Ben Levy, MD: Let’s move on to ALK. We’ve come a long way since the days of crizotinib. Fernando, do you want to walk us through the ALEX and ALTA-1L data? Then I’ll let Misako talk about CROWN. Then we can talk about what we do with these data. Fernando, do you want to start with ALEX and ALTA-1L?

Fernando C. Santini, MD: Yes. I’ll try to be brief because this space is very crowded. ALEX and ALTA-1L were the 2 big international randomized phase 3 trials testing alectinib or brigatinib vs first-generation crizotinib. We all know they both were positive for PFS [progression-free survival] in their first analysis. We recently saw the final PFS and exploratory OS [overall survival] data from both trials, which showed that there’s a continuation of the benefit. It’s quite the same.

[Here are] some numbers to try to illustrate how there’s a continuing benefit with time from the ALEX trial. The estimated 5-year overall survival rate for these patients is almost 62%, which is remarkable; 43% of these patients will be event-free in 4 years. Regarding the brigatinib data, there was also the final safety and efficacy for PFS and OS. Regarding the PFS in the first analysis, the hazard ratio was positive for brigatinib at around 0.49. After 4 years, the hazard ratio remains 0.48. The 4-year event-free survival in the brigatinib arm was almost 36%. There are still compelling data for intracranial control from brigatinib at 3 years in all population. The event-free survival in the brain is almost 60%.

This shows that these are 2 very powerful second-generation TKIs with very good brain activity. Adverse effects are a little different, but they’re very safe drugs. In all of this final safety analysis, they didn’t show any new safety signals from either alectinib or brigatinib. The incidence of discontinuation rate is really low from both drugs. It showed that they’re powerful drugs that work for quite a long time.

Ben Levy, MD: Great overview of competing strategies. We have 1 more drug, lorlatinib. Masako, briefly give a high-level overview of the CROWN data.

Misako Nagasaka MD, PhD: CROWN was a global randomized phase 3 study comparing lorlatinib, a third-generation ALK inhibitor, with crizotinib, a first-generation ALK inhibitor. The design was very similar to ALEX and ALTA-1L in the first line. The primary end point was progression-free survival by blinded independent central review.

From the November 2020 New England Journal of Medicine publication by Dr [Alice] Shaw and colleagues, CROWN reported that the 12-month PFS was 78% for the lorlatinib group and 39% for the crizotinib group. The hazard ratio was 0.28, which was much lower than what has been reported for alectinib and brigatinib. Also striking were the CNS [central nervous system] data. In the intent-to-treat population, the time to CNS progression was significantly longer with lorlatinib than with crizotinib. The percentage of patients who were alive without CNS progression at 12 months was 96% with lorlatinib and 60% with crizotinib, with a hazard ratio of 0.07. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events than crizotinib, but they were mainly altered lipid levels.

Ben Levy, MD: Once again, we’ve got challenges with what to do in the front line. We’ve got 3 phase 3 trials comparing next-generation ALK-directed therapy with crizotinib, all showing monster benefits in PFS and improvements in intracranial response rates. Misako, how do you choose between the 3? If you do cross-trial comparisons, lorlatinib has the edge in the hazard ratio. But lorlatinib has activity postalectinib, which we haven’t been able to go over. How do you choose? How do you sequence?

Misako Nagasaka MD, PhD: That’s a great question. The question will remain unanswered for some time because lorlatinib has very good efficacy, and it’s going to take more time for us to get the median PFS in months, which is something that’s a little easier to compare than hazard ratio being 0.28 vs 0.48. In my practice, I’ve put patients on the lorlatinib for first-line use, but I don’t put everyone on lorlatinib in the first line because it’s a little more difficult to manage than other drugs, like alectinib. Alectinib doesn’t have many adverse effects. It’s the inconvenience of patients having to take a lot of pills.

With lorlatinib, I don’t worry about the hyperlipidemia or hypercholesterolemia—that can be well managed by adjusting statins and fenofibrates—but I worry more about the cognitive adverse effects. For example, I hesitate to start lorlatinib in patients who have a very demanding intellectual type of work or patients who are living alone and don’t have anyone to watch over them. It depends on each patient’s situation. In addition to the social situation, the presence or absence of brain metastases is something to consider. There are potentially some data, although it’s preclinical, suggesting that perhaps in certain variants like variant 3, we might need to take a more aggressive approach.

Ben Levy, MD: We’re still learning about these variants and the prognostic significance and predictive nature of them. We’ll have to see in future data sets how this all shakes out.

Transcript edited for clarity.