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Protein Tyrosine Kinase Inhibitors

Overview

Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of tyrosine residues. These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling, and neurite outgrowth. Unregulated activation of these enzymes, through mechanisms such as point mutations or overexpression, can lead to various forms of cancer as well as to benign proliferative conditions. More than 70% of the known oncogenes and protooncogenes involved in cancer encode PTKs.

A number of protein tyrosine kinase inhibitors have been developed and approved for cancer treatment. These include inhibitors of c-Abl (imatinib, for treatment of chronic myelogenous leukemia); HER2 (trastuzumab [Genentech/Roche’s Herceptin], for treatment of breast cancer); vascular endothelial growth factor receptor (bevacizumab [Genentech/Roche’s Avastin], for treatment of metastatic colorectal cancer); and the epidermal growth factor receptor (EGFR) gefitinib (AstraZeneca’s Iressa, also known as cetuximab (ImClone/Merck & Co./BMS’s Erbitux), for treatment of lung and colorectal cancer, respectively.

Mechanism Of Action

The rationale for developing tyrosine kinase inhibitors for the treatment of cancer is based on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. In chronic myelogenous leukemia, affected cells have a consistent cytogenetic abnormality, the Philadelphia chromosome, which carries a BCR-ABL fusion gene encoding a tyrosine kinase oncoprotein. Imatinib mesylate is a specific inhibitor of this oncoprotein.

Imatinib

Protein Tyrosine Kinase InhibitorsImatinib mesylate (Novartis’s Gleevec/Glivec, formerly STI-571) was first launched in the United States in May 2001 for the treatment of blastic- and accelerated-phase chronic myelogenous leukemia and chronic-phase disease after failure of interferon-a therapy. Imatinib had previously been awarded fast-track status for the myeloid blastic phase indication of chronic myelogenous leukemia and granted orphan drug designation in the United States, European Union, and Japan. In December 2002, the FDA approved the product for first-line therapy in all phases of chronic myelogenous leukemia, after data from the imatinib arm of the International Randomized Study of Interferon Versus ST-1571 (IRIS; discussed subsequently) showed high cytogenetic response rates and delay in disease progression, suggesting that imatinib improves long-term survival. The dose of 400 mg per day of imatinib administered orally, the same dose used in the IRIS trial, is considered standard therapy for patients with newly diagnosed chronic myelogenous leukemia in the chronic phase. In February 2002, the FDA also approved imatinib for the treatment of inoperable and metastatic malignant gastrointestinal stromal tumors. The product is also being investigated for the potential treatment of other cancers that express tyrosine kinases, including acute lymphocytic leukemia and certain solid tumors.

Imatinib is a 2-phenylamino-pyrimidine derivative that specifically inhibits the tyrosine kinase activity of the ABL proteins c-ABL and BCR-ABL. The BCR-ABL fusion gene present in chronic myelogenous leukemia encodes an oncoprotein, p210BCR-ABL, that has dysregulated tyrosine kinase activity that is central to the pathogenesis of chronic myelogenous leukemia. Imatinib competitively inhibits the interaction of adenosine triphosphate (ATP) with these oncoproteins, thereby lessening their ability to phosphorylate and activate downstream target proteins.

The initial approval of imatinib was based on data from Phase II studies involving approximately 1,230 patients in 32 centers located in five countries. The trial endpoints included hematologic and cytogenetic response rates. In one study, a total of 532 patients with late chronic-phase chronic myelogenous leukemia in whom previous therapy with interferon-a had failed were treated with 400 mg of oral imatinib daily. Imatinib induced MCRs in 60% (69% of these patients displayed a cytogenetic response) and CHRs in 95% of the patients. The time to onset of an major cytogenetic response ranged from 2.4 months to 19 months, and the median time to a CHR was 0.7 months. After a median follow-up of 18 months, chronic myelogenous leukemia had not progressed to the accelerated or blastic phases in an estimated 89% of patients, and 95% of the patients were still alive. Only 2% of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred.

Data from some ongoing Phase III IRIS trials demonstrated superior response rates in imatinib-treated patients compared with interferon-a. The IRIS study was the largest study of chronic myelogenous leukemia patients ever conducted, enrolling 1,106 patients (553 randomized to each treatment arm) with newly diagnosed Ph-positive chronic myelogenous leukemia between June 2000 and January 2001 in 16 countries. The study compared imatinib at 400 mg per day with interferon-a plus subcutaneous low-dose cytarabine (LDAC) (IFN+LDAC) as first-line treatments; patients were allowed to cross over to the other treatment arm if they experienced loss of response, lack of response, or intolerance to the treatment. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression.

After a median follow-up, the estimated rate of an major cytogenetic response at 18 months was 87% in the imatinib group and 35% in the IFN+LDAC-treated group. The estimated rates of cytogenetic response were 76% and 14%, respectively. At 18 months, the estimated rate of freedom from progression to accelerated or blastic-phase chronic myelogenous leukemia was 97% in the imatinib group and 91% in the combination-therapy group. Imatinib was better tolerated than IFN+LDAC. It is worth noting that 89% of patients receiving IFN+LDAC had already switched to imatinib therapy after a median of only 8 months into the study. Therefore, the survival benefit with imatinib compared with IFN+LDAC has not yet become apparent with long-term follow-up because most patients treated with IFN+LDAC are benefiting early on from the added sequential imatinib therapy.

An additional follow-up to the IRIS trial at 42 months confirmed durable response with first-line imatinib therapy while demonstrating the effect of cytogenetic response on long-term outcomes. Of newly diagnosed patients treated with imatinib, 98% had achieved CHR, while 91% had achieved an major cytogenetic response, and 84% had achieved a cytogenetic response. For patients who had achieved cytogenetic response and a thousandfold (3 log) or greater reduction in BCR-ABL transcript level (i.e., a molecular response) at 12 months, the probability of remaining progression-free was 98% at 42 months. This probability compared with 90% for patients with cytogenetic response and less than a thousandfold reduction in BCR-ABL transcript level, and 75% for patients who had not achieved cytogenetic response. Responses to imatinib were found to be durable at the 42-month follow-up; an estimated 91% of patients maintained CHR, 91% of patients maintained major cytogenetic response, and 87% of patients maintained cytogenetic response.

A follow-up study monitored the molecular response for a median of 42 months in all 28 patients enrolled in the IRIS trial in Australia and New Zealand who commenced imatinib as their first-line therapy. The study’s aim was to determine if the BCR-ABL levels continued to decrease after 24 months. A cytogenetic response (approximately equivalent to a greater than 2-log reduction of BCR-ABL) was achieved in 24 of the 28 patients. Of the four patients without a cytogenetic response, all had disease progression, and in one patient a BCR-ABL mutation was detected, followed by rapid progression to blastic-phase disease. The data demonstrate that, although the frequency of achieving an major molecular response increased between 12 and 42 months, most of the improvement occurred between 12 and 24 months. Thirteen patients achieved an major molecular response by 12 months, and all 13 achieved a 4-log reduction (equivalent to undetectable levels of BCR-ABL transcripts) at 42 months. These results suggest that, in patients achieving an major molecular response by 12 months, leukemic cell mass is still decreasing after 3.5 years of imatinib therapy.

Common side effects of imatinib treatment are superficial edema, nausea, and muscle cramps. Some patients may experience severe toxicity, leukopenia, thrombocytopenia, and anemia. The most common adverse events experienced in the IRIS trial were hematologic and hepatic toxicities and included severe (NCI grades 3/4) neutropenia (16.2%), anemia (4.0%), thrombocytopenia (9.3%), and elevated liver enzymes (5.4%). Other drug-related adverse events occurred in 15.8% of patients.

Another study, conducted by researchers at the M.D. Anderson Cancer Center in Houston, Texas examined the optimal dose of imatinib therapy. In this trial, 222 previously untreated early chronic-phase chronic myelogenous leukemia patients were split into two groups. One group of patients was treated with the 400 mg daily dose of imatinib, while another group was treated with 800 mg daily. Patients in the higher-dose group had an estimated progression-free survival rate of 99% at 12 months compared with 92% in the standard dose group. Researchers concluded that the 800 mg daily imatinib dose resulted in higher rates of CCRs and MMRs. Extramedullary toxicity (toxicity outside the bone marrow) was similar in the two groups, but myelosuppression was more common with the higher dose. At 12 months, the median actual dose for the high-dose group was still 800 mg daily, with 36% of evaluable patients having required dose reduction, compared with 14% of those treated with the standard dose.

Acquired resistance to imatinib among patients with chronic-phase disease appears to be rare and can often be overcome by increasing the dose. In a follow-up study, 261 patients with chronic myelogenous leukemia in chronic-phase post-interferon-a failure received an escalated daily dose of 600-800 mg of imatinib orally after demonstrating a poor response or relapse at the standard dose (400 mg daily). Among patients treated for hematologic resistance or relapse, 65% achieved a complete or partial hematologic response. Among patients treated for cytogenetic resistance or relapse, 56% achieved a complete or major cytogenetic response.

In contrast, 70% of patients in myeloid blast crisis exhibit resistance to imatinib. Furthermore, all patients in lymphoid blast crisis relapse within six months of responding to imatinib. This resistance appears to arise from a variety of mechanisms, including acquired mutations in the ABL kinase domain, BCR-ABL overexpression, P-glycoprotein overexpression reducing the cellular uptake of imatinib, selection of preexisting mutant cells, and possibly, excessive degradation of the BCR-ABL protein.

Several studies have shown that imatinib is not as effective in the treatment of accelerated and blastic-phase chronic myelogenous leukemia as it is in the treatment of chronic-phase disease. A Phase II study investigated the hematologic and cytogenetic responses of 260 patients in myeloid blast crisis treated with 400-600 mg imatinib daily. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least four weeks in 31% of patients, including CHRs in 8%. In patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced MCRs in 16% of patients, and 7% of the responses were complete. Median survival time was 6.9 months. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions.

Another Phase II study involving 235 patients showed that imatinib 400-600 mg daily induced hematologic and cytogenetic responses in accelerated-phase chronic myelogenous leukemia. Imatinib induced a hematologic response in 82% of patients and sustained hematologic responses lasting at least four weeks in 69%, and complete responses in 34%. The rate of major cytogenetic response was 24%; complete responses were achieved by 17%. Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. In comparison with 400 mg, imatinib doses of 600 mg led to more cytogenetic responses (28% compared with 16%), longer duration of response (79% compared with 57% at 12 months), time to disease progression (67% compared with 44% at 12 months), and overall survival (78% compared with 65% at 12 months) with no clinically relevant increase in toxicity.

Several groups have investigated the combination of imatinib plus LDAC using the hypothesis that resistance to imatinib would be less frequent. The chronic myelogenous leukemia French Group performed a Phase II trial to determine the safety and tolerability of the combination in 30 previously untreated patients in chronic-phase chronic myelogenous leukemia. Treatment was administered in 28-day cycles. Patients were treated continuously with imatinib at a dose of 400 mg daily. LDAC was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m2/day via subcutaneous injection. Adverse events were frequently observed: grade 3 or 4 hematologic toxicities and nonhematologic toxicities occurred in 53% and 23% of patients, respectively. At 6 months, 100% of patients achieved a CHR, and the cumulative incidence of cytogenetic response at 12 months was 83%. The researchers concluded that the combination was safe and promising, given the rates of response.

The STI-571 Prospective International Randomized Trial (SPIRIT) is a Phase III study underway to compare imatinib monotherapy, imatinib plus cytarabine, and imatinib plus interferon-a as first-line treatment in randomized, newly diagnosed chronic myelogenous leukemia patients.

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