Personalized Medicine: Crizotinib, a New Targeted Therapy in Non–Small-Cell Lung Cancer Published on November 11th, 2010

Personalized Medicine: Crizotinib, a New Targeted Therapy in Non–Small-Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase first identified as part of the t(2;5) chromosomal translocation associated with most anaplastic large cell lymphomas (ALCL) and a subset of T-cell non-Hodgkins lymphomas. The deregulated expression of full length ALK and ALK fusions has recently been observed in several nonlymphoid neoplasms.

A subset of Non-Small-Cell lung Cancers (NSCLCs) harbor a transforming echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusions , The truncated EML4 protein retains a coiled-coil oligomerization domain allowing dimerization. EML4-ALK translocations seems to be a rare aberration, most common in Asian nonsmokers or light-smokers with the adenocarcinoma subtype of NSCLC, forming a distinct subgroup from patients harboring EGFR, KRAS, or NKX2-1 aberrations. The initial frequency of EML4-ALK fusion transcripts was approximately 6.7% in Japanese NSCLC tumor samples, but subsequent studies showed lower frequencies of 3% or less. Direct demonstration of EML4-ALK as a dominant oncogenic driver in NSCLC included transformation of mouse 3T3 fibroblastic cells with forced overexpression of human EML4-ALK and de novo lung adenocarcinoma formation in mice engineered to express EML4-ALK targeted to the lung alveolar epithelial compartment.

Inflammatory myofibroblastic tumor (IMT) is a rare tumors of mesenchymal origin that arises in multiple tissues, possesses metastatic potential, and is only minimally responsive to conventional chemotherapy or radiation therapy. IMT is associated with various ALK translocations, including TPM3-ALK and TPM4-ALK, CARS-ALK, and CLTC, but not to date with fusion partners seen in NSCLC.

Crizotinib inhibits the anaplastic lymphoma kinase (ALK) gene’s receptor, tyrosine kinase, which has been linked to several types of cancer. Indeed, more than half of selected patients with advanced NSCLC responded to treatment with crizotinib, according to findings of a phase I multicenter clinical trial reported in the Oct. 28 issue of the New England Journal of Medicine. Dr. Kwak and her colleagues of Massachusetts General Hospital Cancer Center, Boston found that NSCLC with ALK rearrangements – which occurred in approximately 5% of the patients screened for participation in this trial – were highly sensitive to ALK kinase inhibition.

In a group of 82 patients, many of whom had undergone numerous anticancer therapies for advanced ALK-positive tumors, the overall partial and complete response rate was 57% (10% response rate seen in similar cancers treated with second-line multiagent chemotherapy) and disease stabilized in an additional 33%.

The probability of 6-month progression-free survival was estimated to be 72% with crizotinib therapy (at a maximal dose of 250 mg twice daily) , compared with a rate of 27% for similar tumors treated with second-line chemotherapy. Treatment response was quite rapid, with a disease-control rate of 87% at 8 weeks. Adverse effects were mild.

Two separate case reports were published in the same issue of the journal with crizotinib therapy. In the first one Dr. Young Lim Choi of Jichi Medical University, Tochigi, Japan, and associates suggested that de novo mutations may arise within the kinase domain of the ALK gene. Whether the resistant clones were present initially or developed secondarily, during treatment has not been determined. Such result strongly emphasize that further research should be devoted to the development of ALK inhibitors addressing the mutations and the resistance. Indeed, a number of such drugs are in the pipeline, including a new ALK inhibitor.

In another study, Dr. James E. Butrynski of the Dana-Farber Cancer Institute, Boston, and his associates treated two patients with IMT with crizotinib in December 2008. One patient responded to the treatment and has maintained complete radiographic remission until present time. The second patient did not respond to crizotinib, showing continued disease progression. Further analysis showed that the tumor in patient 1 had ALK rearrangements while that in patient 2 did not. Together, these two cases indicate that crizotinib is effective only in those IMTs with ALK rearrangements.

Bengt Hallberg, Ph.D., and Ruth H. Palmer, Ph.D., wrote in an editorial that in groups of patients with cancers in which ALK is implicated, a standard genotyping approach will be important for a more personalized therapeutic protocol.

Dr. Kwak and colleagues note that mutations or translocations of the ALK gene also have been implicated in anaplastic large-cell lymphoma and neuroblastoma. The latter, a devastating childhood cancer in which ALK mutations have been reported in approximately 10% of cases, makes a particularly attractive target for crizotinib, especially in view of the drug’s tolerability during long-term use in these phase I studies.

Selected References :

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. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703.

Butrynski JE, D’Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC, Ladanyi M, Capelletti M, Rodig SJ, Ramaiya N, Kwak EL, Clark JW, Wilner KD, Christensen JG, Jänne PA, Maki RG, Demetri GD, Shapiro GI. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010 Oct 28;363(18):1727-33.

Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H; ALK Lung Cancer Study Group. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010 Oct 28;363(18):1734-9.

Schönherr C, Yang HL, Vigny M, Palmer RH, Hallberg B. Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells. Oncogene. 2010 May 13;29(19):2817-30.

See also:

Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009 Sep 10;27(26):4247-53.

Elsevier Global Medical News by Mary Ann Moon (Wednesday, October 27, 2010) from which the above text has been derived


According to the Oct 28 2010  New York Times , Pfizer plans to submit crizotinib to the Food and Drug Administration in the first half of next year at the same time that it submits a FISH gene diagnostic test being developed with Abbott to identify patients most likely to benefit from the drug.

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