A Retrospective Look at ALK-Rearranged NSCLC Management

Transcript: Lyudmila A. Bazhenova, MD: Drug development in ALK-rearranged non—small cell lung cancer has become a poster child for modern drug development in oncology. ALK fusion was first identified by Manabu Soda, MD, PhD, and published in Nature in 2007. Just 4 years later, in 2011, we had the first ALK trials in kinase inhibitors approved, and that was also the first time the FDA approved something that’s called a companion diagnostic, which is a test to discover ALK fusion non—small cell lung cancer.

We have been very busy since 2007. We now have 5 ALK trials in kinase inhibitors FDA approved in the United States. We first proved that crizotinib is a better agent than second-line chemotherapy, then we moved crizotinib to the first line, proving that crizotinib is a better agent than platinum doublet. Then there was a discovery of second-generation ALK inhibitors such as ceritinib, alectinib, and brigatinib, where all 3 of the drugs showed efficacy in the patients who failed crizotinib. Then slowly we tried moving all those second-generation ALK inhibitors to the first line. We have trials comparing ceritinib versus platinum doublet, where ceritinib was superior to platinum doublet, and most recently we have 2 head-to-head trials looking at second-generation ALK inhibitors versus first-generation ALK inhibitors, such as alectinib versus crizotinib, which is the ALEX trial, and brigatinib versus crizotinib, which is an ALTA-1L trial. We also now have an option for patients who have failed second-generation ALK inhibitors, which is lorlatinib. We have evidence that lorlatinib has activity in patients who have failed ceritinib as well as alectinib.

The main distinctions in ALK tyrosine kinase inhibitors rely on the ability of different ALK TKIs [tyrosine kinase inhibitors] to cover certain resistant mutations. The first tyrosine kinase inhibitor that was approved was crizotinib, and we quickly learned that median progression-free survival with crizotinib was about 10 to 11 months, 9 months in some trials, and resistance will ultimately develop. Second-generation ALK TKIs, such as alectinib, brigatinib, and ceritinib, have efficacy against some of the resistant mutations that develop after crizotinib.

There is a difference in coverage. For example, the I1171 mutation is generally resistant to alectinib, but will be sensitive to ceritinib and brigatinib, and the L1198 mutation would be resistant to ceritinib, but sensitive to both alectinib and brigatinib. There is a notorious mutation called G1202R, and this is a mutation that we have seen as a resistant mechanism to crizotinib, ceritinib, alectinib, not as much with brigatinib, and not usually a resistant mechanism to lorlatinib. So when one makes a decision in using ALK TKIs, second-generation ALK TKI after crizotinib, post-progression therapy I believe is important because you want to make a decision on second-generation TKI looking at the type of resistance your patient developed.

How is that going to translate into first line we do not know, because as you remember, those resistant mutations have been mostly discovered in patients who develop resistance to crizotinib. Our patients who are just diagnosed with ALK-mutant non—small cell lung cancer have not been exposed to crizotinib. But at least knowing that G1202R mutation is a common resistant mutation for all 3 drugs, crizotinib, ceritinib, and alectinib, I think it might make sense to use the drug that has coverage against the G1202R mutation. This is what we thought when we were designing clinical trials in alectinib versus crizotinib and brigatinib versus crizotinib. Based on the ALTA-1L trial, the progression-free survival of brigatinib looks very similar to progression-free survival of alectinib. Certainly there is a possibility that maybe when there is long-term follow-up, we might see a difference, but right now, despite the fact that brigatinib has coverage against G1202R, it doesn’t appear to differentiate itself against alectinib to the point of median follow-up that we have seen in brigatinib trials.

Transcript Edited for Clarity