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

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

2 PI3K Pathway mutations do correlate with pathway activation in lymphoma How to measure pathway activation? Physiologic signaling Receptor tyrosine kinase PIP 2 PIP 3 Activated oncogenic signaling Receptor tyrosine kinase PIP 2 PIP 3 p85 PTEN p85 PTEN p11 PI 3-kinase AKT p11 PI 3-kinase AKT mtorc1 mtorc1 S6K1 4EBP1 S6K1 4EBP1 Protein translation/synthesis Protein translation/synthesis

3 Recurrent mtorc1-activating RRAGC mutations in follicular lymphoma Jessica Okosun, Rachel L Wolfson, Jun Wang, Shamzah Araf, Lucy Wilkins, Brian M Castellano, Leire Escudero-Ibarz, Ahad Fahad Al Seraihi, Julia Richter, Stephan H Bernhart, Alejo Efeyan, Sameena Iqbal, Janet Matthews, Andrew Clear, José Afonso Guerra-Assunção, Csaba Bödör, Hilmar Quentmeier, Christopher Mansbridge, Peter Johnson, Andrew Davies, Jonathan C Strefford, Graham Packham, Sharon Barrans, Andrew Jack, Ming-Qing Du, Maria Calaminici, T Andrew Lister, Rebecca Auer, Silvia Montoto, John G Gribben, Reiner Siebert, Claude Chelala, Roberto Zoncu, David M Sabatini & Jude Fitzgibbon Nature Genetics 48, (216) Frequency 17%

4 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

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

6 Leading Molecular Targets and Drugs in Lymphoma Pathway Target Drug PI3K/AKT/ mtor B Cell Receptor (BCR) Response Rate DLBCL FL MCL SLL/C LL 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 IPI-145 % 67% 67% 54% 33% 33% PI3K-αδ BAY % 4% 71% 67% 5% - BKM12 12% 25% 23% Syk Fostamatinib 22% 1% 11% 55% % - Btk Ibrutinib 26% 28% 75% 67% - - HL Apoptosis Bcl-2 Venetoclax 15% 34% 75% 77% Immune checkpoint PD1 Nivolumab 36% 4% % Pambrolizumab %

7 Phase 2 Idelalisib Monotherapy in Refractory inhl Lymph Node Response SPD of Measured Lymph Nodes, Best % Change from Baseline 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

8 Phase 2 Idelalisib Monotherapy in Refractory inhl Duration Of Response and PFS % Continued Response (71) 3 (54) 6 (34) Median DOR = 12.5 months 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 () % Progression-Free (125) 3 (1) 6 (59) 9 (39) Median PFS = 11 months 12 (2) 15 (13) Time from Start of Idelalisib, Months (N, Patients at Risk) 18 () Gopal et al. NEJM 214

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

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

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

12 Copanlisib (BAY )

13 Copanlisib (BAY )

14 Measuring Drug Efficacy Response Rate vs PFS Drug A: HDACi Drug B: r BV

15 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

16 BCL21/idelalisib combo in FL and MCL

17 Cooperation Between PI3K and BCR Signaling Pathway

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

19 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

20 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)

21 CUDC-97 Activity in Lymphoma Drug, um MYC BCL2 TP53 EZH2 MLL2 CREBBP EP3 MTOR CD79B MYD88 CARD11 A2 IC5 72HRS 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 GCB ABC DH BL HL Wilde type Mutation Translocatio namplification %Cell Viability 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 L428 %Cell Viability %Cell Viability SUDHL-6 4 SUDHL DMSO 4 CUDC.1 CUDC CUDC.1 SUDHL-8 CUDC CUDC 1 CUDC 5 1 CUDC 1 T T24h T48h T72h T T24h T48h T72h T T24h T48h T72h -1 HBL-1 TMD8 6 DMSO DMSO U CUDC.1 8 CUDC.1 CUDC.5 CUDC CUDC.1 CUDC.1 CUDC.5 CUDC.5 4 CUDC 1 2 CUDC 1 CUDC 5 2 CUDC 5 CUDC 1 CUDC 1 T T24h T48h T72h T T24h T48h T72h -2 T T24h T48h T72h NUDHL-1 DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 T CUDC T24h 5 T48h T72h CUDC 1 KMH-1 T T24h T48h T72h SUDHL-1 DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC 1 T T24h T48h T72h HDLM2 T T24h T48h T72h DMSO DMSO CUDC.1 CUDC.5 CUDC.1 CUDC.5 CUDC 1 CUDC 5 CUDC CUDC-97,µM

22 CUDC-97 Induces Apoptosis In Lymphoma Cell Lines PI Annexin V-FITC SUDHL-6 HBL-1 NUDHL-1 KMH-2 % apoptotic % Cells Death cells % apoptotic % Cells Death cells % apoptotic % Cells Death cells % apoptotic % Cells Death cells SUDHL-6 HBL-1 HBL-1 ** NUDHL-1 NUDHL-1 ** KMH-2 ** KMH-1 ns DMSO CUDC-97 (.1 µm) ABC GCB 24h DMSO CUDC 97.1uM Caspase 3 Cleaved Caspase3 SUDHL-6 HBL-1 NUDHL-1 KMH PARP Cleaved PARP Beta-Actin

23 DLBCL: Maximum Target Lesion Change per Investigator Assessment Younes, A et al, Lancet Oncology (In Press)

24 Conclusions PI3K Pathway inhibitors have single agent activity in FL, CLL, and MCL Idelalisib is approved for reapsed CLL and FL Toxicity profile varies based on PI3K isoform selection Duration of administration Combinations Mutation in the PI3K/mTOR pathway in FL may explain sensitivity in FL