug for treating ALK-positive lung cancer.
- Brigatinib drug was found to overcome the drawbacks that were associated with the earlier approved Crizotinib drug.
Cancers caused due to the abnormal proliferation of the cells in the lungs are referred to as Lung cancer. Around 3-5% of lung cancers are caused due to the changes in gene Anaplastic lymphoma kinase (ALK).
The study results were published in the Journal of Clinical Oncology.
‘Brigatinib drug receives approval from FDA to treat ALK-positive lung cancer as second-line therapy.’
The FDA accelerated approval for crizotinib drug in 2011 to target anaplastic
lymphoma kinase (ALK). However, the drug was found to show two major problems:
- Crizotinib drug does not pass into the brain and therefore is unable to target lung cancer in the central nervous system.
- Genetic diversity of cancer also allows the later growth of subpopulations that can resist the drug which could lead to renewed growth.
The research team also have been trying to develop next-generation ALK-inhibitors.
The phase 2 clinical trial of brigatinib drug (next-generation ALK inhibitor) was conducted on 222 participants.
Brigatinib drug at 180mg/day when used after the failure of crizotinib drug showed a 54% response rate and 12.9-month progression-free survival.
Dr. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the CU Cancer Center and director of Thoracic Oncology at the CU School of Medicine, said,
"What brigatinib at this higher dose shows is comparable response rates to other next-generation ALK inhibitors post-crizotinib but - and this is important - the duration of this benefit appears to be significantly longer."
Camidge also pointed that many patients who enrolled on trial would continue to control cancer and the survival rate was also found to increase for a period of 16 months.
"Once a cancer resists crizotinib, other next-generation ALK inhibitors control cancer for about 7 months or about 9 months. This publication showing 12.9-month progression-free survival and our updated data showing even longer control suggest that these drugs are not all the same."
The research study along with the data collected from the phase 1 trial showed relatively fewer side effects and led to the FDA approval of brigatinib as a second-line therapy for non-small cell lung cancer.
Crizotinib and Brigatinib belong to a group of drugs called kinase inhibitors. They help to silence the signaling related to various cancer-causing proteins by their energy.
The ALK-inhibitor drugs mainly act by prohibiting the protein signaling, that could result from the expression of ALK fusion gene. This could be a root cause called ALK-positive lung cancer.
Brigatinib drug is a next-generation ALK inhibitor that has better penetration to the brain and works on different mutations when compared to crizotinib drug.
Camidge assumed that all the drugs were found to work on a common resistant mechanism since the response rate tends to be similar.
"However, the duration of benefit, which really appears to differ between these newer agents, may be much more determined by their ability to suppress the less common ALK mutations - the second and third mechanisms of resistance that would otherwise emerge next month or the month after that."
Brigatinib drug also has a broad spectrum of resistance mechanisms when compared to other next generation drugs which are given at a high dose. Therefore, the broader the coverage of spectrum, the longer to control the disease.
Potential Promise of Brigatinib Drug
The use of brigatinib drug was found to increase with an increase in its dose. The drug is usually well-tolerated along with fewer side effects.
The author also found that beyond just 90mg and 180mg in the trial, further research will help to explore intra-patient dose escalation. This means that if a cancer continues to progress after brigatinib treatment, instead of discontinuing it, an increased dose could reduce cancer.
However, this could be in contrast to other genetic changes that cause lung cancer. Example, In EGFR lung cancer, doubling the drug dose wouldn't show much difference. But, in ALK-postive lung cancer, you could inhibit the dose and push cancer cells past the tipping point.
The next generation ALK-inhibitors may offer activity against ALK-positive lung cancer in the brain and better activity against genetic changes.
- Dong-Wan Kim et al, Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial, Journal of Clinical Oncology (2017). DOI: 10.1200/JCO.2016.71.5904