What is the difference between ALK inhibitors?
What is the difference between ALK inhibitors?
Of those with ALK positive lung cancer, many present with distant disease (cancer spread beyond the chest) at diagnosis. Fortunately, there is very effective treatment with ALK-inhibitor pills. Although not a cure, can control the disease in most people for many years. There are a number of different ALK-inhibitors now routinely used and this article explains the various treatments in different generations of development.
First-generation ALK-inhibitor
Crizotinib
Crizotinib was the first ALK inhibitor widely used in patients with ALK-positive lung cancer. The PROFILE 1014 clinical trial[1] showed that the response rate (where the cancer substantially shrinks in size) was higher with crizotinib (74%) compared to first-line chemotherapy (45%). Both length of life and time between starting treatment and cancer substantially growing (known as the progression free survival) was longer with crizotinib compared to chemotherapy[1] . Crizotinib was generally well tolerated with common side effects that include changes in vision, abdominal symptoms and swelling of the legs and body.
Second-generation ALK-inhibitors
Lung cancer can spread to the brain, and the newer “second-generation” ALK-inhibitors were designed to get into the brain better than crizotinib. These second-generation inhibitors are now the preferred initial treatment for ALK-positive distant lung cancer.
Ceritinib
Ceritinib was the first of the second-generation ALK inhibitor. In the ASCEND-4 clinical trial[2] ceritinib resulted in longer progression free survival compared to first-line chemotherapy. However, ceritinib had considerable side effects, the most common were nausea, vomiting, diarrhoea, fatigue and abnormal liver function blood tests with over 50% of patients experiencing serious side effects .
Alectinib
Alectinib is a commonly used first-line ALK-inhibitor evaluated in three large trials, the ALEX trial[3], the Japanese J-ALEX trial[4] and the East Asian ALESIA trial[5] comparing alectinib against crizotinib in patients who had not previously received treatment or ALK-inhibitors. In all three trials, alectinib significantly prolonged progression free survival compared with crizotinib. Importantly, alectinib also significantly prolonged the time taken for the cancer to grow or spread to the brain. Alectinib was well tolerated with common side effects that include nausea, vomiting, diarrhea and abnormal liver function blood tests.
Brigatinib
Brigatinib, also a commonly used first-line ALK-inhibitor was evaluated in the ALTA-1L trial[6] that compared brigatinib with crizotinib as first-line treatment in ALK-positive disease. Participants who received brigatinib had a better progression free survival than those who received crizotinib. At 3 years, 43% of patients receiving brigatinib had not progressed (their cancer had not grown substantially) compared to 19% with crizotinib. Brigatinib also significantly prolonged the time before progression of cancer in the brain. The most common side effects with brigatinib were gastrointestinal side effects, cough, and abnormal liver function blood tests.
Ensartinib
In 2021, the results of the eXalt3 clinical trial[7] compared ensartinib against crizotinib in patients with ALK-positive lung cancer. Like the other second-generation ALK inhibitors, patients treated with ensartinib had a longer progression free survival and a longer CNS progression free survival compared with crizotinib. Common ensartinib side effects included rash, abnormal liver function blood tests, itch, constipation and swelling. Ensartinib is not yet FDA or EMA approved but may be another promising first-line treatment for ALK-positive lung cancer.
Third-generation ALK-inhibitor
Although ALK-inhibitors are very effective, eventually the cancer ‘gets wise’ to the ALK inhibitor and begins to grow again after initially responding. The third-generation ALK inhibitors were designed to combat some of the genetic changes (called resistance mutations) that may be driving this growth, and remain very effective in preventing cancer growth in the brain.
Lorlatinib
For those with ALK-positive lung cancer whose disease have become resistant to first or second-generation ALK-inhibitors, lorlatinib has been shown to shrink the cancer (again) in 47% of patients[8] . Importantly, patients who had brain metastases also responded: 63% had substantial shrinkage of their brain metastases. Lorlatinib was mostly well tolerated with side effects that included high cholesterol, swelling, weight gain, numbness in the hands and feet (peripheral neuropathy), and changes in memory and concentration. Lorlatinib is currently FDA and EMA approved for use in patients with ALK-positive lung cancer whose cancers have grown on other ALK-inhibitors.
More recently, the CROWN trial[9] was published , which looked at using lorlatinib or crizotinib as the first-line treatment in patients with ALK-positive lung cancer. Lorlatinib significantly improved progression free survival compared to crizotinib: at 12 months, 78% of patients receiving lorlatinib had not progressed (their cancer had not substantially grown) compared to 39% of patients receiving crizotinib. Lorlatinib also improved the time to progression of brain metastases by 93% compared to crizotinib. Lorlatinib was recently approved by the FDA for the first-line treatment of ALK-positive advanced lung cancer.
On the whole the development of new treatments for ALK positive lung cancer has been fast paced providing newer and better treatments over the last few years alone.
The author Dr Wanda Cui has received funding from Janssen that manufactures amivantamab.
References
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