New ALK Agents: Lung Cancer's 'Second Miracle'?

Giorgio V. Scagliotti, MD, PhD; D. Ross Camidge, MD, PhD


October 07, 2013

In This Article

Getting a Bead on Brain Metastases

Dr. Scagliotti: I would like to return to the issue of brain metastasis because we saw the same thing with gefitinib and erlotinib. The proportion of patients who are relapsing with brain metastases is higher than what we expect with chemotherapy, so to me, the story of brain metastases and drug penetration in the brain is still confusing. What is your opinion about brain metastases and ALK-inhibiting agents?

Dr. Camidge: There are 3 main pieces of evidence. The first is a very nice study that was led by Alice Shaw.[7] It was a retrospective look at patients who were ALK-positive who had been treated with crizotinib, and a group of patients whom she had found to be ALK-positive by looking at archival specimens but who had died before crizotinib was available, or who for whatever reason weren't eligible for the crizotinib studies. They tried to determine the natural history of the disease in the presence and absence of crizotinib. To balance the groups, Alice looked at the incidence of brain metastases in the 2 groups, and it was almost identical -- around 46% and 52%. That doesn't tell you when the brain metastases occurred, but it is a strong suggestion that crizotinib didn't alter the natural history of the disease.

At last year's ASCO, we presented data from our center that looked at the incidence of brain metastases occurring on crizotinib.[8] Again the numbers were stunningly similar: 46% of patients on crizotinib experienced first progression within the brain, and in 85% of those cases, the brain was the only site of progression.

The third piece of data is a single case report from Dan Costa[9] at Beth Israel Hospital in Boston, of a young man whose lung cancer progressed in the brain while he was taking crizotinib. The Beth Israel team managed to get matched blood and cerebrospinal fluid (CSF) levels and found less than 0.3% of the blood level of crizotinib in the CSF, suggesting that progression in the brain may be a drug penetration issue.

Dr. Scagliotti: Is this an issue specific to crizotinib? And do you believe that the new generation of ALK inhibitors will be more active against brain metastases?

Dr. Camidge: That problem can be addressed in 2 ways. You would like to get a higher percentage of the drug in, but if the drug is also more potent, what gets in is going to work harder. I don't know which of these factors, or maybe both, are addressed by the second-generation ALK inhibitors. We are still at the case report level. People will give presentations showing an MRI with a lesion getting smaller, and that's great, but that is the beginning of the dataset. If we were doing a study on a drug that we thought was going to work systemically, you would show me the progression-free survival and the waterfall plot, not just show me a CT scan and say, "Look, this drug works in lung cancer."


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