S884 COMBINATION OF ASCIMINIB PLUS NILOTINIB (NIL) OR DASATINIB (DAS) IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA (CML): RESULTS FROM A PHASE 1 STUDY

Background: Asciminib is a potent and specific BCR‐ABL1 inhibitor that binds to the myristoyl pocket of ABL1. Preclinical data suggest cooperativity when asciminib is combined with ATP‐competitive TKIs. In a mouse xenograft model, asciminib plus NIL prevented emergence of resistance mutations and provided durable complete tumor regression that persisted for >3 mo after stopping treatment. We report results from pts treated with asciminib plus NIL or DAS in a phase 1 study (NCT02081378). Aims: To assess treatment with asciminib+NIL or asciminib+DAS in CML pts. Methods: Pts with CML in chronic phase (CP) or accelerated phase (AP) and resistance or intolerance to ≥2 prior TKIs were eligible; pts with uncontrolled CV conditions were excluded. Pts were assigned (based prior intolerance of NIL or DAS) to treatment in continuous 28‐d cycles. For asciminib+NIL, pts received asciminib 20 or 40 mg BID combined with NIL 300 mg BID. For asciminib+DAS, pts received asciminib 40 mg BID or 80 mg QD combined with DAS 100 mg QD. Data cut‐off date: 15 Jul 2018. Results: 17 pts each enrolled in the asciminib+NIL and asciminib+DAS cohorts; 1 pt in each cohort had CML‐AP. Pt characteristics are shown in the Table. At the data cut‐off, 9 (53%) and 14 (82%) pts with asciminib+NIL and asciminib+DAS, respectively, were ongoing. Reasons for discontinuation were pt/physician decision (n = 4), progressive disease (n = 3), and AEs (n = 1; myelodysplastic syndrome and decreased neutrophil count) with asciminib+NIL, and physician decision (n = 2) and AEs (n = 1; peripheral sensory neuropathy and fluid retention) with asciminib+DAS. With asciminib+NIL, rates of any‐grade and grade 3/4 drug‐related AEs were 82% (14/17) and 53% (9/17), respectively; most common any‐grade AEs were myalgia (35%), increased lipase (29%), and increased amylase, fatigue and pruritus (24% each). 1 pt had a dose‐limiting toxicity (DLT) of maculopapular rash during cycle 1. With asciminib+DAS, rates of any‐grade and grade 3/4 drug‐related AEs were 88% (15/17) and 29% (5/17), respectively; most common any‐grade AEs were increased lipase (35%) and diarrhea, headache and nausea (18% each). 1 pt had a DLT of increased lipase during cycle 1. Peripheral arterial occlusive disease was reported in 1 pt with asciminib 40 mg BID + NIL; pt had a history of CV disease. 2 pts each with asciminib+NIL and asciminib+DAS had pleural effusion. 1 pt in asciminib+NIL cohort progressed to AP; none progressed to blast phase. There were no cases of clinical pancreatitis or on‐treatment deaths in either cohort. Drug‐drug interaction (DDI) was observed between asciminib and NIL: asciminib AUC and C max increased by ≈2‐fold when combined with NIL 300 mg BID, whereas the PK of NIL appeared unaffected by asciminib. No DDI was observed between asciminib and DAS. Among pts without BCR‐ABL1 IS <1% at baseline (BL), 6/14 (43%) and 5/9 (56%) pts in the asciminib+NIL and asciminib+DAS cohorts, respectively, achieved this response by 48 wks. Among evaluable pts without major molecular response (MMR; BCR‐ABL1 IS ≤0.1%) at BL, 4/13 (31%) and 5/14 (36%) pts, respectively, achieved MMR by 48 wks. In pts with MMR at BL, no MMR loss was observed. 2/14 (14%) and 1/14 (7%) pts also achieved MR 4.5 ( BCR‐ABL1 IS ≤0.0032%) by 48 wks with asciminib+NIL and asciminib+DAS, respectively. Summary/Conclusion: Asciminib combined with NIL or DAS showed promising preliminary efficacy and a good safety profile in these heavily pretreated CML pts. Based on PK, safety and preliminary efficacy data, these reported combinations may be further explored in clinical trials.