PI3K Inhibitors. July 20, 2012

Transcription

1 PI3K Inhibitors Roy S. Herbst, MD, PhD Professor of Medicine and Pharmacology Chief of Medical Oncology Director, Thoracic Oncology Research Program Associate Cancer Center Director for Translational Research July 20, 2012

2 PI3K/AKT/mTOR Axis PI3Ks: family of lipid kinases that propagate intracellular signaling regulating cell development, growth, metabolism, and survival Courtney KD et al, JCO 2010 Pathway activated in cancer through several mechanisms (mutations, amplifications, deletions) RTKs (EGFR, HER2, PDGFR) engage PI3K pathway P110 binds Ras directly Tumor initiation and maintenance Mutations can be transforming Alterations in axis signaling usually at multiple levels Signaling can be AKT- independent PI3K/AKT/mTOR as a therapeutic target Inhibit growth and proliferation Sensitize to programmed cell death

3 PI3K pathway relevant from early development process to established Lung Cancer Airway PI3K pathway activation is an early and reversible event in lung cancer Involvement in tobacco carcinogen-induced cellular transformation and invasion Increased expression of genes induced by PI3K activation in smokers with dysplasia Frequent AKT activation / mtor phosphorylation in NSCLC >70% NSCLC patients have active AKT specifically in tumor Association with shorter OS pakt overexpression and PTEN loss confers poor prognosis in NSCLC Dysregulated PI3K/AKT/mTOR signaling involved in upregulation of CXCR4 - metastasis Gustafson et al, 2010; Balsara et al, 2004; West et al. 2004; Tsurutani et al. 2006; Tang et al. 2006; Phillips et al. 2005

4 Engelman JA, Nat Med 2008 Faber AC et al, PNAS 2009 Targeting PI3K/AKT/mTOR Pathway in Lung Cancer Murine established lung cancers induced by mutant PIK3CA are highly sensitive to single agent PI3K-mTOR inhibitor But this scenario may not be the most common one clinically Single agent PI3K-mTOR inhibitor not very active against EGFR mutantdriven lung cancer but combined PI3K-mTOR and MEK inhibition will effectively suppress growth Growth of KRAS mutated lung tumors can be suppressed with combined PI3K and MEK inhibitors

5 PI3K Pathway and Mechanisms of Acquired Resistance to RTKIs Reactivation of PI3K pathway is associated with acquired resistance to EGFR TKI Sequist L V et al. Sci Transl Med 2011 Engelman JA, Nat Rev Ca 2009

6 Combined PI3K/MEK Targeting Can Overcome An Antiapoptotic State PI3K signaling promotes MCL-1 expression and MEK signaling inhibits BIM expression in EGFR mutant NSCLC Combined PI3K and MEK inhibition is necessary for optimal cell death Effect observed in both EGFR L858R/T790M transgene murine lung cancer and xenografts of human NSCLC with both mutations Faber AC et al, PNAS 2009 & Cell Cycle 2010

7 Targeting PI3K Axis in Lung Cancer Optimal targeting the PI3K/AKT/mTOR pathway will be dependent on better understanding the molecular and signaling profile of a given tumor Vertical vs. Horizontal blockade of the pathway Single agent (in PIK3CA activating mutations) Combinations (i.e. MEK inhibitors) in KRAS or EGFR mutated cancers Other combinations: Antiangiogenic agents, IGF1R inhibitors, Embryonic Signaling inhibitors, c-met inhibitors, etc. Right choice of type of PI3K inhibitors

8 PI3Kinase Pathway Inhibitors in Clinical Trials Dual-PI3K and mtor inhibitors (catalytic site inhibitors of p110 isoforms and mtor) BEZ235, BGT226, XL765, PF Pan PI3K inhibitor Irreversible - PX 866 Reversible XL147, GDC-0941, BKM120 PI3K-Isoform-specific inhibitors (PI3Ka) Cal-101, GDC-0032, BYL719, INK1117 AKT inhibitor MK-2206, GDC-0068 mtor inhibitors Catalytic site - AZ8055, AZ2014, INK128 Rapalogs (mtorc1) Temsirolimus, Everolimus P. LoRusso, TAT 2011

9 BEZ235 Novartis Pharma imidazo[4,5-c]quinoline derivative 1 st -in-class dual pan-class I PI3K and mtor inhibitor Binds ATP-binding cleft of p110α subunit of PI3K (mutant and nonmutant forms) & mtor complexes 1/2 Potent, oral, highly selective, and reversible Broad antiproliferative effect in different tumor type models Pro-apoptotic effect in PI3K-pathway activated models Antiangiogenic Courtesy: adapted from David Spigel, S. Ramalingam, and P. LoRusso Maira SM. Mol Cancer Ther, Serra V. Cancer Res, 2008.

10 BEZ235 FIH Phase I Multicenter Study N=59 (22% breast, 17% CRC) Doses of mg/oral once daily No DLTs N/V, diarrhea, fatigue, anemia, and anorexia (mild-moderate, reversible) AUC and C max increased non-proportionally with dose Exhibited dose- and day-dependent PI3K inhibition measured by elevation of plasma C-peptide levels 51% w/decreased 18FDG uptake 2 PR (1 LC Cowden syndrome, 1BC) 16 MR 27% SD x 4 mos (29% BC) 43% with PI3K abnormalities (PIK3CA mut, PTEN mut) New formulation in study Burris H, ASCO Abst 3005, 2010

11 BEZ 235: Ongoing/Planned Phase 1 Combinations and Phase 2 Lung Ca Trials PhI oral BEZ235 in combination with weekly paclitaxel (with trastuzumab in a breast cancer cohort) PhI/II BEZ235 plus MEK inhibitor MEK162 EGFR mutant NSCLC progressors post EGFR inhibitor TNBC Ras/BRaf mutant solid tumors

12 BKM120: An Orally Available Potent Selective Inhibitor of PI3K ATP competitive, highly specific inhibition of class I PI3K Antiproliferative activity in tumor cell lines (GI nm) Pro-apoptotic activity in PIK3CA-mutated breast cancer cell lines Potent anti-tumor activity in tumor xenograft models with or without PI3K/PTEN mutations Class I PI3Ks Class III PI3Ks H 2 N F F N F Enzyme O N N N N O IC 50 (nm) p110a 52 ± 37 p110a-h1047r 58 ± 2 p110a-e545k 99 ± 6 p110b 166 ± 29 p110d 116 p110g 262 ± 94 mtor 4610 ± 1860 DNAPK >5000 Panel of >18 protein kinases >10000 Courtesy: adapted from A. Jimeno and S. Ramalingam U

13 BKM120 Phase I: Summary MTD of BKM120 on a continuous daily schedule is 100 mg BKM120 demonstrates a favorable PK profile at the MTD Consistent pharmacodynamic effects Compensatory increases in fasting C-peptide Suppression of S6 phosphorylation in skin (30-80% decrease) Tumor metabolic response observed in most patients Evidence of single-agent activity in patients with heavily pretreated advanced cancer with and without PI3K pathway alterations (45 evaluable for response) 2 PR (TNBC w/kras & p53 mut; mbc w/pik3ca mut) 58% (26/45) with SD as best response Median duration on treatment 7.5 wks Update ASCO 2011, B. Grana et al. (abstr 3043) U

14 Best percentage change from baseline in sum of longest diameters BKM120 Phase I: Clinical Efficacy by Radiologic Assessment and Overall Response PIK3CA PTEN KRAS Resp a PD PD PD PD PD PD PD SD NA SD SD SD PD SD SD SD NA SD SD SD SD SD SD PR WT / Normal Altered (mutation/expression) Colorectal Breast Other -70 n=24 patients had measurable disease and baseline and post-baseline target lesion assessments -90 Pt Dose (mg) Courtesy: adapted from A. Jimeno and S. Ramalingam U

15 BKM120 Phase I: BKM120 Decreases ps6 Levels in Skin Pre Post % change in H-score 75% 85% 64% Patient mg/day Patient mg/day Patient mg/day Courtesy: adapted from A. Jimeno, U. Colorado U

16 Most Frequent AEs All Grades Decreased appetite (33%) Rash (27%) Diarrhea (27%) Nausea (27%) Fatigue (24%) Hyperglycemia (24%) Anxiety (20%) Depression (18%) Mucositis (18%) Update ASCO 2011, B. Grana et al. (abstr 3043)

17 BKM120: Ongoing/Planned Phase 1 Combinations and Phase 2 Lung Ca Trials Phase II: Pretreated squamous and non-squamous NSCLC Pathway activated tumors PI3K mutation PTEN mutation Loss of PTEN (IHC) Randomization to docetaxel or pemetrexed or BKM120 Primary endpoint: PFS PhI/II BKM120 plus MEK inhibitor MEK162 EGFR mutant NSCLC progressors post EGFR inhibitor TNBC Ras/BRaf mutant solid tumors PhI BKM120 plus carbo/taxol in advanced solid tumors PhI BKM120 plus GSK (MEK inhibitor) in RAS/RAF mutant tumors and TNBC

18 PX 866 Synthesis of PX-866 In-vivo irreversible reaction between PX- 866 and PI-3 kinase Covalently bound complex Wortmannin PX-866 PX-866 and PI-3K adduct Diallylamine PI-3 kinase Diallylamine Orally available pan-isoform inhibitor Only irreversible inhibitor in development as of now Potent (nanomolar) and selective PI-3K inhibition Covalent binding to PI-3K Preclinical: active in nanomolar concentrations as a single agent and in combination

19 Phase 1 PX-866 Single Agent Study 71 patients enrolled and treated Once daily oral dosing Intermittent (d1-5, 8-12) and continuous (d1-28) schedules; repeating 28 day cycles Intermittent (n=51): MTD 12 mg/day Continuous (n=20): MTD 8 mg/day Overview Continuous schedule with similar safety, better disease control (42%) than intermittent schedule Most common AEs diarrhea, nausea, vomiting, reversible ALT/AST elevation Jimeno et al. ASCO 2010, EORTC/NCI/AACR 2010 Courtesy: adapted from A. Jimeno, U. Colorado 19

20 Treatment History, Best Response, Mutational Status, and Time on Study Courtesy: adapted from A. Jimeno

21 PX 866: Ongoing/Planned Phase 1/2 Combinations and Lung Ca Trials Phase I/II of PX 866 plus cetuximab Phase I: dose escalation- RPh2D for PX 866 with standard dose cetuximab Phase II: Randomized design Progressive, recurrent/metastatic HNSCC Progressive or recurrent KRAS-WT CRC Ph I/II of PX 866 plus docetaxel Single arm 2 stage design 2 nd /3 rd line NSCLC 2 nd /3 rd line HNSCC

22 GDC-0941 Wagner et al, ESMO 2010

23 GDC-0941 Wagner et al, ESMO 2010

24 GDC-0941 Wagner et al, ESMO 2010

25 GDC-0941 Wagner et al, ESMO 2010

26 GDC-0941: Ongoing/Planned Phase 1/2 Combinations and Lung Ca Trials Phase Ib of GDC-0941with carbo/paclitaxel with or without bevacizumab in NSCLC Arm A (Bev ineligible): GDC-0941 dose escalation- C AUC 6/P 200 q 3 wks Arm B (Bev eligible): GDC-0941 dose escalation C6/P200/B 15 mg/kg q 3 wks Both arms: GDC-0941 once daily, D 1-14 So far 18 pts enrolled. Cohorts 60, 100 and 165 mg (Arm A) and 100, 165, 250 mg (Arm B) Most treatment-related AEs G1 and 2 G3 (16%) and G4 (11%) neutropenia (not dose-limiting) Target exposures achieved in 250 mg cohort MTD not yet reached. Dose escalation will continue up to 400 mg Confirmed PRs in 8/18 (44%) Besse B et al, ASCO 2011 Ph I GDC-0941 plus erlotinib in advanced solid tumors and NSCLC

27 MK-2206 P. LoRusso, TAT 2011

28 MK-2206 P. LoRusso, TAT 2011

29 MK-2206 P. LoRusso, TAT 2011

30 MK-2206 P. LoRusso, TAT 2011

31 Phase II Trial of Erlotinib + MK2206 in Advanced NSCLC (California & Chicago N01s) Advanced NSCLC Progressed on Erlotinib after prior response Tumor Tissue Available S T R A T I F Y EGFR Mutant EGFR WT Erlotinib + MK2206 Erlotinib + MK2206 MK2206: ~45 mg QOD Erlotinib: 150 mg/d Erlotinib + MK2206 in NSCLC: Potentiation of Activity & Reversal of HGF-induced Resistance PI: LARA

32 Other Ongoing/Planned PI3K Pathway Inhibitors Clinical Trials (Combos & Lung Ca) PhI XL765 and erlotinib in solid tumors PhI XL147 and Carbo/paclitaxel in solid tumors, nsclc, ovarian ca, endometrial ca. PhI XL147 and MEK inh MSC B, locally advanced or metastatic solid tumors with alterations in PI3K or MAPK pathways.

33 PI3K and Lung Cancer PI3K+ MEK inhibitor- KRas mutant NSCLC PI3K inhibitors as single agents in select patients with PI3K driven NSCLC PI3K inhibitors in treating those with acquired resistance to EGFR TKI?

34 The rationale for dual pathway targeting MK-2206 MK-2206 AZD Inhibition of proximal + distal signaling to circumvent limited efficacy of downstream pathway inhibition by release of feedback loops. - Blockade of RAS/RAF axis + PI3K signaling (parallel) may overcome reciprocal pathway activation through release of negative feedback loops+ compensatory activation of redundant pro-survival pathways. Adapted from Drug Resistance Updates 2008; 11:32-50

35 Pathways Targeted in BATTLE-2 GF EGFR TKI (erlotinib) Ras Raf/VEGFRi Sorafenib AKTi (MK-2206) MEKi (AZD6244)

36 Selumetinib (AZD6244, ARRY ) H O O H N O H N C l N N F B r Potent uncompetitive inhibitor of MEK 1/2. IC nm > 300-fold selective vs 33 other kinases tested In vitro inhibitory activity on growth of cancer cell lines: CRC, pancreatic, melanoma, NSCLC, multiple myeloma, thyroid cancer Particularly potent in inhibiting V600E BRAF and KRAS mut carrying cells Initial formulation phase I: oral suspension, currently capsule formulation (AZD6244 Hyd- Sulfate). RPTD: 75 mg bid (rash, fatigue, diarrhea, n/v, edema) Clinically demonstrated monotherapy activity in NSCLC (no difference in PFS compared to pemetrexed), responses (KRAS mut status unknown), improved PFS in combination with docetaxel vs docetaxel (PASCO 2012)

37 Combination Treatment with MEK and AKT inhibitors MDACC-AZ Alliance Meng J et al.one, 2010 Tolcher et al, ASCO 2011

38 A phase I dose escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; ARRY ) (MEK inhibitor) in patients with advanced or metastatic solid tumors. Baseline Cycle 4 Day 1 NSCLC KRAS Mutant, PR after Course 2 Tolcher AW et al, ASCO 2011, abstr#77652, NCT

39 BATTLE-2 Schema Discovery Markers: EML4-ALK Fusion or EGFR Μut exclusion Protocol enrollment Biopsy performed Stage 1: (n=200) Adaptive Randomization by KRAS mut status Statistical modeling and biomarker selection Stage 2: (n=200) Refined Adaptive Randomization Best discovery markers/signatures Protein expression (IHC): FOXO3A, nuclear EGFR, p-akt (Ser473), PTEN, HIF-1a, LKB1 Mutation analysis (Sequenom): PI3KCA, BRAF, AKT1, HRAS, NRAS, MAP2K1 (MEK1), MET, CTNNB1, STK11 (LKB1) mrna pathways activation signatures: Affymetrix - BATTLE-1: WT-EGFR- Erlotinib, EMT, and Sorafenib - BATTLE-2: new discovery signatures Erlotinib Sorafenib Erlotinib+AKTi MEKi+AKTi Protein profiling RPPA (n=174) Primary endpoint: 8-week disease control (N = 400) 1R01CA funding MDACC/Yale (Herbst/Papadimitrakopoulou)

40 Clinical trial accrual updates Total 4/27/12-5/24/12 Patients screened Patients consented &registered Biopsies performed Screen Failures 39 6 Patients Randomized 75 2 Patients Treated 73 2 Tx Tarceva 4 0 Tx Tarceva/MK (4) 1 Tx MK-2206/AZD (6) 1 Tx Sorafenib 26 0 Primary endpoint reached 68 8 Screen failures: 2 EGFR+, 4-pathology, 6 complicating illness, 11-QTc prolong, 2-ALK+, 1-insurance, 2-LVEF, 2-CrCl, 2-Prog. Br mets, 2-gen.lab, 1-hemoptysis, 1-alt Tx, 2-no measurable disease

41 7/26/ /5/2011 Treatment: Arm 4, sorafenib KRAS mut in codon 12 (GGT to GAT) Gly to Asp (G12D)

42 Safety profiles MK selumetinib MK-2206 Rash (generally maculo-papular) Fatigue Diarrhea Nausea Vomiting Increases in blood glucose Pruritis Pyrexia Dry skin Anorexia Stomatitis selumetinib Rash (including dermatitis acneiform and exfoliative rash) Fatigue Diarrhea Nausea Vomiting Facial and/or peripheral oedema Dyspnea Blurred vision Hypertension Increases in ALT/AST Mucositis Hyperphosphataemia Combination AES: Diarrhea, vomiting, fatigue, skin rash DLT:Rash (4), diarrhea (1), stomatitis (1), Detached retinal pigment epithelium (1)

43 Targeting the PI3K/AKT/mTOR Signaling Pathway: Conclusions PI3K pathway is a valid target in NSCLC Inhibitors of PI3K/AKT/mTOR are currently under development Activity as monotherapy is limited in unselected patients Studies in pathway-driven tumors are under development Still, even in selected patients with specific mutation/deletions, single agents may be inadequate Rational combinations are needed Challenges Understanding of tumor biology and signaling interactions (compensatory pathways, resistance) Right patient population Reliable PD markers Feasibility of combinations: Relevant doses / Schedules / Toxicities