Targeting the PI3K Pathway in the Therapy of Breast Cancer: Current Status and Future Directions. José Baselga MD, PhD Physician-in-Chief
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1 Targeting the PI3K Pathway in the Therapy of Breast Cancer: Current Status and Future Directions José Baselga MD, PhD Physician-in-Chief
2 PI3K and Breast Cancer Overview The Pathway PI3K drives resistance to Anti-HER2 therapy Clinical Trial Results ER activation upon PI3K inhibition PI3K inhibitors in TNBC
3 The PI3K/Akt/mTOR pathway and Breast Cancer HER2/HER3 Constitutive activation of the PI3K pathway is frequent. PTEN PI3K PIP 3 Ras Raf PI3K pathway activation conveys malignant transformation, cell growth and invasion and tumor neoangiogensis. TORC2 S6 Akt PDK1 Tuberin Rheb TORC1 S6K 4EBP1 MEK Erk Rsk Known mechanisms of PI3K pathway activation include activating mutations of RTKs, gain-of-function mutation of the PIK3CA gene, and loss-offunction mutations of PTEN. PI3K mutations may confer resistance to anti-her2 and hormonal therapy
4 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, CLEOPATRA: Study design 1,2 n = 406 Placebo + trastuzumab PD Patients with HER2-positive MBC Centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD n = 402 Docetaxel* 6 cycles recommended Primary endpoint: Independently-assessed progression-free survival (PFS) Collection of tumor tissue (archival in >90%) and serum samples was mandatory Study dosing q3w: Pertuzumab/placebo: Trastuzumab: Docetaxel: 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated * < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretion 1. Baselga J, et al. SABCS 2011 (Abstract S5-5); HER2, human epidermal growth factor receptor 2; PD, progressive disease 2. Baselga J, et al. N Engl J Med 2012; 366: Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 4
5 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 Prognostic effects independent of treatment arm Intracellular pathway markers, both arms pooled PFS Covariate effect 15 n* HR 95% CI p-value PIK3CA WT , PTEN Cyt H-score , PTEN Nuc H-score , pakt Cyt H-score , pakt Nuc H-score , Target:cen. ratio (c-myc) , * Slide High biomarker levels with better prognosis Low biomarker levels with better prognosis The treatment benefit with the addition of pertuzumab was maintained in all cases HR < 1.00 in all cases (p = < )* Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 5
6 Independently-assessed PFS (%) San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 PIK3CA mutation associated with poorer prognosis Trastuzumab plus placebo arm Pla+T+D: WT 101 events 63 events Time (months) n at risk Pla+T+D WT Pla+T+D Mut Pla+T+D: Mut Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 6
7 Independently-assessed PFS (%) San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 PIK3CA mutation associated with poorer prognosis Both arms n at risk Pla+T+D WT Pla+T+D Mut Ptz+T+D WT Ptz+T+D Mut Pla+T+D: WT Ptz+T+D: WT 101 events 63 events Time (months) Pla+T+D: Mut Ptz+T+D: Mut 83 events 45 events Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 7
8 PI3K pathway inhibitors in clinical trials PI3K PTEN PIP 3 TORC2 Akt PDK1 Tuberin Rheb TORC1 S6 S6K 4EBP1 eif4e-f-g
9 BKM120XUS13T (Mayer) Summary of Phase Ib BKM120 + letrozole in ER+ MBC ER+ HER2 MBC FPFV: Jan2011 Arm A: BKM mg QD (N=20) Arm C: BKM mg 5/7 days (N=31) Arm B: BEZ mg BID (N=20) Endpoints Primary: Toxicity Secondary: Anti-tumor effect Exploratory PIK3CA mut PTEN/Akt1 FDG-PET/CT Current Status: 43/51 pts progressed on an AI DLTs: 1 in Arm A (G3 transaminitis); 1 in Arm C (G3 depression) Arm A: 1 CR, 1 PR; CBR 6 (30%) Arm C: CBR 9 (29%), all still ongoing Arm C better tolerated overall Toxicity Grade 3 Continuous Intermittent Hyperglycemia 10% Fatigue 5% Transaminitis 15% 9% Anxiety 5% Depression 5% 3% Rash 5% 3% Mayer et al. ASCO 2012
10 BKM BELLE-2 Study design overview FPFV July countries ~300 sites 30pts/month Patient Population: HR+/HER2- locally advanced/mbc Post-menopausal AI Resistant No more than 1 prior chemo line allowed for MBC Measurable lesion or bone lesions lytic/mixed mtori naive Adequate amount of tumor tissue for molecular screening (PI3K pathway activation testing) Mood questionnaires All eligibility criteria verified E N T R Y R U N - I N Molecular screening: PI3K activation status determination by Genoptix Fulvestrant 500 mg cycle 1 day 1 R A N D O M I Z A T I O N Stratification Visceral disease PI3K pathway status BKM mg daily + fulvestrant day 15 cycle 1 and day 1 every cycle N=~421 1:1 N=~842 At least 334 PI3K activated Placebo 100 mg daily + fulvestrant day 15 cycle 1 and day 1 every cycle N=~421 Endpoints (patients group) Co-primary PFS (full) PFS (PI3K activated) Co key secondary OS (full) OS (PI3K activated) Secondary PFS, OS (PI3K nonactivated/unknown) ORR, CBR (full, PI3K activated, PI3K nonactivated/unknown) Safety (full) BKM120 and fulvestrant PK EORTC QLQ-C30 (full, PI3K activated) Exploratory Biomarkers SCREENING PHASE From day -21 to day -1 Note: tumor tissue collection & shipment to central lab from day 21 to day -7 Cycle 1 Day 1 RUN-IN TREATMENT PHASE From cycle 1 day 1 to day 14 Cycle 1 Day 15 ( -3 days) RANDOMIZED TREATMENT PHASE From cycle 1 day 15 Fulvestrant and BKM120/placebo start at cycle 1 day 15 (+3 days) Note: all patients will be randomized regardless of PI3K activation status. Enrollment will stop once at least 334 patients with PI3K activated pathway SAFETY, EFFICACY and SURVIVAL FOLLOW UP PHASE
11 PI3K pathway inhibitors in clinical trials PI3K PTEN PIP 3 TORC2 Akt PDK1 Tuberin Rheb TORC1 S6 S6K 4EBP1 eif4e-f-g
12 BYL719: a selective inhibitor of PI3K Biochemical assay IC 50 (nm) Alpha wt 4.6 Alpha E545K 4 Alpha H1047R 5 Beta 1156 Delta 290 Gamma 250 Vps34 >9100 mtor >9100 Cellular assay IC 50 (nm) Alpha 74 Beta 2249 Delta 1213 mtor >10,000 pp53ser15 >30,000 patmser1981 >10,000 Christine Fritsch. AACR 2012 # 3748.
13 BYL719 Amax (% inhibition) BYL719 displays preferential sensitivity in PIK3CA mutated cell lines PIK3CA mut PIK3CA wt Color by PIK3CA mut (74%) (31%) 233 Mut wt Sensitive BYL719 EC50 ( M) BYL719 EC50 ( M) p=1x10-6 by Fisher s Exact Test (two tailed) PIK3CA mutation is associated with sensitivity across different tumor types Amplifications of PIK3CA or ERBB2 are also associated with BYL719 sensitivity (p=0.001) Juric D, et al. Presented at AACR Annual Meeting, March 31 April 4, 2012
14 RESULTS Figure 7. Best percent change from baseline in SLD and best overall response as per local review in patients treated with BYL719 (patients with metastatic breast cancer) ER, estrogen receptor; PD, progressive disease; PgR, progesterone receptor; PR, partial response; SD, stable disease; SLD, sum of longest diameters. Data cut-off: 12 September
15 RESULTS Most of the patients who achieved tumor shrinkage >20% had received multiple prior lines of therapy (Table 3), including endocrine therapy. Table 3. Summary of prior therapies and duration on study for patients with tumor shrinkage 20% Starting dose Best % change from baseline in target lesions Number of prior therapies Prior therapies Duration on study 270 mg/day 52.5 [PR] 4 Doxorubicin + cyclophosphamide (adjuvant) Tamoxifen Exemestane 10 cycles Fulvestrant + lapatinib 400 mg/day 34.8 [PR*] 2 Tamoxifen Anastrozole 6 cycles 400 mg/day Leuprolide (adjuvant) Paclitaxel + trastuzumab (adjuvant) Capecitabine + trastuzumab 14 cycles Lapatinib + zoledronic acid + trastuzumab 400 mg/day Doxorubicin + cyclophosphamide + paclitaxel (adjuvant) Tamoxifen (adjuvant) Anastrozole (adjuvant) Letrozole (adjuvant) Capecitabine 6 cycles Doxorubicin + docetaxel (adjuvant) Tamoxifen (adjuvant) 400 mg/day Anastrozole 6 cycles Fulvestrant Capecitabine 400 mg/day Doxorubicin + cyclophosphamide (adjuvant) 5 cycles * Unconfirmed PR. PR, partial response. Data cut-off: 15 November
16 RESULTS Figure 6c. CT scans demonstrating tumor shrinkage in a patient treated with BYL mg/day Baseline Cycle 19 Patient had tumor shrinkage of 26.3% as per RECIST. 16
17 PI3K pathway inhibitors in clinical trials PI3K PTEN PIP 3 TORC2 Akt PDK1 Tuberin Rheb TORC1 S6 S6K 4EBP1 eif4e-f-g
18 GDC-0032 PI3K inhibitor is active in PI3K mutant breast cancer cell lines 18 &"! # GDC-0032 potency in breast cancer cells H81*!! 5&#I1 $! #JK) L # %"$# %"! #! "$# Breast cancer cells Cell Titer-Glo assay 4 days! "! # PI3K Mutant/ampl HER2+ PTEN Null ' ( ) *%+#, -. /# 011*&! &# 234$*5! # 6, 735# ) 89*) 7*/$5# : /48# 011*%/%+# 7: /4/# 011*&&%; # 9< $=$# ' ( ) *%+&9# 011%+$/# ) 1( 4*>?@A0' 3&# ) ( ) &&5# 08B *- %# 1CD#; $*%# ) E*%# ' F69*: # 7: $/+# 06#$4; : *%G&# 011*%%/5# 19. *%&! # ) 89*) 7*/5=# 19) 9*%# ) 89*) 7*/=; # 011*%/&; # In a panel of 27 breast cancer cell lines, PI3K mutants are the most sensitive to GDC-0032 Jeff Wallin, Lori Friedman, Genentech
19 GDC-0032 induces apoptosis in PI3K mutant breast cancer cells at low concentrations 19 PI3K H1047R mutant HCC-1954 breast cancer cells PI3K WT HDQ-P1 breast cancer cells DMSO GDC-0032 DMSO GDC-0032 Cleaved Parp pakt S473 ps6 S235/236 bactin GAPDH -10 μm highest dose; 2-fold dose titration -Lysates collected 18hrs post dosing PI3K pathway knockdown correlates with the induction of apoptosis Jeff Wallin, Lori Friedman, Genentech
20 PI3K inhibitors in Breast Cancer What we know today Relatively high activity in PI3K mutant breast cancer Additional determinants of resistance and sensitivity to be identified Strong interaction with ER signaling
21 PI3K inhibitors and Hormonal Therapy Combined Fulvestrant and PI3K inhibitor 2.0 MCF7 XG Average of each treatment arm Fold change in tumor size from Day Control Fulvestrant 200 mg/kg BYL mg/kg Combo Fulvestrant to Combo BYL to Combo Days of tx Day 7: combo initiated on single agent fulvestrant and BYL arms
22 PAM50 MCF7 cells.
23 PI3K/mTOR inhibition induces ER expression Control Control Control Fulv 100nM Fulv 100nM Fulv 100nM Fulv 1000nM Fulv 1000nM Fulv 1000nM BYL 250nM BYL 250nM BYL 250nM BYL 500nM BYL 500nM BYL 500nM F100 + B250 F100 + B250 F100 + B250 F100 + B500 F100 + B500 F100 + B500 F B250 F B250 F B250 F B500 F B500 F B500 RAD 10nM RAD 10nM No Media Δ RAD 50nM RAD 50nM No Media Δ No Media Δ KPL1 ER- ER- ZR75-1 ER- ER- BT474 ER-
24 AI (letrozole or exemestane) + BYL719 Phase 1 study with expansion BYL719 PI3K α inhibitor Primary endpoint: Recommended phase 2 dose Expansion phase: 10 patients in each arm to further define the safety, feasibility and signal of efficacy PIs: Dickler and Chandarlapaty
25 PI3K inhibition induces DNA damage Sample ID Source PTEN IHC (H-Score) PI3KCA status (MassArray) BRCA status (Sanger) PAM50 TNBC1 Metastatic 0 PIK3CA H1047R Wildtype Basal TNBC2 Primary 0 Wildtype Wildtype Basal Ibrahim et al. Cancer Discovery. 2012
26 PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA proficient triple negative breast cancer to PARP inhibition Ibrahim et al. Cancer Discovery. 2012
27 Targeting the PI3K Pathway in Breast Cancer Summary Pan-PI3K inhibitors have shown clinical activity and are under late clinical development in combination with antiestrogens. PI3K inhibitors have shown remarkable clinical activity in PI3K breast cancer PI3K inhibition results in the compensatory activation of ER levels and transcription Strong rationale to combine PI3K inhibitors and hormonal therapy In TNBC, PI3K inhibitors downregulate BRCA expression and are synergistic with PARP inhibitors. Clinical trials ongoing
28 Acknowledgements Baselga s lab Maurizio Scaltriti Pieter Eichhorn Dejan Juric Moshe Elkabets Violeta Serra Yasir Ibrahim Jessie Tao Peter Ip Sara Marlow Natasha Morse Ana Bosch Pau Castel MGH Jeff Engelman Sadhna Vora Beth Israel Lew Cantley M.S.K.C.C. Neal Rosen Sarat Chandarlapaty Novartis Alang Huang Cornelia Quadt Cleopatra Study J Cortés, S-A Im, E Clark, A Kiermaier, G Ross, S M Swain
29 Acknowledgements Baselga s lab Maurizio Scaltriti Pieter Eichhorn Dejan Juric Moshe Elkabets Violeta Serra Yasir Ibrahim Jessie Tao Peter Ip Sara Marlow Natasha Morse Ana Bosch Pau Castel MGH Jeff Engelman Sadhna Vora Beth Israel Lew Cantley M.S.K.C.C. Neal Rosen Sarat Chandarlapaty Novartis Alang Huang Cornelia Quadt Cleopatra Study J Cortés, S-A Im, E Clark, A Kiermaier, G Ross, S M Swain
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