- Ceretinib (also known as ceritinib), a second-generation ALK inhibitor, not only reduces drug resistance and effectively crosses the blood-brain barrier, but is also effective against multiple lung cancer mutation targets. Combined, it is superior to the first-generation ALK inhibitor, crizotinib, in many ways.
- Ceretinib was launched in China in 2018 (trade name: Zangda).
Ceritinib is a second-generation inhibitor of mesenchymal lymphoma kinase (ALK). As a novel targeted agent, ceritinib enables a precise strike against ALK-positive metastatic non-small cell lung cancer (NSCLC).
Compared to the first-generation ALK inhibitor (crizotinib), it not only overcomes the generation drug resistance challenge, but also works better in patients with brain metastases.
Approval of second-line therapy, a “replacement” after crizotinib failure
Since the introduction of the first ALK inhibitor, crizotinib has been the first-line drug of choice for patients with ALK-positive NSCLC. However, with crizotinib, some patients quickly developed drug resistance, which greatly reduced the expected treatment effect. In response to this shortcoming, second-generation ALK inhibitors have become a hot topic in the development of targeted therapies for NSCLC, and ceritinib has emerged.
In 2014, ceritinib received accelerated marketing approval from the Food and Drug Administration (FDA) for metastatic NSCLC that has progressed after treatment with crizotinib or is intolerant to crizotinib.
This trial validated the efficacy and safety of ceritinib in patients with ALK-positive metastatic NSCLC who progressed on crizotinib or were intolerant to crizotinib. The results showed that patients treated with ceritinib had an objective response rate of 44%, a median duration of response of 7.1 months, and discontinuation due to adverse events of only 10%.
This makes ceritinib a second-line treatment for ALK-positive NSCLC patients as an “alternate” after crizotinib.
“Upgrade” from second-line to first-line drug
Since ceritinib works so well in second-line therapy, could it replace crizotinib as a first-line agent? Based on this hypothesis, investigators conducted a clinical trial (ASCEND-4) that ultimately confirmed this suspicion.
In 2017, an expanded indication application for ceritinib was approved by the FDA, successfully advancing it to first-line treatment for patients with ALK-positive metastatic NSCLC.
Results from the ASCEND-4 trial showed that first-line treatment with ceritinib (750 mg/day of ceritinib alone) was associated with a 45% lower risk of disease progression (median progression-free survival of 16.6 months, 8.1 months, respectively) compared with standard first-line treatment (pemetrexed + cisplatin or carboplatin, continued with pemetrexed after 4 cycles of treatment).
It is worth noting that ceritinib also showed good efficacy in ALK-positive NSCLC with brain metastases in the study, with an efficacy rate of more than 70%. Based on these findings, ceritinib first-line regimen received breakthrough therapy designation and priority approval.
Ceretinib’s current status and future prospects
In light of the study results, the 2018 edition of the US NCCN guidelines recommends ceritinib for the treatment of patients with ALK-positive NSCLC, including crizotinib-intolerant or resistant second-line therapy, as well as first-line regimens.
In fact, the therapeutic targets of ceritinib are not only ALK, but also include c-ros proto-oncogene 1 tyrosine kinase (repressor of gene Silencing 1, ROS1), among others.
The 2018 edition of the NCCN guidelines states that ceritinib can be used as first-line therapy for patients with ROS1-positive NSCLC. This recommendation is based on the results of a phase II clinical study in 2017. The study showed that ceritinib was 62% effective in patients with ROS1-positive NSCLC, with a median effective duration of treatment of 21 months.
Summary: Since its launch abroad, ceritinib has been an important targeted agent in the treatment of ALK-positive NSCLC and is recommended by the NCCN guidelines for second- and first-line therapy. When it comes to China, we expect it to benefit more Chinese patients.