- Crizotinib, an ALK inhibitor targeting the EML-4-ALK fusion gene, is superior to standard chemotherapy for the treatment of ALK-positive advanced non-small1 cell lung cancer (NSCLC), both as a first- and second-line agent, and may be more beneficial in patients with brain metastases.
- Crizotinib, there are two main types of resistance mutations: either mutations that reappear at the initial mutation site, or ALK itself is not mutated, but other mutations occur, most commonly c-KIT amplification, EGFR mutation or phosphorylation, KRAS mutation, etc.
To understand crizotinib, let’s start with the rearrangement of the ALK gene.
Recently, the role of mesenchymal lymphoma kinase (ALK) rearrangements in NSCLC pathogenesis was confirmed by the professional community, with ALK rearrangements occurring in approximately 2% to 5% of NSCLC patients, with echinoderm microtubule-like protein-4 (EML-4)-ALK fusion genes being the most common.
The birth of a “weird” tumor protein
Originally, the genes encoding AL K and EML-4 lived peacefully on our chromosome 2, but in some NSCLC patients, the gene encoding ALK broke in two, one “turned around” and inserted into the EML-4 gene, and one stayed in its place. The EML-4 gene, seeing its place occupied, also reversed its direction to fill in the vacant part of the ALK gene.
This rearrangement resulted in the formation of an EML-4-ALK fusion gene on chromosome 2, resulting in a protein that is neither ALK nor EML-4, but rather “EML-4-ALK”. The presence of this “weirdo” allows the cells to overproliferate and not die easily, causing tumors.
It is worth noting that patients with positive ALK fusions have certain characteristics, such as non-smoking, younger age, and a tissue type of adenocarcinoma with printed cells. In addition, in contrast to other mutations more commonly seen in NSCLC (e.g., EGFR or KRAS mutations), the ALK fusion is independent, and its presence means that these patients have a poor response to EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitors, the predominant class of targeted therapeutics available today, such as gefitinib and erlotinib), poor efficacy of platinum-based chemotherapy and short overall survival.
Inhibiting abnormal ALK, crizotinib was born
.
Drugs that target the EML-4-ALK target are called ALK inhibitors, and crizotinib is a typical example.
Crizotinib was first used in humans in 2006. Investigators mapped it out and eventually set its optimal oral dose at 250 mg twice daily for 28 days in one cycle. Notably, the 19 patients with ALK-positive NSCLC who participated in the study had an objective response rate (ORR) to crizotinib of 53%, which is a very good result.
In the 2008 clinical trial, the investigators increased the number of patients and achieved an ORR of 57%, with 33% of patients having stable disease. In terms of adverse effects, most patients had gastrointestinal reactions, 41% had mild visual disturbances, and 6% had mild transaminase elevations, but these were tolerable or could be improved with the drug.
In PROFILE 1014, published in 2014, the investigators again compared it to standard first-line chemotherapy (pemetrexed + cisplatin or carboplatin). The results showed that crizotinib was superior as first-line treatment in an Asian population; control of brain metastases was significantly better than chemotherapy, and patients had a 55% lower risk of intracranial disease progression than with chemotherapy.
In summary, crizotinib is superior to standard chemotherapy for ALK-positive advanced NSCLC, whether as a first- or second-line agent, and patients with brain metastases may benefit even more.
Crizotinib was launched in China in 2013. The 2018 update of the CSCO lung cancer guidelines recommends crizotinib as first-line therapy for advanced NSCLC patients with ROS-1 fusion gene positivity.
The problem facing crizotinib: drug resistance
However, no one is perfect, and no drug is perfect. Although crizotinib has made it all the way through, there is no escaping the problem of drug resistance after 10 to 12 months of treatment.
By mechanism, there are two main types of resistance mutations (see Table 2), one is a reoccurrence of mutations at the initial mutation site, including secondary mutations in the ALK kinase region (accounting for 31% of cases, resulting in impaired crizotinib binding) and/or amplification of ALK gene replication. The second is that ALK itself is not mutated, but other mutations occur, most commonly c-KIT amplification, EGFR mutation or phosphorylation, and KRAS mutation.
Table 2 Mechanisms of crizotinib resistance
|
Mechanisms of drug resistance |
Mutation type |
|
ALK second mutations (L1196M and C1156Y) (31%) ALK amplification (13%) both (6%) |
|
|
ALK Irrelevant (50%) |
EGFR mutation (19%) KRAS mutation (12%) unknown (may contain KIT, EGFR, or HER-2 variants) (19%) |
For drug resistance due to ALK gene remutation or amplification, second-generation ALK inhibitors such as aletinib and third-generation loratinib are available. In Europe, the United States, Japan, and other countries, aletinib has been approved for ALK-positive NSCLC patients who have failed crizotinib therapy or are intolerant to crizotinib, and was launched in China in August 2018. in April 2017, the US Food and Drug Administration (FDA) granted permission to use loratinib for ALK-positive metastatic NSCLC patients who have received one or more ALK inhibitors in the past. NSCLC patients.