Adapted from the NCI Cancer Bulletin, vol. 7/no. 21, November 2, 2010 (see the current issue).
New data from a phase I trial of crizotinib, a small-molecule drug that targets cancer-causing chromosomal rearrangements involving the gene ALK, in patients with non-small cell lung cancer (NSCLC) add to positive results presented [NCI Cancer Bulletin for June 15, 2010 - National Cancer Institute] earlier at the 2010 American Society of Clinical Oncology annual meeting. Researchers led by Eunice Kwak, M.D. Ph.D., of Harvard Medical School reported that more than half of patients who have an ALK rearrangement and who received crizotinib had partial or complete shrinkage of their tumors. The updated results [Anaplastic lymphoma kinase inhibition in non-small... [N Engl J Med. 2010] - PubMed result] were published October 28, 2010, in the New England Journal of Medicine (NEJM).
In comparison, only about 10 percent of lung cancer patients who receive second-line chemotherapy respond to treatment. “It is gratifying to learn of responses like those seen in our study…especially when you consider that most patients had already received two or more therapies by the time they entered the trial,” stated Dr. Kwak in a press release.
The trial, which was sponsored by the drug’s developer, Pfizer, Inc., began as a dose-escalation study in patients with many different solid tumors to determine the maximum safe dose of crizotinib. Later, only patients with solid tumors that had proven molecular abnormalities thought to be targeted by crizotinib, including ALK gene rearrangements in lung cancer, were eligible to enroll.
The NEJM paper reported that 46 of the 82 NSCLC patients had a partial response (their tumors shrank by at least 30 percent in diameter) and one had a complete response. An additional 27 patients had stable disease (i.e., their tumors stopped growing during treatment). The researchers estimated the probability of being alive without progression of disease after 6 months of treatment to be 72 percent. Crizotinib led to few major side effects, and the most common low-grade effects included nausea, diarrhea, and mild visual disturbances.
Additional data from an expanded cohort of 113 patients were presented October 10 at the 2010 European Society for Medical Oncology (ESMO) Congress. Those data showed that response rates remained high, at 56 percent (including partial and complete responses), and that median progression-free survival was 9.2 months.
“As we added more patients to the study, the results remained entirely consistent, and the benefit is consistent across the line of therapy, sex, age, and general fitness,” said Ross Camidge, M.D., Ph.D., from the University of Colorado Cancer Center, an investigator on the trial who presented the data at the ESMO meeting. “That’s consistent with an agent that’s actually addressing the root cause of the cancer.”
Although only 2 to 7 percent of all NSCLC patients have tumors with the ALK genetic change, the sheer number of lung cancer cases diagnosed each year means that “the number of potential patients for crizotinib therapy is substantial, approaching 10,000 annually in the United States alone,” wrote Bengt Hallberg, Ph.D., and Ruth Palmer, Ph.D., from Umeå University in Sweden, in an accompanying editorial in NEJM. A phase III trial comparing crizotinib with standard chemotherapy in patients with advanced NSCLC that harbors an ALK gene rearrangement is ongoing.
Two additional articles in the October 28 NEJM about specific patients in the phase I trial shed some light on the potential future of crizotinib—both the good and the bad. In a case report [Crizotinib in ALK-rearranged inflammatory myofibro... [N Engl J Med. 2010] - PubMed result] published by researchers from Dana-Farber Cancer Institute and their colleagues, crizotinib caused disease regression in a patient with inflammatory myofibroblastic tumor (IMT), a rare type of sarcoma in which ALK gene rearrangements are common. In a second case report [EML4-ALK mutations in lung cancer that confer resi... [N Engl J Med. 2010] - PubMed result], researchers at Jichi Medical University in Japan analyzed how new mutations in the ALK gene of another patient led to emerging resistance of his lung tumor to crizotinib.
The case report from Dana-Farber took a closer look at two patients with IMT who had been enrolled in the original dose-escalation portion of the trial. Although both patients had IMT, only one patient turned out to have an ALK-positive cancer. That patient remained alive and in remission and was still receiving the drug at the time of publication, whereas the ALK-negative patient’s disease progressed almost immediately despite crizotinib treatment.
“Given these positive and negative examples and the rarity of the diagnosis, one can extrapolate that ALK inhibitors are appropriate therapy for people with ALK translocation-positive inflammatory myofibroblastic tumor,” said Robert Maki, M.D., Ph.D., a medical oncologist at Memorial Sloan-Kettering Cancer Center and an author on the paper. Recurrent IMTs are often resistant to traditional chemotherapy drugs.
“There’s increasing interest in targeted drugs for rarer cancers—researchers are branching out more and more,” explained Dr. Maki. “This is one of several recent examples of the personalization of medicine based on the targets that are known to be important in a given person’s tumors.”
Unfortunately, a persistent frustration found in the development of targeted drugs is that most tumors eventually develop mutations that confer resistance to the treatment. In the case report from Japan, researchers studied a patient from the phase I trial who developed resistance to crizotinib after 5 months of treatment.
The researchers identified and sequenced two independent mutations in the patient’s rearranged ALK gene that could block the response to crizotinib. These mutations likely alter the structure of the ALK protein, thereby preventing the drug from binding to the protein and diminishing its activity, explained the authors.
It is unknown how common these specific mutations will be in a larger group of patients, said Dr. Camidge, although it is likely that, through a variety of mechanisms, every patient will eventually develop resistance to the drug, he explained. “Every patient that progresses either has primary resistance—that’s the 10 percent or so of patients who don’t respond at all—or initially responds but then acquires resistance.”
One solution to this problem, said Dr. Maki, will be the development of drugs that can bind to mutated ALK proteins, much as dasatinib binds the BCR-ABL protein in patients with chronic myelogenous leukemia (CML). Dasatinib is used to treat imatinib-resistant CML by more broadly blocking the kinase that drives CML, he explained.
Widespread use of drugs tailored to the mutations that drive individual tumors will require the genotyping of tumors, and methods like those currently being employed at Dana-Farber Cancer Institute, the University of Colorado, and other centers are the first step toward making tumor genotyping a standard part of cancer diagnosis. “That’s going to become part of the routine work-up of cancer [patients],” Dr. Maki said. “The genetic changes found in a tumor are eventually going to be more important than whether the cancer began in the colon or the pancreas or the breast.”
Crizotinib Continues to Show Promise for Some Lung Tumors - National Cancer Institute
crizotinib
An orally bioavailable agent belonging to the class of c-met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors with potential antineoplastic activity. MET tyrosine kinase inhibitor PF-02341066 inhibits the membrane receptor MET and activation of the MET signaling pathway, which may block tumor cell growth, migration and invasion, and tumor angiogenesis in susceptible tumor cell populations. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)
Synonyms: c-met/hepatocyte growth factor receptor tyrosine kinase inhibitor PF-02341066
c-met/HGFR tyrosine kinase inhibitor PF-02341066
MET Tyrosine Kinase Inhibitor PF-02341066
Code name: PF-02341066
Chemical structures:
* 2-Pyridinamine, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H- pyrazol-4-yl]
* 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4- yl)pyridin-2-amine
Definition of crizotinib - National Cancer Institute Drug Dictionary
crizotinib
N Engl J Med. 2010 Oct 28;363(18):1693-703.
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ.
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. ekwak@partners.org
Comment in:
* N Engl J Med. 2010 Oct 28;363(18):1760-2.
Abstract
BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.
METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.
RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.
CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
PMID: 20979469 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances, Secondary Source ID, Grant Support
Anaplastic lymphoma kinase inhibition in non-small... [N Engl J Med. 2010] - PubMed result
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