Inhibidores PI3K AKT -mtor Dr. Raquel Andrés HCU Lozano Blesa

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1 Inhibidores PI3K AKT -mtor Dr. Raquel Andrés HCU Lozano Blesa

2 PI3K/AKT/mTOR: Target For Treatment of HR+ Breast Cancer PI3K/mTOR is the most frequently activated signaling pathway in BC 1, leading to: Tumor growth and progression, 2,3 Resistance to anticancer therapies 1,7 Aberrant activation of the PI3K/mTOR pathway is also a common feature of endocrine-resistant BC 4, PI3K/mTOR pathway activation causes downregulation of hormone receptor expression, leading to endocrine therapy resistance 6 1. Miller TW, et al. Breast Cancer Res 211;13:224; 2. Liu P, et al. Nat Rev Drug Disc 29;8: ; 3. Saal LH, et al. Proc Natl Acad Sci U S A 27;14: ; 4. Hosford SR, Miller TW. Pharmgenomics Pers Med 214;7:23 15; 5. Miller TW, et al. J Clin Invest 21;12: ; 6. Creighton CJ, et al. Breast Cancer Res 21;12:R4. 7, Huang W-C, Hung M-C. J Formos Med Assoc 29;18:18 194;

3 Molecular Characteristics of Breast Cancer Subtypes Molecular analysis of breast cancers provides insight into signaling pathways that are frequently dysregulated in different subtypes, which can guide drug development Subtype Luminal A Luminal B Basal-like HER2-enriched TP53 pathway TP53 mut (12%) MDM2 gain (14%) TP53 mut (32%) MDM2 gain (31%) TP53 mut (84%) MDM2 gain (14%) TP53 mut (75%) MDM2 gain (3%) PIK3CA/PTEN pathway PIK3CA mut (49%) PTEN mut/loss (13%) INPP4B loss (9%) PIK3CA mut (32%) PTEN mut/loss (24%) INPP4B loss (16%) PIK3CA mut (7%) PTEN mut/loss (35%) INPP4B loss (3%) PIK3CA mut (42%) PTEN mut/loss (19%) INPP4B loss (3%) RB1 pathway Cyclin D1 amp (29%) CDK4 gain (14%) Low expression of CDK2NC High expression of RB1 Cyclin D1 amp (58%) CDK4 gain (25%) RB1 mut/loss (2%) Cyclin E1 amp (9%) High expression of CDKN2A Low expression of RB1 Cyclin D1 amp (38%) CDK4 gain (24%) amp, amplification; CDK4, cyclin-dependent kinase 4; CDK2NC, cyclin-dependent kinase inhibitor; INPP4B, inositol phosphatase-4-phosphatase type II; MDM2, mouse double minute 2 homolog; mut, mutation; PIK3CA, phosphatidylinositol 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; TP53, tumor protein 53. The Cancer Genomic Atlas Network. Nature 212;49:61 7.

4 Probability of Progression-Free Survival PFS Based on Local Assessment at 18-mo HR =.45 (95% CI, ) Log-rank P <.1 Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months.4.2 Censoring times EVE+EXE (n/n = 31/485) PBO+EXE (n/n = 2/239) No. at risk EVE+EXE PBO+EXE Time (months) Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Yardley DA, et al. Adv Ther. 213;3:

5 PrECOG 12: Fulvestrant plus Everolimus Prolongs PFS Compared to Fulvestrant Kornblum et al, SABCS 216

6 Real Word Data: BALLET Phase IIIb, European, multi-center, open-label, single-arm, expanded-access study to evaluate the safety of EVE (1 mg/day) and EXE (25 mg/day) in: Postmenopausal women, With HR+/HER2 locally advanced or mbc, That has progressed following NSAI treatment. Patient population Treatment continues until: Postmenopausal women HR +, HER2 - unresectable locally advanced or mbc Recurrence or progression after NSAI No limitation in terms of prior chemotherapy lines TREATMENT PHASE Everolimus (RAD1) 1 mg/day + Exemestane 25 mg/day Disease progression Unacceptable toxicity Death Discontinuation from the study for any other reason Drug locally reimbursed or LPLV Primary objective: Evaluate the safety of EVE + EXE in postmenopausal women with HR+/HER2 locally advanced or mbc after recurrence or progression following NSAI treatment. Secondary objective: Characterize Grade 3 and 4 adverse events (AEs) in routine clinical practice with EVE + EXE. HER2, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; LPLV, last patient last visit; mbc, metastatic breast cancer; NSAI, non-steroidal aromatase inhibitor Jerusalem, G. et al. Abstract # P SABCS 9-13 Dec 214

7 Safety profile Adverse events Adverse Events Suspected to Be Related to EVE Treatment (>5% All Grades; Safety Set) The majority of patients (86.2%) experienced at least one EVE-related AE. The most common EVE-related AEs were stomatitis (51.2%), rash (15.%), and asthenia (14.8%). The primary reason for discontinuation during the first 3 months of treatment was AEs. PATIENTS N=264 Adverse event, n (%) All grades Grade 3/4 Stomatitis 157 (51.2) 195 (9.4) Rash 39 (15.) 19 (.9) Asthenia 36 (14.8) 52 (2.5) Decreased appetite 223 (1.8) 14 (.7) Diarrhea 219 (1.6) 18 (.9) Fatigue 215 (1.4) 22 (1.1) Hyperglycemia 19 (9.2) 43 (2.1) NIP 182 (8.8) 37 (1.8) Anemia 168 (8.1) 48 (2.3) Hypercholesterolemia 156 (7.6) 1 (.) Nausea 155 (7.5) 11 (.5) Dysgeusia 137 (6.6) Pruritus 124 (6.) 4 (.2) Edema peripheral 115 (5.6) 9 (.4) Cough 111 (5.4) 4 (.2) NIP, non-infectious pneumonitis. Jerusalem, G. et al. Abstract # P SABCS 9-13 Dec 214

8 Safety profile Adverse events by EVE+EXE treatment line Time to onset stomatitis: overall and by grade of stomatitis

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10 Correlative Analysis of Genetic Alterations and Everolimus Benefit: Bolero-2 Benefit from Everolimus Regardless of Mutation Status 29/485 (43%) on the everolimus arm and 93/239 (39%) on placebo No difference in PFS in the NGS subgroup Most frequently altered genes were: PIK3CA (47.6%), CCND1 (31.3%), TP53 (23.3%), and FGFR1 (18.1%) Greater benefit from everolimus in those with a lower chromosomal instability score Lower CIN: larger PFS benefit (effect seen only in the everolimus arm) CIN score <75th% had a 5.5 month gain in PFS (8.4 v 2.9 mos) CIN > 75% had a median PFS gain of 1.5m in (5.6 v 4.1 mos) Hortobagyi. J Clin Oncol 34:

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12 BOLERO-4: PFS in the 1L setting

13 BOLERO-4: PFS in the 2L setting

14 BOLERO-4: Best overall responses

15 The PI3K-AKT-mTORC1/C2 inhibitors active in preclinical and clinical trials

16 Buparlisib Breast Cancer registration trials ER+ Neo-adjuvant 1 st line 2 nd /3 rd line, AIresistant, mtor naive 3 rd /4 th line AI & mtor pre-treated BELLE-2: Fulvestrant ± BKM12 (Phase III) BELLE-3: Fulvestrant ± BKM12 (Phase III) Postmenopausal women with ER+ and/or PgR+ and HER2 inoperable locally advanced or metastatic breast cancer Disease progression on/after AI therapy: Recurrence during or 12 months from end of adjuvant AI therapy Progression on AI therapy for advanced/metastatic breast cancer Belle-3: Refractory to mtor-inhibitor/ endocrine combination therapy

17 Probability of Progression-free Survival, % BELLE-2 Met the Primary Endpoint for PFS Improvement in the Full Population Buparlisib + fulvestrant (n/n=349/576) Placebo + fulvestrant (n/n=435/571) Full Population (N=1147) Median PFS, months (95% CI) Buparlisib + Fulvestrant n= ( ) HR (95% CI).78 (.67.89) One-sided P value <.1 Placebo + Fulvestrant n= (4. 5.2) Time (Months) A similar PFS improvement was observed in the main population (HR.8 [95% CI:.68.94]; one-sided P value.3) Follow-up for OS analysis is ongoing, with a pre-specified target of 588 deaths in the full population At the time of primary PFS analysis, OS data were immature (281 deaths in the full population), with a trend in favor of the buparlisib arm CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

18 Probability of PFS, % Probability of PFS, % Progression-free Survival by PIK3CA Status Mutant Wild-type 1 Tissue (mutant) Buparlisib + Fulvestrant Placebo + Fulvestrant 1 Tissue (WT) Buparlisib + Fulvestrant Placebo + Fulvestrant Primary tumor tissue (PCR) N= Median PFS, months (95% CI) HR (95% CI) 4.7 ( ) 1.4 ( ).39 (.23.65); p< Median PFS, months (95% CI) HR (95% CI) 2.8 (2. 3.7) 2.7 ( ).83 ( ); p=.117 PIK3CA mutant: 34% ctdna (mutant) Buparlisib + Fulvestrant Placebo + Fulvestrant 1 ctdna (WT) Buparlisib + Fulvestrant Placebo + Fulvestrant ctdna samples at study entry (BEAMing) N=348 PIK3CA mutant: 39% Median PFS, months (95% CI) HR (95% CI) 4.2 ( ) 1.6 ( ).46 (.29.73); p< Median PFS, months (95% CI) HR (95% CI) 3.9 ( ) 2.7 ( ).73 (.53 1.); p=.26 PCR, polymerase chain reaction; WT, wild-type. p-values are one-sided Time, Months Time, Months

19 San Antonio Breast Cancer Symposium December 6 1, 216 Novartis PI3K Inhibitors in Clinical Development Buparlisib (BKM12) is an oral pan-pi3k inhibitor targeting all four isoforms of class I PI3K (ɑ, β, γ, δ) 1 Targeting all class I isoforms may ensure broad activity in tumors with a range of molecular drivers 2 5 Alpelisib (BYL719) and Taselisib (GDC-32) is an oral inhibitor selectively targeting the α isoform of class I PI3K 6,7 Inhibition of the α isoform may reduce off-target toxicity 5,6 PI3K Buparlisib α β γ δ Pan-PI3K inhibitor Catalytic subunit (4 isoforms: α β γ δ) p11 IC 5 (nm) Regulatory subunit p85 Alpelisib Taselisib PI3Kα inhibitor α 1. Maira SM, et al. Mol Cancer Ther 212;11: ; 2. Liu P, et al. Nat Rev Drug Disc 29;8: ; 3. Kang S, et al. Proc Natl Acad Sci USA 26;13: ; 4. Hernandez-Aya LF, et al. Oncologist 211;16:44 414; 5. Jia S, This et al. presentation Curr Opin is Cell the intellectual Biol 29;21:199 28; property of the author/presenter. 6. Fritsch C, Contact et al. them AACR at angelo.dileo@uslcentro.toscana.it 212; Abstr 3748; 7. Juric D, for et permission al. AACR to reprint 212; and/or Abstr distribute. CT-1. 22

20 SOLAR-1: Phase III Study of Alpelisib + Fulvestrant in Men and Postmenopausal Women With HR+/HER2 ABC Which Progressed on or After AI Treatment A Phase III Randomized Double-blind, Placebo Controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With HR+/HER2 Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment Men and postmenopausal women with HR+/HER2 ABC, whose disease progressed on prior AI treatment (N 56) Screening assessments Alpelisib (3 mg QD) + fulvestrant* (5 mg IM q4w) PIK3CA-mutant cohort (n 34) Randomization (1:1) Placebo (QD) + fulvestrant* (5 mg IM q4w) PIK3CA-nonmutant cohort (n 22) Randomization (1:1) Alpelisib (3 mg QD) + fulvestrant* (5 mg IM q4w) Enrolment status: Ongoing Estimated study completion: Jul 219 Study start date: Jul 215 Estimated primary completion date: Jul 219 Placebo (QD) + fulvestrant* (5 mg IM q4w) clinicaltrials.gov (NCT ); CBYL719C231 Study Protocol; v1 (March 216). ABC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; HER2, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; IM, intramuscular; PI3K,phosphoinositide 3-kinase; q4w, every 4 weeks; QD, once daily; WT, wild-type. *Treatment until disease progression, death, unacceptable toxicity or withdrawal of consent. Fulvestrant administered on Days 1 and 15 of cycle 1; 28-day dosing cycles. Stratification by: Liver and/or lung metastases Prior treatment with any CDK4/6 inhibitor

21 SANDPIPER: Phase III Study of Taselisib + fulvestrant

22 CONCLUSIONES La vía de señalización PI3K/AKT/mTOR está frecuentemente alterada en CM y ha sido asociada con progresión tumoral y resistencia a terapia endocrina. Everolimus en combinación con exemestano ha demostrado mejorar la PFS en pacientes que progresan a un IANE (BOLERO-2,. Median PFS was significantly longer with everolimus + exemestane vs placebo + exemestane (P<.1) Investigator review: 7.8 vs 3.2 months Buparlisib en combinación con terapia endocrina ha demostrado actividad en cáncer de mama pero su perfil de tolerabilidad ocasiona un porcentaje elevado de abandonos de tratamiento. Análisis exploratorios demuestran que los inhibidores PI3K son eficaces en CM mut PI3K (BELLE-2, BELLE-3). Existen varios inhibidores alpha-pi3k en fase avanzada de investigación.