Institute of Biomedical University of Salamanca Research Center Research of Salamanca

Novel Drugs in the pipeline

Enrique M. Ocio University Hospital & Cancer Research Center University of Salamanca Spain Disclosures

Type Company

Amgen; Celgene; Novartis; BMS, Janssen, Honoraria Takeda

Celgene; Amgen; Novartis, Takeda, Abbvie, Consultancy Pharmamar, Seattle Genetics

Array Pharmaceuticals; Mundipharma; Celgene; Research Funding Amgen, Sanofi, MSD Treatment of MM

1844 1960 1970 1980 1990 2000 2003 2004 2013 2015  2018

Mr. Melphalan McBean (1958, Blokhin) HD chemo 1844 Ann NY Acad Sci ASCT Bortezomib Lenalidomide Melphalan Glucocorticoids Thalidomide Panobinostat (1969) Ixazomib Combination chemo Vincristine Doxorubicin Carfilzomib Dexamethasone Pomalidomide

Chemotherapy Era Targeted Therapy Era Do we need other agents with novel MoA? New drugs and mechanisms of action in MM

CS-1 Elotuzumab CDK 1, 2, 5, 9 Dinaciclib / TG02 CD38 Daratumumab / FGFR3 Dovitinib / AB1010 / MFGR 1877S CD138 nBT062-DM4 cKit /PDGFR Imatinib / Dasatinib MoAb CD56 Lorvotuzumab VEGF-R CD40 Dacetuzumab / IGF-1R AVE1642 / CP-751, 851 BAFF Tabalumab Kinase Inh. EGF-R KiR IPH2101 PKC Enzastaurin PD1/PDL1 / / Pidilumab BTK Ibrutinib

IL-6 Cell cycle Inh. Lymph. Ras NK cell KSP Inh Filanesib Aurora K Inh MLN8237 Raf PI3K CDK 4/6 Inh Seleciclib IMIDs MEK Akt Thalidomide Lenalidomide Alkylators Pomalidomide mTORC1 mTORC2 Melphalan Cyclophosphamide MAPK Bendamustine Melflufen Signaling Pathways TH-302 AKT Perifosine / Afuresertib mTORC1 Everolimus / Temsirolimus mTOR C1/C2 MLN0128 / INK128 Other DNA damaging Farn Transf Tipifarnib Proteasome Inh. p38/MAPK inh SCIO-469 DNA Damaging Zalypsis DACi p38/JNK act Aplidin Bortezomib MEK Selumetinib PARP Inhibitor Veliparib Panobinostat Carfilzomib Hsp-90 Inh. Bcl-2 Venetoclax Vorinostat Ixazomib XPO Selinexor Tanespimycin Romidepsin Oprozomib PIM PIM447 AUY922 Givinostat Marizomib Rocilinostat Approved Ocio, Leukemia 2014. Updated Are there alternative alkylators or should we forget them for the future? Melflufen: clever alkylator Melflufen is a peptidase enhanced therapy with an alkylating payload

1. Amino- peptidases highly Peptidase potentiated activity in over expressed in 5. Melflufen and MM cells results in: multiple myeloma hydrophilic (MM) cells alkylating • Approx. 50-fold higher intra- 1,5 moieties binds cellular exposure in MM cells directly to DNA • Approx. 50-fold higher anti-MM potency1,2,5 • Alkylation of DNA with limited or no induction of DNA repair3,5 • Strong anti-angiogenic properties 1,4,5 • Therapeutic index of 20 - 40 (MM cells compared with peripheral 2. Lipophilic blood mononuclear cells)1,5 melflufen rapidly traverses cell membranes Melflufen Amino-peptidase Alkylating moiety

3. Amino-peptidase potentiated release of 1. Chauhan et al. (2013) Clin Cancer Res 19(11): 3019-303. hydrophilic alkylating 4. Hydrophilic moieties alkylating 2. Wickstrom et al. (2008) Invest New Drugs 26(3): 195-204. moieties trapped 3. Ray et al. (2016) Br J Hematol 174: 397-409 inside the cell 4. Strese et al. (2013) Biochem Pharmacol 86: 888–895. 5. Wickström et al. (2017) Oncotarget E-pub June 08. Melflufen + Dex

Phase II O-12-M1 trial PFS 5.7 m (95% CI: 3.7-9.3) RRMM pts ≥ 2 prior lines including Len and Btz and refr. to last line.

n=45 4 (2-14) prior lines; 64% double refr.; 53% Alkylator refr.

ORR 41% ...... 5 VGPR & 9 PR 36% in Alkylator refr.

G3/4 rel. TEAEs: Thromboc. (58%), Neutropenia (51%), Anemia: 42% DOR for ≥ PR: 8.4 m Richardson P. ASH 2017

Phase II Horizon trial *

RRMM pts ≥ 2 prior lines including IMiD & PI and refr to Pom and/or Dara

n=38 6 (3-11) prior lines; Alkylator refr. 57% Pom refr; 96%; Pom & Dara Refr: 62%

ORR 27% ...... 2 VGPR & 6 PR

G3/4 rel. TEAEs: Thromboc. (45%), Neutropenia (39%), Anemia: 21% * 11 prior lines including Allo-SCT Mateos MV. ASH 2017

Melflufen 40 mg iv every 28 days + Dex 40 mg weekly Melflufen ongoing studies in RR MM

Phase 2 Phase 3 Phase 1/2 – Triple combination Single Arm Multi-refr. study Randomized study study

How does melflufen work in How does melflufen compare to QUESTION How is melflufen dosed in triple RRMM patients with limited standard of care in late-stage ASKED combinations in RRMM? treatment options? RRMM?

Recruitment ongoing Recruitment ongoing Recruitment ongoing COMMENT Combination with bortezomib or Pomalidomide- and/or H2H melflufen vs pomalidomide daratumumab-refractory patients daratumumab EDO-S101: bendamustine derivative (tinostamustine)

Bendamustine

Purine-like HDAC Benzimidazole ring HDAC DAC Inhibitor Alkylator HDAC

Ac Ac

Butyric acid group DNA Alkylation Moiety Ac Ac Ac EDO-S101

Purine-like Benzimidazole ring

DACi Moiety

DNA Alkylation Moiety EDO-S101 induces potent DNA Damage Response

EDO-S101 Induces DSBs

Control MM1S EDO-S101 5 μM

EDO-S101 activates sensors of DNA damage

EDO-S101 5 µM (hours)

0 12 24 48

pATR - 300

pCHK1 -56

pATM - 350 Bendamustine EDO-S101 MW C12.55 C12.5525 pCHK2 -62 (Kd) P-CHK1 -56 -53 pP53 P-CHK2 -62 pH2AX pH2AX -17 -17 Ac-H3 -17 Tubulin -55

Lopez Iglesias et al, J. Hematol Oncol 2017 In vivo activity of EDO-S101

Small tumors Big tumors 6000 Treatment period 350 Control EDO-S101 5000 300 ) 3 Treatment period 250 Control EDO-S101 4000 200 150 3000

Tumor volume (%) 100 2000 50

Tumor volumeTumor (mm 0 1000 1 8 19 31 43 Time in days 0 0 102030405060708090 Time in days Vk12653 model 1,0

0,8 EDO-S101 is the only drug

0,6 with single agent activity in the Vk12653 model, where is 0,4 also able to prolong survival 0,2 Cumulative survival

0,0 0 20 40 60 80 100 Time in days Lopez Iglesias et al, J. Hematol Oncol 2017 Which other pathogenetic features can be targeted in MM?

Is there any Bcr/Abl or t(15;17) in MM? Cyclin D dereg. an early and common event

Bergsagel. Blood 2005 Filanesib (KSP inh.) in MM

Kinesin spindle protein is required for cell cycle progression

• ARRY-520 induces mytotic arrest and subsequent apoptosis

• Particularly effective in Mcl-1 dependent cells

• Efficacy inversely correlates with serum AAG levels

 ARRY-520 + G-CSF ………………………...... … ≥ PR 16%; ≥ MR 19%

n= 32 exp. to BTZ & IMID. Median lines 6 (2-19)

 ARRY-520 + G-CSF + Dex……………………..…….….. ≥ PR 16%; ≥ MR 22%

n= 50 refr. to BTZ, Len, Dex. Median lines 9 (5-13)

Gr 3/4 AEs: neutropenia (38%, 38%), thromboc. (44%, 42%), anemia (38%, 50%), fatigue (16%,8%), leukop. (13%, 4%)

Lonial S. ASH 2013. Abstract 285 Rationale for this combination

Inhibition of KSP in MM1S cells (% of monopolar spindles) Control In vivo activity of PDF

Bipolar spindles 14%

Bipolar spindles

Bipolar spindles

Filanesib 10 nM x 24 h

97%

Monopolar spindles

Hernández-García S. Haematologica 2017 Phase I/II Pomdefil: Pom-Dex + Filanesib in RRMM

n= 44 3 (2-6) prior lines & 76% double refr. Influence of baseline AAG levels Alpha-1-Acid Glycoprotein ORR 60% … (1 CR; 4 VGPR, 13 PR) Median level was 85.5 mg/dL (50.6-179.9)

• No pt. with AAG values over the median 1.0 PFS responded (1 SD and 4 PD) 0.8 • All 6 pts with AAG below the median 0.6 achieved ≥MR (1 VGPR, 3 PR and 2 MR) 0.4 PFS according to AAG levels 0.2 Cum. Survival 7 m (4.1 - 9.9) 1.0 0.0 0 5 10 15 20 25 0.8 Months 0.6 Low (below median) High (above median) 0.4 OS 24 m (9.8 - 38.1) Cum. Survival 0.2

0.0 Main toxicity was hematological: 0 2 4 6 8 10 12 G3/4 Tx related Neutrop. (56%); Thrombocytop. (17%) & Anemia (25%) Months

Median follow-up of 8 months (0-27) Ocio et al. ASH 2017 RAS family members are the most frequently mutated genes in MM

41 oncogenes and tumor suppressor genes were Massively parallel sequencing of 38 tumor genomes tested using MassARRAY/Sequenom mass and their comparison to matched normal DNAs spectrometry–based methodology in 133 RRMM. Chapman et al. Nature 2011 Mulligan et al. Blood 2014

23% 24% 26% 20% 2%

Massively parallel 23% 20% sequencing of paired tumor/normal samples from 6% 203 multiple myeloma (MM)

Lohr et al. Cancer Cell 2014 New drugs and mechanisms of action in MM

Lymph. Ras NK cell

Raf PI3K

MEK Akt

mTORC1 mTORC2 MAPK Signaling Pathways AKT Perifosine / Afuresertib mTORC1 Everolimus / Temsirolimus mTOR C1/C2 MLN0128 / INK128 Farn Transf Tipifarnib p38/MAPK inh SCIO-469 p38/JNK act Aplidin MEK Selumetinib Bcl-2 Venetoclax XPO Selinexor PIM PIM447

Approved Ocio, Leukemia 2014. Updated Venetoclax (Bcl-2 inhibitor)

• Venetoclax (ABT-199 / GDC-0199) is a potent, selective, orally bioavailable, small- molecule, BCL-2 inhibitor1

• Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival2

• Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14),which correlates with higher ratios of BCL2 to MCL1 and BCL2 to 2,3 BCL2L1 (BCL-XL) mRNA

2. Touzeau C, et al. Leukemia. 2014; 28(1): 210-212. 1. Souers AJ, et al. Nat Med. 2013; 19(2): 202-208. 3. Punnoose E et al. Mol Cancer Ther 2016 Venetoclax monotherapy n= 66 pts. 5 prior lines (1-15). 79% refr. to last line; 61% double refractory to Btz & Len. t(11;14): 46%

Time to Progression 100%

t(11;14) 6.6 (3.9-10.2) Non t(11;14) 1.9 (1.2-2.3)

88% in t(11;14) with a high BCL2:BCL2L1 ratio

Main toxicities are mild GI symptoms; thrombocytopenia (32% G3-4) and neutropenia (27% G3-4) 30-1200 mg po (MTD: 1200 mg) Kumar, et al. Blood 2017

Venetoclax + Dex: 65% in 20 pts with t(11;14) & 3 prior lines of therapy Kauffman, et al. ASH 2017 Venetoclax plus bortezomib and dexamethasone n= 66 patients after >=1 prior lines of therapy (median 3). 39% refractory to Btz

ORR: 67% (mainly in Btz non-Rfr. & 1-3 prior lines) ORR: 94% in Bcl2 high pts

BCL2 quantitation using ddPCR performed on CD138-selected bone marrow mononuclear cells collected at baseline. BATTing was used to estimate a threshold of BCL2 to provide optimum selection of patients likely to have a response.

Similar responses irrespective of t(11;14) status

TTP 9.5 m (95% CI, 5.7, 10.4) & DOR 9.7 m (95% CI, 7.4, 15.8)

AEs were manageable. Mild GI toxicity; G3-4 AEs: Thrombocytopenia (29%), anemia (15%), neutropenia (14%), diarrea (6%), PN(3%), dyspnea (6%) Moreau P, et al. Blood 2017 XPO1-Inhibitors: Selinexor

. Exportin 1 (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eIF4E-bound oncoprotein mRNAs

. Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression.

Tai et al. Leukemia 2014 Selinexor plus dex (STORM study)

n=78 pts median of 7 prior lines of therapy: 48 pts quad refractory (bor, carf, len & pom) & 30 penta refractory (bor,carf, len, pom & CD38 mAbs)

100% 100% ORR CBR N* VGPR PR MR (%) (%) (%) (%) (%)

OS: 9.3 months 16 26 Overall 78 4 12 10 (21%) (33%) (5%) (15%) (13%)

Quad 10 14 48 2 8 4 Refractory (21%) (29%) (4%) (17%) (8%) PFS: 2.3 months

Penta 6 12 30 2 4 6 Refractory (20%) (40%) (7%) (13%) (20%)

Median DOR: 5 months Main toxicities are thrombocytopenia (59% G3-4) and neutropenia (17% G3-4), anemia (28% G3-4), fatigue (15% G3-4), which are manageable with dose modifications Vogl , et al. JCO 2017

Eltanexor (2nd gen. XPO1 inh) n=36 pts. 7 prior lines +/- Dex Cornell, et al. ASH 2017 Selinexor Combinations

PI IMiDs

Bort-Dex* Cfz-Dex Len-Dex Pom-Dex

n 42 21 18 29

Prior lines 3 (1-11) 4 (2-10) 1 (1-7) 4 (2-9)

83% ORR 63% 73% 54% in non PI refr. pts In pts Refractory 42% 67% 1uPR / 4 29% to the backbone non PI refr.: NR PFS 3.7 m 6.6 m 11.6 m PI refr.: 9 m

Bahlis. ASH 2017 Jakubowiak. ASH 2016 White. ASH 2017 Baz. ASH 2017

Doxil-Dex (n=27) Not continued Baz, et al. ASH 2017 Daratumumab (n=6) Too early Gasparetto, et al. ASH 2017 * Phase III Boston trial (SVd vs Vd) ongoing in MM GSK2857916: BCMA-ADC in MM (DREAMM-1)

• Humanized afucosylated IgG1 anti-BCMA Ab conjugated to MMAF ADC 1 ADCC 1 Fc • Phase I: n=38. RD: 3.4 mg/Kg in 1h/3w BCMA receptor Lysosome BCMA Effector 3 cell At high doses ≥3.4 mg/kg (n=10) ORR 67% 3 BCMA 4 2 BCMA4 Cohen et al. ASH 2016 Abstract 1148 x Malignant plasma GSK2857916 Cytotoxic – MMAF (non-cell cell permeable, highly agent potent auristatin

• Phase II n=35 MM pts @ the RD Afucosylation – Enhanced ADCC

–Stable in Linker Cell death circulation • 57% ≥5 prior lines. 91% Refr. to IMiDs; 97% PI; 37% Dara

• No selection by BCMA expression Corneal AEs (63%)

• Safety Maximum Grade, n (%) Preferred term 1 2 3 Total • Most frequent ≥Grade 3 AEs were thrombocytopenia Vision blurred 2 (6) 14 (40) 0 16 (46) Dry eye 6 (17) 5 (14) 1 (3) 12 (34) (34%) and anemia (14%) Photophobia 5 (14) 3 (9) 0 8 (23) Lacrimation increased 2 (6) 2 (6) 0 4 (11) • SAEs occurring in ≥2 patients included IRR (n=2) Keratitis 0 1 (3) 2 (6) 3 (9) Eye pain 1 (3) 0 1 (3) 2 (6) and lung infection (n=2) Keratopathy 1 (3) 1 (3) 0 2 (6) Eye pruritus 1 (3) 0 0 1 (3) Night blindness 0 1 (3) 0 1 (3) Trudel et al. ASH 2017 Any event 4 (11) 15 (43) 3 (9) 22 (63) GSK2857916: BCMA-ADC in MM (DREAMM-1)

DREAMM-1 Part 2: Maximum % Reduction in M-Protein or Free Light Chain from Baseline

ORR=60% (21/35; 95% CI: 42.1%, 76.1%) •1 sCR, 2 CR, 15 VGPR, 3 PR

PFS: 7.9 (3.1- NA); DOR:NR Trudel et al. ASH 2017 Adoptive T cell therapy: CAR-T cells

• CAR T or NK cells are engineered anti-tumor immune cells with high affinity chimeric antigen receptors specific for tumor antigens1

Chimeric Antigen Receptor Structure1

Single-chain antibody able to recognize tumor-associated antigens in a non-MHC– specific manner

Molecular hinge region derived from CD8 to provide flexibility to allow reorientation to bind antigen

Cytoplasmic domain of CD28 and additional signaling domains, including CD137, were added to later generation CARs to enhance cytokine secretion and tumor growth inhibition

Cytoplasmic signaling domain of CD3ζ

1. Kershaw MH et al. Nat Rev Cancer. 2013;13:525-541. Turtle CJ, Hudecek M, Curr Opin Immunol, 2012 BCMA CAR-T cell for MM

CRS ORR/CR/PFS/ NPLRefrto: Comments Treatment (Grade3-4) MRD

94%/56%/- 6 bb2121 7 PI (70%) 150-300x10 as IMiD’s (85%) 2 (10%) 9/10 pts dose for future 21 (3-14) Flu+Cy Dara (50%) MRD -ve trials

9 44% (1 sCR, 2 3 (33%) The addition of Cy U. Penn 1-5 x 108 VGPRs, 1 PR) Dual (96%) does not improve a 7 lot but higher dose of 5 Quad (54%) - 1 pt PR 7 CAR-T associated Anti-BCMA +/- Cy+ 1-5 x 10 (3-13) Penta (42%) cyclophosphamide with better responses 10 60% (1 CR, 1 8 5 (50%) (1-5 x10 ) Cy 1-5 x 108 VGPR, 4 PR) MCARH171 Acceptable 7 No efficacy - safety: safety as 6 (6-10) 2 (33%) reported Human scFv BCMA CAR-T end point CD19 + BCMA CAR-T 4 PI/IMiD’s Feasible to 2 (20%) 100%/20% Flu+Cy 10 (2-7) (80%) combine both 1x107 CD19 (day 0) 4.5 x107 BCMA (days 2&3) LCAR-B38M 100%/95%/ Updated results Flu+Cy 19 2 (10%) 7 pts in CR presented at ASH in 3 smaller infusions Targets two MRD -ve pts with EMD regions of the BCMA antigen Conclusions

• New MoA approved in the last years: DACi, MoA, Immunotherapy.

• Several new agents & mechanisms coming

• New alkylators (Melflufen); CelMods; Targeted agents against the RAS/RAF pathway (MEK, Erk, AKT, PIM); Selinexor; Venetoclax;

• Immunotherapy such as BCMA-ADC or CAR-T cells

• Probably in the near future these agents will be incorporated into the treatment backbones based on the patients’ profile:

• t(11;14) or Bcl-2 for Venetoclax, MEK for Trametinib, AAG for Filanesib Maintain hope and keep working so we could advance in the next 5-10 years as much as we have improved in the last ones Acknowledgments

Cancer Research Center University Hospital

Laboratory 12 Department of Hematology Mercedes Garayoa Mª Victoria Mateos Teresa Paíno Ramón García-Sanz Ana Alicia López Iglesias Norma C. Gutiérrez Susana Hernández García Noemí Puig Macarena Algarín Pedro Mogollón Jesús F. San Miguel Laura San Segundo Montserrat Martín Lorena González

University of Salamanca - Spain Institute of Biomedical University of Salamanca Cancer Research Center Research of Salamanca

Novel Drugs in the pipeline

Enrique M. Ocio University Hospital & Cancer Research Center University of Salamanca Spain