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WCLC 2025 | Comparing and managing second and third generation TKIs in lung cancer
Jay Lee, MD, University of California, Los Angeles, CA, describes the safety profile of ALK TKIs for non-small cell lung cancer (NSCLC). Earlier generation TKIs such as alectinib have low serious adverse events, with minimal drug reduction and discontinuation rates. However, third-generation ALK TKIs, such as lorlatinib, which has been assessed in the CROWN trial (NCT03052608), carry a different toxicity profile, including significant mood changes, weight gain, and hyperlipidemia, which may be less tolerated for long-term use. This interview took place at 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain.
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Transcript
Unfortunately, alectinib has a very good safety profile. When we look at the grade 3, 4 toxicities that are treatment related, as well as serious adverse events, the rates are quite low. The drug reduction in the dosing as well as the discontinuation rates are actually quite low with alectinib. So the second generation drugs are overall very well tolerated. Now as we move to the third generation and eventually fourth generation ALK TKIs and as they move into the early stage setting, they carry a different toxicity profile...
Unfortunately, alectinib has a very good safety profile. When we look at the grade 3, 4 toxicities that are treatment related, as well as serious adverse events, the rates are quite low. The drug reduction in the dosing as well as the discontinuation rates are actually quite low with alectinib. So the second generation drugs are overall very well tolerated. Now as we move to the third generation and eventually fourth generation ALK TKIs and as they move into the early stage setting, they carry a different toxicity profile. Although lorlatinib has shown really profound and impressive survival data in the CROWN trial, there is no equivalent in the early stage setting. There are two phase two adjuvant trials with lorlatinib that are currently being conducted right now. However, it has not been approved in the early stage setting. So lorlatinib carries a different side effect profile. There can be significant mood changes, weight gain, and hyperlipidemia. So these types of toxicities are different in an early stage setting and may be less tolerated for long-term use in the order of years. But these are things that the medical oncologists are managing. But I do think that the toxicity profile is quite unique to each generation of ALK TKIs that require particular attention.
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