Summary of Key AML Abstracts Presented at the European Hematology Association (EHA) June 22-25, 2017 Madrid, Spain

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1 Summary of Key AML Abstracts Presented at the European Hematology Association (EHA) June 22-25, 2017 Madrid, Spain EHA 2017 ANNUAL MEETING: ABSTRACT SEARCH PAGE: DefeatAML had attended the following presentations during the 2017 EHA Annual Meeting. Please consult the EHA webpage above for a SEARCH of full list of AML abstracts. (Listing does not imply any endorsement of the investigational products cited or not cited) A. First-Line AML Abstract: S472 Presentation during EHA22: On Saturday, June 24, 2017 from 16:15-16:30 SAFETY AND EFFICACY OF VENETOCLAX (VEN) IN COMBINATION WITH DECITABINE OR AZACITIDINE IN TREATMENT-NAIVE, ELDERLY PATIENTS ( 65 YEARS) WITH ACUTE MYELOID LEUKEMIA (AML) K. Pratz et al Background Newly diagnosed patients (pts) with AML aged 65 years and ineligible for standard induction therapy have limited treatment options, and low overall survival. VEN is an orally bioavailable, selective BCL-2 inhibitor that has displayed single-agent activity in pts with relapsed/refractory AML. VEN at escalating doses combined with hypomethylating agents (HMAs) has demonstrated antileukemic activity, with an overall response rate (ORR) including complete remission [CR], and CR with incomplete marrow recovery of 60%. Combining VEN with HMAs, such as decitabine (DEC) or azacitidine (AZA), may provide a novel low-intensity approach for treating AML. Preliminary results from the expansion stage of a phase 1b trial comparing 2 doses of VEN plus either DEC or AZA (NCT ) are reported. Aims To evaluate the safety and efficacy of VEN at 400-mg vs 800-mg doses plus DEC or AZA. Methods

2 This open-label, nonrandomized, two-stage phase 1b study evaluated the safety and efficacy of VEN plus DEC or AZA in treatment-naive pts 65 years with AML. Eligibility included: ECOG PS 2; ineligible for standard induction therapy; intermediate- or poor-risk karyotype. Pts received DEC (Arm D, 20 mg/m2/day [d]; intravenous [IV]) on d 1 5, or AZA (Arm E, 75 mg/m2/d; subcutaneous or IV) on d 1 7 of each 28-d cycle (C) in combination with once-daily oral VEN. The dose-expansion stage consisted of 2 VEN dose cohorts (continuous 400-mg and interrupted 800-mg dosing) in each arm (D1, D2, E1, and E2, respectively) to determine optimal dose. Tumor lysis syndrome (TLS) prophylaxis was administered in C1 to all pts during VEN dose ramp-up until final dose was reached. All pts provided informed consent. Results As of 13/09/16, 100 pts were enrolled in the expansion stage: 25 pts in each arm. Overall, 61% pts were male; 59% had ECOG PS 1 and 15% ECOG PS 2; mean age was 73.9 (range 65 86); 53% had adverse karyotype; and 22% had secondary AML. Median time on study was 6 (4 9), 6 (0.2 9), 5 (0.5 9), and 4 (1 8) mo for arms D1, D2, E1, and E2, respectively. The incidence of adverse events (AEs) was generally comparable between the 4 arms. Overall, the most common treatment-emergent AEs (TEAEs; in 30% of pts) were nausea (59%), diarrhea (42%), febrile neutropenia (FN; 41%), constipation (39%), fatigue, and decreased white blood cell count (31% each). The most frequent grade 3/4 TEAE and serious AE was FN (41% and 29%, respectively). No TLS was observed. Overall, 29 pts discontinued the study for 1 reason, including progressive disease (PD) per protocol (n=10), other (n=10; 9/10 proceeded to stem cell transplantation) and AEs not related to progression (n=10). A total of 16 deaths occurred; 12 pts died within 30 d of initiating VEN and HMA due to AEs (n=12) and PD (n=1). The ORR was 68%, with rates of 76% (19/25), 71% (17/24), 68% (17/25), and 60% (15/25) observed in arms D1, D2, E1, and E2, respectively. Median follow-up time of 5.4 mos. Conclusion Overall, the safety profile was favorable when combining VEN at either dose with DEC or AZA in treatment-naive elderly AML pts. Promising activity with high ORRs was observed at the lower 400-mg VEN dose in both HMA arms. A Phase 3 study of VEN plus AZA is planned.

3 Abstract: S473 Presentation during EHA22: On Saturday, June 24, 2017 from 16:30-16:45 UPDATED SAFETY AND EFFICACY RESULTS OF PHASE 1/2 STUDY OF VENETOCLAX PLUS LOW- DOSE CYTARABINE IN TREATMENT-NAÏVE ACUTE MYELOID LEUKEMIA PATIENTS AGED 65 YEARS AND UNFIT FOR STANDARD INDUCTION THERAPY AH Wei et al Background Incidence of acute myeloid leukemia (AML) increases with age, and patients (pts) 65 years have a poor prognosis, with 5-year survival rates of <10%. Treatment with low-dose cytarabine (LDAC) in this population results in modest complete remission (CR)/CR with incomplete blood count recovery (CRi) rates of 11 19% and median survival of 5-6 months. Venetoclax (VEN), an orally bioavailable, potent, selective BCL-2 inhibitor, has shown singleagent activity in heavily pretreated pts with relapsed/refractory AML (Konopleva et al 2016). In combination with LDAC, the recommended phase 2 dose (RP2D) of VEN is 600 mg QD (Lin et al, ASCO 2016); preliminary data show the combination is tolerable and exhibits significant and durable activity in older AML pts ineligible to receive intensive induction chemotherapy (Wei et al, ASH 2016). Updated safety and efficacy data from the RP2D 600-mg dose cohorts of this study (NCT ) are presented. Aims Evaluate the safety and efficacy of VEN+LDAC in older pts with untreated AML. Methods In this open-label phase 1/2 study, pts 65 years with untreated AML, ineligible for standard induction chemotherapy, with an ECOG performance status of 0 2 received oral VEN QD on days (d) 1 28 and subcutaneous LDAC 20 mg/m2 QD on d 1 10 of each 28-d cycle. VEN target dose evaluation followed a 3+3 design, ranging from mg; 18 pts were enrolled and the RP2D was established as 600 mg. Safety and efficacy of VEN at RP2D were evaluated in the expansion phase. All pts were hospitalized and received prophylaxis before a dose rampup of VEN during cycle 1 to mitigate the risk of tumor lysis syndrome (TLS). Adverse events (AEs) were graded by NCI CTCAE V4.0. Pts enrolled as of May 2016 are included in this analysis; data cutoff was August All pts provided informed consent. Results In total, 61 pts, including 8 from phase 1, were treated at the RP2D of 600 mg (median age 74 years; ECOG %; adverse karyotypes 31%; secondary AML 44%; prior hypomethylating agent [HMA] 28%). AEs (all grade; 30% pts; excluding cytopenias) were nausea (72%), hypokalemia (46%), diarrhea (44%), fatigue (43%), and decreased appetite (41%). Grade 3/4 AEs ( 10% pts) were febrile neutropenia (34%), hypokalemia (15%), hypophosphatemia

4 (13%), and hypertension (10%). No pts had clinical TLS; 1 pt had laboratory TLS, which was managed. The 30-d and 60-d mortality rates were 3% and 15%, respectively. The CR/CRi rate was 54% (33/61; 21% CR and 33% CRi). The overall response rate (ORR; CR+CRi+partial remission) was 61% (37/61). VEN+LDAC was shown to be active across a wide range of cytogenetic mutations and pt profiles (ORR: 70% in pts 75 years; 52% in secondary AML; 47% in pts with adverse karyotypes; 53% in pts with prior HMA). Among response-evaluable pts, those achieving an objective response have longer survival than pts who do not achieve an objective response. Conclusion VEN (RP2D 600 mg) and LDAC exhibited an acceptable safety profile and durable efficacy in pts aged 65 years with untreated AML who are ineligible for or unable to receive intensive induction chemotherapy. ORR highly correlated with overall survival, with better survival observed in responders compared with nonresponders. A planned phase 3 randomized trial has commenced. B. Consolidation and Relapsed/Refractory AML Abstract: S471 Presentation during EHA22: On Saturday, June 24, 2017 from 16:00-16:15 ENASIDENIB (AG-221) IN MUTANT-IDH2 RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (R/R AML): RESULTS OF A PHASE 1 DOSE-ESCALATION AND EXPANSION STUDY EM Stein et al Background Recurrent mutations in isocitrate dehydrogenase 2 (midh2) occur in ~12% of AML patients (pts). midh2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of midh2 proteins. Differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib. In preclinical studies, bone marrow blasts from pts with midh2 AML exposed to enasidenib ex vivo were shown to produce mature, fully functioning neutrophils with conserved midh2 allele frequency, indicating differentiation of mature cells from the midh2 blasts (Yen et al, Cancer Discov, 2017). Additionally, no apoptosis was observed in midh2-r140 erythroleukemia (TF-1) cells treated with enasidenib for 7 days in vitro. Aims Evaluate the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) profiles, safety, and clinical activity of enasidenib in pts with midh2 advanced myeloid malignancies.

5 Methods This phase 1/2 study included pts aged 18 years (yrs) with midh2 WHO-defined AML, or with midh2 MDS with refractory anemia with excess blasts, and ECOG PS scores 2. Pts were relapsed or refractory (R/R) to prior anti-cancer therapy, or had untreated AML if aged 60 years and not eligible for standard-of-care treatment (Tx). Safety for all pts and clinical efficacy in the largest pt subgroup, those with R/R AML, from the phase 1 dose-escalation and expansion phases are reported. Results In all, 239 pts received enasidenib. Median age was 70 yrs. In the dose-escalation phase (n=113), pts received daily enasidenib doses of mg. The MTD was not reached. Median 2HG reductions from baseline at cycle 2 day 1 were 92%, 90%, and 93% for pts receiving <100mg, 100mg, and >100mg/day, respectively. Enasidenib 100mg QD was chosen for the expansion phase (n=126) based on PK/PD profiles and demonstrated efficacy. Median number of enasidenib cycles was 5 (range 1 25). Grade 3-4 investigator-reported Tx-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (IDH-DS; ie, retinoic acid syndrome) (7%). Of 176 R/R AML pts, 94 (53%) had received 2 prior AMLdirected Tx. Overall response rate (ORR; complete remission [CR] + CR with incomplete hematologic recovery + morphologic leukemia-free state + partial remission) in R/R AML pts was 40.3%, including 34 pts (19.3%) who attained CR (Table). Median time to 1st response was 1.9 months (mos); 87.3% of responding pts attained a 1st response by cycle 5. Median response duration was 5.8 mos. Of pts who achieved CR, 7 pts (21%) did so by cycle 3, 23 (68%) by cycle 5, and 28 (82%) by cycle 7. Median duration of CR was 8.8 mos. ORR with enasidenib 100mg/day was 38.5% (Table). Seventeen pts (11%) proceeded to stem cell transplant. Response was associated with cellular differentiation, typically with no evidence of aplasia. Median overall survival (OS) of R/R AML pts was 9.3 mos. For pts who attained CR, OS was 19.7 mos. Pts who had received 2 prior AML Tx had a median OS of 8.0 mos.

6 Conclusion Enasidenib was well tolerated, induced CRs in R/R AML pts, and was associated with OS of >9 mos in pts who had failed prior AML Tx. A randomized phase 3 study of enasidenib vs conventional care in older pts with late-stage R/R AML is ongoing (NCT ).

7 Abstract: S474 Presentation during EHA22: On Saturday, June 24, 2017 from 16:45-17:00 PHASE IB/II STUDY OF NIVOLUMAB IN COMBINATION WITH AZACYTIDINE (AZA) IN PATIENTS (PTS) WITH RELAPSED ACUTE MYELOID LEUKEMIA (AML) N. Daver et al Background Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, AACR 2016). AZA up-regulates PD-1 and interferon-gamma signaling in AML and the up-regulation of PD-1 has been associated with emergence of resistance to AZA (Yang et al., Leukemia 2013). Aims To assess the best response to Aza+Nivo at the end of 3 courses of combination therapy. Methods Pts were eligible if they had AML and failed prior therapy, had adequate performance status (ECOG 2), and organ function. The first six pts received AZA 75mg/m2 Days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated every 4-5 weeks indefinitely. Only one of six pts had a dose limiting toxicity (grade 3 pneumonitis) and this dose was RP2D. 60 additional pts have been treated at the RP2D. Results 66 pts with a median age of 71 years (range, 44-90), secondary AML (39%), poor risk cytogenetics (35%), median number of prior regimens 2 (range, 1-7) have been enrolled. All 66 pts had baseline next generation sequencing: TP53 (n=14), DNMT3A (n=12), ASXL1 (n=10), TET2 (N=9), and RAS (n=9), IDH2 (n=9), IDH1 (n=6), CEBPA (n=7). 63 pts are evaluable for response: 14 (22%) achieved complete remission (CR)/complete remission with insufficient recovery of counts (CRi) (3 CR, 11 CRi), 7 (11%) had hematologic improvement (HI), 13 (21%) had 50% BM blast reduction, 5 pts (8%) had stable disease >6 months, and 24 (38%) had progression. 3 pts are too early for response assessment (<3 courses). The median number of courses to CR/CRi/HI was 2 (range, 1-4+). The med OS among the CR/CRi patients was 15.3 months (range, ), HI pts was 9.7 months (range, ), and NR was 5.0 months (range, ). The 4- and 8-week mortality were 5% and 11%, respectively. The median OS for the 63 evaluable pts on Aza+Nivo compares favorably to historical median OS with AZA-based salvage protocols in similar pts treated at MDACC (P=0.10) (Fig 1A and Fig 1B) Grade 3/4 and Grade 2 immune toxicities were observed in 8 (12%) and 7 (11%) pts, respectively. The most common Grade 3/4 AEs on treatment included pneumonitis, colitis, nephritis, skin rash, and hypophysitis. One pt died from grade 4 pneumonitis/epiglottitis. In the remaining 14 cases the toxicities responded rapidly to steroids and 13 of these pts were successfully rechallenged with nivolumab. Time to onset of toxicities ranged from 4 days to 3.5 months.

8 Multicolor flow-cytometry studies and Mass-cytometry (CyTOF) studies are conducted by the Immunotherapy Platform on baseline and on-treatment BM aspirate (end of cycle 1, 2, 4, 8). Baseline and end of cycle (EOC) 1 and 2 BM was evaluated in 6 responders and 19 non-responders. Pts who achieved a response had a baseline higher live total CD3 (P=0.10), CD8+ T-cells (P=0.02), and lower live CD4+Foxp3+PD1+ T-regulatory (T-reg) cells (P=0.01) infiltrate in BM. Patients who had a response had progressive increase in BM CD3+ cells and BM CD8+ cells, with increased ICOS (activation) marker on BM CD4-effector cells at EOC 1 and EOC 2 as compared to those who had no response. The CTLA4 on CD8 T-cells went up in both responders and non-responders after PD1 based therapy. Conclusion Full dose AZA and nivolumab are tolerable and produce an encouraging response rate with durable responses in relapsed AML with poor risk features. Immune mediated toxicities occur and may be adequately managed with early recognition and systemic steroids. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML and suggest role for combination therapy. -end-