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Medicine Matters oncology

At the recent ESMO 2020 virtual meeting, we presented results of the CROWN study. And the CROWN study is a phase III study that compared lorlatinib to crizotinib as first line treatment for patients with advanced ALK-positive cancer. The key take home message is that it's highly effective in controlling both disease systemically and also intracranially. And both areas are important.



The hazard ratio of 0.28 is quite remarkable, and it is different to the hazard ratio that's been seen in other studies with second generation inhibitors where the hazard ratio compared to crizotinib has been closer to 0.5. I think the control in the brain is really important, because progression in the brain is a pretty significant event for a patient with lung cancer.



So to prevent brain metastases, I think is a big deal. The safety profile is important to note. And it's important for clinicians treating patients with lorlatinib to understand this profile and to be able to actively manage toxicities related to lorlatinib. Just as when you're using any other agent, it's important to be able to manage the toxicities.



And in terms of where it sits, in terms of first line options, I think it probably looks like the most effective first line option. But there is a limitation of this study that we're not able to make direct comparisons with second generation inhibitors, such as alectinib or brigatinib, because as the phase III studies with those agents were done in comparison with crizotinib at the same was the case in this study.



It's great that we've got options in terms of second and third generation inhibitors. I think as with everything, it comes down to balancing efficacy and toxicity. And I think it is a general principle in oncology that we tend to use our best option first, because we don't necessarily get an option to use it later.



So I think there will be some debate amongst people who would prefer to start with a second generation inhibitor and then save the lorlatinib as a third line option. But I think there are arguments and in fact compelling efficacy arguments provided by this study to use the lorlatinib as a first line option, in terms of getting effective control straight up, effective and durable control straight up, and preventing progression in the brain.



I think we will learn with longer term follow up from this study additional data regarding, for example, the median progression free survival, which has not yet been reached in the study. And eventually I think long term follow up will also provide us more information about brain control and mechanisms of resistance.