PI3K Inhibitors. Anas Younes, M.D. chief, Lymphoma Service Memorial Sloan Kettering Cancer Center

Transcription

1 PI3K Inhibitors Anas Younes, M.D. chief, Lymphoma Service Memorial Sloan Kettering Cancer Center

2 Targeting PI3K/AKT/mTOR Pathway PI 3-kinase Α, β, γ, δ Idelalisib Duvelisib Copanlisib TGR-122 Buparlisib Survival Prolifera on Growth Metabolism Apoptosis Mo lity BAD GSK3 FOXO p53 AKT mtorc1 MK-226 XL-418 VQD2 Everolimus Temsirolimus Ridaforolimus BEZ-235 BGT226 XL765 S6K1 4EBP1 Younesa, A et al, Nature Rev Clinical Oncol 217

3 Leading Molecular Targets and Drugs in Lymphoma Pathway Target Drug PI3K/AKT/mT OR Response Rate DLBCL FL MCL SLL/CL L T-Cell mtor Everolimus 3% 5% 32% 18% 63% 42% Temsirolimus 36% 56% 38% 1% - - AKT MK226 % 25% 9% (5%) % 2% PI3K-δ Idelalisib - 57% 4% 72% - 12% TGR % 42% 33% 63% - 13% PI3K-γδ Duvelisib % 67% 67% 54% 33% 33% PI3K-αδ Copanlisib 25% 46% 71% 67% 5% - BKM12 12% 25% 23% HL B Cell Receptor (BCR) Syk Fostamatinib 22% 1% 11% 55% % - Btk Ibrutinib 26% 28% 75% 67% - - Apoptosis Bcl-2 Venetoclax 15% 34% 75% 77% Immune checkpoint PD1 Nivolumab 36% 4% % Pambrolizumab % Younes et al, Nature Rev Clin Oncol 217

4 Response Rate Single-agent Activity in Relapsed Follicular (and indolent) Lymphoma 1% 75% 5% 25% % Updated from Younes A & Berry D. Nat Rev Clin Oncol 212;9:

5 SPD of Measured Lymph Nodes, Best % Change from Baseline Phase 2 Idelalisib Monotherapy in Refractory inhl Lymph Node Response a -75 9% had improvement in lymphadenopathy 57% had 5% decrease from baseline -1 Individual Patients (N=125) a Criterion for lymphadenopathy response [Cheson 27] b 3 subjects no post baseline eva 2 subjects NE 1 subject PD luation:by Lymph Node biopsy Gopal et al. NEJM 214

6 % Continued Response % Progression-Free Phase 2 Idelalisib Monotherapy in Refractory inhl Duration Of Response and PFS 1 Median DOR = 12.5 months 1 Median PFS = 11 months (71) 3 (54) 6 (34) 9 (17) Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments 12 (9) 15 () Time from Response, Months (N, Patients at Risk) 18 () (125) 3 (1) 6 (59) 9 (39) 12 (2) 15 (13) Time from Start of Idelalisib, Months (N, Patients at Risk) 18 () Gopal et al. NEJM 214

7 TGR-122 Profile Next generation PI3Kδ Inhibitor Significant structural differences compared to other PI3Kδ inhibitors Favorable PK profile that allows once-daily oral dosing Differentiated safety profile from other PI3Kδ inhibitors Fold-selectivity Isoform PI3Kα PI3Kβ PI3Kγ PI3Kδ TGR-122 >1 >5 > Idelalisib >3 >2 >4 1 2 IPI-145 >64 >34 >11 1 7

8 TGR : Single Agent Efficacy 94% of CLL patients (16/17) achieved a nodal PR, remaining patients still on study pending further evaluation 59% (1/17) achieved a response per iwcll (Hallek 28) criteria O Connor et al, ASH 215

9 Integrated Analysis: CLL/SLL Efficacy TGR-122 Monotherapy +/- Ublituximab Patients Treated at Higher Doses of TGR-122 Best Percent Change from Baseline in Disease Burden Recently added patients with early response assessment Higher Doses: 12 mg of the initial formulation, or 6 mg of the micronized formulation Burris et al, ASCO 216, Mato et al EHA 216

10 Integrated Analysis: TGR-122 Monotherapy and TGR Ublituximab: DLBCL Efficacy Patients Treated at Higher Doses of TGR-122 Best Percent Change from Baseline in Disease Burden 38% (6/16) Combo Responders 4% (4/1) Single Agent Responders Burris et al, ASCO 216

11 Phase II Study of Buparlisib (BKM12) in Patients with Relapsed/Refractory Lymphoma Younes. A, et al, ASH 215

12 Phase II Study of Buparlisib (BKM12) in Patients with Relapsed/Refractory Lymphoma Younes. A, et al, ASH 215

13 Phase II Study of Buparlisib (BKM12) in Patients with Relapsed/Refractory Lymphoma Younes. A, et al, ASH 215

14 Copanlisib, a selective inhibitor of PI3K-δ and PI3K-α Copanlisib demonstrates inhibitory activity against PI3K-α and PI3K-δ at sub-nanomolar concentrations 1 PI3K-δ is an established oncogenic driver in indolent NHL, and is the predominant PI3K isoform expressed in both FL and DLBCL 2,3 Recent emerging data indicate that PI3K-α is upregulated in relapsed/refractory mantle cell lymphoma (MCL) and is postulated to be a tumor escape mechanism 4 Copanlisib IC 5, half-maximal inhibitory concentration Biochemical activity Copanlisib 1 Idelalisib 5 PI3K-α IC 5.5 nm 82 nm PI3K-β IC nm 565 nm PI3K-γ IC nm 89 nm PI3K-δ IC 5.7 nm 2.5 nm 1. Liu N et al. Mol Cancer Ther 213;12: Tzenaki N et al. Front Oncol 213;3:4. 3. Thye LS et al. Hematol Oncol 215;33: (abstr 267).4. Iyengar S et al. Blood 212;121: Lannutti BJ et al. Blood 211;117:

15 Study design Phase II open-label study of copanlisib Part A: Open-label, uncontrolled, Phase IIa study to evaluate the efficacy and safety of copanlisib as a single agent in patients with relapsed/refractory NHL Patient population 3rd-line relapsed/refractory NHL N=67 Copanlisib.8 mg/kg i.v. (3 weeks on/1 week off) until disease progression or toxicity Primary outcome: ORR Secondary outcomes: PFS, time to response, lesion size 15

16 Percent change Percent change Copanlisib: Tumor shrinkage Percent best change in target lesion size from baseline in the indolent and aggressive cohorts Indolent Aggressive Data cutoff for primary efficacy analysis: November 4, 213. Dreyling A et al. Presented at: the EORTC-NCI-AACR Symposium; November 18 21, 214; Barcelona, Spain. 16

17 Copanlisib: Progression-free survival Median PFS for patients with indolent NHL was 288 days Indolent Data cutoff for primary efficacy analysis: November 4, 213. Dreyling A et al. Presented at: the EORTC-NCI-AACR Symposium; November 18 21, 214; Barcelona, Spain. 17

18 PI 3-kinase AKT mtorc1 Idelalisib IPI-145 BKM-12 BY XL-147 GDC-941 GSK MK-226 XL-418 VQD2 Everolimus Temsirolimus Ridaforolimus BEZ-235 BGT226 XL765 Myc Translation Everolimus Temsirolimus Silvestrol Myc Bcl2 ABT-199 Myc Transcription HDACi BETi

19 Blocking Resistance Mechanisms Rationale for combining PI3Ki and BCL2i PI 3-kinase Α, β, γ, δ Idelalisib Duvelisib Copanlisib TGR-122 Buparlisib AKT MK-226 XL-418 VQD2 BEZ-235 BGT226 XL765 mtorc1 Everolimus Temsirolimus Ridaforolimus S6K1 4EBP1 MCL1 BCL2 Venetoclax

20 BCL21/idelalisib combo in FL and MCL

21 Cooperation Between PI3K and BCR Signaling Pathway

22 Nature Immunology 4, (23) PI3K and Btk differentially regulate B cell antigen receptormediated signal transduction Harumi Suzuki 1, 6, 7, Satoshi Matsuda 1, 2, 6, Yasuo Terauchi 2, 3, Mari Fujiwara 1, 2, Toshiaki Ohteki 1, 8, Tomoichiro Asano 3, Timothy W. Behrens 4, Taku Kouro 5, Kiyoshi Takatsu 5, Takashi Kadowaki 2, 3 & Shigeo Koyasu 1, 2

23 Phase I/II Of Ibrutinib + BKM12 in relapsed lymphoma

24 TGR Ibrutinib in Relapsed/Refractory CLL or MCL: Efficacy (n=28) High response rates in both CLL and MCL CLL (n=11): ORR 88% (CR 6%; PR 82%) 5 PRs with >8% SPD decrease, nearing radiographic CR Responses in 3 patients with prior PI3Ki and 1 patient with prior ibrutinib MCL: ORR 73% (all PR) Clinical benefit observed in 2 additional patients Davids MS, et al. ASH (Oral Presentation) 216. Abstract 641.

25 MYC and PI3K Cooperate in Lymphomagenesis Sander, S and Rajewsky, K: Cancer Cell (212)

26 CUDC-97 Oral, dual inhibitor of HDAC and PI3K GCB ABC DH 24h DMSO CUDC-97 ppras4(t246) + - SU-DHL HBL NUDHL HDACi PI3Ki p4ebp1 (Thr 37/46) ps6 (S235/236) cmyc Ac Histone H3 PARP Cleaved PARP Caspase 3 Cleaved Caspase 3 Beta Actin Beta Actin Beta Actin Enzyme HDAC PI3K Isotype α δ β γ IC5 (nm) Mondello P, et al: Oncotarget 217

27 %Cell Viability %Cell Viability HDLM2 KMH2 SUDHL4 L-428 BJAB HBL1 DB NUDHL1 SUDHL-1 RAMOS RAJI Ri-1 U2932 CA 46 SUDHL6 LY-19 SUDHL8 TMD8 LY-1 U-2973 %Cell Viability Drug, um MY C BCL2 TP53 EZH2 MLL2 CREBBP EP3 MTOR CD79B MY D88 CARD11 A2 CUDC-97 Activity in Lymphoma IC 5 72h IC5 72HRS GCB ABC DH BL HL Wilde type Mutation Translocatio n Amplification DOSE CURVE 72 HRS Drug,μM SUDHL4 SUDHL6 SUDHL-8 OCY-LY-19 DB U2932 TMD8 HBL1 Ri-1 OCI-LY-1 NUDHL1 SUDHL-1 U2973 HDLM-2 KMH-2 L SUDHL-6 T T24h T48h T72h SUDHL-4 SUDHL- 4 DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC 1 T T24h T48h T72h HBL-1 1 TMD8 6 DMSO U-2932 DMSO 8 CUDC.1 CUDC.1 CUDC.5 CUDC CUDC.1 CUDC.1 CUDC.5 4 CUDC.5 CUDC 1 2 CUDC 1 2 CUDC 5 CUDC 5 CUDC 1 CUDC 1 T T24h T48h T72h T T24h T48h T72h DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC 1 SUDHL-8 T T24h T48h T72h T T24h T48h T72h NUDHL-1 DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 TCUDC T24h 5 T48h T72h CUDC 1 KMH-1 2 DMSO CUDC.1 15 CUDC.5 CUDC.1 1 CUDC.5 5 CUDC 1 CUDC 5 CUDC T 1 T24h T48h T72h DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC 1 SUDHL-1 T T24h T48h T72h DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC 1 HDLM2 T T24h T48h T72h DMSO DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC-97,μM CUDC 5 CUDC 1 Mondello P, et al: Oncotarget 217

28 DLBCL: Maximum Target Lesion Change per Investigator Assessment Younes, A et al, Lancet Oncology 216

29 Conclusions Activated PI3K Pathway is frequently observed in a variety of lymphomas PI3K inhibitors have high single agent activity in FL, CLL, and MCL Idelalisib is the only PI3K inhibitor approved by the FDA and EMA (relapsed CLL and FL/SLL) Toxicity profile of PI3Ki vary based on PI3K isoform selection Duration of administration Combinations Mechanism-based combination strategies will be required to improve treatment outcome, but should be balanced by safety

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