New drug shows promise for Non-Small Cell Lung Cancer patients

Uniting Against Lung Cancer spoke with Medical Committee member, Dr. William Pao, Associate Professor of Medicine at Vanderbilt University about a new drug currently in clinical trials for non-small cell lung cancer. The latest results were recently publicized at the ASCO meeting in Chicago.

UALC: There has been a lot of information in the news lately about a new drug for lung cancer, crizotinib.  What is this new drug and how does it work?

Dr. Pao: Crizotinib is a new small molecule pill that can fight lung cancer very effectively in a subset of patients. In this subset of patients, the tumors are driven by the specific target that is inhibited by crizotinib. Crizotinib is an ALK inhibitor; ALK is a tyrosine kinase, a signaling molecule just like the EGF receptor (EGFR). Similar to patients whose tumors harbor activating mutations in the EGF receptor and have disease very sensitive to EGFR inhibitors, like Iressa and Tarceva, there are some patients whose tumors have activating mutations in ALK. When you target ALK in these specific lung cancers, the tumors shrink.

UALC: What did the trial results actually show?

Dr. Pao: The trial was a Phase 1 trial. In most Phase 1 trials, investigators are looking to see if a drug is safe to give, what is the best dose of drug to give, and what are the side effects. A Phase 1 trial isn’t usually designed to determine in a specific population of patients whether a drug is going to be an effective anti-cancer medicine. In this trial, it turned out that while investigators were figuring out what dose to give to patients, they saw a lot of anti-tumor activity in patients who had ALK-driven lung cancers. They ended up expanding the trial to include more patients who had this specific mutation. They showed that 57% of patients had their tumors shrink significantly after at least two cycles of crizotinib. An additional 30% of patients had stable disease. If you add the two together, there was a disease control rate of 90% (the disease control rate means partial response and stable disease together), which is highly remarkable for any drug in lung cancer.

UALC: What kind of side effects did people experience?

Dr. Pao: Some people experienced visual disturbances. These don’t appear to be related to anything wrong with patients’ eyes, but patients report seeing some light/dark streaks that happen at night. Some patients experienced nausea and vomiting and some mild liver function abnormalities, but overall, the drug seems pretty well tolerated.

UALC: What is happening with this drug now?

Dr. Pao: Normally you would go to a Phase 2 study, but because the activity is so remarkable, Pfizer is going to a Phase 3 study. In a Phase 3 study, you compare the new treatment with the standard of care, which in these patients is regular chemotherapy. In the Phase 3 trial, in the second line setting (meaning patients who have already had a first-line treatment), patients who have ALK-mutated lung cancer will be randomized to crizotinib or regular chemo. Although patients may not like that, we have to have this kind of study in order to determine if crizotinib is the best treatment for this disease. Patients whose disease progresses on chemotherapy in this trial will then be able to get crizotinib in a separate study.

UALC: How many patients would you say have this mutation?

Dr. Pao: Right now it’s estimated that maybe 3-5% of non-small cell lung cancer patients have this mutation. If you look in specific subsets, for example never-smokers, it may be higher. The data from a number of groups are now showing these ALK mutations to be more likely to occur in patients who have either little or no smoking history. And then if you look in subsets that do not have EGF receptor mutations, the number may also be higher.

UALC: The mutation for ALK was only discovered in 2007. There’s been a lot of excitement regarding how rapid the path was from discovery to a Phase 3 trial. Why did this happen so much faster than with EGFR?

Dr. Pao: One reason is that the link between EGFR mutations in lung cancer and sensitivity to EGFR inhibitors was an unexpected finding. Another reason is that having gone through the whole EGFR inhibitor experience, people are now more prepared to link genetic alterations in lung cancer with sensitivity to kinase inhibitors in specific subsets of patients. It’s really a culmination of decades of cancer biology research, in which advances in our understanding of the basic biology behind cancers is leading to much more rapid translational discoveries.

UALC: How would patients find out if they are eligible for trials with crizotinib?

Dr. Pao: Patients need to have their tumor tissue studied, and it needs to be positive for the ALK mutation. When patients are undergoing biopsy, attempts should be made to get as much tissue as possible. Currently the ‘gold standard’ test involves an ALK FISH test, which stands for fluorescent in situ hybridization. It’s a molecular way of looking at the DNA of the tumor to see if your ALK gene is normal or mutated.

There’s a large international trial ongoing, so patients should ask their doctors if they could be eligible. Although ALK mutations are found more often in never smokers, they can be found in current and former smokers, so clinical characteristics can be misleading. Molecular testing is very important. One group of patients who might be especially motivated for testing is never smokers whose disease does not respond at all to Iressa or Tarceva.

Dr. Pao is a member of the Uniting Against Lung Cancer Medical Committee. He declares no conflict of interest regarding Pfizer, Inc.(which manufactures crizotinib) or Abbott Laboratories (which is developing the ALK FISH test).

Click here to read more about studies on crizotinib funded by Uniting Against Lung Cancer.

Find our more about ongoing clinical trials with EmergingMed.