DAVAOncology, LP...facilitating successful drug development

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Marilyn Parsons
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1 DAVAOncology, L Tyrosine Receptor Kinase I3K p85 p110 TEN TORC1 RAS I2 I3 Efficacy of targeted therapy is challenged by the complexity of tumor biology, including cross talk and redundancies between divergent branches of signaling pathways The I3K/mTOR as well as the RAS/ pathways, both downstream of tyrosine kinase receptors, are frequently activated in many different tumor types ERK Successful inhibition of these signaling pathways depends on hitting the appropriate target within the molecular context of an individual tumor >40 agents in the clinic

2 DAVAOncology, L GFR inhibition EGFR HER2 HER3 VEGFR IGF-1R DGFR FGFR MET an I3K BKM120 (Novartis) GDC0941 (Roche) XL147 (Sanofi Aventis) BAY (Bayer) X866 (Oncothyreon) ZSTK474 (Zenyaku Kogyo; Japan) Other: GDC0032 (Roche) I3K-alpha BYL719 (Novartis) CH (Chugai; Japan) I3K-delta CAL-101 (Gilead) AMG 319 (Amgen) Dual I3K/mTOR BEZ235 (Novartis) GDC0980 (Roche) XL765 (Sanofi Aventis) GSK (GSK) F (fizer) F (fizer) MK2206 (Merck) GSK (GSK) GDC-0068 (Roche) AZD-5363 (AstraZeneca) Other: erifosine (Keryx) mtorc 1/2 AZD-8055 (AstraZeneca) AZD-2014 (AstraZeneca) OSI-027 (Astellas) INK-128 (Intellikine) CC-223 (Celgene) Rapalogues (mtor1) Temsirolimus (fizer) Everolimus (Novartis) Ridaforolimus (Merck) RG7204 (Roche) BMS (BMS) GSK (GSK) RO (Roche) GDC0973 (Roche) RO (Roche) GSK (GSK) AZD6244 (AstraZeneca) BAY (Bayer) MSC B (EMD Serono) TAK-733 (Millennium) 162 (Novartis) D (fizer) Same target(s) many agents: roduct Differentiation

3 DAVAOncology, L BACK IC50 (nm; in vitro) p110a p110ß mtor Dosing K AEs BKM GDC XL >15000 BEZ GDC XL MK hase II single agent dose: qd, 100 mg tablet hase I comparing O qd and bid; MTD exceeded, intermediate dose tested hase II single agent dose: qd, 600 mg capsule MTD for sachet formulation is 1600 mg/d and R2D MTD at 50 mg for qd; dose escalation ongoing for qw. MTD at 50 mg bid and 90 mg qd (Gelatin capsules in 5, 10, and 50mg ) hase II dose: 60 mg qod, or 200 mg qw T 1/2 is 40 hrs; 3-fold steady state accumulation T 1/2 is hrs T 1/2 is 5 days; 5 to 13-fold steady state accumulation T 1/2 between hrs with tablet formulation; with sachet Ongoing study on bioavailability of capsule and tablet formulations T 1/2 is 3-9 hrs T 1/2 is hrs Rash, hyperglycemia, mood disorders DLTs: hyperglycemia, rash, T-wave inversion Rash, mucositis DLTs: fatigue, thrombocytopenia DLTs: rash, pneumonitis, hyperglycemia DLTs: rash, T-wave inversion DLT: Rash Tumor references

DAVAOncology, L BACK Breast cancer most crowded with 7 agents in development;

Endometrial tumors as prototype for I3K/mTOR pathway activation; Novartis planning

phase III trial with inhibitor perifosine in r/r colorectal cancer; KRASmut subset

erifosine GDC0941 MK 2206 GSK-1795 Breast Cancer XL147 GDC0980 XL765 BEZ235

4 DAVAOncology, L BACK Breast cancer most crowded with 7 agents in development; particular focus on HER2(+) and HR(+) subsets no registration trials planned, yet Endometrial tumors as prototype for I3K/mTOR pathway activation; Novartis planning two relatively large phase II studies, potential quick to market strategy Ongoing phase III trial with inhibitor perifosine in r/r colorectal cancer; KRASmut subset targeted by Roche and Novartis/GSK with I3K/ dual inhibition MK 2206 BKM120 erifosine GDC0941 MK 2206 GSK-1795 Breast Cancer XL147 GDC0980 XL765 BEZ235 Endometrial BKM120 XL147 GDC0980 BEZ235 Colorectal MK 2206 BKM120 GDC0941 GDC0980 Lung MK 2206 BKM120 GDC0941 XL147

5 DAVAOncology, L Tyrosine Receptor Kinase I3K p85 p110 TEN TORC1 RAS I2 I3 Activation of I3K by either GFR signaling or activating mutations in either p85 or p110a IK3R1 (85) mutation Endometrial: 20% Breast: 2% Colon: 8% IK3CA (110) mutation Endometrial: 40% Breast: 26% Colon: 13% I3K mutations are not prognostic for patient outcome, but are predictive for response to I3K inhibition ERK Competitor Challenge: Novartis

6 DAVAOncology, L BACK While first to clinic with BEZ235, bioavailability issues prompted reformulation into drinkable solution planned phase II trials appear contingent on ongoing phase I of twice daily dosing with sachet formulation BKM120 associated with mood disorders; ongoing studies exclude pts with history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, CTCAE grade 3 anxiety BKM120 Breast Lung Endometrial Glioblastoma Solid tumors + Trastuzumab in HER2(+) + ac ± Trastuzum ab h IIb: vs. Doc or em h II: Single Agent h II: + Bevacizumab + GSK () + ac/carbo BEZ235 lanned h II in HR(+): Single Agent Tam ± BEZ235 (SU2C) lanned h II: Single Agent Sachet Formulation ac ± Trastuzumab BYL719 Single Agent, (I3Kmut/ TENwt) 3 phase III trials with everolimus in BC: BOLERO 1: 1L HER2(+) MBC BOLERO 2: 2L HR(+) MBC BOLERO 3: 2L+ HER2(+) MBC BYL719 is a p110a-specific inhibitor; TEN mutations predict for resistance because of signaling through p110ß

7 DAVAOncology, L Tyrosine Receptor Kinase I3K p85 p110 TEN TORC1 RAS I2 I3 TEN loss, but not I3K mutational status, predicts for I3K pathway activation I3K and TEN loss both predictive for sensitivity to I3K pathway inhibition Endometrial HR+ breast HER+ breast IK3mut TEN loss TEN/I3K Triple negative breast ERK Colorectal

DAVAOncology, L Tyrosine Receptor Kinase I3K p85 p110 TEN TORC1 RAS I2 I3 hosphorylated is a biomarker for I3K pathway activation Activation of requires phosphorylation of both the threonine residue

8 DAVAOncology, L Tyrosine Receptor Kinase I3K p85 p110 TEN TORC1 RAS I2 I3 hosphorylated is a biomarker for I3K pathway activation Activation of requires phosphorylation of both the threonine residue through I3K as well as the serine residue by TORC2 p473 p308 TEN I3Kmut ERK IK3CA kinase domain mutation IK3CA helical domain mutation IK3CA other mutation 1 E17K mutation Competitor Challenge: Merck

9 DAVAOncology, L BACK Merck opened up the development of MK2206 to several cooperative groups, a collaboration with MDACC, and various investigator-initiated studies. This utilization of MK2206 in a wide variety of tumor types may result in relevant OC data supportive of a registrational strategy Merck s internal development plan for targeted agents focuses on a mix & match strategy, including combinations of MK2206 with IGF1R Mab dalutuzumab and rapalogue ridaforolimus MK2206 (Merck-sponsored) MK2206 (Other sponsor) Breast Lung Colorectal Solid tumors + Trastuzumab + T/Lapatinib + Dalotuzumab (IGF1R) + Dalotuzumab (IGF1R) + Ridaforolimus + aclitaxel/carbo + Docetaxel Breast Lung Colorectal Renal rostate Endometrial h II: Single Agent (I3Kmut and/or TEN loss) + Lapatinib in HER2(+) + AI in HR(+) + aclitaxel + ac/h in HER2(+) + Erlotinib or AZD6244 (BATTLE-2) + Gefitinib (Taiwan) h II: Single Agent (I3Kmut and KRASwt) + AZD6244 h IIb: MK2206 vs. Everolimus h IIb (ECOG): Bicalutamide ± MK2206 h II: Single Agent All potential registrational strategies

10 DAVAOncology, L TEN Tyrosine Receptor Kinase I3K p85 p110 TORC1 I2 I3 RAS I3Kmut loss predicts for response to I3K/mTOR inhibition: MDACC phase I population receiving I3K/mTOR pathway inhibitors: 6% ORR in unselected pts vs. 21% in I3Kmut pts Simultaneous RAS mutation associated with resistance: ORR in pts with I3KCA mutations without simultaneous KRAS mutations is 31% vs. 6% in those with simultaneous KRAS mutations Response rate: 21% (15/71; 95% CI ERK RECIST change in % Colorectal Endometrial Cervical squamous Head and neck Small intestine Gastric # -80 Ovarian Breast Anal Renal -100 Non-small cell lung Simultaneous KRAS mutation + Simultaneous NRAS mutation # Simultaneous B mutation

11 DAVAOncology, L BACK Response rate: 21% (15/71; 95% CI RECIST change in % Colorectal Endometrial Cervical squamous Ovarian Breast Head and neck Small intestine Gastric Anal Renal # -100 Non-small cell lung Simultaneous KRAS mutation + Simultaneous NRAS mutation # Simultaneous B mutation

12 DAVAOncology, L Tyrosine Receptor Kinase I3K p85 p110 TEN TORC1 I2 I3 RAS ERK hase I Combinations h I: BKM120 (I3K) + GSK () [Novartis; n:60; 2Q 10] h I: GDC-0941 (I3K) + GDC-0973 () [Genentech; n:62; 4Q 09] h I: MK2206 () + AZD6244 () [NIH; n:38;1q 11] h I: GSK () + GSK () [GSK; n:125;2q 10] Dual inhibition of the RAS/ and I3K/ mtor pathway KRAS mutation and I3K pathway activation may occur simultaneously Alternatively, I3K pathway inhibition may be synergistic with inhibition in KRAS or B mutated tumors Biological Rationale for Dual Inhibition in mcrc

DAVAOncology, L BACK KRASmut only Bmut only KRASmut and I3K/TEN Bmut and I3K/TEN I3K/TEN only wildtype Quadruple negative: EGFR mabs KRASmut or Bmut only: &

13 DAVAOncology, L BACK KRASmut only Bmut only KRASmut and I3K/TEN Bmut and I3K/TEN I3K/TEN only wildtype Quadruple negative: EGFR mabs KRASmut or Bmut only: & inhibitors? Synergy with I3K/ mtor inhibition I3K pathway only: I3K/mTOR inhibitors KRASmut and I3K pathway: + I3K/mTOR inhibitors (Shimizu. ASCO 2011: #2502)

10/15/2012. Overcoming Endocrine Therapy Resistance. The Problem in ER+ Tumors is Endocrine Therapy Resistance

10/15/2012. Overcoming Endocrine Therapy Resistance. The Problem in ER+ Tumors is Endocrine Therapy Resistance Overcoming Endocrine Therapy Resistance Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology US Oncology Slide Credits: Hope Rugo, MD The Problem in ER+ Tumors is Endocrine Therapy Resistance