Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis

Efficacy and Safety of Midostaurin in Advanced Systemic MastocytosisT h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 374;26 nejm.org June 30, 20162530
From the Hematology Division, Stanford University School of Medicine–Stanford Cancer Institute, Stanford, CA (J.G.); Faculty of Medical Sciences, University Medical Cen- ter Groningen, University of Groningen, Groningen, the Netherlands (H.C.K.-N.); De- partment of Pathology, University of New Mexico, Albuquerque (T.I.G.); Mastocytosis Center, Brigham and Women’s Hospital, Boston (C.A.); Institute of Pathology, Ludwig- Maximilians-University Munich, Munich (K.S., H.-P.H.), Department of Dermatology and Venereology, University of Cologne, Cologne, and University of Luebeck, Luebeck (K.H.), and Department of Hematology and Oncol- ogy, University Hospital Mannheim of the University of Heidelberg, Mannheim (A.R.) — all in Germany; University of Paris Des- cartes, Institut Imagine INSERM Unité 1163 and Centre National de la Recherche Scienti- fique ERL8654, Centre de Reference des Mas- tocytoses, Paris (O.H.); Division of Hematol- ogy, Department of Internal Medicine, Ohio State University Comprehensive Cancer Cen- ter, Columbus (F.T.A.); Division of Hematol- ogy/Oncology, Abramson Cancer Center, Uni- versity of Pennsylvania, Philadelphia (E.H.); Myeloproliferative Neoplasms Program, Me- morial Sloan Kettering Cancer Center, New York (M.J.M.); Novartis Pharmaceuticals, East Hanover, NJ (D.W.S., E.J.S.); Novartis Pharma, Basel, Switzerland (M.V., A.H.L.); and the Department of Internal Medicine I, Division of Hematology and Hemostaseolo- gy, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna (P.V.). Address reprint requests to Dr. Gotlib at Stan- ford University School of Medicine–Stanford Cancer Institute, 875 Blake Wilbur Dr., Rm. 2324, Stanford, CA, 94305-5821, or at jason . gotlib@ stanford . edu.
N Engl J Med 2016;374:2530-41. DOI: 10.1056/NEJMoa1513098 Copyright © 2016 Massachusetts Medical Society.
BACKGROUND Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multi- kinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.
METHODS We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive sys- temic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.
RESULTS The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were −59% and −58%, respectively. The median overall survival was 28.7 months, and the median pro- gression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not esti- mated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.
CONCLUSIONS In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.)
A BS TR AC T
Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis Jason Gotlib, M.D., Hanneke C. Kluin-Nelemans, M.D., Ph.D.,
Tracy I. George, M.D., Cem Akin, M.D., Ph.D., Karl Sotlar, M.D., Olivier Hermine, M.D., Ph.D., Farrukh T. Awan, M.D., Elizabeth Hexner, M.D.,
Michael J. Mauro, M.D., David W. Sternberg, M.D., Ph.D., Matthieu Villeneuve, M.Sc., Alice Huntsman Labed, Ph.D.,
Eric J. Stanek, Pharm.D., Karin Hartmann, M.D., Hans-Peter Horny, M.D., Peter Valent, M.D., and Andreas Reiter, M.D.
Original Article
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Midostaurin in Advanced Systemic Mastocytosis
Systemic mastocytosis is a myeloid neoplasm that is caused by the accumula- tion of abnormal mast cells in the bone
marrow, liver, spleen, and skin.1 The KIT D816V mutation, which is detected in approximately 90% of patients, encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis.2,3
The World Health Organization (WHO) classi- fication of advanced systemic mastocytosis in- cludes aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm (also termed systemic mastocytosis with an associated hematologic non–mast-cell- lineage disease), and mast-cell leukemia (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).4 Symp- toms are caused by the release of vasoactive mediators and by organ damage related to infil- tration by neoplastic mast cells. Clinical find- ings that are related to organ damage from in- filtrating mast cells are referred to as C-findings4,5 and include cytopenias, liver-function abnormali- ties, hypoalbuminemia, weight loss, ascites, and osteolytic bone lesions.6 Aggressive systemic mastocytosis is characterized by at least one C-finding, whereas mast-cell leukemia is defined by a bone marrow aspirate with at least 20% mast cells.4,7 The associated hematologic neo- plasm is usually a myeloid disease such as an overlap myelodysplastic–myeloproliferative disor- der8 and often reflects multilineage involvement of KIT D816V.9 In systemic mastocytosis, elevated serum levels of tryptase correlate with the dis- ease burden.1,4
Advanced systemic mastocytosis is associated with a poor prognosis, with a median overall survival of 3.5 years in patients with aggressive systemic mastocytosis, 2 years in those with systemic mastocytosis with an associated hema- tologic neoplasm, and less than 6 months in those with mast-cell leukemia.10-12 Cladribine and interferon alfa6 have been associated with limited response rates and duration of response in most- ly small, retrospective studies.13-19 Although ima- tinib is approved by the Food and Drug Admin- istration for the treatment of aggressive systemic mastocytosis in patients without KIT D816V or with unknown KIT mutation status,20 this indi- cation is applicable to approximately 10% of patients.2,3 The orally active small-molecule agent midostaurin inhibits multiple kinases, including nonmutant and mutant KIT D816V21,22 and has
shown promising activity in an initial phase 2 trial involving patients with advanced systemic mastocytosis.23
We conducted an international, multicen- ter, single-group, open-label, phase 2 study (CPKC412D2201) of the efficacy, safety, and patient-reported outcomes of midostaurin treat- ment in patients with advanced systemic masto- cytosis.
Me thods
Patients
Adults (≥18 years of age) with aggressive sys- temic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, or mast-cell leukemia according to WHO criteria (Table S2 in the Supplementary Appendix) were eligible for inclusion in the study.24,25 All eligible patients had an Eastern Cooperative Oncology Group perfor- mance status of 0 to 3 (on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing tumor-associated disability) and adequate hepatic and renal function. Patients who had received three or more treatments for mastocytosis or who had a cardiac ejection frac- tion of less than 50% were excluded. Patients with at least one measurable C-finding (e.g., anemia or thrombocytopenia) that was consid- ered to be related to mastocytosis were eligible for the primary efficacy population; eligibility for inclusion in this population was adjudicated by the steering committee. Only measurable C-findings (not ascites or osteolytic lesions) were accepted. The intention-to-treat population included eligi- ble patients (the primary efficacy population) as well as ineligible patients, who could not be evaluated for response owing to a lack of mea- surable C-findings or to C-findings that were considered to be unrelated to mastocytosis. Ad- ditional eligibility criteria are listed in the Sup- plementary Appendix.
Study Oversight and Review
The study was designed by the sponsor (Novartis Pharmaceuticals) and by steering committee mem- bers. The full protocol (available at NEJM.org) was approved by the institutional review board or ethics committee at each participating institu- tion, and the study was conducted in accordance with the provisions of the Declaration of Hel- sinki. All the patients provided written informed consent. The sponsor collected and analyzed the
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
data in conjunction with the authors, who had full access to the data. The manuscript was writ- ten by the first, second, and last authors with support from ArticulateScience, funded by the sponsor. All the authors contributed to manu- script draft revisions and attest to the accuracy and completeness of the data and to the fidelity of this report to the study protocol.
The steering committee evaluated patient eli- gibility and performed post hoc adjudication of responses for each of the first 12 treatment cy- cles and every third cycle thereafter. Histopatho- logical findings were reviewed centrally by two of the academic authors, and KIT genotyping was performed by a third academic author.
Study Treatment and Design
Patients received open-label oral midostaurin at a dose of 100 mg twice daily in 4-week continu- ous cycles. Dose reductions to 50 mg twice daily or interruptions of no more than 21 days were allowed if toxic effects occurred (Table S3 in the Supplementary Appendix). Treatment continued until protocol-defined disease progression, death, the development of unacceptable toxic effects, or withdrawal of consent. Concurrent antineoplas- tic therapy was not allowed. Patients who were receiving glucocorticoid therapy (prednisone at a dose of >10 mg daily or the equivalent for ≥1 treatment cycle) were classified as unable to be evaluated for response.
The study used an adapted Fleming two-stage design (Fig. S1 in the Supplementary Appendix). The planned sample size for stage 1 was 40 pa- tients. If efficacy was declared, an extension phase would be initiated in which 40 additional patients would be enrolled. According to the study protocol, the primary analysis required at least 12 months of patient follow-up, which cor- responded to a data-cutoff date of July 9, 2013.
Study Outcomes
The primary outcome was best overall response that occurred in the first six 4-week treatment cycles and was maintained for at least 8 weeks (Tables S4 and S5 in the Supplementary Appen- dix). The primary outcome was adjudicated by the steering committee with the use of modified Valent response criteria1 and Cheson criteria for transfusions.26,27 The overall response rate repre- sents the percentage of patients whose best
overall response was a major response (defined as complete resolution of ≥1 C-finding) or a partial response (defined as >50% improvement in ≥1 C-finding [good partial response] or as >20% to ≤50% improvement in ≥1 C-finding [minor partial response]). Secondary outcomes included overall survival, progression-free sur- vival, duration of response, safety, and toxic ef- fects. Exploratory outcomes included patient- reported symptoms (assessed by means of the Memorial Symptom Assessment Scale)28 and quality of life (assessed by means of the Medical Outcomes Study 12-Item Short-Form Health Sur- vey [SF-12]).29,30 Details of these outcomes are provided in the Supplementary Appendix. Effi- cacy outcomes were based on the primary effi- cacy population unless otherwise indicated, whereas outcomes with respect to safety, toxic effects, and quality of life are reported for all patients.
Assessments
Eligibility was determined during the 30-day screening period. Responses and patient-reported outcomes were assessed at baseline, every cycle during the first 12 cycles, and every 3 cycles thereafter until disease progression, development of unacceptable toxic effects, or the end of the study, whichever occurred first. Imaging stud- ies and central evaluations of bone marrow specimens and KIT D816 mutations31 were per- formed at baseline, the end of cycles 3 or 6 (or both), every 6 cycles thereafter, and the end of treatment. Details on the frequency of other as- sessments, including measurement of serum tryptase levels, are provided in the Supplemen- tary Appendix. All patients were followed for safety or toxic effects (until 28 days after discon- tinuing the study drug) and for long-term sur- vival. Adverse events were classified and graded according to the National Cancer Institute Com- mon Terminology Criteria for Adverse Events, version 3.0.
Statistical Analysis
The null hypothesis that the overall response rate among enrolled patients would be no more than 30% was tested with the use of an exact binomial test at a one-sided overall nominal type I error rate of 0.025. The associated power to reject the null hypothesis was 84% overall and
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Midostaurin in Advanced Systemic Mastocytosis
68% at the end of stage 1 when a response rate of at least 50% was considered as the fixed alter- native hypothesis. The primary outcome is ex- pressed as the frequency of confirmed responses occurring in the first six cycles, along with the exact two-sided P value and the Clopper–Pearson 95% confidence interval. Overall survival, pro- gression-free survival, and duration of response were summarized with the use of Kaplan–Meier estimates and associated 95% confidence inter- vals. Laboratory values were summarized as the best percentage change from baseline.
R esult s
Patients
From January 2009 through July 2012, a total of 116 patients with advanced systemic mastocyto- sis were enrolled at 29 sites. Of these patients, 89 were eligible for inclusion in the primary ef- ficacy population, including 16 with aggressive systemic mastocytosis, 57 with systemic masto- cytosis with an associated hematologic neo- plasm, and 16 with mast-cell leukemia. Baseline characteristics are listed in Table 1, and Tables S6 and S7 in the Supplementary Appendix. The rea- sons that patients could not be evaluated for re- sponse were the absence of measurable C-find- ings (in 14 patients) and measurable C-findings that were considered to be unrelated to masto- cytosis (in 13 patients) (Fig. S2 in the Supple- mentary Appendix).
Efficacy Overall Response
At the end of stage 1 (40 patients), the response rate was 60% (95% confidence interval [CI], 43 to 75), which was significantly greater than the prespecified 30% threshold for rejection of the null hypothesis (P<0.001). The response rate for the primary efficacy population (stage 1 plus extension phase, 89 patients) was also 60% (95% CI, 49 to 70; P<0.001), with 45% having a major response and 15% having a partial response (Table 2). All the patients who could not be evaluated for response were classified as not having had a response; the overall response rate in the intention-to-treat population was 46% (53 of 116 patients). The median duration of treat- ment was 11.4 months (range, 0.3 to 51.5) in the intention-to-treat population; the median follow-
up was 26 months (range, 12 to 54). Among the 53 patients who had a response, the median duration of response was 24.1 months (95% CI, 10.8 to not estimated); 14 of these patients were continuing treatment at the time of data cutoff (Fig. S3 in the Supplementary Appendix). Major responses occurred primarily in the first 3 months and were maintained during the first year (Fig. S4 in the Supplementary Appendix).
The response rate was 75% (95% CI, 48 to 93) among patients with aggressive systemic masto- cytosis, 58% (95% CI, 44 to 71) among those with systemic mastocytosis with an associated hematologic neoplasm, and 50% (95% CI, 25 to 75) among those with mast-cell leukemia (Ta- ble 2). The median duration of response was not reached in patients with aggressive systemic mastocytosis (95% CI, 24.1 months to not esti- mated) or in patients with mast-cell leukemia (95% CI, 3.6 months to not estimated) and was 12.7 months (95% CI, 7.4 to 31.4) in patients with systemic mastocytosis with an associated hematologic neoplasm (Fig. S3 in the Supple- mentary Appendix). Of eight patients with mast- cell leukemia who had a response, seven had a major response; at the time of data cutoff, four major responses were ongoing for 8, 19, 33, and 49 months. Responses were observed in all sub- groups (response rates, 44 to 75%), including patients who were positive for KIT D816V (re- sponse rate, 63% [95% CI, 51 to 74]) and those with a negative or unknown status with respect to KIT D816V (response rate, 44% [95% CI, 20 to 70]) (Fig. S5 in the Supplementary Appendix).
Reversal of organ damage was observed across all types of C-findings (Table S8 in the Supplementary Appendix). Eight of 20 patients (40%) who had been dependent on red-cell transfusions at baseline became transfusion- independent, and 4 of 4 patients who had been dependent on platelet transfusions became trans- fusion-independent. Major or partial responses with respect to liver-function abnormalities were observed in 44% of the patients who had had elevated levels of bilirubin at baseline, 58% of those who had had elevated levels of alkaline phosphatase, and 50% of those who had had elevated levels of aspartate or alanine amino- transferase. Three of 12 patients (25%) who had had a medically documented loss of at least 10% of body weight within 6 months before study
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entry regained their lost weight; in this group, the median relative weight change during the first 12 cycles was 8.6% (range, −7.5 to 44.6), and the median absolute weight change was 5.5 kg (range, −7.0 to 25.9). Benefits with respect to weight and liver function were paralleled by normalization of albumin levels in 58% of the patients who had had hypoalbuminemia at base- line. In the 58 patients with at least two C-findings at baseline, 40% had responses with respect to at least two types of organ damage (Table S9 in the Supplementary Appendix).
Overall and Progression-free Survival The median overall survival was 28.7 months (95% CI, 18.1 to not estimated) in the primary efficacy population and 33.9 months (95% CI, 20.3 to 45.5) in the intention-to-treat popula- tion (Fig. 1A); the longer median overall sur- vival in the intention-to-treat population is due to the inclusion of the 27 patients who could not be evaluated for response. Among patients with aggressive systemic mastocytosis, the me- dian overall survival was not reached (95% CI, 28.7 months to not estimated); the median overall survival was 20.7 months (95% CI, 16.0 to 44.4) among patients with systemic masto- cytosis with an associated hematologic neoplasm and 9.4 months (95% CI, 7.5 to not estimated) among patients with mast-cell leukemia (Fig. S6A in the Supplementary Appendix). At the time of data cutoff, 48 patients were alive. The median progression-free survival was 14.1 months in the primary efficacy population (Fig. 1B) but was longer among patients with aggressive systemic mastocytosis (28.7 months) than among patients with systemic mastocytosis with an associated hematologic neoplasm (11.0 months) and patients with mast-cell leukemia (11.3 months) (Fig. S6B in the Supplementary Appendix).
In a post hoc analysis, the median overall survival was significantly longer among patients who had a response than among those who did not have…