Pharmacology Updates in Breast Cancer Chris Vaklavas, M.D.

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1 Pharmacology Updates in Breast Cancer Chris Vaklavas, M.D. Assistant Professor Department of Medicine, Division of Hematology/Oncology University of Alabama at Birmingham NP2540M th Avenue South Birmingham, AL Office Assistant: Jacqueline Jones Fax

2 Financial Disclosures Research support paid to my institution: Roche, Incyte, Pharmacyclics, Pfizer One-time consultation honorarium: Alexion Pharmaceuticals Unpaid Thought Leader: Genentech No investigational therapies will be discussed

3 Clinical Pharmacology in Medical Oncology The pharmacologic treatment of human malignancies involves the clinical use of some of the most challenging agents in all medicine Risk for serious toxicities Narrow efficacy profiles High interpatient variability DEVITA, HELLMAN, AND ROSENBERG S CANCER > PART 2 Principles of Oncology > Chapter 25: Pharmacology of Cancer Chemotherapy

4 Clinical Pharmacology in Medical Oncology What is a drug? Any compound that alters a normal physiologic process. Pharmacokinetics (PK) is the mathematical study of drug disposition (absorption, distribution, metabolism, and excretion). PK studies what the body does to the drug. Pharmacodynamics (PD) is the study of the dose-response relationship (the core principle of pharmacology). Principle PD tenet is that the magnitude of the effect(s) produced is related to the concentration of drug at the site(s) of action. PD is what the drug does to the body.

5 Clinical Pharmacology in Medical Oncology Pharmaceutical Phase Drug administration Pharmacokinetic Phase Accumulation Pharmacodynamic Phase Therapeutic Effects Body Organism Absorption Disposition Active Site Pharmacologic Effects Distribution Elimination Excretion Metabolism Toxic effects

6 Graph obtained from: Bioavailability (first pass effect) F= AUCpo/Dpo AUCiv/Div Volume of Distribution Vd= AUC (measure of systemic drug exposure) AUC ~ Concentration/CL amount of drug concentration CL= Hydrophobicity Tissue permeability Tissue-binding Serum protein binding Local organ blood flow Clearance elimination rate concentration Elimination Rate Constant k = CL Vd Half-life ln2 Vd T½ = CL

7 Dose Proportionality (linear pharmacokinetics) First-Order Elimination (Abraxane) Rate of elimination is proportional to drug concentration. elimination rate amount of drug CL= = kvd = k concentration concentration Constant fraction of drug eliminated per unit time Zero-Order Elimination (Taxol) Rate of elimination constant regardless of drug concentration Constant amount of drug eliminated per unit time

8 Clinical Pharmacology in Medical Oncology PKs usually assessed in Phase I clinical trials. However, statistical power to detect deviations is poor.

9 Clinical Pharmacology in Medical Oncology: Pharmacodynamic concepts Relate drug effect(s) with drug exposure (most commonly AUC) PD endpoints in oncology most often have been toxicity related (problematic with targeted therapies where toxicities may not be directly dose related). Drug effect(s) may not relate with AUC: many chemotherapies have highly schedule-dependent antitumor effects and adverse event profiles.

10 Clinical Pharmacology in Medical Oncology: PK/PD variability Ron H.J. Mathijssen et al. Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: does it make a difference? The Oncologist 2007;12:

11 Clinical Pharmacology in Medical Oncology: PK/PD variability We traditionally normalize drug dose to BSA. However, the correlation between BSA and CL is poor, hence the development of modern therapeutics on the basis of flat-fixed regimens. Ron H.J. Mathijssen et al. Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: does it make a difference? The Oncologist 2007;12:

12 DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology > 15:Pharmacokinetics and Pharmacodynamics of Anticancer Drugs

13 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors (palbociclib, ribociclib, abemaciclib) Tripathy D. et al. Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors. Clin Cancer Res Jul 1;23(13):

14 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, PK/PD properties Ribociclib (Kisqali; LEE011) Palbociclib (Ibrance; PD ) Abemaciclib (LY ) IC 50 (nmol/l) on-target CDKs CDK4 cyclin D CDK6 cyclin D1/2/ IC 50 (nm) on other CDKs CDK1 cyclin B 113,000 >10, CDK2 cyclin A/E 76,000 >10, CDK5 p25 43,900 >10, CDK9 cyclin T NR NR 57 Kinase partition index Lipophilicity (clogp) IC 50 against bone marrow mononuclear cells (nmol/l) 1,700 ± ± ± 27 Half-life hours hours hours T max 1 5 hours 6 12 hours 4 6 hours Dose 600 mg PO daily 3 wks on/1 wk off 125 mg PO daily 3 wks on/1 wk off 150 mg PO BID continuously

15 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, palbociclib Trial Phase Study design/arms Study population Efficacy Most common AEs PALOMA- 1/TRIO-18 II 1. Palbociclib + letrozole 2. Letrozole Postmenopausal women ER+, HER2 ABC First line treatment mpfs months months mos months months ORR 1. 36% 2. 27% Neutropenia Leukopenia Fatigue Anemia Nausea PALOMA-2 III 1. Palbociclib + letrozole 2. Placebo + letrozole Postmenopausal women ER+, HER2 ABC Who have not received any prior systemic anticancer treatment for advanced disease mpfs months months ORR % % Neutropenia Leukopenia Fatigue Nausea Alopecia PALOMA-3 III 1. Palbociclib+fulvestrant 2. Placebo + fulvestrant Pre-/peri-/postmenopausal women HR+, HER2 MBC Disease has progressed after prior ET mpfs (9.5) months (4.6) months ORR % % Neutropenia Leukopenia Fatigue Nausea

16 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, ribociclib Trial Phase Study design/arms Study population Efficacy Most common AEs MONALEE SA-1 II 1. Ribociclib (600 mg) + letrozole 2. Ribociclib (400mg) + letrozole 3. Letrozole Postmenopausal women HR+, HER2 EBC Pre-surgical Mean decrease in Ki67-expressing cells 1. 92% 2. 96% 3. 69% Nausea Decreased appetite Diarrhea Abdominal pain Fatigue Asthenia MONALEE SA-2 III 1. Ribociclib + letrozole 2. Placebo + letrozole Postmenopausal women HR+, HER2 recurrent or MBC Not received previous systemic therapy for advanced disease mpfs 1. not reached months ORR % % Neutropenia Nausea Infection Fatigue Diarrhea

17 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, abemaciclib (*Breakthrough designation) Trial Phase Study design/arms Study population Efficacy Most common AEs neomonar CH II 1. Abemaciclib + anastrozole 2. Abemaciclib 3. Anastrozole Postmenopausal women HR+, HER2 BC Neoadjuvant Reduction in Ki67a % % % Diarrhea MONARCH 2 III 1.Abemaciclib + fulvestrant 2. Placebo + fulvestrant Pre-/peri-/postmenapausal women HR+, HER2 ABC Progressed while receiving neoadjuvant or adjuvant ET, 12 months from the end of adjuvant ET, or while receiving first line ET for metastatic disease mpfs months months ORR % % Diarrhea Neutropenia Nausea Fatigue Abdominal pain

18 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, Adverse Event profiles Palbociclib + Letrozole N = 444 Ribociclib + Letrozole N = 334 Abemaciclib + Fulvestrant N = 441 Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any grade Neutropenia Leukopenia Fatigue Nausea Anemia Headache Diarrhea Thrombocytopenia NA NA NA Neutropenia represents an on-target effect, is reversible, not cumulative, represents a cytostatic effect on neutrophil precursors (unlike cytotoxic chemotherapy which induces apoptosis). Febrile neutropenia is very rare. GI (Nausea & Diarrhea): management with metoclopramide, prochlorperazine, haloperidol, or serotonin 5-HT3 antagonists (avoid IV ondansetron with ribociclib, risk for QT prolongation).

19 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, monitoring & management of neutropenia Spring LM et al. Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations. Oncologist 2017 Jul 13.

20 Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, challenges and future prespectives 1. Does every patient with HR+ Her2- MBC need a CDK4/6 inhibitor? Some patients have indolent disease and can achieve long term remission with endocrine therapy alone. Conversely some patients may progress rapidly through endocrine therapy either with or without CDK4/6 inhibitors. 2. What is the optimal therapy after CDK4/6 inhibitors fail? Is any CDK4/6 inhibitor superior to others? Response to CDK4/6 inhibitors seems to be a class effect; one would expect that switching CDK4/6 inhibitor upon progression may not provide an advantage. 3. Do CDK4/6 inhibitors work in Her2+ disease and in what context? Trials in Her2+ breast cancer are ongoing. 4. CDK4/6 inhibitors in the adjuvant setting in high-risk local or locally advanced HR+ Her2- disease after completion of definitive therapy. Griggs JJ and Wolff AC. Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Breast Cancer: More Breakthroughs and an Embarrassment of Riches. JCO 2017 Jun 3.

21 Pharmacology Updates in Breast Cancer: Pertuzumab Approved: 1. in combination with trastuzumab and docetaxel for first-line metastatic HER2-positive metastatic breast cancer (CLEOPATRA). 2. in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer (NeoSphere). Singh JC et al. HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. British Journal of Cancer (2014) 111,

22 Pharmacology Updates in Breast Cancer: Approval of pertuzumab in the neoadjuvant setting pcr in ITT population pcr and N at surgery pcr and N+ at surgery Trastuzumab plus docetaxel (group A; n=107) Pertuzumab, trastuzumab, and docetaxel (group B; n=107) Pertuzumab plus trastuzumab (group C; n=107) Pertuzumab plus docetaxel (group D; n=96) 31 (29 0%, ) 49 (45 8%, ) * 18 (16 8%, ) 23 (24 0%, ) 23 (21 5%, ) 42 (39 3%, ) 12 (11 2%, ) 17 (17 7%, ) 8 (7 5%, ) 7 (6 5%, ) 6 (5 6%, ) 6 (6 3%, ) pcr in ER+ and/or PR+ pcr in ERand PR- 10/50 (20 0%, ) 21/57 (36 8%, ) 13/50 (26 0%, ) 3/51 (5 9%, ) 8/46 (17 4%, ) 36/57 (63 2%, ) 15/55 (27 3%, ) 15/50 (30 0%, ) Gianni L et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.. Lancet 2012 Jan;13(1):

23 Pharmacology Updates in Breast Cancer: Approval of pertuzumab in the neoadjuvant setting Although there is no difference in PFS at 5 years, the achievement of a pcr is associated with a PFS advantage at 5 years. Principle: in Her2+ disease, dual Her2 inhibition is better than single inhibition. Gianni L et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016 Jun;17(6):

24 Pharmacology Updates in Breast Cancer: Pertuzumab, PK Loading dose DIARRHEA Linear PK CL: 0.24L/day T½: 18 days (humanized mab) Steady state achieved after 1 st maintenance dose Quartino AL et al. Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer. Cancer Chemother Pharmacol Feb;79(2):

25 Pharmacology Updates in Breast Cancer: Pertuzumab, PK/PD relationship No dose-response relationship appreciated; i.e. any dose is equally likely to induce a pcr. Quartino AL et al. Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer. Cancer Chemother Pharmacol Feb;79(2):

26 Thank You Chris Vaklavas, M.D. Assistant Professor Department of Medicine, Division of Hematology/Oncology University of Alabama at Birmingham NP2540M th Avenue South Birmingham, AL Office Assistant: Jacqueline Jones Fax