West's Points: Evolving Issues With ALK Rearrangements

OBTNMay 2010
Volume 4
Issue 5

H. Jack West, MD, takes a moment to talk about what he is finding in regard to anaplastic lymphoma kinase (ALK) rearrangements seen in approximately 4% of patients with non�small cell lung cancer, as reviewed by Shaw et al in a September 2009 issue of the Journal of Clinical Oncology.

Journal of Clinical Oncology

I thought I would take a moment to talk about what I am finding in regard to anaplastic lymphoma kinase (ALK) rearrangements seen in approximately 4% of patients with non—small cell lung cancer, as reviewed by Shaw et al in a September 2009 issue of the . The Plenary Session at the upcoming American Society of Clinical Oncology annual meeting in June will feature a presentation on a small subset of patients with ALK rearrangements. Crizotinib, also known as PF-02341066, is a first-in-class experimental ALK inhibitor. In early trials, it has produced a high rate of response in patients with ALK rearrangements. Our center is participating in two of the early Pfizer-sponsored trials for patients with an ALK rearrangement as defined by testing at a central laboratory arising from the collaboration between Abbott and Pfizer. One is a phase III trial randomizing patients to second-line therapy with pemetrexed or docetaxel compared with crizotinib. The other is a companion single-arm phase II study of crizotinib for more extensively treated patients or for patients who were randomized to chemotherapy in the phase III second-line trial.

Several patients are finding their way to me after having their tumor tissue tested for ALK rearrangement at a laboratory that is performing this work outside of an official trial capacity. I have encountered patients who had their tumor tissue tested commercially through the pathology departments at the University of Colorado and Massachusetts General Hospital (MGH), and I understand that Genzyme is now offering ALK testing. Other laboratories are rapidly working toward offering testing. Previously, testing for ALK was available only through the oncology centers conducting the crizotinib trials. While this barrier to testing has been knocked down in the past few months, new challenges have emerged.

Although patients can have tumor tissue tested at an outside laboratory and found to be positive for an ALK rearrangement, this will not satisfy testing requirements to get a patient into a crizotinib trial. Tissue must still be sent to the central laboratory. Some patients will have run out of available tissue after their preliminary ALK test and may need another biopsy to obtain tissue for the official ALK test at the central laboratory—the one that counts. This even applies to patients whose tumor tissue was tested at MGH, which was the reference laboratory before Abbott got its own laboratory up and running earlier this year.

I have had my first patient who tested positive at an outside laboratory and then received a result of “negative for ALK rearrangement” for tissue tested at the Abbott laboratory. It is unclear whether this represents heterogeneity of tumor tissue or an error in technique for testing at either laboratory. The limited studies to assess heterogeneity of epidermal growth factor receptor (EGFR) mutations have certainly established that there is a disturbing precedent of tissue heterogeneity for the occurrence of an EGFR mutation within a tumor. It would not surprise me if different areas of cancer in the same person, or even different areas of the same tumor, might produce different results in terms of detecting ALK rearrangements. Yet, the only way a patient can be treated with crizotinib is to have a positive test for an ALK rearrangement at the central laboratory. I cringe to think that this lack of concordance might be a recurring observation. I have learned the hard way that the only thing worse than telling patients hopeful about crizotinib that they do not have an ALK rearrangement is telling patients that have come to my center from another state to enroll in a crizotinib trial that they tested negative at the central laboratory after testing positive initially.

Another new, surprising situation is that one of my patients who had tumor tissue sent for ALK rearrangement testing at an outside laboratory received reportedly positive results, despite having a significant smoking history over many years and having a poorly differentiated cancer. We have largely observed that ALK rearrangements are seen in patients with little to no smoking history and with a clearly identifiable adenocarcinoma. What if we find that as we test more broadly, this demographic profiling is an oversimplification? This is particularly concerning because the benefit of an agent like crizotinib for a patient with a demonstrated ALK rearrangement can be profound. Crizotinib is not commercially available, and the company is screening the demographic profiles of patients who they will accept for testing at the central laboratory—refusing to even test samples from patients who, except for this criterion, are otherwise eligible per the protocol. When the only way to get crizotinib is through a Pfizer clinical trial, and the only way to get on the trial is to have a tumor test positive for an ALK rearrangement at the central laboratory, to have the company then exclude potential beneficiaries of crizotinib treatment because they do not fit a narrow demographic profile is a serious problem.

For now, I presume that testing positive for an ALK rearrangement at an outside laboratory at least earns you the opportunity to be tested by the central Abbott/Pfizer laboratory, even if you have smoked more than a typical patient with an ALK rearrangement. I would hate to be the oncologist who is forced to tell patients that Pfizer refused to test their tissue because their smoking history exceeded a threshold for probability of an ALK rearrangement, despite the fact that they tested positive for this rearrangement at an outside laboratory.

These anecdotal experiences in my practice (and likely other practices), as well as evidence in the literature advancing the possibility of tumor heterogeneity, certainly support testing for markers like ALK and EGFR in a broader population. You can’t find a fever if you don’t take a temperature, and you can’t find an ALK rearrangement unless you test for it. When therapy with an ALK inhibitor potentially translates to a survival benefit of years for patients with an ALK rearrangement, it is critical for us not to be overly restrictive in screening, whether it is done through commercial testing or a trial-based mechanism.

Opportunities for personalized approaches to cancer treatment are likely to continue their rapid evolution, as tumor tissue collection becomes more routine, molecular testing becomes more widely available (especially for ALK), and pressure emerges as more companies develop competing targeted agents, such as other ALK inhibitors. It is gratifying to see lung cancer diagnosis and care transition into a new era of molecular oncology in real time, though it is unsettling to contemplate the ramifications for our patients of lost opportunities due to misjudgments.


Dr H. Jack West is a medical oncologist and medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington. He also serves as president of the nonprofit organization Global Resource for Advancing Cancer Education (GRACE).

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