Lung cancer -ALK inhibitors.

January 15, 2010 (Coronado, California) —Targeted therapies, which include monoclonal antibodies and small-molecule inhibitors, are altering the treatment of cancer. A new therapy — ALK inhibitors — might soon be added to the list.
Oncogenic rearrangements of the anaplastic lymphoma kinase (ALK) gene have recently been described in nonsmall-cell lung cancer (NSCLC). Promising results from a phase 1 study, presented here at the American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy, indicate that ALK represents a new therapeutic target in this molecularly defined subset of NSCLC.
PF02341066, an oral ALK inhibitor being developed by Pfizer, has demonstrated efficacy in ALK-positive patients. Thus far, 31 NSCLC patients with the ALK rearrangement have been enrolled in the study, and a response has been observed in 65% of this cohort.
"There are at least 12 easily identifiable oncogenes now for which there are new therapeutic agents," said Paul A. Bunn Jr., MD, professor of medicine and James Dudley chair in cancer research at the University of Colorado, Denver. "ALK is an oncogene and, in lung cancer, is activated not by mutation but by fusion with another gene."
The chromosomal rearrangements that interrupt the ALK gene and fuse it with another gene result in the creation of oncogenic ALK fusion genes. In turn, these enhance cell proliferation and survival.
This drug should be approved for use worldwide, based on these data.
"In my opinion, this drug should be approved for use worldwide, based on these data," said Dr. Bunn, who was not involved in the study. "But the [US Food and Drug Administration] has deemed that there are not enough data to approve it, so there is now a randomized trial — just starting in the United States — in which patients will be randomized to either the experimental agent or standard chemotherapy."
Dr. Bunn also noted that although PF02341066 appears to induce more responses than standard chemotherapy, it is not curative. Presumably, he surmised, patients will become resistant to it sooner or later.
Right Drug to the Right Patient
ALK is a receptor tyrosine kinase, which is normally expressed in discrete regions of the developing nervous system, and oncogenic rearrangements of ALK on the short arm of chromosome 2 were first described in anaplastic large-cell lymphomas more than 10 years ago, according to the study authors. Subsequently, they have been observed in other malignancies, including diffuse large B-cell lymphomas and malignant histiocytosis, and in several solid tumors, including inflammatory myofibroblastic tumors, squamous cell carcinomas of the esophagus, neuroblastoma and, most recently, in NSCLC.
ALK rearrangements in NSCLC are relatively rare, explained lead author D. Ross Camidge, MD, PhD, clinical director of the Thoracic Oncology Program at the University of Colorado, Denver. In an unselected NSCLC population, ALK gene rearrangements occur with a frequency of 3% to 5%.
Aside from the focus on a specific molecular target, Dr. Camidge explained, this study represents a paradigm shift in the way drugs are moved from the laboratory into human trials.
"When the right targeted agent is appropriately matched with the right target in the right patient, molecular efficacy hypotheses can now be tested effectively within first-in-human phase 1 studies," he told Medscape Oncology. "This can dramatically shorten the drug approval time by focusing on patients who may derive the most benefit from the drug."
ALK gene rearrangements occur almost exclusively in adenocarcinoma, and there doesn't seem to be any variation by ethnicity. But it is almost never seen in squamous cell or other types of lung cancer, said Dr. Camidge. In addition, light exsmokers or never-smokers appear to have significantly higher frequencies of ALK gene rearrangements.
Early Results Promising
Dr. Camidge and colleagues began the phase 1 trial in 2006, and the trial was originally focused on tumors with markers of cMET activation, one of the most common genetically altered tyrosine kinases in human cancers. However, during the dose-escalation phase, it was reported that ALK gene rearrangements also occur in NSCLC. At that time, lung cancer patients with proven ALK-gene-rearranged tumors were recruited into the study.
To date, 31 evaluable heavily pretreated NSCLC patients with ALK rearrangements have been recruited into the study, and they are continuing to enroll patients, explained Dr. Camidge. Within this cohort, there have been 19 partial responses and 1 complete response; patients remain on therapy for a median of 24 weeks.
"We have not yet reached progression-free survival," he said.
The effectiveness of PF02341066 validates oncogenic ALK rearrangements as a therapeutic target in this molecularly defined subset of NSCLC patients, and has allowed for the evaluation of PF02341066 in a randomized phase 3 setting without the need for a separate phase 2 study.
Other companies are working on ALK inhibitors, but they are further behind this one, said Dr. Bunn. "This particular drug inhibits both ALK and MET, and it was the first one developed."
Genetic Testing for Most Adenocarcinomas
Dr. Bunn pointed out that this study demonstrates that research can move quickly, given the right circumstances. "The fusion gene was first reported in lung cancer in 2007 and, in 2009, the benefit in patients was reported," he said. "Sometimes research in cancer is criticized for moving too slowly, but this is an example of something discovered in the laboratory that is benefiting patients 2 years later."
It is clear that most patients with adenocarcinomas of the lung should have genetic testing of their tumors.
David Carbone, MD, PhD, Harold L. Moses chair in cancer research and director of the Specialized Program of Research Excellence in Lung Cancer at Vanderbilt-Ingram Cancer, in Nashville, Tennessee, emphasized the increasing importance of genetic testing. "From a wider perspective, with the knowledge of these inhibitors, we think that it is clear that most patients with adenocarcinomas of the lung should have genetic testing of their tumors done on a routine basis," he said.
"This is an extremely important point; none of these patients can be identified by clinical parameters — it is the mutations that identify these patients, and more and more of these drugs are going to become available," said Dr. Carbone, who was not involved with this study.
American Association for Cancer Research-International Association for the Study of Lung Cancer (AACR-IASLC) Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy: Abstract A24. Presented January 13, 2009.