Rigosertib + Azacitidine in Patients With Higher-Risk MDS New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. MDS, myelodysplastic syndrome. This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

Rigosertib + Azacitidine in MDS: Background Azacitidine, a hypomethylating agent, is the current SOC for high-risk MDS[1] Treatment failure and relapse are common and are associated with poor outcomes (median OS: 5.6 mos)[2] Rigosertib: novel anticancer agent with activity in MDS and AML[3] Targets Ras-binding domain, PI3K/AKT, Raf/PLK and other downstream pathways Phase I study of rigosertib + azacitidine suggested clinical activity of this regimen in MDS post-HMA failure with toxicity similar to single-agent azacitidine[4] Current phase II study evaluated safety and efficacy of rigosertib + azacitidine in pts with high-risk MDS or CMML[5] AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; HMA, hypomethylating agent; MDS, myelodysplastic syndrome; SOC, standard of care. 1. Silverman LR, et al. J Clin Oncol. 2006;24:3895-3903. 2. Prébet T, et al. J Clin Oncol. 2011;29:3322-3327. 3. Olnes MJ, et al. Leuk Res. 2012;36:982-989. 4. Navada SC, et al. ASH 2014. Abstract 3252. 5. Navada SC, et al. ASH 2015. Abstract 910. Slide credit: clinicaloptions.com

Rigosertib + Azacitidine in MDS: Study Design Open-label, multicenter phase II study[1] Endpoints: CR, PR, bone marrow response, improvement in neutrophil, platelet, and erythroid counts, safety and tolerability Bone marrow aspiration/biopsy: Wk 4, every 8 wks after 4-wk cycles Adult pts with MDS or CMML; IPSS int-1, int-2, or high; ECOG PS 0-2; adequate organ function; untreated or relapsed/failed prior HMA; no prior rigosertib (N = 37)* Rigosertib 560 mg qAM/280 mg qPM† PO Wk 1-3 + Azacitidine 75 mg mg/m2/day SC or IV Wk 2 No treatment Wk 4 *For this analysis, only MDS pts from phase I and II studies. †Recommended dose from previous phase II study.[2] ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMML, chronic myelomonocytic leukemia; ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agent; int, intermediate; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PS, performance status; ULN, upper limit of normal. 1. Navada SC, et al. ASH 2015. Abstract 910. 2. Navada SC, et al. ASH 2014. Abstract 3252. Slide credit: clinicaloptions.com

Rigosertib + Azacitidine in MDS: Baseline Characteristics MDS Pts (N = 37) Age, median yrs (range) 64 (25-85) Male, % 73 ECOG PS, % 1 2 24 3 Earlier HMA therapy, % Azacitidine Decitabine Both None 27 8 62 Characteristic MDS Pts (N = 37) IPSS risk group, % Intermediate-1 Intermediate-2 High 27 41 32 IPSS cytogenetic risk group, % Good Intermediate Poor Unknown 22 38 24 16 ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PS, performance status. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910.

Rigosertib + Azacitidine in MDS: Response Parameter MDS Pts (N = 37) Evaluable for response,* n 30 Duration of treatment, median mos (range) 4 (1 to ≥ 27) Overall response, % 77 Hematologic response,† % CR PR Bone marrow response SD PD 20 53 3 Hematologic improvement,† % Not evaluable, % 10 Too early to evaluate 13 Parameter MDS Pts (N = 37) Overall‡ (n = 26) Hematologic improvement, n (%) Any lineage‡ Erythroid Plt Neutrophil 13 (50) 11 (42) 12 (46) 7 (27) Bone Marrow CR (n = 16) Evaluable for response, n Too early to evaluate, n Plt + erythroid + neutrophil Plt + erythroid None 12 4 3 (25) 6 (50) IPSS, International Prognostic Scoring System; IWG, International Working Group; MDS, myelodysplastic syndrome; PD, progressive disease; Plt, platelet; SD, stable disease. ‡Includes pts with CR, hematologic improvement, and marrow CR. *Phase I, n = 8; phase II, n = 22. †Per IWG 2006. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910.

Rigosertib + Azacitidine in MDS: Response With Previous HMA Failure Hematologic response in 64% of pts with previous HMA failure vs 84% of HMA-naive pts Parameter MDS Pts (N = 11*) Prior HMA cycles, range 4-20 HMA, n Azacitidine Decitabine Both 8 2 1 Hematologic response,† % CR PR Bone marrow response BM response + HI SD PD 4 3 Trilineage hematologic improvement, % BM, bone marrow; HI, hematologic improvement; HMA, hypomethylating agent; IWG, International Working Group; MDS, myelodysplastic syndrome; PD, progressive disease; SD, stable disease. *Evaluable for response: phase I, n = 3; phase II, n = 8. †Per IWG 2006. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910.

Rigosertib + Azacitidine in MDS: Response by IPSS Subgroup Intermediate-1 Intermediate-2 High Overall (n = 10) HMA Failure (n = 3) (n = 15) (n = 7) (n = 12) (n = 4) CR, n 3 2 1 PR, n Marrow CR, n 6 8 Hematologic improvement, n 3* 1* SD, n 4 PD, n Not evaluable, n Response rate, % 75 67 62 40 100 HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PD, progressive disease; SD, stable disease. *Concurrent marrow CR and hematologic improvement. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910.

Rigosertib + Azacitidine in MDS: Bone Marrow Complete Remission Duration 102-005 101-001 102-006 102-011 101-010 Pts With Marrow CR No prior HMA 102-003 Prior HMA failure 101-011 Bone marrow response ongoing at last assessment* 101-013 101-022 HMA, hypomethylating agent; MDS, myelodysplastic syndrome; mCR, marrow complete response. 101-004 5 10 15 20 Months *12 pts excluded due to pending post-mCR bone marrow assessment. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910. Reproduced with permission.

Rigosertib + Azacitidine in MDS: Safety TEAE, % (N = 37) Cycle 1 Cycles ≥ 2 All Grade ≥ 3 Fatigue 27 -- 19 Nausea 16 Pyrexia 24 8 Thrombocytopenia 14 Constipation 22 Diarrhea 3 Cough Decreased appetite Dysuria Dizziness 11 Hematuria 5 Hypokalemia Injection-site rxn Neutropenia Tachycardia 3 fatal serious AEs, none considered treatment related Multiorgan failure, n = 1 Worsening of AML, n = 1 Sepsis, n = 1 AE, adverse event; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; rxn, reaction; TEAE, treatment-emergent AE. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910.

Rigosertib + Azacitidine in MDS: Conclusions Rigosertib + azacitidine is associated with ORR of 77% in pts with intermediate- and high-risk MDS 64% of pts with prior HMA failure responded to this therapy Combination is well-tolerated with low incidence of grade ≥ 3 AEs, except neutropenia and thrombocytopenia Toxicity profile similar to that of single-agent azacitidine No increase in toxicity reported with ≥ 2 cycles of treatment Authors conclude that this combination should continue to be investigated for the treatment of MDS HMA, hypomethylating agent; MDS, myelodysplastic syndrome. Slide credit: clinicaloptions.com Navada SC, et al. ASH 2015. Abstract 910.

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