Targeting the PI3 kinase mtor pathway in breast cancer. Dr Nicholas Turner. Madrid 2014

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1 Targeting the PI3 kinase mtor pathway in breast cancer Dr Nicholas Turner Madrid 2014

2 Relevant disclosures Honoraria and/or Research funding Novartis AstraZeneca Roche

3 Targeting PI3 kinase mtor pathway ER positive breast cancer Predicting benefit from everolimus PI3 kinase inhibitors HER2 positive breast cancer PIK3CA mutations and resistance to trastuzumab TN breast cancer

4 The PI3K/AKT/mTOR pathway activation in cancer GPCR RTK RAS RTK activation and RAS mutation PI3K PIK3CA mutation PIP 2 PIP 3 PTEN AKT mtorc2 PTEN inactivation Other effectors mtorc1 AKT1 mutation Growth & Proliferation Angiogenesis Metabolism Key role in multiple cellular processes = Genetic aberration Liu P, et al. Nat Rev Drug Discov. 2009;8(8): GPCR, G protein-coupled receptor; mtor, mammalian target of rapamycin; mtorc1, mtor complex 1; PI3K, phosphatidylinositol 3-kinase; PIP 3, phosphatidylinositol-3,4,5-triphosphate; PIP 2,phospha-tidylinositol-3,4,5- diphosphate; RTK, receptor tyrosine kinase.

5 Drugging the PI3K/AKT/mTOR Pathway Rodon J, et al. Nat Rev Clin Oncol. 2013;10(3):

6 ER positive breast cancer PI3 kinase pathway is activated during endocrine resistance

7 Activation of PI3K/AKT/mTOR pathway in endocrine resistance cell lines Zoncu et al Nat Rev MCB 2011 Miller et al J Clin Invest. 2010

8 mtor inhibition to reverse endocrine therapy resistance DiCosmo and Nat Rev Clin Oncol 2010 S6K directly phosphorylates ER on ser167 Yamink JCB 2009

9 TAMRAD STUDY Randomized Phase II Metastatic patients with prior exposure to AI A : Tamoxifen, 20 mg/d (TAM) B : Tamoxifen 20 mg/d + RAD mg/d (TAM + RAD) Stratification: Primary or secondary hormone resistance Primary: Relapse during adjuvant AI; progression within 6 months of starting AI treatment in metastatic setting Secondary: Late relapse ( 6 months) or prior response and subsequent progression to metastatic AI treatment No crossover planned Bachelot et al JCO 2012

10 Everolimus benefit in overall population Time to Progression Overall Survival Bachelot et al JCO 2012

11 Randomized Phase III Trial Exemestane ± RAD001 (everolimus) in postmenopausal women with ER+ve LABC / MBC refractory to letrozole or anastrozole (BOLERO II) ER+ve LABC or MBC Measurable sites of advanced disease, or if bone alone lytic or mixed Refractory to NSAI defined as either as relapse on / <12 mo since adjuvant Rx, or progression on ABC Rx R 2:1 N=705 pts Exemestane + everolimus 10 mg/day Exemestane + placebo Stratification for: - Sensitivity to prior endocrine Rx - Visceral disease Primary Endpoint PFS - powered to detect a hazard rate 0.76 (35% improvement in median PFS 3.7 to 5.0 months)

12 Everolimus to reverse endocrine therapy resistance Median PFS increased from 2.8 months to 6.9 months Response rate 0.4% vs 9.5% p<0.001 Baselga et al NEJM 2012

13 Who benefits from everolimus? Clinical predictors of benefit

14 TAMRAD - Who to select for everolimus? Primary resistance Relapsing on adjuvant AI <6 months AI in advanced setting Secondary resistance Relapsing >6 months after adjuvant AI >6 months AI in advanced setting

15 BOLERO 2 subset analysis No evidence of clinical subgroups that derive relatively more or less benefit

16 Everolimus indication European license Treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.

17 Everolimus in Breast Cancer: Expanding Into the Adjuvant High-Risk Setting SWOG-NSABP Phase III study; N = 3400 Pre and postmenopausal women with HR + HER2 breast cancer Prior standard neoadjuvant or adjuvant chemotherapy Everolimus 10 mg/d for 1 yr + endocrine therapy for 5 yrs Placebo for 1 yr + endocrine therapy for 5 yrs Primary endpoint: Invasive DFS Secondary endpoints: OS, DRFS, biomark ers, safety Stratification: Node negative (all RS >25) 1-3 positive lymph nodes (all RS >25) 4 positive lymph nodes and RS 25 4 positive lymph nodes and RS >25 Neoadjuvant chemotherapy UNICANCER Phase III study; N = 2010 Pre and postmenopausal women with HR + HER2 breast cancer ( 4 + nodes) Relapse-free after 2-3 yrs of adjuvant endocrine therapy Everolimus 10 mg/d for 2 yrs + AI or Tamoxifen Placebo for 2 yrs + AI or Tamoxifen Primary endpoint: DFS at 2 yr Secondary endpoints: OS, biomarkers, saf ety Stratification: Endocrine therapy (Tamoxifen vs AIs) Adjuvant chemotherapy AI, aromatase inhibitor; DFS, disease-free survival; DRFS, distant recurrence-free survival; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; SWOG-NSABP, Southwest Oncology Group-National Surgical Adjunct Breast and Bowel Project; OS, overall survival

18 Biomarkers to select patients for everolimus?

19 Genetics of primary breast cancer TCGA Nature 2012

20 Tumor Sample Analysis in BOLERO-2 Fixed sample slides Sequencing (Illumina HiSeq TM 2000) Analysis Point Mutations Short Insertions/Deletions Copy Number Alterations Rearrangement - n=227 NGS is representative of n=724 ITT DNA extraction, Library construction, Hybrid capture (Agilent SureSelect TM ) - Used routine FFPE samples, but from primary tumour rather than the metastatic disease that being treated Abbreviations: COSMIC, Catalogue of Somatic Mutations in Cancer; dbsnp, Single Nucleotide Polymorphism Database. Hortobagyi et al ASCO

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22 Impact on Treatment by Genetic Status The Most Frequently Altered Single Genes and Pathways Alt : PIK3CA WT : PIK3CA Alt : PI3K WT : PI3K Alt : CCND1 WT : CCND1 Alt : Cell Cycle WT : Cell Cycle Alt : TP53 WT : TP53 Alt : p53 WT : p53 Alt : FGFR1 WT : FGFR1 Alt: FGFR1/2 WT : FGFR1/2 Positive treatment effect in favor of everolimus across the various genetic marker subgroups Pathway composition PI3K: PIK3CA, PTEN, AKT (PIK3CA Alt: 47.6%, total alteration: 55.5%) Cell Cycle: CCND1, CDK4, CDK6, CDKN2A, CDKN2B, (CCND1 Alt: 31.3%, total alteration: 35.7%) p53: TP53, MDM2, MDM4 (TP53 Alt: 23.3%, total alteration: 36.1%) FGFR1/2: FGFR1, FGFR2 (FGFR1 Alt: 18.1%, total alteration: 21.1%) HR of NGS population Genetically altered (Alt) Wild Type (WT) log 10 (hazard) EVE+EXE better 22

23 Why no significant genetic predictors?

24 Pathway activation may be acquired as a common feature of endocrine resistance Zoncu et al Nat Rev MCB 2011 Miller et al J Clin Invest. 2010

25 PIK3CA mutations do not correlate with pathway activation TCGA Nature 2012

26 Tumor Sample Analysis in BOLERO-2 Fixed sample slides Sequencing (Illumina HiSeq TM 2000) Analysis Point Mutations Short Insertions/Deletions Copy Number Alterations Rearrangement - n=227 NGS is representative of n=724 ITT DNA extraction, Library construction, Hybrid capture (Agilent SureSelect TM ) - Used routine FFPE samples, but from primary tumour rather than the metastatic disease that being treated Abbreviations: COSMIC, Catalogue of Somatic Mutations in Cancer; dbsnp, Single Nucleotide Polymorphism Database. Hortobagyi et al ASCO

27 Genetic events are acquired in metastatic breast cancer ESR1 mutations occur in 20% of endocrine resistant ER positive breast cancer Biomarker analysis of primary tumours is limited by acquired genetic events Relevance of ESR1 and RPTOR mutations to everolimus?

28 Acquired mutations causes resistance to everolimus in vitro Rodrik-Outmezguine et a SABCS 2013

29 Acquire mutations causes resistance to everolimus in vitro Rodrik-Outmezguine et a SABCS 2013

30 Why is it hard to biomark everolimus benefit? PI3 kinase mutations do not predict for benefit Acquired changes in the genetics of metastatic breast cancer complicate analysis

31 PI3 kinase inhibitors A way to target PIK3CA mutant breast cancer?

32 PI3 kinase inhibitors in clinical development - Multi-targeting PI3 kinase mtor inhibitors Mainly limited by toxicity rash and pneumonitis - Class 1 PI3 kinase inhibitors (inhibit both alpha/beta) leading agents in later stage trials BKM120 GDC0941 (alpha>beta) Dosing likely limited by combined inhibition - Alpha selective inhibitors

33 Efficacy of BKM120 and letrozole 90% patients prior endocrine therapy in the metastatic setting Baseline Day 15 FDG-PET/CT scans BKM mg/day continuously Letrozole 2.5 mg/day Post-menopausal patients with hormone receptor-positive MBC BKM mg/day intermittent (5 days on, 2 days off) Letrozole 2.5 mg/day ASCO 2012 Mayer et al

34 Efficacy of BKM120 and letrozole Clinical benefit Benefit not restricted to PIK3CA mutant patients ASCO 2012 Mayer et al

35 PIK3CA mutations do not correlate with pathway activation TCGA Nature 2012

36 PIK3CA Mutations in Breast Cancer ~40% of ER positive breast cancer have PIK3CA mutations PIK3CA mutations are oncogenic Adaptor binding domain Ras binding C 2 PIK (helical ) Catalytic domain (kinase) R38H R38C R88Q R93Q R93W N34 5K C42 0R E36 5K E45 3Q P539R E542K E545K E545A Q546K Q546P M1043I M1043V H1047R H1047L H1047Y

37 Selective targeting of PI3K alpha (PIK3CA) Two leading selective inhibitors Inhibit alpha >> beta BYL719 (alpha selective) GDC0032 (beta sparing) Clinical responses with BYL719 in PIK3CA mutant cancer Primary site of cancer Breast Colorectal Head and Neck Other 40 (n = 29) Best % Change From Baseline Treatment group (mg QD): Duric et al AACR 2012

38 Selective targeting of PI3K alpha (PIK3CA) Two leading selective inhibitors Inhibit alpha > beta BYL719 (alpha selective) GDC0032 (beta sparing) Clinical responses with GDC0032 in PIK3CA mutant cancer Duric et al ESMO 2013

39 GDC-0032 and Fulvestrant high activity Duric et alsabcs 2013

40 PIK3CA mutations and resistance to HER2 targeting

41 Activation of PI3 kinase pathway induces resistance to HER2 targeting Loss of PTEN Mutation of PIK3CA Eichhorn et al Cancer Res 2008

42 PIK3CA mutation predicts resistance to anti- HER2/chemotherapy in primary HER2-positive/Hormonereceptor-positive breast cancer prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies Sibylle Loibl, Carsten Denkert, Andreas Schneeweiss, Stephan Paepke, Annika Lehmann, Mahdi Rezai, Peter Zahm, Peter Sinn, Fariba Khandan, Holger Eidtmann, Karel Dohnal, Jens Huober, Sherene Loi, Berit Pfitzner, Peter A. Fasching, Fabrice Andre, Judith Lindner, Christos Sotiriou, Sanxing Guo, Stephan Gade, Valentina Nekljudova, Michael Untch, Gunter von Minckwitz for the GBG and AGO-B study groups Loibl SABCS 2013

43 GeparSixto N=595 centrally confirmed TNBC or R HER2-positive breast cancer PM Surgery PMCb Paclitaxel 80 mg/m² q1w Non Pegylated liposomal doxorubicin (Myocet ) 20 mg/m² q1w Carboplatin AUC 1.5* q1w Her2-pos: Trastuzumab 6(8) mg/kg q3w (for 1 year) Lapatinib 750 mg/d 18 wks TNBC: Bevacizumab 15 mg/kg q3w *reduced from AUC 2 at amendment 1 after enrollment of 330 patients Loibl SABCS 2013

44 pcr rate according to PIK3CA mutation status in GeparSixto study pcr 60% P=0.003 P=0.009 PIK3CA mut PIK3CA wt P= % P= ,1% 40% 41,6% 37,1% 40,0% 30% 20% 22,4% 17,0% 29,9% 10% 0% 6,3% All HER2+ HER2+/HR+ HER2+/HR- N= 512 N= 241 N= 149 N= 92 Loibl SABCS 2013

45 Study X2107: BKM120 Plus Trastuzumab in HER2+ Trastuzumab- Resistant BC Best Percentage Change From Baseline in Sum of Longest Diameters* X X X X X X PD SD PR CR n= *Data shown comprise patients with known percentage change in target lesions. 8% PR, 49% CBR Unconfirmed partial responses. Pistilli B, et al. ESMO. 2012;.

46 Triple negative breast cancer

47 PI3 kinase pathway is active in basal-like breast cancer

48 INPP4B is not expressed in basal-like breast cancer Gewinner et al Cancer Cell 2009

49 PI3K alterations in TN breast cancer PTEN genetically lost in ~10% of TNBC Shah et al Nature 2012

50 Loss of PTEN activates AKT in breast cancer sirna PTEN in TNBC cell line PTEN loss correlates with AKT activation pakt 308 pakt 473 SUM52 PTEN Mut/HOMD PTEN WT TCGA Nature 2012

51 AKT inhibitors targeting loss of PTEN Cancer with PTEN loss may be particularly sensitive to AKT inhibitor GDC-0068 Lin et al CCR 2-13

52 AKT inhibitors show substantial synergy with taxanes Activity of AZD5363 in combination with docetaxel in TN cell line Clinical development Combination in taxane PIK3CA mutant PTEN mutant /deleted Davies MCT 2011

53 Conclusion At this time there are no biomarkers for everolimus benefit (other than ER positive) PIK3CA mutation does not predict for benefit to everolimus but may predict for sensitivity to PI3 kinase inhibitors potentially alpha specific/beta sparing inhibitors PTEN loss may be targetable through AKT inhibition