Multiple TKIs approved in recent months
Bosulif (bosutinib—Pfizer), Iclusig (ponatinib—Ariad), and Cometriq (cabozantinib—Exelixis)
In the last quarter of 2012, FDA approved three tyrosine kinase inhibitors (TKIs) for treatment of cancer: bosutinib (Bosulif—Pfizer), ponatinib (Iclusig—Ariad), and cabozantinib (Cometriq—Exelixis).
The approval of bosutinib and ponatinib for the management of chronic myelogenous leukemia (CML) in patients who are resistant or intolerant to prior tyrosine kinase inhibitors offers new hope for patients with refractory disease. Ponatinib was also approved for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The third agent, cabozantinib, offers new hope for patients with progressive, metastatic medullary thyroid cancer.
Evolution of TKIs
Patients with CML and ALL
Imatinib (Gleevec—Novartis) was approved more than a decade ago as a targeted leukemia therapy (i.e., Bcr-Abl TKI). Since that time, researchers have uncovered much information regarding its resistance mechanisms and potential ways to overcome resistance. Imatinib resistance reportedly occurs in approximately 33% of patients and can be subclassified as Bcr-Abl–dependent or Bcr-Abl–independent. The Bcr-Abl–dependent mechanisms involve Bcr-Abl mutation and amplification, resulting in an alteration of imatinib’s binding affinity to the Bcr-Abl tyrosine kinase. One of the most frequently identified mutations is T315l.
Second-generation TKIs such as dasatinib (Sprycel—Bristol-Myers Squibb) and nilotinib (Tasigna—Novartis) are more potent than imatinib and can be used as first-line agents for the management of chronic-phase CML as well as for imatinib-resistant or -intolerant patients. The new agent bosutinib is also classified as a second-generation TKI. It targets the Bcr-Abl kinase and inhibits Scr-family kinases including Src, Lyn, and HcK. Pharmacologic data have shown that bosutinib inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl kinases expressed in experiential cell lines. This agent, however, has no effect on T315I mutant cells.
Ponatinib is classified as a third-generation TKI. The agent is unique in that it targets cells with a T315I mutation, which makes these cells resistant to all other currently approved TKIs.
Medullary thyroid cancer
Cabozantinib has a different indication and, therefore, targets another set of tyrosine kinases. It has been shown to inhibit proinvasive receptor tyrosine kinases implicated in tumor growth, metastasis, and angiogenesis, including RET, MET, and VEGFR-1, -2, and -3.
Activating mutations in RET have been shown to play a central role in tumorigenesis in both inherited and sporadic forms of medullary thyroid cancer. MET and VEGF have also been implicated in the pathogenesis of this rare thyroid disease.
Efficacy and safety data
Approval was based on data from Study 200, a global, open-label, multi-cohort, Phase I/II study of more than 500 patients with imatinib-resistant or -intolerant Ph+ CML previously treated with one prior TKI (i.e., imatinib) or more than one prior TKI (i.e., imatinib followed by dasatinib and/or nilotinib).
For patients with chronic-phase CML previously treated with imatinib, the major cytogenetic response at 24 weeks was 33.8%. After a follow-up period of 23 months, 53.4% achieved a major cytogenetic response. For patients with chronic-phase CML previously treated with imatinib and at least one other TKI, the major cytogenetic response at 24 weeks was 26.9%. After a follow-up period of 13 months, 32.4% of these patients achieved a major cytogenetic response. Patients with accelerated- (n = 69) or blast-phase (n = 60) CML had complete hematologic response at week 48 of 30.4% and 15%, respectively. Overall hematologic response at week 48 in these two groups was 55.1% and 28.3%, respectively.
The most common all-grade adverse reactions observed for patients with CML included diarrhea (82%), nausea (46%), abdominal pain (37%), thrombocytopenia (41%), and vomiting (39%). The most common grade 3/4 reactions were thrombocytopenia (29%), anemia (13%), and neutropenia (12%).
Approval of ponatinib was based on data from a single-arm clinical trial of 449 patients with various phases of CML and Ph+ ALL; all participants had resistance or intolerance to prior TKI therapy. Major cytogenetic response occurred in 54% of all patients with chronic-phase CML and 70% of patients with the T315I mutation. In addition, 52% of patients with accelerated-phase CML experienced major hematologic response for a median duration of 9.5 months, 31% of patients with blast-phase CML achieved major hematologic response for a median 4.7 months, and 41% percent of patients with Ph+ ALL achieved major hematologic response for a median 3.2 months.
The most common adverse events reported during clinical trials, occurring in 20% or more of patients, were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. Ponatinib was also approved with a boxed warning describing serious arterial thrombotic events and hepatotoxicity.
In the randomized, placebo-controlled, double-blind EXAM (Efficacy of XL184 in Advanced Medullary Thyroid Cancer) trial of 330 patients with progressive, metastatic medullary thyroid carcinoma, partial responses were observed only among patients in the cabozantinib arm (27% vs. 0% with placebo, P < 0.0001). The median duration of objective responses was 14.7 months (95% CI 11.1–19.3) for patients treated with cabozantinib. Progression-free survival was 11.2 months in patients taking cabozantinib, a significant increase over 4.0 months with placebo. There was no statistically significant difference in overall survival between treatment arms at the planned interim analysis.
The most commonly reported adverse events with cabozantinib, occurring in 25% or more of patients, included diarrhea, stomatitis, palmar–plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The product’s FDA-approved labeling contains a boxed warning describing increased risks of hemorrhage and colonic perforations and fistulas.
Where do these agents fit?
TKIs are an important part of treatment for patients with acute and chronic leukemia. Approval of second- and third-generation TKIs such as bosutinib and ponatinib is welcome news for those with resistance or intolerance to other drugs of this class. At present, these agents are not approved as first-line treatment options and should therefore be reserved for use after an initial course of therapy with imatinib, dasatinib, and/or nilotinib. Health professionals should also select agents based on a patient’s mutational status and concurrent comorbidities.
Patients with medullary thyroid cancer can be surgically cured if their cancer is detected early, but treatment options are limited for those with advanced disease. These patients have an overall poor prognosis and have been traditionally treated with cytotoxic chemotherapy. The development of a targeted therapy such as cabozantinib with proven efficacy represents an important milestone for the management of patients with metastatic medullary thyroid carcinoma.
Drug class: Tyrosine kinase inhibitor
Indication: Treatment of chronic-, accelerated-, or blast-phase Philadelphia chromosome–positive chronic myelogenous leukemia with resistance or intolerance to prior therapy
Dosage: 500 mg taken orally once daily with food. Continue until disease progression or patient intolerance.
- A dose escalation to 600 mg daily should be considered for those who do not reach complete hematologic response by week 8 or complete cytogenetic response by week 12 when treated with the 500-mg daily dose.
- Dose modifications are recommended for patients with elevated liver transaminases, severe diarrhea, other moderate to severe nonhematologic toxicities, myelosuppression, and hepatic impairment. Refer to labeling for specific dosing information.
Educate patients on proper administration of bosutinib, including taking the tablet with food and not crushing or cutting the tablet. Instruct patients that if they miss a dose for more than 12 hours, they should take the next dose at the scheduled time. Review potential adverse events, which include diarrhea, nausea, vomiting, and fluid retention. Instruct patients to report fever, any signs of infection, or symptoms suggestive of bleeding or easy bruising to their health care provider immediately.
Drug class: Tyrosine kinase inhibitor
Indication: Treatment of chronic-, accelerated-, or blast-phase chronic myelogenous leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to prior tyrosine kinase inhibitor therapy
Dosage: 45 mg orally once daily with or without food. Continue until disease progression or patient intolerance.
- Dose modifications are recommended for myelosuppression, hepatic toxicity, pancreatitis, elevation of serum lipase, other nonhematologic adverse reactions, and when used concurrently with strong cytochrome P450 3A inhibitors. Refer to labeling for specific dosing information.
Educate patients to take tablets once daily with or without food, not to crush tablets, and not to double doses to make up for missed doses. Inform patients of the numerous adverse reactions that can occur and to report any symptoms suggestive of blood clot (e.g., chest pain, shortness of breath), liver toxicity (e.g., yellowing of the eyes or skin), and other toxicities.
Drug class: Tyrosine kinase inhibitor
Indication: Treatment of progressive, metastatic medullary thyroid cancer
Dosage: 140 mg orally once daily. Patients should not eat for at least 2 hours before and 1 hour after taking the drug.
- Dose modifications are recommended for nonhematologic and hematologic adverse reactions, as well as when used concurrently with strong cytochrome P450 3A inhibitors or inducers. Refer to labeling for specific dosing information.
Educate patients on proper administration of cabozantinib, including swallowing capsules whole, administration in relation to food, not taking missed doses within 12 hours of the next dose, and not ingesting foods or nutritional supplements (e.g., grapefruits, grapefruit juice) that are known cytochrome P450 inhibitors. Review potential adverse events, including diarrhea, nausea, vomiting, progressive or intolerable rash, oral pain, and weight loss.