Sprycel, Dasatinib, Dru137

Independent licensees of the Blue Cross and Blue Shield Association

Medication Policy Manual Policy No: dru137

Topic: Sprycel, dasatinib Date of Origin: November 17, 2006

Committee Approval Date: October 28, 2020 Next Review Date: October 2021

Effective Date: January 1, 2021

IMPORTANT REMINDER This Medication Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medication policy is to provide a guide to coverage. Medication Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description Dasatinib (Sprycel) is an oral tyrosine kinase inhibitor used to treat certain types of cancer. It works by blocking specific proteins that the cancer cells need to grow.

I. Continuation of therapy (COT): Dasatinib (Sprycel) may be considered medically necessary for COT when criteria A and B below are met. A. The patient is established on this therapy AND one of the following situations applies (criterion 1 or 2 below): 1. Prior to current health plan membership AND the medication was covered by another health plan. Note: If the diagnosis is not listed in the coverage criteria below, written documentation of coverage must be provided, such as an approval letter or paid claim.

OR 2. The medication was initiated for acute disease management, as part of an acute unscheduled, inpatient hospital admission AND there is documented clinical benefit.

AND B. If the diagnosis is not listed in the coverage criteria below, documentation of clinical benefit, such as disease stability as detailed in the reauthorization criteria, is provided.

Please note: Medications obtained as samples, coupons, or promotions, paying cash for a prescription (“out-of-pocket”) as an eligible patient, or any other method of obtaining medications outside of an established health plan benefit (from your insurance) does NOT necessarily establish medical necessity. Medication policy criteria apply for coverage, per the terms of the member contract with the health plan.

II. New starts (treatment-naïve patients): Dasatinib (Sprycel) may be considered medically necessary when the criteria below are met: A. Documentation of one of the following conditions in Philadelphia chromosome- positive (Ph+) patients: 1. Chronic myelogenous leukemia (CML) in the chronic phase AND at least one prior tyrosine kinase inhibitor (TKI) therapy for CML has not been effective or is contraindicated (See Appendix 1). OR 2. CML in the accelerated or blast phase when treatment with imatinib is ineffective, not tolerated or contraindicated. OR 3. Acute lymphoblastic leukemia (ALL) when treatment with imatinib is ineffective, not tolerated or contraindicated.

© 2021 Regence. All rights reserved. dru137.18 Page 2 of 9 III. Administration and Authorization Period A. Regence Pharmacy Services considers dasatinib (Sprycel) to be a self- administered medication. B. When pre-authorization is approved, dasatinib (Sprycel) may be authorized in doses of up to 140 mg per day until disease progression. C. Authorization may be reviewed at least annually. Clinical documentation (including, but not limited to chart notes) must be provided to confirm that current medical necessity criteria are met, and that the medication is providing clinical benefit, such as disease stability or improvement.

IV. Dasatinib (Sprycel) is considered not medically necessary when used for previously untreated CML.

V. Dasatinib (Sprycel) is considered investigational when used for all other conditions, including, but not limited to: A. ALL when the Philadelphia chromosome is not present (non-Ph+ ALL). B. CML when the Philadelphia chromosome is not present (non-Ph+ CML). C. Malignant melanoma. D. Multiple myeloma (MM). E. Myeloproliferative disorders (MPD). F. Non-small cell lung cancer. G. Prostate cancer. H. Solid tumors. I. Gastrointestinal stromal tumor (GIST)

Position Statement - Dasatinib (Sprycel) is an orally administered tyrosine kinase inhibitor (TKI) used in the treatment of chronic myelogenous leukemia (CML) and in Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph+ ALL) that is refractory to imatinib. - Most CML and some ALL is caused by an abnormal chromosome translocation that results in the formation of the Philadelphia chromosome which starts the disease process. - TKIs work by suppressing formation of the abnormal Philadelphia chromosome. Efficacy of TKIs is measured using a genetic test that measures the level of suppression of the Philadelphia chromosome (cytogenetic response). - There are three phases of CML: chronic, accelerated, and blast. Chronic phase CML is the most common. Accelerated and blast phase CML are associated with a higher morbidity and mortality. - The intent of this policy is to cover dasatinib (Sprycel) for the indications for which it has been studied and shown to be safe and effective, as detailed in the coverage criteria, with consideration for other available treatment options. © 2021 Regence. All rights reserved. dru137.18 Page 3 of 9 - Imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) have been studied and are used to treat CML in the following clinical settings: * Imatinib has been studied and is used as a first-line therapy for CML in the chronic, accelerated and blast phases. * Dasatinib (Sprycel) has been studied as a first-line therapy for CML in the chronic phase; and as a subsequent therapy for CML in the chronic, accelerated, or blast phase after resistance or intolerance to prior imatinib therapy. * Nilotinib (Tasigna) has been studied as a first-line therapy for CML in the chronic phase; and as a subsequent therapy for CML in the accelerated phase after resistance or intolerance to prior imatinib therapy. It has not been studied in CML in the blast phase. - Imatinib produces cytogenetic response (surrogate measure of efficacy) in the majority of patients with chronic phase CML and is associated with improved overall survival. - Dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) have demonstrated improvement in surrogate markers of disease response compared to imatinib 400 mg daily. However, differences in overall survival or other clinically meaningful endpoints were not observed in comparative trials. - The efficacy of dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) compared to an imatinib 600 mg daily is not known. - Myelosuppression, skin reactions, and hepatic impairment occur with all of the TKIs. Specific adverse events (AEs) may be more prevalent with one TKI versus another: * Higher rates of fluid retention are reported with imatinib than with other TKIs. * Dasatinib (Sprycel) may cause pulmonary AEs such as pleural effusion and pulmonary arterial hypertension. * Nilotinib (Tasigna) is associated QT prolongation. - There are currently no well-controlled studies that establish the safety and efficacy of dasatinib (Sprycel) in other types of leukemias or cancers. - Usual doses of dasatinib (Sprycel) range from 100 mg to 140 mg daily. The safety and efficacy of dasatinib (Sprycel) in doses above 140 mg daily have not been established.

Regence Pharmacy Services performs independent analyses of oncology medication evidence. NCCN clinical practice guidelines assignment of a category 2a/b recommendation does not necessarily establish medically necessity. The Regence Pharmacy Services analysis and coverage policy may differ from NCCN clinical practice guidelines.

© 2021 Regence. All rights reserved. dru137.18 Page 4 of 9 Summary Clinical Efficacy CHRONIC MYELOGENOUS LEUKEMIA (CML) - The quality of evidence for the TKIs [imatinib, dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif)] in CML is reliable and suggests that these medications are effective and that they improve overall survival relative to historical controls. - Imatinib was the first TKI approved for the treatment of CML and is effective in the majority of cases in the first-line setting. Complete cytogenetic response (CCyR) rates at one year range from 57 to 88% in various imatinib studies. - In the first-line treatment of CML, there is evidence that dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) have been shown to improve surrogate markers of disease response compared to imatinib 400 mg daily. However, no difference in overall survival has been demonstrated. The effectiveness compared to imatinib 600 mg daily has not been studied. ∗ A reliable study comparing dasatinib (Sprycel) with imatinib in the first-line treatment of CML reported an 11% improvement in CCyR at one year for dasatinib (Sprycel) over imatinib (77% versus 66%, respectively). [1] However, mature 5-year overall survival was not different between groups (91% vs 90%). ∗ A reliable study comparing nilotinib (Tasigna) with imatinib in the first-line treatment of CML reported a 14% improvement in CCyR (secondary endpoint) at one year for nilotinib (Tasigna) over imatinib (79% versus 65%, respectively). [2] However, mature 5-year overall survival was not different between groups (93.7% vs. 95%). [3] - Incremental improvements in CCyR over imatinib reported in these trials have not translated into an overall survival advantage. - Both imatinib and dasatinib (Sprycel) have demonstrated efficacy in the accelerated and blast phases of CML. There are no formal studies evaluating nilotinib (Tasigna) in the blast phase of CML and it has not received FDA labeling for use in this population. - Current National Comprehensive Cancer Network (NCCN) guidelines consider any of the tyrosine kinase inhibitors [imatinib, dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif)] as potential first-line treatments for CML in the chronic phase. Selection of second-line therapies when resistance to first-line therapy is suspected may be guided by mutational analysis. [4] - Current NCCN guidelines recommend dasatinib (Sprycel), nilotinib (Tasigna), or bosutinib (Bosulif) for moderate to high risk chronic-phase CML patients in the first line setting based on subgroup analysis of surrogate markers. Mature overall survival data for dasatinib (Sprycel) and nilotinib (Tasigna) have shown no difference in overall survival compared to imatinib 400 mg daily in the first-line setting. [4] - NCCN recommends that imatinib 600 mg daily as the most appropriate dose for future clinical trials based on observed improvements in CCyR and MMR rates compared to imatinib 400 mg daily. As dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) have not been compared to imatinib 600 mg daily, the comparative efficacy is not known.

© 2021 Regence. All rights reserved. dru137.18 Page 5 of 9 Ph+ ACUTE LYMPHOBLASTIC LEUKEMIA (Ph+ ALL) - The overall quality of evidence for tyrosine kinase inhibitors [imatinib and dasatinib (Sprycel)] in Ph+ ALL is poor because the trials were not blinded, and they did not employ a comparator. However, because they suppress the Philadelphia chromosome which is a useful surrogate marker for control of this disease, they have become standard therapies in the treatment of Ph+ ALL. - Dasatinib (Sprycel) was studied in patients who either experienced resistance to imatinib therapy (they did not achieve a hematologic or cytogenetic response or had progression of disease after an initial response) or could not tolerate imatinib doses of 400 mg or more per day. [5,6] - Current NCCN guidelines consider dasatinib (Sprycel) a treatment option for Ph- positive ALL with resistance or intolerance to prior therapy. Selection of second-line therapies when resistance to first-line therapy is suspected may be guided by mutational analysis. [7] - There is insufficient evidence to establish that dasatinib (Sprycel) is safer or more effective than imatinib for 1st-line treatment of Ph+ALL. The evidence for dasatinib (Sprycel) in the 1st-line setting is limited to non-comparative, observational data. Furthermore, the incremental improvement in cytogenetic response in the CML population has not been shown to correspond with improved clinical outcomes like overall survival. [4] Safety [5] - Adverse events commonly reported with dasatinib (Sprycel) in clinical trials included: * Suppression of bone marrow including thrombocytopenia, neutropenia, and anemia. * Bleeding, including severe gastrointestinal hemorrhage. * Severe fluid retention, including pleural effusion. * Gastrointestinal events including diarrhea, nausea, abdominal pain and vomiting. * QT segment prolongation. * Headache, musculoskeletal pain, infection, and pleural effusion. Dosing and administration [5] - Dasatinib (Sprycel) tablets should be swallowed whole. They may be taken with or without a meal. - Standard dosing of dasatinib (Sprycel) ranges from 100 mg to 140 mg per day and is dependent on the condition being treated. - Adjustment of the dasatinib (Sprycel) dose is recommended for bone marrow suppression and during concomitant administration with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital).

© 2021 Regence. All rights reserved. dru137.18 Page 6 of 9 Use in Other Conditions - The current NCCN guidelines list dasatinib (Sprycel) as category 2A recommendation for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on imatinib, sunitinib (Sutent), and regorafenib (Stivarga) when the D842V mutation is present. [8] * There are no high-quality controlled trials evaluating dasatinib (Sprycel) in this condition. - A small, preliminary trial studied dasatinib (Sprycel) in patients with Philadelphia chromosome- negative (Ph-) chronic myeloproliferative disorders, including systemic mastocytosis (n = 33), acute myeloid leukemia (n = 9) and primary myelofibrosis (n = 9). [9] Larger, well-controlled trials are necessary before a clinical benefit can be established in these populations. - Several small, uncontrolled, preliminary trials have been done in patients with non-small cell lung cancer and advanced prostate cancer. [10-12] Larger, well-controlled studies are necessary to determine if dasatinib (Sprycel) provides clinical benefit in these conditions. - Additionally, dasatinib (Sprycel) is being studied in other solid tumors, malignant melanoma, and multiple myeloma. [13] However, results from these studies have not been reported.

Appendix 1: Tyrosine Kinase Inhibitors (TKIs) Used in the Treatment of Chronic Myelogenous Leukemia (CML) [listed in alphabetical order]

Bosutinib (Bosulif) [PA required]

Dasatinib (Sprycel) [second generation TKI] [PA required]

Imatinib (Gleevec) [first generation TKI]

Nilotinib (Tasigna) [second generation TKI] [PA required]

Ponatinib (Iclusig) [PA required]

Appendix 2: Treatment Options Based on BCR-ABL KD Mutation Status [6]

Mutation Treatment Recommendation

T315I HSCT, clinical trial, ponatinib (Iclusig), or omacetaxine (Synribo)

V299L, T315A, F317L/V/I/C nilotinib (Tasigna)

Y253H, E255K/V, F359V/C/I dasatinib (Sprycel)

E255K/V, Y253H, T315A, bosutinib (Bosulif) F317L/V/I/C, F359V/C/I

Bosulif, bosutinib, Medication Policy Manual, Policy No. dru285

Iclusig, ponatinib, Medication Policy Manual, Policy No. dru292

Tasigna, nilotinib, Medication Policy Manual, Policy No. dru151

Sutent, sunitinib, Medication Policy Manual, Policy No. dru128

Cycle Management Program, Medication Policy Manual, Policy No. dru404

Codes Number Description

HCPCS J8999 Oral chemotherapeutic drug, not otherwise classified

References 1. Kantarjian, H, Shah, NP, Hochhaus, A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. PMID: 20525995 2. Saglio, G, Kim, DW, Issaragrisil, S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. PMID: 20525993 3. Kantarjian, HM, Hochhaus, A, Saglio, G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. PMID: 21856226 4. NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia v.2.2021 (Updated August 28, 2020). [cited; Available from: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf 5. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2018. 6. Talpaz, M, Shah, NP, Kantarjian, H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. PMID: 16775234 7. NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia v.1.2020. [Updated January 15, 2020]. [cited 9/12/2020]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf 8. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma v.2.2020 [Updated May 28, 2020]. [cited 8/3/2020]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf 9. Verstovsek, S, Tefferi, A, Cortes, J, et al. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008 Jun 15;14(12):3906-15. PMID: 18559612 10. Haura, EB, Tanvetyanon, T, Chiappori, A, et al. Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer. J Clin Oncol. 2010 Mar 10;28(8):1387-94. PMID: 20142592

© 2021 Regence. All rights reserved. dru137.18 Page 8 of 9 11. Miller, AA, Pang, H, Hodgson, L, et al. A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010 Mar;5(3):380-4. PMID: 20087228 12. Yu, EY, Wilding, G, Posadas, E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009 Dec 1;15(23):7421-8. PMID: 19920114 13. National Institutes of Health, Clinicaltrials.gov [website]. [cited periodically]; Available from: www.clinicaltrials.gov

Revision History

Revision Date Revision Summary

10/28/2020 Updated policy with standard continuation of care (COT) language (no change to policy intent).

10/23/2019 No criteria changes with this annual update.

10/25/2018 • Removed documentation requirements from policy.

06/15/2018 • Add step therapy with another TKI for chronic phase CML. The use of dasatinib for previously untreated CML is not medically necessary. • The authorization period was clarified to state that dasatinib can be covered in the stated doses ‘until disease progression’. This was always the intent of the policy, but is now explicitly stated.

12/08/2017 Removed step therapy with nilotinib (Tasigna) when dasatinib (Sprycel) is used for CML in the chronic phase.

01/13/2017 No criteria changes with this annual update.

01/08/2016 Gastrointestinal stromal tumor designated as investigational use

Drug names identified in this policy are the trademarks of their respective owners.