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

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


October 07, 2013

In This Article

Toxicity Levels of New ALK Inhibitors

Dr. Scagliotti: Can you talk about the toxicity profile of these ALK inhibitors? Obviously these agents are administered until progression, and with progression-free survival that reaches or exceeds 10 months, chronic toxicity could be an issue.

Dr. Camidge: You are absolutely right. When we develop these drugs, of course we look at acute toxicity, but when these drugs are licensed and are out there in the community, we find toxicities that aren't in the patient information sheet. It puts the onus on the treating physician to be vigilant and identify effects that weren't described. Crizotinib is a great example; it's licensed and it's out there. You helped us with the study in which we showed that the drug drops testosterone levels in men.[10] Only the Italians' testosterone levels didn't drop. I thought you were faking the data on that one.

ALK Inhibition Beyond Progression

Dr. Scagliotti: There is another important clinical issue that I would like you to address: treatment beyond progression. We started looking at this treatment possibility with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).[11] It looks to be the same with the ALK inhibitor. Can you talk a bit about that?

Dr. Camidge: The easiest explanation is this: If a patient progresses in the brain, and everything else is controlled, most people are comfortable saying, "Give radiotherapy to the brain, and maybe send the patient to the neurosurgeon." But no one would say that you should stop the drug when it's controlling the systemic disease. When we looked at that, on average, it took up to 7 months to get any evidence of progression within the body.[8]

The more controversial issue -- but there is an increasing body of evidence to support it -- is whether to continue treatment when the progression is within the body, but maybe only in 1 site. The biological mechanisms of resistance occur through Darwinian evolution. The cancer doesn't suddenly get smart; it's just one of the funny-looking cells at the back of the class that developed some difference that allowed it to grow in the presence of crizotinib. That will be the 1 resistant clone that pops up. If you see that, and the remaining 99% of the disease is still being suppressed, you can treat that with radiotherapy and occasionally perform surgery. The logic is that you want to keep that drug going because it's still inhibiting most of the disease.

A series of patients with EGFR mutations at Memorial Sloan-Kettering were very carefully selected to have only 1 site of disease; after resection, it took at least 10 months before the cancer returned.[12] In our study we had more generous criteria, allowing 3-4 lesions to be growing. We tended to treat them with radiotherapy, and on average it was 4-5 months before another lesion appeared.[8] If you look at the average time to first progression, which contributes to progression-free survival, it's not game-over. If you can pull that 1 weed out of the garden and keep the drug going, you can probably double the duration of benefit from the original TKI.

Dr. Scagliotti: Do you believe that we need a randomized clinical trial to prove this concept or could it be adopted into clinical practice straight away?

Dr. Camidge: It is always great to have a randomized study. Do I need that to change my practice? No, because it is what I am doing already. At some point, however, we should do a health economic assessment of stereotactic body radiation therapy as a relatively expensive technique. Having a randomized study would help that. You have to be very careful about the design, but it's feasible.


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