Medicine Matters oncology

So this Friday, we had two very interesting brain metastasis studies. The first study was a study in non-small cell lung cancer patients with an ALK translocation, the ASCEND-7 Study. This was with ceritinib.

And interestingly, in the study, only patients with active brain metastases were included, also performance status 2 patients were eligible, patients with stable neurological symptoms, and patients with leptomeningeal metastases. And patients with leptomeningeal metastases were discussed in another session that day.

Based on prior brain radiotherapy and prior ALK inhibition, patients were divided into four cohorts, and all these cohorts were treated with ceritinib 750 mg fasted.

Based on the cohorts, so approximately 40 patients were included in each cohort, except for one. The objective response rate was around 30% in the brain in those that were pre-treated with ALK inhibition, and around 50% in those that were untreated with another ALK inhibitor.

Disease control rate in the brain was very high, it was above 80%. And duration of response was 9 to 12 months. And if you compare that to the ASCEND-4 and ASCEND-5 data, I think results are very similar and very promising in this setting.

So how to put this into context? Well, we also have the ASCEND-8 data. So ceritinib 450 mg with food that results in less adverse events. But if you look at the PK data of the ASCEND-8 compared to the ASCEND-7, to the 750 mg without food, then PK data are similar. So you would expect that with ceritinib 450 mg with food, you would have the same brain results than 750 mg without food, but it would be very interesting to see these results from the ASCEND-8 trial.

So how to move forward? I think, well, we need to be aware that we need to design clinical trials for this specific patient population, so lung cancer patients with brain metastases. We need to have by bicompartmental endpoints, so you need to define what to do with the brain and what to do with the extracranial disease sites, as it is possible that some patients respond in one compartment and other patients only in the other compartment.

We need to evaluate whether TKI concurrent with cranial radiotherapy are safe and effective, and whether it can prevent a disease flare. And I think we should focus on the next generation ALK inhibitors that have high blood brain barrier concentration. But I think it's very difficult to compare all these trials because inclusion criteria were very heterogeneous across all trials. But in general, they are all very promising.

So moving on to the next abstract, we know that brain metastases are associated with a lower quality of life. And it would be very interesting whether we could predict which patients have brain metastasis and which patients have not.

So in a small Asian series, patients with a synchronous brain metastasis, 18 patients, and patients without brain metastases, still that's 31, were included. They had matched tissue of the brain and the primary. And the authors evaluated whether molecular alterations could predict which patients had brain metastases. But they were not able to do that.

Interestingly, they did also methylation analysis and with certain methylation blocks they could fairly accurately predict which patients had brain metastases and which patients had not.

So how to move forward? Well, I think they should be validated in a larger series prospective with extensive information on staging. But it would be the best if this signature was also predictive for development of brain metastasis in the future. So in the end that you can design trials which really aim at predicting brain metastasis development in high risk patients, for example, the prophylactic cranial irradiation or epigenetic drugs.