Bosutinib As Third-Line Therapy in Patients (Pts) with Chronic Phase Chronic Myeloid Leukemia (CP CML) Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 48-Month Update of a Phase 1/2 Study
Authors: Gambacorti-Passerini Carlo , Khoury H. Jean , Kantarjian Hagop M. , Lipton Jeffrey H. , Kim Dong-Wook , Schafhausen Philippe , Matczak Ewa M. , Leip Eric , Noonan Kay , Brümmendorf Tim H. , Cortes Jorge E. 
Published: October 2019

Abstract
Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This long-term update of an ongoing open-label, phase 1/2 study evaluated the efficacy and safety of BOS as 3rd-line therapy in CP CML pts after prior TKI failure.
Pts (n=119) were aged ≥18 y with prior imatinib (IM) failure plus dasatinib (D) resistance (D-R; n=38) or intolerance (D-I; n=50), nilotinib (N) resistance (N-R; n=26), or N-I or D-R/I + N-R/I (n=5) and received BOS starting at 500 mg/d. Median (range) age was 56 (20-79) y; time from CML diagnosis was 6.6 (0.6–18.3) y; follow-up duration was 31.1 (0.3–89.1) mo; and BOS treatment duration was 8.6 (0.2–87.7) mo. Escalation to BOS 600 mg/d occurred in 22 (19%) pts. For the last enrolled pt, time from first dose was ≥48 mo (24% still receiving BOS at 4 y).
Major cytogenetic response (MCyR) was newly attained or maintained from baseline by 33% and 7% of pts, respectively (32% attained/maintained complete cytogenetic response [CCyR]) (Table). Kaplan-Meier probability of maintaining MCyR or CCyR at 4 y was 69% and 54%, respectively.
At baseline, 95 pts had known mutation status. Twenty unique BCR-ABL mutations occurred in 39 (41%) pts, including 11 with >1 mutation; common mutations were F317L (n=8), T315I (n=7), G250E, and Y253H (n=6 each). MCyR rate was similar in pts without mutations (37%) and pts with 1 mutation (38%); 27% of pts with >1 mutation and 14% of pts with T315I had MCyR. Of 57 pts assessed for mutations at end of treatment, 13 had new mutations (V299L, n=6; T315I, n=3; G250E, n=2 [1 pt also had a new V299L mutation]; F359C, L248V, and L273M, n=1 each; 10 pts had prior mutation); 11/13 pts with new mutations discontinued BOS due to progressive disease (PD) or lack of efficacy.
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 4 y was 24%; 52% of pts discontinued before 4 y without an event. Overall survival (OS) at 2 y was 84% (Table; pts followed for OS for only 2 y after BOS discontinuation]). Cumulative incidence of on-treatment transformation* at 4 y was 4%; 71% discontinued before 4 y without transformation. No pt transformed to BP. There was limited follow-up of patients after treatment discontinuation.
Overall, 90 (76%) pts discontinued treatment within 4 y, most commonly due to adverse event (AE; n=28 [24%]) as primary reason for treatment discontinuation. Twenty-six (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=12) or AE (n=11; 1 related to BOS); 3 had unknown cause.
Non-hematologic treatment-emergent AEs (TEAEs) commonly included (all grades; grade 3/4) diarrhea (83%; 9%), nausea (48%; 1%), and vomiting (38%; 1%); hematologic toxicities included thrombocytopenia (39%; 26%), neutropenia (21%; 16%), and anemia (20%; 7%). Cardiac events (MedDRA system organ classification of cardiac disorders) occurred in 18% of pts (8% grade 3/4). Overall incidence of newly occurring TEAEs for pts on treatment during specific years was 99% in year 1 (y1; n=118/119), 74% in y2 (n=37/50), 64% in y3 (n=25/39), and 72% in y4 (n=23/32). The most common TEAEs were diarrhea in y1 (n=98), pleural effusion in y2 (n=6), abdominal pain in y3 (n=5), and pleural effusion in y4 (n=5). TEAEs were managed primarily by dose delays (66%) and dose reductions (50%). Discontinuations due to AEs were most common in y1 (19% [n=23/119]); 2, 2, and 3 pts discontinued due to AEs in y2, y3, and y4, respectively. The most common reason for discontinuation due to AE was thrombocytopenia (6%).
After ≥48 mo follow-up, third-line BOS therapy shows efficacy and manageable toxicity in CP CML pts. Table 1IM + D-R (n=38)IM + D-I (n=50)IM + N-R (n=26)IM + N-I orD-R/I+ N-R/I (n=5)Total (n=119)Evaluable,a n3645265112MCyR, n (%)14 (39)19 (42)10 (39)2 (40)45 (40)CCyR , n (%)8 (22)18 (40)8 (31)2 (40)36 (32)Probability of maintaining MCyR at 4 yb43%87%78%NR69%Probability of maintaining CCyR at 4 yb17%66%63%NR54%Treated, n3850265119PD/death at 4 yc24%16%35%NR24%OS at 2 yb80%83%92%NR84% NR=not reported (small sample size). aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint. bBased on KM estimates. cBased on cumulative incidence, *adjusting for competing risk of treatment discontinuation without event.

Disclosures
Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Kantarjian:Pfizer Inc: Research Funding. Lipton:Ariad: Equity Ownership, 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; 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. 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; Bristol-Myers Squibb: 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. Schafhausen:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria. Matczak:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Noonan:Pfizer Inc: Employment. Brümmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patent on the use of imatinib and hypusination inhibitors Patents & Royalties. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer Inc: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.