The Impending D eath of Cancer: A Herculean Task Emerging Therapies 2016 - PowerPoint Presentation

The Impending Death of Cancer:A Herculean TaskEmerging Therapies 2016 Ruemu E. Birhiray, MDCEO, Indy Hematology Education, IncPartner, Hematology Oncology of Indiana, PC

herculean        adj  1    requiring tremendous effort, strength, etc.  a herculean task     2    sometimes cap   resembling Hercules in strength, courage, etc.  

Can·cer [ˈ kansər] DEFINITION astronomy a constellation (the Crab), said to represent a crab crushed under the foot of Hercules . It is most noted for the globular star cluster of Praesepe (the Beehive cluster). astrology the fourth sign of the zodiac, which the sun enters at the northern summer solstice (about June 21 ). medical the disease caused by an uncontrolled division of abnormal cells in a part of the body: a malignant growth or tumor resulting from the division of abnormal cells: synonyms : malignant growth · cancerous growth · tumor · [more] malignancy · carcinoma · sarcoma · melanoma · lymphoma · myeloma

Hydra A monstrous serpent with nine heads, the hydra attacked with poisonous venom. Nor was this beast easy prey, for one of the nine heads was immortal and therefore indestructible.

HYDRA: The Nine Headed MonsterA: NINE HEADED APPROACH:1. Naked monoclonal antibodies: Rituxan and Obinotuzumab2. Anti PD1/PDl-1 antibodies: Nivolumab (Optivo) and Pembrolizumab (Keytruda)3. Immunotoxins : Brentuzimab vedotin ( Adcetris ) 4. Tyrosine inhibitors : Cell signal interference ( Gleevec , Imbruvica , Zydelig)5. Bi-specific antibodies: Blinatumumab6. Immunomodulating drugs (iMIDS): Revlimid, Pomolyst, Thalidomide7. Proteosome inhibitors: Cell “garbage disposal inhibitors” (Velcade, Kyprolis, Ninlaro)8. Epigenetic targeting drugs: targeting external modifications to DNA that turn genes “on” or “off” (vorinostat, romidepsin , panabinostat, vidaza)9. CART-T cells: T cells re-engineered with viruses to target cancer associated proteins (antigens)B: THE ROCK: Chemotherapy: anti DNA toxinsBendamustine, CHOP, Cytarabine, Idarubicin etc

RATIFY (MIDOSTAURIN) TRIAL: Most Significant Advance in AML in 30 years ! FLT3 mutations present in 25% pts with AML, a poor prognostic indicator, with higher incidence of relapse FLT3 inhibitor midostaurin: Active against ITD-mutated leukemic cell lines Current study investigated midostaurin added to standard chemotherapy in FLT3-mutated AML 23% improvement in relapse

Acute LeukemiaCLARA: 20% improvement in relapse riskClofarabine plus Ara-C consolidation in intermediate and high risk AMLAPL: Arsenic Trioxide consolidation; safer and less relapse compared with Ara-C chemo

APL 2006: Arsenic trioxide plus idarubicin Evaluate roles of ATO and ATRA plus idarubicin instead of cytarabine plus idarubicin in consolidation for standard-risk APLMedian follow-up: 55 mos Deaths, n: AraC, 6; ATO, 7; ATRA, 5. RESULTS All 3 regimens associated with high CR rates with few relapses in pts with standard-risk APL 5-yr CIR, % (n): AraC 3.89 (4); ATO 0 (0); ATRA 7.41 (7); P = .03 Deaths, n: AraC, 6; ATO, 7; ATRA, 5.ATO + idarubicin regimen significantly reduced relapse rates vs those attained with non-ATO regimens Ades L, et al. ASH 2015. Abstract 451Mos Post-CR Cumulative Incidence of Relapse 0.00 0.05 0.10 0.15 0.20 0.25 0 20 40 60 80 ARA C + Ida arm ATO + Ida arm ATRA + Ida arm

AML: Elderly PatientsFrontline Venetoclax + HMAs in Elderly Pts With AML[1] Anti-death protein BCL-2 inhibitor venetoclax Combination of venetoclax with decitabine or azacitidine tolerable, similar safety profile in both treatment arms High overall response rate, (CR, CRi, and PR) - 76%. The CR and CRi rates were both 35%. Pracinostat + Azacitidine in Elderly Pts With Newly Diagnosed AML [2] Inhibitor of DNA unfolding protein: HDAC inhibitor pracinostat combined with azacitidinePreviously untreated AML, unsuitable for intensive chemotherapy, intermediate- or high-risk cytogenetics (N = 50)Complte response: 42%1. DiNardo C, et al. ASH 2015. Abstract 327.2. Garcia-Manero G, et al. ASH 2015. Abstract 453.

Frontline Mini-HCVD + Inotuzumab in Older ALL Patients(1) 1.Jabbour E, et al. ASH 2015. Abstract 83. 2. Park JH, et al. ASH 2015. Abstract 682. Inotuzumab ozogamicin humanized ant-CD22 monoclonal antibody linked with chemotherapy calicheamicin targeting leukemia cells, and released into cell, inducing cell death S tudy evaluated safety and efficacy of reduced-dose HCVD + inotuzumab as frontline therapy in older adult pts with ALL Complete response: 80%19-28z CAR T Cells in R/R B-Cell ALL(2)Engineered T cells targeting CD19 molecule on leukemia cells, used in relapsed or refractory B-cell ALLHigh complete response rate (82%), often without detectable disease with molecular studies associated with superior survival.Efficacy/safety of CART cells similar in patients treated with/without prior allogeniec stem cell tranmsplantation

Blinatumomab in ALL Blinatumomab: Immune match marker – brings immune cells to match cancer cells and kill cancer cells Targets T cells to CD19+ B cells – expressed on B cell Acute lymphoblastic leukemia ALCANTARA: Blinatumomab in Philadelphia Chromosome Positive ALL (1)Adults relapses andf refarcatory Acute lymphoblastic leukemia ; failed targeted drugs (N = 45) Complete response rate: 36% Response to therapy was independent of T315l mutation ( drug resistant mutation)100% of responders with ABL-kinase domain mutations had complete MRD responseMedian survival: 7.1 mosBlinatumomab in MRD-Positive BCP ALL(2)80% of MRD-positive BCP ALL pts achieved complete MRD response on blinatumomab therapyAchieving complete (vs incomplete) MRD response was associated with improved outcomesOS: 38.9 vs 12.5 mos; P = .002RFS: 23.6 vs 5.7 mos; P = .003DOR: NR vs 17.2 mos; P = .04967% of pts in CR following blinatumomab were able to receive allo -SCT 1 . Martinelli G, et al. ASH 2015. Abstract 679. 2. Gökbuget N, et al. ASH 2015. Abstract 680

GRAALL-R: Rituximab in ALL Multicenter, randomized, phase III study from 2005-2014[1]CD20 expressed in 30% to 40% of B-cell precursor ALL pts, associated with worse outcomes R ituximab added to chemotherapy demonstrated clinical benefit versus chemotherapy alone in adult patients with CD20+, Ph- BCP-ALLImproved event free survival: 65 vs 52% Prolonged overall survival in patients not receiving allo -transplant after first complete remission Well-tolerated safety profile in the rituximab group vs standard chemo aloneFurther study required to determine optimal rituximab dosing1. Maury S, et al. ASH 2015. Abstract 1. CD20+ Ph- tx-naïve BCP-ALL pts 18-59 yrs of age with ≥ 20% CD20+ blasts(N = 220)Standard Chemo + RituximabIV 375 mg/m2 16-18 infusions(n = 105) Standard Chemo w/out Rituximab (n = 104)

Chronic Myeloid LeukemiaPONATINIB Observational study of pooled data of TKI inhibitor ponatinib Ponatinib achieved significantly longer survival in patients with T315I+ Chronic Phase-CML compared with allo-transplant Survival was similar for ponatinib compared with allo-transplant in AP-CMLIn BP-CML and treatment-naïve Ph+ ALL, survival was longer for pts receiving allo -transplantRadotinib vs Imatinib in CML In phase III trial of 2 doses of radotinib vs imatinib in (Asian) pts with newly diagnosed chronic-phase CMLRadotinib associated with significantly higher molecular response rate Safety profiles different, with relatively low incidence of severe side-effectsHigher grade 3/4 laboratory abnormalities with radotinib1. Nicolini FE, et al. ASH 2015. Abstract 480. 2. Kwak J-Y, et al. ASH 2015. Abstract 476.

Myeloma: Proteosome Inhibition SWOG S0777: TRIPLE THRAPY in untreated MyelomaVelcade plus Revlimide/ dex (VRd) induction in untreated MM without a planned immediate ASCT after induction Significantly longer progression free survival and overall survival, Deeper responses, Acceptable safety profileENDEAVOR: Kd vs Vd in Relapsed/Refractory Myeloma Higher dose Kyprolis : Improved progression free survival and response rate For pts with 1 prior line, median PFS: 22.2 mos with Kd vs 10.1 mos with Vd; ORR: 82% for Kd vs 66% for Vd. For pts with ≥ 2 prior lines, median PFS: 14.9 mos with Kd vs 8.4 mos with Vd; ORR: 72% for Kd vs 60% for VdTOURMALINE-MM1: Ixazomib plus RD in Relapsed/Refractory MyelomaRandomized, double-blind, placebo-controlled, phase III trial: IRd resulted in fast/durable responses35% improvement in progression free survival vs Rd alone (20.7 mo vs. 14.6 mo) Significantly prolonged progression free survival vs placebo in high risk patients with del(17p) mutation Significantly improved time to preogression and response rates vs placebo Ixazomib plus Rd has tolerable safety profile with limited additional toxicity over Rd alone Durie B, et al. ASH 2015. Abstract 25 . Berenson J, et al. ASH 2015. Abstract 373

Relapsed/Refractory MyelomaARRAY-520-216 (1): Filanesib: novel, selective, orally active, inhibitor of Kinesin Spindle Protein (KSP), a protein that plays an essential role in mitotic spindle formation Randomized, open-label, multicenter phase II trial, with Kyprolis + filanesib PFS with kyprolis + filanesib : 2.8 mos vs 8.5 mos with high vs low AAGPhase I/II CHAMPION-1(2): Weekly Carfilzomib + Dex in Relapsedf/Refractory MyelomaORR: 77%; 63% in velcade-refractory ptstwice-weekly 20 mg/m2 and 36 mg/m2Tolerable safety profileRates of grade ≥ 3 AEs and discontinuations similar or lower than historic twice-weekly dosing1.Zonder JA, et al. ASH 2015. Abstract 728. 2. Berenson J, et al. ASH 2015. Abstract 373.

ASCT in Myeloma: IFM/DCFI 2009 Parameter RVD (n = 350) Transplantation (n = 350) Death, n 48 54 Cause of death, n (%) Myeloma Toxicity Secondary primary malignancies Other 40 (83) 4 (8) 1 (2) 3 (6) 35 (65) 9* (16) 6 (11) 4 (7) 4-yr survival, % 83 81 HR (95% CI); P value 1.2 (0.7-1.8); NS *Includes transplant-related death, n = 5. Attal M, et al. ASH 2015. Abstract 391. Triplet-regimen RVD with and without ASCT for frontline management ASCT superior to RVD in pts with untreated MM is associated with: 31% reduced risk of progression or death (P < .001) Improved TTP and rate of MRD negativity Similar, low rate of mortality

Myeloma ImmunotherapyDaratumumab plus Len/Dex 81% ORR in relapsed/refractoryMyelomaDaratumumab plus Pom/Dex shows active in heavily pretreated R/R MM: 71% ORR; 67% ORR in pts double-refractory to PI/IMiD ELOQUENT-2: 3-yr follow-up, pts receiving elotuzumab had 27% reduction in risk of progression or death vs Revlimid / dex alone BCMA-Targeted CAR T cells active - sCR in pt with a chemo-resistant MM. PD-1/PD-L-1 INHIBITION IN MYELOMA: Pembrolizumab in combination with len/dex: ORR - 76% Pembrolizumab in combination with pomalidomide/ dexamethasone shows promising activity in heavily pretreated relapsed/refractory MM: ORR - 60%

Follicular Lymphoma: Frontline Ibrutinib Plus Rituximab - Response Current study evaluates chemotherapy-free combination ibrutinib plus rituximab as frontline therapyORR of 82% (49 of 60); CR of 30%Median follow-up: 13.8 mos with a median time to best response of 2.7 mosMedian duration of ibrutinib treatment: 12.55 mos Fowler NH, et al. ASH 2015. Abstract 470. -100 -50 0 50 100 Improvement From Baseline SPD (Max %) CR PR N = 60 * *Response recorded in database is SD; unresolved query SD

Follicular Lymphoma: GADOLINEfficacy and safety of Obinutuzumab + Bendamustine followed by Obinutuzumab maintenance therapy in Rituximab -refractory Indolent NHL Investigator-assessed median PFS O-B vs B: 29.2 vs 14.0 mos , respectively; HR: 0.52 (95% CI: 0.39-0.70; P < .0001) No significant OS difference observed in interim analysisNo unanticipated adverse events reportedSehn LH, et al. ASCO 2015. Abstract LBA8502. . 0 0.2 0.4 0.6 0.8 1.0 Median follow-up: 21 mos O + B B Censored 0 6 12 18 24 30 36 42 48 54 Mos 14.9 Probability of PFS IRF-Assessed PFS Events, n (%) Median PFS, mos (95% CI) Stratified HR (95% CI) Log-rank P value O + B (n = 194) 71 (37) NR (22.5-NR) B (n = 202) 104 (51) 14.9 (12.8-16.6) 0.55 (0.40-0.74) .0001

Idelalisib ± Bendamustine /Rituximab in Relapsed/Refractory CLL Study 115 Bendamustine + rituximab is an established regimen for frontline and R/R CLL treatment Current study evaluated the combination of idelalisib and BR in R/R CLL: Results Decreased risk of disease progression and deathExtended progression free survivalIncreased overall survivalAdvantage consistent across patient subgroups, regardless of high-risk prognostic factors such as TP53/del(17p), IGHV mutation status, and refractory disease Zelenetz AD, et al. ASH 2015. Abstract LBA-5.

Study 115: PFS Zelenetz AD, et al. ASH 2015. Abstract LBA-5.   IDELA + BR Placebo + BR Median PFS, mos 23.1 11.1 HR (95% CI) 0.33 (0.24-0.45) P < .0001 Pts a t risk, n (events) IDELA + BR 207 (0) 154 (25) 74 (51) 27 (61) 6 (63) 1 (64) Placebo + BR 209 (0) 145 (46) 36 (111) 11 (126) 1 (131) 0 (132) Median follow-up time: 12 mos 100 80 60 40 20 0 PFS (%) 0 6 12 18 24 30 Mos IDELA + BR Placebo + BR

Study 115: OS Zelenetz AD, et al. ASH 2015. Abstract LBA-5. Pts at risk, n (events) IDELA + BR 207 (0) 181 (14) 104 (27) 52 (30) 13 (33) 1 (34) Placebo + BR 209 (0) 180 (20) 93 (35) 33 (47) 8 (51) 0 (51)   IDELA + BR Placebo +BR Median OS, mos NR NR HR (95% CI) 0.55 (0.36, 0.86) P = .008 (stratified) or .023 (unstratified) 100 80 60 40 20 0 Survival (%) 0 6 12 18 24 30 Mos IDELA + BR Placebo + BR

HELIOS: iBRRandomized, placebo-controlled phase III trial of ibrutinib in combination with BR in pts with previously treated CLL/SLL PFS benefit in all subgroups analyzed, including bulky disease, IgVH mutation status, no. prior therapies, presence of del11q OS results confounded by crossover of 90 (31%) pts in placebo arm to ibrutinib arm after PD Chanan -Khan AAA, et al. ASCO 2015. Abstract LBA7005. 100 80 60 40 20 0 PFS (%) 32 0 4 8 16 20 24 28 12 Mos Placebo + BR ( mPFS – 13.3 mos ) Ibrutinib + BR ( mPFS – NR) 100 80 60 40 20 0 OS (%) 32 0 4 8 16 20 24 28 12 Mos Placebo + BR Ibrutinib + BR PFS OS HR (95% CI): 0.203 (0.150-0.276) P < .0001 Median OS NR in either arm HR (95% CI): 0.628 (0.385-1.024) P = .0598 Risk of death reduced by 37% with ibrutinib despite crossover of 31% of patients on placebo arm No unexpected toxicities reported with the combination of ibrutinib plus BR

Relapsed/Refractory CLLVenetoclax and Rituximab in Refractory or Relapsed CLL(1) Venetoclax + rituximab highly activeOverall response rate: 86% with 47% complete responseNo detectable residual disease (MRD) in bone marrow of 55% of pts, and all MRD-negative pts maintained response at time of reporting 11 pts stopped venetoclax after achieving MRD negativity or CRNo MRD-negative pts progressed after stopping therapy Phase I/II Trial of Acalabrutinib (ACP-196) for Relapsed/Refractory CLL (2) First-in-human study of second-generation BTK inhibitor acalabrutinib . No major bleeding or atrial fibrillation reported in this studyAt median follow-up of 14.3 mos:Overall response: 95%Overall response in patients with del(17p) 100%Best responses over timeMa S, et al. ASH 2015. Abstract 830. 2. Byrd JC, et al. ASH 2015. Abstract 831

Hodgkin’s Lymphoma: Check Point InhibitorsKEYNOTE-013: PEMBROLIZUMAB (1)Pembrolizumab after brentuximab vedotin failure is safe and active in cHL Response rate: 65%Response rate in transplant failure subgroup: 73%Response rate in the transplant ineligibility subgroup: 44% Durattion of response ≥ 24 wks: 71%Pembrolizumab treatment increases circulating numbers of T and NK cells, upregulates TCR/IFN- γ signaling Nivolumab in R/R cHL : Phase I Dose Expansion Cohort (2) At a median follow-up of 101 wks, most patients have ongoing response1.Armand P, et al. ASH 2015. Abstract 584.2. Ansell S, et al. ASH 2015. Abstract 583.

PACE-MDS: Phase II Study in MDS(1) Inhibition of erythroid precursor maturation by excessive Smad2/3 signaling via the TGF-β pathway leads to anemiaLuspatercept (ACE-536): TGF-β ligand trap that suppresses Smad2/3 activationHematologic improvement and reduced transfusion in pts with lower-risk MDS Of 22 pts transfused prior to study, 11 (50%) achieved RBC-transfusion independence for ≥ 8 wksSustained Hb increases, prolonged transfusion independence seen with treatment up to 1 yr, safe, well tolerated Imetelstat in RARS and RARS-T (2) Imetelstat : Potent telomerase inhibitor of malignant progenitor cells with a high level of telomerase activity Imetelstat clinically active and safe in with RARS/RARS-T Of 8 patients who were transfusion dependent at baseline, 3 achieved transfusion independence on study Giagounidis A, et al. ASH 2015. Abstract 92.Tefferi A, et al. ASH 2015. Abstract 55.

Myelofibrosis PRM-151: a recombinant human PTX-2(1)PTX-2 regulates tissue repair by preventing and reversing fibrosis, PTX-2 levels are low in pts with MF 13 pts completed 72 wks of treatment with PRM-151, well tolerated with few side effectsReductions in BM fibrosis observed at wk 12 and sustained through wk 72 Hemoglobin level increased with decreased need for RBC transfusionsPlatelet counts increased with a decreased need for platelet transfusions62% improved symptom score reduction of > 50% and 2 pts with > 50% reduction in splenomegalyDanish COMBI Trial (2) : Combination of ruxolitinib and interferon active in PV or hyperproliferative MF, including pts who failed IFN- α 2 alone 63% of pts achieved a complete response; most by week 2 and all within 3 monthsSignificant symptom burden reduction by 3 mos (P = .007)Treatment regimen generally well tolerated 1. Verstovsek S, et al. ASH 2015. Abstract 56. 2. Mikkelsen SU, et al. ASH 2015. Abstract 824.

Waldenstrom’s Macroglobulinemia IMO-8400: Oligonucleotide antagonist of endosomal TLRs 7, 8 and 9 amplified by MYD88 L265P mutation (90% of WM) well tolerated and active in Denintuzumab Mafodotin in B-Lineage Non-Hodgkin Lymphoma Anti-CD19 immunotoxin, Phase I trial 38% - Overall response rate, 23% - Complete response rate ,15% - Partial response 22% - Stable disease, 24% - Progressive disease

Hercules, Hydra and CancerHercules lured hydra from the safety of its den by shooting flaming arrows at it. The monster however wound one of its coils around Hercules' foot. With his club, Hercules attacked the many heads of the hydra, but as soon as he smashed one head, two more would burst forth in its place! To make matters worse, the hydra had a friend of its own: a huge crab (CANCER) began biting the trapped foot of Hercules.

Hercules, Hydra, Cancer and IolausHercules called on Iolaus his nephew and servant to help him out.Each time Hercules bashed one of the hydra's heads, Iolaus held a torch to the headless tendons of the neck. The flames prevented the growth of replacement heads. Once he destroyed the eight mortal heads, Hercules chopped off the ninth, immortal head. This he buried and covered with a heavy rock. As for the rest of the hapless hydra, Hercules slit open the corpse and dipped his arrows in the venomous blood.

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