Update on Systemic Treatment of Breast Cancer

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1 Update on Systemic Treatment of Breast Cancer Christoph C. Zielinski Clinical Division of Oncology Department of Medicine I and Comprehensive Cancer Center ( Medical University Vienna - General Hospital, Vienna, Austria

2 Spectrum of Targeted Anticancer Agents in Clinical Development. Garraway L A JCO 2013;31: by American Society of Clinical Oncology

3 Aims of Investigational New Drugs in Breast Cancer Amelioration of Targeting Familiar Targets Overcoming or Reducing Treatment Resistance Identification of New Targets which can be Translated into Therapeutic Efficacy

4 Trastuzumab: Escape-mechanisms

5 The HER Family of Receptors Ligands TGF-α EGF Epiregulin Betacellulin HB-EGF Amphiregulin No ligandbinding activity* Heregulin Heregulin (neuregulin-1) Epiregulin HB-EGF Neuregulins-3, -4 Ligandbinding domain Tyrosine kinase domain Erb-B1 HER1 EGFR *HER2 dimerizes with other members of the HER family. Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433. Erb-B2 HER2 neu Erb-B3 HER3 Erb-B4 HER4

6 Her-2/neu Targeting Antibodies Trastuzumab Pertuzumab T-DM1 (Cytotoxic Drug Conjugate) Tyrosine Kinase Inhibitors (erbb) Lapatinib Afatinib Neratinib mtor Inhibition Everolimus

Her-2 - TK-Inhibition: Example Afatinib Li D. et al. Oncogene 2008; 27:4702 11.

7 Her-2 - TK-Inhibition: Example Afatinib Li D. et al. Oncogene 2008; 27: Afatinib is an orally available, irreversible ErbB Family Blocker, with high efficacy potential: Phase III Trial for Her-2/neu Inhibitor Resistance (LUX-Breast-2 and Breast 3 Phase II Trials, recruiting) Rationale: Inhibition of ErbB Family receptor heterodimerization

8 Targeting by 2 nd Generation Irreversible EGFR and Her-2 TKI Inhibition for Her-2/neu Positive MBC: Study Examples Afatinib Neratinib** Phase II, Completed* Phase III, Recruiting (LUX) Phase II, Completed*** Phase II Trials Ongoing * Lin et al., Breast Cancer Res Treat 2012 ** ExteNET randomized adjuvant trial: Prolongation of DFS by 33% vs. Placebo (HR = 0.67; P =.0046) *** Burstein et al., JCO 2010; Saura et al., JCO 2014

9 Phase II Study of Afatinib (BIBW 2992) in 41 Patients with HER2-Positive MBC Progressing after Trastuzumab. N.U. Lin et al., Breast Cancer Res Treat 133: 1057, 2012 Responses: PR: 11% of Patients SD: 37% of patients CB: 46% of patients Time Variables: median PFS: 15.1 weeks (95% confidence interval [CI]: ) median OS: 61.0 weeks (95% CI: 56.7-not evaluable)

10 Neratinib + Capecitabine in HER-2 Positive MBC: Phase I / II Trial C. Saura et al., J Clin Oncol 32: 3626, 2014 Phase I, MTD: Neratinib 240mg/day, Capecitabine 1500mg/m 2 /day Phase II: ORR: No Prior Lapatinib: 64% (n= 39 of 61) Prior Lapatinib: 57% (n= 4 of 7) Median PFS: No Prior Lapatinib: 40.3 weeks Prior Lapatinib: 35.9 weeks

11 Safety and Efficacy of Neratinib + Capecitabine in Her- 2/+++ MBC without Prior Lapatinib Treatment Saura C et al. JCO 2014;32: by American Society of Clinical Oncology

12 Investigational Her-Dependent TKIs for Her-2/neu Positive Breast Cancer: Afatinib and Neratinib Trial Phase and status Treatment Inclusion Criteria NCT (LUX Breast 1) Phase 3: recruiting Vinorelbine + T vs 1st and 2nd line MBC vinorelbine + afatinib NCT Phase 2: recruiting Afatinib alone or in combination HER2 pos. inflamm. BC with vinorelbine NCT (LUX Breast 3) Phase 2: recruiting Afatinib alone or in combination HER2 pos. BC, brain mets, T with vinorelbine NCT Phase 2: completed Afatinib in combination Hormone resistant MBC with letrozozole NCT Phase 2: completed Afatinib monotherapy vs HER2 pos. treatment-naïve EBC T vs lapatinib (neoadjuvant) NCT Recruiting Paclitaxel + T + Afatinib vs. Her2 pos. treatment-naive EBC Paclitaxel + T vs. (enoadjuvant) Paclitaxel + Afatinib NCT Recruiting Pacliatxel + T + Neratinib vs. Her2 pos. Treatment-naive EBC Paclitaxel + T vs. (neoadjuvant) Paclitaxel + Neratinib

13 Trastuzumab: Escape-mechanisms

14 PI3K - Akt - mtor Pathway Alterations in Cancer p-akt, 23% 50% PTEN, 24% Ras, 30% EGFR, 32% 60% Lung Breast p-akt, 42% PI3K, 18% 26% PTEN, 15% 41% HER2, 30% 36% TSC1/TSC2 p-akt, 38% NET TSC1/TSC2 IGF-1/IGF-1R VHL PTEN, 31% TGFa/TGFb1, 60% 100% VHL, 30% 50% IGF-1/IGF-IR, 39% 69% Kidney Colon p-akt, 46% PI3K, 20% 32% PTEN, 35% Ras, 50% EGFR, 70% % Incidence mutations

15 PI3K - Akt - mtor Pathway Most frequently mutated pathway in breast cancer Mutation = gain of function Amplifications / Mutations affect almost all relevant molecular components Her-2, FGFR1, IGF-R1 AKT1, AKT2 KRAS (= PI3K Activator) PTEN, INPP4B (= negative PI3K regulators)

16 Frequency of Somatic Gene Mutations in the HER2 and PI3K/AKT Pathway in Breast Cancer Subtypes.

17 PI3K - Akt - mtor Pathway in Breast Cancers Biological Importance? in: Her-2/neu Overexpression and Treatment Resistance ER-Positivity and Endocrine Resistance Triple Negativity

18 PI3K Inhibitors Overcome ErbB Drug Resistance in vitro ErbB drug resistant T47D breast cancer cells PI3K/AKT/mTOR inhibitors sensitize the cells against ErbB drugs Cell Number (% of Control) Pelitinib Pelitinib+BEZ235 Pelitinib+Rapamycin Pelitinib+Akti-1/ Pelitinib (µm) Cell Number (% of Control) Canertinib Canertinib+BEZ235 Canertinib+Rapamycin Canertinib+Akti-1/ Canertinib (µm) MAPK inhibitors do NOT sensitize the cells against ErbB drugs Cell Number (% of Control) Pelitinib Pelitinib+AZD6244 Pelitinib+UO Pelitinib (µm) Cell Number (% of Control) Canertinib Canertinib+AZD6244 Canertinib+UO Canertinib (µm) Brünner-Kubath et al., submitted

19 PI3K - Akt - mtor in Her-2 Overexpression PI3K activation via mutation or PTEN loss correlated with resistance towards Her-2/neu - targeting drugs. Resulting hypothesis: Reversibility by PI3K blockade?

20 Vertical Signaling Inhibition of the PI3K - Akt - mtor Pathway Liu et coll. Nature Reviews Drug Discovery 2009

21 Everolimus: Oral mtor Inhibitor HO O O O N O OH O O O O O OH RAD001 (Everolimus) O O Active rapamycin derivative 1 Orally bioavailable; T 1/2 ~ 30 hours; CYP3A4 metabolism 1 Sustained inhibition of mtor via daily administration 1 Crosses blood-brain barrier 2 Broad anti-tumour activity 3 Inhibits cell growth and angiogenesis Potential synergy with chemotherapy, radiation, and other targeted agents Demonstrated single-agent efficacy and safety in several pivotal phase 3 trials 1. Afinitor prescribing information. Novartis. July Anders CK, et al. J Clin Oncol. 2012;20(suppl; Abstract TPS656). 3. Lane HA, et al. Clin Cancer Res. 2009;15:

22 Everolimus in Trastuzumab-Resistant, HER2-Positive MBC (BOLERO-3) Design: Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial Study Population: HER2-positive, Trastuzumab-Resistant, Advanced Breast Cancer, Pretreatment by Taxanes. Randomization: Everolimus (5 mg/day) plus Weekly Trastuzumab (2 mg/kg) Plus Vinorelbine (25 mg/m 2 ) vs. Placebo plus Trastuzumab plus Vinorelbine Primary Endpoint: Progression-Free Survival (PFS) O Reagen AM et al. J Clin Oncol 2013;31(Suppl.15):#505. Andre F et al. Lancet Oncol. doi: /s (14)70138,, May 2014

Relative Risik, % Everolimus in Trastuzumab-Resistant, HER2-Positive MBC (BOLERO-3) O Reagen AM et al. J Clin Oncol 2013;31(Suppl.15):#505. Andre F et al. Lancet Oncol. doi:10.

23 Relative Risik, % Everolimus in Trastuzumab-Resistant, HER2-Positive MBC (BOLERO-3) O Reagen AM et al. J Clin Oncol 2013;31(Suppl.15):#505. Andre F et al. Lancet Oncol. doi: /s (14)70138,, May Hazard Ratio = 0.78; 95% CI 0,65-0,95 p= Median PFS Everolimus: 7.00 Months 95% CI 6,74-8,18 Placebo: 5.78 Months 95% CI 5,49-6, Everolimus (n/n = 196/284) Placebo (n/n = 219/285) Weeks

24 Phase I Study of Neratinib with Temsirolimus in Her-2/neu Positive MBC L. Gandhi et al.: J Clin Oncol, doi: /JCO , Patients Drug Related and Dose Limiting Toxicities: Diarrhea: 93% Nausea: 53% Stomatitis: 53% Anemia: 48% Responses: - Her-2 amplified breast cancers resistant to Trastuzumab, - Her-2 mutant lung cancer and - tumor types without mutations in the HER-Pi3K-mTOR pathway.

25 mtor Inhibition to Modulate Aromatase Inhibitor Resistance in Endocrine Dependent MBC Moy B, et al. Clin Cancer Res. 2006;12:

26 PI3K - Akt - mtor Pathway in ER-Positivity PIK3CA most commonly mutated gene in luminal BC PI3K activation leads to endocrine resistance by crosstalk between ER and pathway-activating RTKs Ligand-independent activation of ER by mtorc1

27 Everolimus Enhances Activity of Letrozole in vitro *P<0.001 (synergistic drug interaction). Boulay A, et al. Clin Cancer Res. 2005;11:

nonsteroidal aromatase inhibitors; OS = overall survival; PFS = progression-free survival;

28 Everolimus Plus Exemestane in Nonsteroidal Aromatase Inhibitor Resistant MBC (BOLERO-2) ABC = advanced breast cancer; HER2- = human epidermal growth factor receptor 2-negative; NSAI = nonsteroidal aromatase inhibitors; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics. Baselga J, et al. Eur J Cancer Suppl. 2011;47(suppl 2):Abstract 9LBA.

29 BOLERO-2 Primary Endpoint: PFS (Central Assessment) Baselga J, et al. Eur J Cancer Suppl. 2011;47(suppl 2):Abstract 9LBA.

30 BOLERO-2: ORR and Benefit Rate (Local Assessment) Baselga J, et al. Eur J Cancer Suppl. 2011;47(suppl 2):Abstract 9LBA.

31 Everolimus Plus Tamoxifen (TAMRAD) A Randomized GINECO Phase II Trial: OS in the Intention-to-Treat Population. Bachelot T et al. JCO 2012;30: by American Society of Clinical Oncology

32 mtor Inhibition and Anti-Endocrine Treatment in MBC: More Effective in Endocrine Resistance? FOR this Assumption: BOLERO-2 Trial TAMRAD Trial HORIZON Trial* AGAINST this Assumption: Neoadjuvant Letrozole, RR: 59% Neoadjuvant Letrozole + Everolimus, RR: 68% Suspected Mechanisms: PI3K Mutation (exon 9, PIK3CA)** PTEN Loss p53 Mutation * Temsirolimus plus Letrozole vs. Letrozole in the First-Line Setting, A. Wolff et al., J Clin. Oncol. Doi: /JCO ** J. Baselga et al., J. Clin. Oncol. 27: 2630, 200

33 BOLERO-2: OS Everolimus+Exemestane: 31.0 months (95% CI= months) Placebo+Exemestane: 26.6 months (95% CI= months) HR=0.89; 95% CI= ; log-rank P=0.14 M. Piccart et al., Ann Oncol (2014), doi: /annonc/mdu456 First published online: September 17, 2014

34 BOLERO-2: What do Endpoints Tell Us? Response: Relevance of the Targets and its Susceptibility to Therapeutic Intervention: GOOD Progression Free Survival: Duration of Occurrence of Resistance to a Certain Therapeutic Intervention: (PROTRACTED) DEVELOPMENT OF RESISTANCE Overall Survival: Result of the Sum of Effective Therapeutic Options: UNINFLUENCED BY AFFINITOR

35 PI3K Inhibition in Breast Cancer (SABCS 2013) Pairing of a PI3K inhibitor (the pan inhibitor GDC-0941, or BYL-719) with a CDK4/6 inhibitor (LEE-011) was synergistic in vitro. The combination led to tumor regression in mice. 1 Phase I study: the pan-pi3k inhibitor BKM120 plus fulvestrant produced PR or SD >6mons. in 10 of 18 patients with ER+ MBC. 2 Phase IIT study ongoing. BKM120 as a single agent or with fulvestrant iwere given in a mouse model of everolimus resistance and achieved strong tumor growth inhibition with either treatment. 3 The combination of the alpha-specific PI3K inhibitor GDC-0032 combined with fulvestrant yielded ORR of 73% in an international phase Ib study. 4 1 Vora SR,et al: Abstr. S4-04; 2 Ma CX, et al: Abstr. PD1-4; 3 O Brien NA, et al: Abstr. PD1-5.; 4 Juric D, et al: Abstr PD1-3.

36 PI3K Inhibition in Endocrine Dependent MBC Phase I Trial of pan-pi3k Inhibitor BKM120 plus Fulvestrant 18 Patients In 10, PR or SD for >6 Months Ma CX et al., SABCS 2013, Abstract PD1-4

37 Drugs Targeting the PI3K - Akt - mtor Pathway Pan-PI3K Inhibitors (Phase I-III) XL147, BKM120 (2 Phase III trials, combination with fulvestrant), GDC-0941 PI3K-alpha and PI3K-beta Inhibitors (Phase I-II) BYL719, GDC-0032, GSK Akt Inhibitors (Phase I-II) MK-2206, AZD5363 mtor C1/2 Inhibitors (Phase I) INK128, AZD2014 PI3K + mtor Inhibitors (Phase I-II) XL-765, BEZ235, GDC-0980, GSK

38 Emerging Targets and Drug Development in Breast Cancer Zardavas, D. et al. (2013) Emerging targeted agents in metastatic breast cancer Nat. Rev. Clin. Oncol. doi: /nrclinonc

39 Trastuzumab: Escape-mechanisms

40 Trials on Molecular Targets in Breast Cancer: The Neoadjuvant Setting Target Her-2 Her-3 EGFR c-met FGF PI3K MAPK PARP CDK Drugs Afatinib, Neratinib, T-DM1 MM-121 (monoclonal anti Her-3 antibody) Cetixumab, Panitumumab Ondartuzumab BIBF1120 BKM120, Everolimus, GDC0032 Selumetinib Veliparib, Iniparib, Carboplatin Palbociclib (positive for PFS in the PALOMA trial)

41 Emerging Targeted Drugs for Breast Cancer Treatment: Conclusions Following the discovery of crucial molecular signalling mechanisms, targeted drugs have been developed. Although generally applicable as a concept, the identification of a true driver pathway, the identification of biomarkers for patient selection and, finally and most importantly, the therapeutic efficacy of targeting have to be proved for each BC subtype and each setting. An abundance of drugs is in development which challenge the scientific community to develop appropriate models for the clinical testing of these compounds.

42 Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines A.Q. Butt, K.H.G. Mills, Oncogene 2013

Recent Update in Management of Breast Cancer: Medical Oncology. Jin Hee Ahn, M.D., PhD. 23-April-2015

2015 GBCC & 4 th IBCS 1/37 Recent Update in Management of Breast Cancer: Medical Oncology Jin Hee Ahn, M.D., PhD. 23-April-2015 Department of Oncology, Asan Medical Center, UUCM, Seoul, Korea 2/37 3/37