Crizotinib, An Experimental Drug for Some Lung Cancers and Other Tumors With Alk Mutations

ML is excited upon reading the latest New England Journal of Medicine (NEJM) which she still receives in print. Today’s issue includes four articles, if you count the accompanying editorial, on an experimental pill for treating some forms of lung cancer and other tumor types with distinct genetic profiles.

The new drug, called crizotinib, is manufactured by Pfizer and targets cellular enzymes including ALK (anaplastic lymphoma kinase). Sound like a mouthful? Well, it turns out that ALK acts up in some cases of non-small-cell lung cancer – an old-fashioned, catch-all oncology term that refers to most types of lung cancer in the U.S. that, literally, don’t comprise cells that look small when examined with a microscope. This tumor category, which affects nearly 200,000 people in the U.S. each year, includes three main subtypes: adenocarcinoma – the kind of lung cancer most common in non-smokers, squamous cell carcinoma and what’s called (seriously) “large cell” lung cancer.

In approximately 5% of non-small-cell lung cancers the malignant cells have a particular chromosomal defect that renders them vulnerable to crizotinib: the gene encoding ALK, on the short arm of human chromosome 2 (2p) is rearranged nearby the gene encoding EML-4 (echinoderm microtubule-associated protein like 4), such that an abnormally active, fusion protein is active in the tumor cells. This hybrid gene product, the result of a particular chromosomal abnormality, is implicated in tumor cell growth and proliferation. Some of these and other investigators have previously demonstrated that crizotinib inhibits ALK activity in cells in vitro and in some animal models.

OK, so in the first of the NEJM papers*, 31 authors (including 16 in Boston, at Harvard affiliated-medical institutions and 5 based at Pfizer, in La Jolla, CA),  report on the trial of 82 men and women with non-small-cell lung cancer who qualified for the study. All had “advanced” tumors, meaning tumors that couldn’t be removed surgically, and 94% had tried other treatments before starting crizotinib. Each enrolled patient had a chromosomal rearrangement, identified by a molecular FISH study, resulting in the EML-4-ALK fusion protein. After some initial phase I work to test tolerance to this new drug, the patients were prescribed 250 mg by mouth, twice daily.

The results were dramatic, as things go for clinical studies of advanced non-small-cell lung cancer: 57% of the subjects responded (partially in all but one apparent instance, meaning that the tumors shrank but didn’t disappear). In an additional 33% of patients enrolled, the disease stabilized (meaning that the tumors didn’t get significantly smaller, but stopped growing as they were before treatment). Upon 6 months of treatment, the probability of progression-free survival was estimated at 72%, but the median had not yet been reached.

According to the study authors, the drug was well-tolerated overall, and most of the patients elected to remain on treatment after completion of the planned protocol. Among the 82 patients, 34 reported “mild” visual disturbances, according to the authors: “the events were most frequently described as trails of light following objects moving relative to the observer, particularly noticed during changes in ambient lighting…” These were considered “Grade 1,” according to Table 2 in the paper. Grade 3 and 4 toxicities were few, and mainly included abnormal liver enzymes affecting 5 or 6% of the patients.

The second paper is a case report, astonishing firstly because there are 18 authors describing the drug’s activity in 2 patients, and secondly because of the interesting nature of the tumor described, a condition called inflammatory myofibroblastic tumor (IMT). I don’t think I’ve ever seen a case of this, either in real-life practice or in preparing for my oncology boards, so for now I’ll quote the paper and say that IMTs occur mainly in young people and consist of malignant myofibroblasts – cells that, when normal, usually form muscle and related soft tissue structures. The ALK gene is rearranged and abnormally expressed in about half of these tumors.

Summary of the second paper: the investigators tried crizotinib in 2 patients with difficult cases of chemo-refractory IMT. One, a 44 year old man with a distinct ALK abnormality who’d undergone extensive abdominal surgery and received multiple chemotherapies, responded fabulously. The other IMT patient, a 21 year old man without evidence for an ALK rearrangement, didn’t respond to the drug.

The third paper, by a Japanese group with a corresponding author based at Jichi Medical University in Tochigi, Japan, describes the development of two secondary, acquired and resistance-conferring mutations in ALK in one lung cancer patient who was taking crizotinib. Among other methods, they performed deep sequencing to check the ALK sequence in many of the patients’ cells, and then confirmed the presence of 2 (but not 3, as were found by this method) mutations using Sanger sequencing. They performed some neat PCR tricks to amplify DNA that was specific to the tumor’s EML4-ALK hybrid, and determined that the two de novo mutations within the tumor cells were mutually exclusive: the patient seems to have developed two resistant tumor clones while on treatment with the ALK inhibitor.

Finally there’s an editorial, by two molecular biologists, Drs. B. Hallberg and R. Palmer, based in Sweden’s Umeå University. This drug has a lot of potential, is the gist of it. ALK mutations don’t just occur in some lung tumors and IMTs, but also in some childhood tumors called neuroblastomas and, more than occasionally, in some anaplastic lymphomas.

I am aware, also, from the NCI’s website and by reading, including some of the above articles, that crizotinib has activity against some other kinases, including c-MET and other signaling receptor molecules, some of which are implicated in cancer growth.

I contacted Pfizer today, and a representative informed me by email that pricing for crizotinib has not yet been determined. I asked about FDA plans, and he wrote: “Pfizer plans to submit crizotinib (PF-02341066) data in the first half of next year to the U.S. Food and Drug Administration (FDA) for regulatory approval.”

Now, there are several ongoing clinical trials of this drug, some for patients with non-small-cell lung cancer and some for patients with other “ALK+” tumors, meaning cancers that bear a mutation in the ALK gene.

Why am I blogging about this drug, a pill, that works imperfectly in perhaps most of 5% of non-small-cell lung cancer patients and, maybe, in some other rare tumors? Because this is the future of oncology and, ultimately I think, will provide cost-effective medicine that’s based in evidence and science.

The key is that the investigators tried the experimental drug in lung cancer patients with a specific genetic profile, one that predicts a response to this agent. If, in 3 or 5 or 10 years we could sequence a patient’s tumor and check for specific mutations, we could give medications tailored to what they’ve got, and avoid treating them with drugs that are unlikely to work. This kind of approach should, if done properly, reduce the costs of cancer care, if the drugs are reasonably-priced.

How drugs like crizotinib could save money:

1. This drug is a pill; slash the costs of IVs, pumps, bags of saline, nurses to administer…

2. Don’t give it to patients without a relevant genetic mutation;

3. Monitor patients for resistance and stop giving drugs when they no longer help the individuals for whom their prescribed.

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