Bosutinib As Second-Line Therapy in Patients (Pts) with Chronic Phase Chronic Myeloid Leukemia (CP CML) Resistant or Intolerant to Prior Imatinib: 60-Month Update of a Phase 1/2 Study
Authors: Brümmendorf Tim H. , Cortes Jorge E. , Khoury H. Jean , Kantarjian Hagop M. , Kim Dong-Wook , Schafhausen Philippe , Zeremski Mirjana , Shapiro Mark , Leip Eric , Gambacorti-Passerini Carlo , Lipton Jeffrey H. 
Published: October 2019

Abstract

The dual Src/Abl tyrosine kinase inhibitor (TKI) bosutinib (BOS) is indicated for adults with Ph+ CML resistant/intolerant to prior therapy. This long-term update of an ongoing open-label, phase 1/2 study evaluated 2nd-line BOS in CP CML pts aged ≥18 y following imatinib resistance (IM-R) or intolerance (IM-I).
This analysis included IM-R (n=195) or IM-I (n=89) CP CML pts receiving BOS starting at 500 mg/d. Median (range) age was 53 (18–91) y; time from CML diagnosis was 3.7 (0.1–15.1) y; treatment duration was 25.6 (0.2-94.9) mo; and follow-up duration was 45.1 (0.6–94.9) mo. BOS dose was escalated to 600 mg/d in 13% of pts. For the last enrolled pt, time from first BOS dose was ≥60 mo (41% of pts still receiving BOS at 5 y).
Major cytogenetic responses (MCyR, including complete cytogenetic response [CCyR]) newly attained (54% of pts) or maintained from baseline (6%) are summarized (Table).
In 224 pts assessed at baseline, 42 unique BCR-ABL mutations occurred in 78 (35%) pts, including 12 with >1 mutation; common mutations were T315I and F359V (n=9 each), M351T (n=8), G250E and M244V (n=6 each). MCyR rate was similar in pts without mutations (58%) and with 1 single mutation (61%); 45% of pts with >1 mutation and 22% of pts with T315I had MCyR. During therapy, of 92 pts evaluable for mutations, 20 acquired a new BCR-ABL mutation (T315I, n=9; V299L, n=4; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n=1 each [all in different pts]; 11 of these 20 pts had baseline mutations); 19 of these 20 pts discontinued due to either progressive disease (PD; n=12), lack of efficacy (n=6), or death (n=1).
Cumulative incidence of on-treatment PD (ie, transformation to accelerated-/blast-phase [AP/BP] CML, increasing white blood cell count, loss of confirmed complete hematologic response or unconfirmed MCyR) or death* at 5 y was 19% (Table); 40% of pts discontinued BOS prior to 5 y without an event. Kaplan-Meier (KM)–estimated overall survival (OS) at 2 y was 91% (Table; per protocol, pts were followed for OS for only 2 y after BOS discontinuation). Cumulative incidence of on-treatment transformation to AP/BP CML* at 5 y was 4%; 55% of pts discontinued BOS prior to 5 y without transformation. In 12 pts with transformations, 6 were to AP and 6 were to BP. There was limited follow-up of patients after treatment discontinuation.
Overall, 168 (59%) pts discontinued BOS within 5 y, commonly due to adverse event (AE; n=64 [23%]) or disease progression (n=47 [17%]) as primary reason for discontinuation. Forty-four (16%) deaths occurred on study, 10 within 30 d of last BOS dose. Most deaths were due to disease progression (n=26; IM-R: 23 pts; IM-I: 3 pts) or AE unrelated to BOS (n=16; IM-R: 14 pts; IM-I: 2 pts); 2 were due to unknown causes. No deaths were reported as BOS-related.
The most frequent (≥30%) hematologic treatment-emergent AE (TEAE; all grade/grade 3/4) was thrombocytopenia (42%/26%); common non-hematologic TEAEs were diarrhea (86%/10%), nausea (47%/1%), vomiting (37%/4%), and rash (36%/9%). Cardiac events (MedDRA system organ classification of cardiac disorders) occurred in 17% of pts (8% grade 3/4). Toxicities were managed by ≥1 dose delay in 73% of pts (IM-R: 67%; IM-I: 85%) and by ≥1 dose reduction in 50% of pts (IM-R: 46%; IM-I: 58%). AEs led to BOS discontinuation in 68 (24%) pts (IM-R: n=32 [16%]; IM-I: n=36 [40%]); the most common reason was thrombocytopenia, in 16 (6%) pts (IM-R: n=6 [3%]; IM-I: n=10 [11%]). Overall incidence of newly occurring TEAEs for pts on treatment during specific years was 100% (n=283/284) in year 1 (y1), 74% (n=139/189) in y2, 68% (n=100/148) in y3, 52% (n=68/130) in y4, and 57% (n=70/124) in y5. Discontinuations due to AEs were most common in y1 (18% [n=50/284]); 8, 3, 3, and 1 pts discontinued due to AEs in y2, y3, y4, and y5.
After ≥60 mo of follow-up, BOS shows efficacy and manageable toxicity in CP CML pts following IM-R or IM-I.
Table IM-R (n=195) IM-I (n=89) Total (n=284) Evaluable,a n 182 80 262 MCyR, n (%) 107 (59) 49 (61) 156 (60) CCyR , n (%) 88 (48) 42 (53) 130 (50) Probability of maintaining MCyR at 5 yb 67% 80% 71% Probability of maintaining CCyR at 5 yb 72% 68% 71% Treated, n 195 89 284 PD/death at 5 yc 23% 10% 19% OS at 2 yb 88% 98% 91% aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint; responses newly attained or maintained from baseline. bBased on KM estimates. cBased on cumulative incidence, *adjusting for competing risk of treatment discontinuation without event.

Disclosures
Brümmendorf: Patent on the use of imatinib and hypusination inhibitors: Patent on the use of imatinib and hypusination inhibitors Patents & Royalties; Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:Pfizer Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Zeremski:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.