At ASCO 2024 I had the benefit of presenting the CROWN 7-year progression free survival data. Now, CROWN is a randomised phase III study that compared lorlatinib with crizotinib in patients with advanced non-small cell lung cancer harbouring ALK translocation. This study actually was initially presented in 2020 in The New England Journal of Medicine and with that actually we did not reach the median progression free survival but we had a hazard ratio of 0.28. So we just waited and in 2024, after five years, we looked at the data again but again we did not reach the median progression free survival with a hazard ratio of 0.19. So we were obligated to continue and now we have the seven year data.

After 83 months of median progression free survival, as it turned out, we still had not reached the median. At 84 months 55% of patients are still progression free. So this is probably one of the longest progression free survival data that we ever had and we can pretty well project the median is going to be beyond 84 months.

With such a curve we were able to look at the dynamic changes over the years. In the first year, actually, there were 20% of patients had progression. In the second year about 10%, but from the second year onwards it’s only single digit, until now – 55%. So what we can tell the patients is that if the patients actually have no progression at the end of the second year there is a 79% chance that the patient may be progression free by the end of seven years. I think that is a very important message for the patients, especially if they get advanced stage lung cancer.

The other important aspect that we looked into is the brain. We meticulously repeated the MRI of the brain every eight weeks for the first five years and every 16 weeks for the subsequent years. Then with that we were able to say conclusively at the end of seven years the non-progression rate in the brain is actually 92%. Especially for the patients who did not have brain mets in the beginning and then at the end of seven years still 96% of them have no CNS progression. So that gives us a concept to say maybe the drug is preventive of brain occurrence. So I think it’s an important message.

With these results also come toxicity. The common ones known to lorlatinib may include weight gain, oedema, hypercholesterolemia, and cognitive dysfunction. At the seven-year analysis we compared with the five-year analysis, there is no obvious abnormality, no obvious difference. One important aspect is that after a long follow-up we want to look into cardiovascular events because high cholesterol is common and may be related to cardiovascular events. So we looked into that but there is no difference in the total number of cardiovascular events between the lorlatinib and the crizotinib arms.

Approximately one third, 34% of patients, had dose reduction and most of the dose reductions the median time to dose reduction was about 25 weeks. So we have to ask the question, for patients who had dose reduction, do they perform worse or the same? We did an analysis looking at the patients with dose reduction by week 26 and then compared it to patients who did not have the dose reduction. The progression free survival as well as the intracranial progression are almost exactly the same.

So now the CROWN seven years can reassure us that, yes, we have very long progression free survival not reached and 55% at seven years. If someone who was able to have a progression free by the second year, there’s a 79% chance that they may continue to be well until seven years. Intracranial response is excellent at 92% as well as the toxicity is manageable by dose reduction and that will not affect the outcome of the treatment.

What impact could these findings have?

In a sense now that we have this finding, this is not a new, new finding, it’s an update of the five-years finding. The five-year finding already had changed practice a lot. But I just think we have the obligation as a doctor to share this information with the patient. If someone who is newly diagnosed knows that ALK+ lung cancer, that one of the current standards is a second generation TKI alectinib, but for that I reported that previously the median progression free about 34 months, median overall survival of about 83 months. Great data. However, now we’ve got a median progression free not reached at seven years. I think the patients have the right to know about it. Then they have to balance between the toxicity and make a decision how best to treat themselves.