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December 19, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf

On December 19, 2017, the Food and Drug Administration granted accelerated approval to bosutinib (BOSULIF®, Pfizer Inc.) for treatment of patients with newly-diagnosed chronic phase (CP) Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML).

Approval was based on data from an open-label, randomized, multicenter trial (BFORE, NCT02130557) in 487 patients with Ph+ newly-diagnosed CP CML who were randomized to receive either bosutinib 400 mg once daily or imatinib 400 mg once daily. The major efficacy outcome measure was major molecular response (MMR) at 12 months, defined as ≤0.1% BCR ABL ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 ABL transcripts as assessed by the central laboratory. MMR at 12 months was 47.2% (95% CI: 40.9, 53.4) in the bosutinib arm and 36.9% (95% CI: 30.8, 43.0) in the imatinib arm (p=0.0200).

Most common adverse reactions in patients with newly-diagnosed CML (incidence ≥20%) are diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase.

FDA first approved bosutinib in 2012 for treatment of patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The recommended dose of bosutinib for newly-diagnosed chronic phase Ph+ CML is 400 mg orally once daily with food.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf

FDA granted priority review and Orphan Drug designation to bosutinib for this application. As a condition of accelerated approval, further follow-up of patients in the BFORE trial is required. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 


Pharmacist's Applications to Practice

Bosutinib for the Treatment of Adult Patients with Newly Diagnosed Chronic-Phase
Philadelphia Chromosome–Positive Chronic Myeloid Leukemia

Authors: Ekaterina Kachur, PharmD, and Allison Martin, PharmD
Pharmacist Clinical Coordinators, Hematology Oncology and BMT
Levine Cancer Institute, Carolinas HealthCare System Charlotte, NC

What is the potential role for bosutinib in the treatment of newly diagnosed chronic-phase
Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML)?

  • Imatinib was the first tyrosine kinase inhibitor (TKI) approved for the treatment of chronic-phase chronic myeloid leukemia (CML) and has significantly increased the overall survival (OS) of patients with CML. Long-term outcomes data estimate an OS of 83.3% at 10 years.1 It is difficult to determine the OS benefit from imatinib on the basis of the landmark IRIS trial because 65.6% of patients assigned to the interferon alfa plus cytarabine comparator group crossed over to receive imatinib within a median of 0.8 months.1 Roy and colleagues completed a historical comparison and discerned that at 42 months, 91.5% of patients assigned to imatinib and 80.4% of patients assigned to interferon alfa plus cytarabine were still alive.2
  • Unfortunately, 20%–30% of patients on imatinib develop TKI resistance and 5%–10% of patients will discontinue therapy because of intolerance.3 Second-generation TKIs including dasatinib, nilotinib, and bosutinib have different resistance patterns and toxicities, allowing for individualized therapy.3 Table 1 describes adverse events that were commonly observed in clinical trials.4-6
  • In chronic-phase CML, the National Comprehensive Cancer Network (NCCN) endorses the use of either a first-generation TKI, second-generation TKI (bosutinib, dasatinib, or nilotinib), or clinical trial as primary treatment. All options have a category 1 designation for patients with a low-risk Sokal score. For patients with intermediate- or high-risk scores, NCCN designates category 1 recommendations to the second-generation TKIs, whereas imatinib is a category 2A recommendation. This is based on long-term follow-up and preliminary data suggesting preferential benefit from second-generation TKIs in this group of patients.7
  • Although the second-generation TKIs have no head-to-head comparisons, all have been studied against imatinib. Major end points are listed in Table 2.4-6
  • The front-line designation of bosutinib was established as a result of outcomes demonstrated in the ongoing phase 3 BFORE trial (N = 536), which compared bosutinib to imatinib as first-line treatment for chronic-phase CML.3 The primary end point of major molecular response (MMR) at 12 months was 47.2% in the bosutinib group compared with 36.9% in the imatinib group (p = .02).3 Complete cytogenetic response (CCyR) at 12 months was also significantly improved in the bosutinib group (77.2% vs. 66.4%,  p = .0075).3
  • Prior to the BFORE trial, bosutinib was indicated only after the failure of prior therapy due to resistance or intolerance.4,7 Adding bosutinib as a front-line option allows providers another option in patient individualization because the side-effect profile differs between TKIs.

Table 1. Comparative Toxicity of Imatinib, Bosutinib, Nilotinib, and Dasatinib (Incidence 10% or Greater)

 Imatinib4-6Bosutinib4Nilotinib5Dasatinib6
Nonhematologic Vomiting
Diarrhea
Abdominal pain
Muscle spasm
Myalgia
Arthralgia
Muscle inflammation
Musculoskeletal pain
Edema
Rash
Infections
Fatigue
Headache
Nausea
Vomiting
Diarrhea
Abdominal pain
Arthralgia
Rash
Infections
Fatigue
Headache
Pyrexia
Asthenia
Decreased appetite
Nausea
Myalgia
Rash
Headache
Pruritus
Fatigue
Diarrhea
Musculoskeletal pain
Rash
Headache
Fluid retention (pleural effusion 10%)
Hematologica Neutropenia
Thrombocytopenia
Anemia
Thrombocytopenia
Anemia
Neutropenia
Thrombocytopenia
Neutropenia
Anemia
Anemia
Thrombocytopenia
Neutropenia
Biochemical Increased ALT, AST
Increased alkaline phosphatase
Decreased phosphate
Increased bilirubin
Increased glucose
Increased lipase
Increased amylase
Increased creatinine
Increased ALT, AST
Increased lipase
Increased ALT, AST
Increased alkaline phosphatase
Decreased phosphate
Increased bilirubin
Increased glucose
Increased lipase
Increased amylase
Not reported

ALT = alanine aminotransferase; AST = aspartate aminotransferase.
aSide effects are listed in the order of their frequency.

 

Table 2. Comparative Efficacy of Bosutinib, Nilotinib, and Dasatinib

 Bosutinib4Nilotinib5Dasatinib6
MMR at 3 months 4.1% 9% 8%
MMR at 6 months 35% 33% 27%
MMR at 9 months 42.3% 43% 39%
MMR at 12 months 47.2% 44% 46%
CCyR at 12 months 77.2% 80% 77%
Progression to AP or BP 1.6% <1% 1.9%
OS at 12 months 99.6% 99.2% 97%

AP = accelerated phase; BP = blast phase; CCyR = complete cytogenetic response; MMR = major molecular response; OS = overall survival.

What role can the pharmacist play in the management of patients on bosutinib?

  • Pharmacists should be aware of two different dosing recommendations for bosutinib. The recommended initial dose for newly diagnosed Ph+ CML is 400 mg daily. The initial dose for Ph+ CML patients with resistance or intolerance to prior TKI therapy is 500 mg daily.8
  • Pharmacists should assess patient’s renal and hepatic function prior to initiating therapy and recommend appropriate dose adjustments, if necessary.8 It should be noted that no clinical data are available on bosutinib efficacy at the dose of 200 mg daily.7,8
  • During treatment, dose modifications are recommended for grade 3-4 hematologic toxicities (neutropenia and thrombocytopenia) and nonhematologic toxicities.8 For patients with resistant neutropenia or thrombocytopenia, use of growth factor support in combination with bosutinib may be considered.7
  • No new safety signals arose in the BFORE trial compared to the previously reported toxicity profile. The most common adverse events of any grade included diarrhea (70.1%), nausea (35.1%), thrombocytopenia (35.1%), and elevated transaminases (alanine aminotransferase [ALT], 30.6%; aspartate aminotransferase [AST], 22.8%). The most common adverse events leading to discontinuation of bosutinib were liver function abnormalities (ALT [4.9%] and AST [2.2%] increase).4,8     
  • Pharmacists can play an integral role in achieving optimal therapy responses by providing patient counseling and monitoring of adherence to bosutinib therapy.7  
  • Pfizer Oncology Together is a patient assistance program dedicated to aid with co-pay support and financial assistance programs regardless of insurance coverage. Additionally, the Bosulif (bosutinib) website has several useful patient resources such as guides for dosing and side-effect management. More information is available at https://www.bosulif.com/financial-assistance.

Clinical Pearls

  • Up to two dose escalations for suboptimal response (at months 3 and 6) were permitted in the clinical trial in absence of unacceptable toxicity. In the bosutinib group, 17.2% of patients required at least one dose escalation.4,9
  • Based on the bosutinib toxicity profile as compared to other TKIs approved in the first-line setting, bosutinib may be favored for patients with a history of lung disease or pleural effusions.7
  • Bosutinib is available as 100-mg, 400-mg, and 500-mg tablets. Tablets should be taken with food and should not be crushed or chewed.8
  • Bosutinib is categorized by the National Institute for Occupational Safety and Health (NIOSH) as a group 1 hazardous agent, and appropriate precautions are required.10
  • Bosutinib is primarily metabolized by cytochrome P450 3A4 (CYP3A4), and concurrent use of strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers should be avoided, if possible.8
  • Concomitant use with proton pump inhibitors may decrease bosutinib’s efficacy. Short-acting antacids or H2 blockers separated by at least 2 hours from a bosutinib dose may be used as an alternative.8

References

  1. Hochhaus A, Larson R, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917-927.
  2. Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood. 2006;108(5):1478-1484.
  3. Pophali P, Patnaik M. The role of new tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J. 2016;22(1):40-50.
  4. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36(3):231-237.
  5. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259.
  6. Kantarjian H, Shah N, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270.
  7. National Comprehensive Cancer Network. Chronic Myeloid Leukemia. Version 4.2018. www.nccn.org. Accessed March 19, 2018.
  8. Bosulif (bosutinib) [prescribing information]. New York, NY: Pfizer; December 2017.
  9. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. Data Supplement. http://ascopubs.org/doi/suppl/10.1200/JCO.2017.74.7162 Accessed January 23, 2018.
  10. U.S. Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016. www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed January 23, 2018
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