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Trials target abnormal fusion gene in lung cancer

Non-small cell lung cancer (NSCLC), the most commonly fatal malignancy in the United States, accounts for approximately 85 percent of all lung cancer. Most patients are diagnosed late and face poor survival odds because no curative drugs exist yet. However, a new phase III trial is studying the efficacy and safety of the current standard of care versus an ALK inhibitor in a distinct NSCLC subpopulation — patients whose tumors harbor an anaplastic lymphoma kinase (ALK) fusion gene — in hopes of finding a more effective standard of care.

The ALK gene normally plays a role in development and then lies dormant. But a peculiar chromosomal translocation reawakens ALK. During this translocation (others lead to different cancers), portions of the dormant ALK gene break away from the chromosome and fuse with portions of a neighboring active gene, EML4, on the same chromosome. The EML4-ALK fusion gene, identified in 2007, reactivates ALK and forces its expression. This “cut-and-paste” genetic blunder drives a small but identifiable subtype of NSCLC. “Since lung cancer is so common, the 3 percent of patients found with the ALK translocation actually represent a large number of patients diagnosed annually,” observes Pasi Jänne, MD, PhD, associate professor of medicine at DFCI.

“Based on data from a phase I trial, we now know that patients with this ALK translocation do very well on an ALK inhibitor,” observes Jänne. The inhibitor binds to the ALK portion of the fusion gene and shuts down its expression. The phase I findings, as well as preclinical research conducted in Jänne’s laboratory, quickly led to a phase III clinical trial, which began enrolling patients in 2009. “That’s extraordinarily fast,” notes Jänne, who is the DFCI Principal Investigator for the trial. “It shows how rapidly basic scientific discoveries can yield clinical impact.”

In the phase III study, patients with NSCLC known to carry the EML4-ALK fusion gene, as determined by a FISH assay, are randomized into 2 arms: Arm A, given the ALK inhibitor; and Arm B, given the current standard of care: either pemetrexed or docetaxel. The primary objective of the study is to ascertain whether the ALK inhibitor, PF-02341066, prolongs progression-free survival compared to the chemotherapy regimen and secondarily, to compare the inhibitor’s safety and tolerability.

Concurrently, investigators launched a related trial to expand the number of NSCLC patients who might benefit from an ALK inhibitor. This phase II single-arm study examines the efficacy and safety of the ALK inhibitor and, importantly, gives patients a trial to turn to if: (1) they carry the EML4-ALK fusion gene but, for some other reason, are deemed ineligible for the 2-arm study; or (2) they receive pemetrexed or docetaxel in the 2-arm study and their disease progresses.

Jänne believes that the ALK inhibitor will prove to be more effective than chemotherapy and, consequently, will become the new standard of care for this unique population of patients. Jänne likens these trials to those testing an inhibitor of the epidermal growth factor receptor (EGFR), a gene that is mutated in other types of lung cancer. “Now when patients come to clinic, we test for both EGFR mutations and ALK translocations,” he says. If patients have an EGFR mutation, we treat with an EGFR inhibitor, now the standard of care. And, if they carry the ALK translocation, we try to get them onto one of these trials.”

If these trials are positive, Jänne adds, the ALK inhibitor will gain regulatory approval and soon be available in the market. “We’re moving away from a one-size-fits-all approach to treating lung cancer patients based on their genetic profile.”

Official title of phase III trial
Investigational Drug, PF-02341066 Is Being Studied Versus Standard of Care in Patients With Advanced Non-Small Cell Lung Cancer With a Specific Gene Profile Involving the Anaplastic Lymphoma Kinase (ALK) Gene

Official title of phase II trial
An Investigational Drug, PF-02341066, Is Being Studied in Patients With Advanced Non-Small Cell Lung Cancer With a Specific Gene Profile Involving the Anaplastic Lymphoma Kinase (ALK) Gene

Overall principal investigator
Alice Shaw, MD, PhD (MGH)

DFCI site principal investigator
Pasi Jänne, MD, PhD (DFCI)

For more information on:
The phase III clinical trial of ALK inhibitor PF-02341066 versus standard of care, go to NCT00932893 on ClinicalTrials.gov.

The phase II clinical trial of ALK inhibitor PF-02341066 for patients who are ineligible for phase III study or who progress while on pemetrexed or docetaxel, go to NCT00932451 on Clinical Trials.gov.

— Lonnie Christiansen