Luis Manso MD PhD Unidad T Mama y Ginecológicos Oncología Médica Hospital 12 de Octubre
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1 Luis Manso MD PhD Unidad T Mama y Ginecológicos Oncología Médica Hospital 12 de Octubre
2 AGENDA Vía PI3K/AKT/mTOR. Alteraciones genéticas en PI3K/AKT: dependencia oncogénica. ER+ breast cancer. Her2+ breast cancer. TNBC breast cancer. Selección, Combinaciones.
3 Vía PI3K/AKT/mTOR.
4 PIK3CA Alteraciones genéticas en PI3K/AKT: dependencia oncogénica Exon 9 Exon 20 E542K H1047R E545K Mutation: Endometrial % Breast %
5 Alteraciones genéticas en PI3K/AKT: dependencia oncogénica Koboldt DC. Nature 2012.
6 ER+ breast cancer Interaction between mtor and ERα Growth factors Effect of rapamycin and hormonal therapy on cell proliferation mtor E S6K1 ERα Ser 167 P Transcription ER-Responsive Element Cell proliferation *P<.05, 2-tailed paired Student s t test 1. Adapted with permission from Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 2. Johnston SRD. Clin Cancer Res. 2005;11(2, Suppl.):889S-899S.
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8 - Refractory to previous letrozole or anastrozole, defined as recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 1 month after the end of treatment for advanced disease. - Stratified according to the presence of visceral metastasis and previous sensitivity to endocrine therapy. The latter was defined as at least 24 months of endocrine therapy before recurrence in the adjuvant setting or a response or stabilization for at least 24 weeks of endocrine therapy for advanced disease.
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11 NP4: Progression-Free Survival, % Progression-Free Survival, % BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable in Elderly vs Younger Patients A Age < 70 y PFS Events, n (%) Censored, n (%) Median PFS, mo HR (95% CI) EVE+EXE Progression 235 (65) 121 (33) (0.36, 0.54) Death 8 (2) PBO+EXE Progression 163 (83) 31 (16) 4.01 Death 2 (1) Censoring Times EVE+EXE (n/n = 243/364) PBO+EXE (n/n = 165/196) Time, wk Number of patients still at risk Everolimus Placebo B Age 70 y EVE+EXE PBO+EXE Progression Death Progression Death PFS Events, n (%) Censored, n (%) Median PFS, mo HR (95% CI) 59 (49) 54 (45) (0.30, 0.68) 8 (7) 35 (81) 8 (19) Censoring Times EVE+EXE (n/n = 67/121) PBO+EXE (n/n = 35/43) Time, wk Number of patients still at risk Everolimus Placebo Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; wk, weeks. Pritchard KI, et al. Clinical Breast Cancer. 2013; 13(6):
12 Probability of Event, % Probability of Event, % Progression-Free Survival, % BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable in Patients With (A) Visceral Metastases, (B) Without Visceral Metastases, and (C) With Bone-Only Metastases A B C 100 HR=0.47 (95% CI, ) 100 HR=0.41 (95% CI, ) 100 HR=0.33 (95% CI, ) 80 Kaplan-Meier medians EVE+EXE: 6.83 mo PBO+EXE: 2.76 mo 80 Kaplan-Meier medians EVE+EXE: 9.86 mo PBO+EXE: 4.21 mo 80 Kaplan-Meier medians EVE+EXE: mo PBO+EXE: 5.29 mo Censoring times Censoring times EVE+EXE (n/n=188/271) EVE+EXE (n/n=122/214) PBO+EXE (n/n=116/135) 0 PBO+EXE (n/n=84/104) 0 Censoring Times EVE+EXE (n/n=48/105) PBO+EXE (n/n=33/46) Patients at risk EVE+EXE PBO+EXE Time, wk Patients at risk EVE+EXE PBO+EXE Time, wk Patients at risk Time, wk EVE+EXE PBO+EXE Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Reprinted from Campone M, et al. Eur J Cancer. 2013;49:
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15 BOLERO-2 (18-mo f/up): Common Adverse Events Were Consistent With the Established Safety Profile of Everolimus Table 4. Most common adverse events (reported in 10% of pacients) RA (término preferido) EVE+EXE (n=482), % PBO+EXE (n=238), % Grado Grado Todos Todos Stomatitis <1 0 Rash Fatigue < Diarrhea < <1 0 Nausea <1 < Decreased appetite <1 0 Weight decreased Cough < Dysgeusia Dyspnea < <1 <1 Headache < Arthralgia < <1 0 Peripheral edema <1 <1 0 Anemia < <1 <1 Epixtasis Vomiting < <1 <1 0 Pyrexia < <1 <1 0 a Adverse events of clinical interest. Yardley DA, et al. Adv Ther. 2013;30:
16 Probability of Event, % Incidence and Distribution of Grade 2 Stomatitis and Related Events Over the BOLERO-2 Study Period EVE+EXE PBO+EXE Censoring Times EVE+EXE (n/n = 160/482) PBO+EXE (n/n = 7/238) 9% 2% <1% ~88% No AEs (grade 0) Grade 1 Grade 2 Grade 3 Grade Time, months Number of Patients still at Risk EVE+EXE PBO+EXE Incidence of stomatitis and related events was higher in the EVE+EXE arm (59%) vs PBO+EXE arm (12%) Incidence of new stomatitis/related events (grade 2) plateaued at wk 6 Most patients (97%; n = 38) with grade 3 stomatitis in the EVE+EXE arm experienced resolution to grade 1 at median 3.1 wk, and 32 patients (82%) had complete resolution at median 7.4 wk Rugo H, et al. St Gallen International Breast Cancer Conference 2013, abstract 274 (poster) and Rugo H, et al. Ann Oncol. Mar 10 [Epub ahead of print].
17 SWISH:Stomatitis prevention in PMW with HR+, HER2- MBC using a DEX based mouth wash
18 Probability of Event, % Incidence and Distribution of Grade 2 Non-infectious Pneumonitis and Related Events Over the BOLERO-2 Study Period EVE+EXE PBO+EXE ~79% 9% 7% 4% <1% <1% ~99% No AEs (grade 0) Grade 1 Grade 2 Grade 3 Grade Censoring Times EVE+EXE (n/n = 55/482) PBO+EXE (n/n = 0/238) Time, months Number of Patients Still at Risk EVE+EXE PBO+EXE Incidence of noninfectious pneumonitis and related events was higher in the EVE+EXE arm (20%) vs PBO+EXE arm (< 1%) 16 patients (80%) with grade 3 noninfectious pneumonitis in the EVE+EXE arm experienced resolution to grade 1 at median 3.8 wk, and 15 patients (75%) had complete resolution at median 5.4 wk Rugo H, et al. St Gallen International Breast Cancer Conference 2013, abstract 274 (poster) and Rugo H, et al. Ann Oncol. Mar 10 [Epub ahead of print].
19 BOLERO-2 Biomarker Analyses
20 Genetic Alterations and Everolimus Efficacy in Hormone Receptor positive, HER-2 negative Advanced Breast Cancer: Preliminary Correlative Results From BOLERO-2 Gabriel Hortobagyi, Martine Piccart, Hope Rugo, Howard Burris III, Mario Campone, Shinzaburo Noguchi, Alejandra Perez, Ines Deleu, Mikhail Shtivelband, Louise Provencher, Norikazu Masuda, Shaker Dakhil, Ian Anderson, David Chen, Amy Damask, Alan Huang, Douglas Robinson, Rob McDonald, Adnan Derti, Tetiana Taran, Tarek Sahmoud, David Lebwohl and José Baselga Presented at ASCO 2013 Abstract LBA509
21 Patients With No or Single Genetic Alteration in PIK3CA/ PTEN/CCND1 or FGFR1/2 Derive Greater PFS Benefit With EVE Subgroup N Events (%) Median PFS (d) HR* (95%CI) EVE: WT (44%) PBO: WT (78%) 203 ( ) EVE: Single (63%) PBO: Single (89%) 77 ( ) EVE: multiple (71%) PBO: multiple (82%) 128 ( ) *HR adjusted with imbalanced covariates Subgroup Definition Size, % WT Single No alteration in PIK3CA AND PTEN AND FGFR1/2 AND CCND1 27% Minimal Single alteration only in PIK3CA OR PTEN OR FGFR1/2 OR CCND1 49% 76% Multiple Two or more alterations in PIK3CA OR PTEN OR FGFR1/2 OR CCND1 genes Multiple 24% 24% Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; WT, wild type.
22 ER+ breast cancer
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27 OPPORTUNE 2 wks The primary end point was change in Ki-67.
28 OPPORTUNE P =.004 mean percentage suppression of Ki-67 was 66.0% (95% CI,<75.4%) mean percentage suppression of Ki-67 was 83.8% (95% CI, >79.0%)
29 OPPORTUNE
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31 GeparQuattro, GeparQuinto, GeparSixto, NeoALTTO, CHERLOB PIK3CA mutation rate 20% aprox
32 CLEOPATRA Shorter median PFS observed with mutated PIK3CA while treatment effect is maintained Pla+T+D PIK3CA status Patients, n Events Ptz+T+D Median, months Patients, n Events Median, months Mut WT Overall HR (95% CI) 0.64 (0.43, 0.93) 0.67 (0.50, 0.89) 0.62 (0.51, 0.75) The prognostic impact of PIK3CA mutations cannot be attributed to a specific mutation, nor to mutation(s) in a specific exon, based on the available dataset 182 mutations detected overall (32%) Exon 7: 12; exon 9: 39; exon 20: 131 Baselga J. SABCS 2012; JCO Nov 2014 Mut, mutated; WT, wild-type
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34 Lancet Oncol 2014 Lancet Oncol 2015 BOLERO-3: Primary endpoint progression-free survival by local assessment BOLERO-1: Primary endpoint progression-free survival by local assessment HR -
35 NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer (NeoPHOEBE) ClinicalTrials.gov: NCT NeoPhobe: Phase II, randomized, double-blind, placebo-controlled, parallel-cohort study Population (N = 220) Adult women with HER2+, untreated primary noninflammatory BC Known PIK3CA mutation status ECOG PS 1 PIK3CA mutant or wild-type [wt] 1:1 Buparlisib (100 mg/day) or Buparlisib (80 mg/day) PBO + TRAS (4 mg/kg) loading dose then 2 mg/kg for 6 wks or TRAS (2 mg/kg/week) and PAC (80 mg/m 2 )/week for 12 wks
36 Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2+ MBC Jain (Abstract # 588) Objectives To determine the MTD, safety and activity of alpelisib (BYL719) in combination with T-DM1 in HER2+ MBC who progressing on prior T-DM1 therapy Methodology Phase I, 3+3 dose expansion study N = 15 cohort 1 BYL mg PO q day HER2+ locally advanced and MBC Disease progressed on trastuzumab and/or taxanecontaining regimens in the metastatic setting or within 6 months in the adjuvant setting ECOG PS 2 Results In cohort 1, no grade 3 or higher AEs were reported The MTD for alpelisib was established as 250 mg daily The median PFS in whole population was 8.4 months No prior TDM-1 vs Prior TDM-1: 9.8 mo vs 5.6 mo cohort 1 1 BYL mg PO q day cohort 2 BYL mg PO q day cohort 3 3 BYL mg PO q day Conclusions ALP + T-DM1 treatment was safe, well tolerated, and clinically efficacious in pts with HER2+ MBC who progressed on prior T-DM1 therapy A further phase II study is planned + Figures: Progression-free Survival T-DM1 (3.6 mg/kg IV q cycle 2 ) Response assesments 4 MTD, safety and efficacy PK/PD evaluation FOLLOW UP 5 Most common AEs ( 40%) Poster AEs, n (%) Gr 1/2 Gr 3 AST increased 11 (73) - Nausea 8 (53) - Fatigue 8 (53) - 1.Starting dose = cohort 1; 2.1 cycle = 21 days; 3. An expansion cohort of 10 patients will be treated at the MTD; 4.Treatment continued until progression, excessive toxicity, or patient preference; 5.Once off treatment, patients will be followed every 3 months until disease progression or initiation of next therapy; * Additional 7 patients will be enrolled; AE, adverse events; AST, aspartate aminotransferase; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; HER2+, human epidermal growth factor receptor 2 positive; MTD, maximum tolerated dose; MBC, metastatic breast cancer; PK, pharmacokinetics; PD, pharmacodynamics; PFS, progression free survival; PO, Orally; T-DM1, ado-trastuzumab emtansine Hyperglycemia 7 (47) 2 (13) Maculopapular rash - 6 (40)
37 TNBC breast cancer - PTEN loss and activating PI3K pathway (TCGA samples). - PDX models TNBC -> Inh mtor/akt (Xu S, Mol Cancer Ther. 2013). - Ph 1 single-agent BKM102, 1 PR en TNBC (Bendell J, JCO 2013). - RB, MYC, TP53 limit the antitumor activity of PI3K inh.
38 Selección, Combinaciones
39 Alpelisib Breast Cancer Program Overview Combination Neo-adjuvant mbc Letrozol CBYL719A2201: Letrozole ± BKM120 or BYL719 (Phase II) CBYL719XUS03T Letrozole + BYL719 (Phase Ib) CLEE011X2107: Letrozole + LEE011 ±BYL719 (Phase I/II) Fulvestrant CBYL719X2101 Fulvestrant+ BYL719 (Phase I) SOLAR-1 Fulvestrant ± BYL719 (Phase III) (1/2L) CLEE011X2108: Fulvestrant + LEE011 ± BKM120 or BYL719 (Phase I/II) TAM + goserelin B-YOND: TAM + Goserelin with BKM120 or BYL719 (Phase Ib) T-DM1 BYL719 + T-DM1 (Phase Ib) 43 Registration Trial
40 Ph I study of BYL719 (Alpelisib) plus fulvestrant in PIK3CA-altered and wild type (wt) ER+/HER2 mbc Kaplan Meier Plot for Patients With PIK3CA-altered and PIK3CA WT, ER+, HER2, Locally Advanced or Metastatic Breast Cancer PI3KCA-altered PI3KCA WT Efficacy summary The estimated median PFS was longer in the PIK3CA-altered group compared with the PIK3CA WT group (8.3 months vs 4.7 months), HR 0.28 (95% CI: ; p<0.001). In the PIK3CA-altered and PIK3CA WT group, 54.0% and 41.9% of patients were censored, respectively. CBYL719X2101/NCT Janku, F. et al. SABCS Abstract #PD5-5; December 2014
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42 Selección, Combinaciones
43 - The BET family of proteins consists of 4 members, BRD They contain two tandem bromodomains (BRD). - Facilitate the recruitment of transcription factors and chromatin organizers required in transcription initiation and elongation.
44 Conclusiones - PI3K/AKT pathway is the most frecuently mutated network in human cancer. - The diversity of alterations in this pathway (p110, p85, AKT, mtor, PTEN, etc.) provides multiple molecular targets for therapy. - In ER+ breast cancer addition of everolimus to exemestane prolongs PFS in patients with HR +, HER2 breast cancer after a nonsteroidal aromatase inhibitor. Median 7.8 vs 3.2 months HR = 0.45, P < Biomarkers that identify PI3K-dependent cancers are not yet known. - On-target toxicities manageable but not insignificant. Should be avoidable by PIK3CA-mutant-specific inhibitors??. - The benefit of these drugs will require development of rational combinations.
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