Pharmacology Updates in Breast Cancer Chris Vaklavas, M.D. Assistant Professor Department of Medicine, Division of Hematology/Oncology University of Alabama at Birmingham NP2540M 1802 6th Avenue South Birmingham, AL 35294-3300 Office 205 934 5677 cvaklavas@uabmc.edu Assistant: Jacqueline Jones 205 975 2914 Fax 205 975 3910
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
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
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.
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
Graph obtained from: https://nootropix.com/ 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
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
Clinical Pharmacology in Medical Oncology PKs usually assessed in Phase I clinical trials. However, statistical power to detect deviations is poor.
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.
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;12:913-923
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;12:913-923
DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology > 15:Pharmacokinetics and Pharmacodynamics of Anticancer Drugs
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. 2017 Jul 1;23(13):3251-3262
Pharmacology Updates in Breast Cancer: CDK4/6 Inhibitors, PK/PD properties Ribociclib (Kisqali; LEE011) Palbociclib (Ibrance; PD-0332991) Abemaciclib (LY2835219) IC 50 (nmol/l) on-target CDKs CDK4 cyclin D1 10 11 2 CDK6 cyclin D1/2/3 39 16 10 IC 50 (nm) on other CDKs CDK1 cyclin B 113,000 >10,000 1627 CDK2 cyclin A/E 76,000 >10,000 504 CDK5 p25 43,900 >10,000 355 CDK9 cyclin T NR NR 57 Kinase partition index 0.99 0.96 0.88 Lipophilicity (clogp) 2.3 2.7 5.5 IC 50 against bone marrow mononuclear cells (nmol/l) 1,700 ± 231 240 ± 43 230 ± 27 Half-life 33 42 hours 26 27 hours 17 38 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
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 1. 20.2 months 2. 10.2 months mos 1. 37.5 months 2. 33.3 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 1. 24.8 months 2. 14.5 months ORR 1. 42.1% 2. 34.7% 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 1. 9.2 (9.5) months 2. 3.8 (4.6) months ORR 1. 10.4% 2. 6.3% Neutropenia Leukopenia Fatigue Nausea
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 2.14.7 months ORR 1. 40.7% 2. 27.5% Neutropenia Nausea Infection Fatigue Diarrhea
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 1. 93.5% 2. 93.1% 3. 71.0% 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 1. 16.4 months 2. 9.3 months ORR 1. 48.1% 2. 21.3% Diarrhea Neutropenia Nausea Fatigue Abdominal pain
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 439 98.9 276 62.2 60 13.5 329 98.5 221 66.2 50 15 435 98.6 241 54.6 26 5.9 Neutropenia 353 79.5 249 56.1 46 10.4 248 74.3 166 49.7 32 9.6 203 46 104 23.6 13 2.9 Leukopenia 173 39 107 24.1 3 0.7 110 32.9 66 19.8 4 1.2 125 28.3 38 8.6 1 0.2 Fatigue 166 37.4 8 1.8 0 122 36.5 7 2.1 1 0.3 176 39.9 12 2.7 Nausea 156 35.1 1 0.2 0 172 51.5 8 2.4 0 199 45.1 12 2.7 Anemia 107 24.1 23 5.2 1 0.2 62 18.6 3 0.9 1 0.3 128 29 31 7 1 0.2 Headache 95 21.4 1 0.2 0 74 22.2 1 0.3 0 89 20.2 3 0.7 Diarrhea 116 26.1 6 1.4 0 117 35 4 1.2 0 381 86.4 59 13.4 Thrombocytopenia 69 15.5 6 1.4 1 0.2 NA NA NA 69 15.6 9 2 6 1.4 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).
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.
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.
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, 1888 1898.
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%, 20 6 38 5) 49 (45 8%, 36 1 55 7) * 18 (16 8%, 10 3 25 3) 23 (24 0%, 15 8 33 7) 23 (21 5%, 14 1 30 5) 42 (39 3%, 30 0 49 2) 12 (11 2%, 5 9 18 8) 17 (17 7%, 10 7 26 8) 8 (7 5%, 3 3 14 2) 7 (6 5%, 2 7 13 0) 6 (5 6%, 2 1 11 8) 6 (6 3%, 2 3 13 1) pcr in ER+ and/or PR+ pcr in ERand PR- 10/50 (20 0%, 10 0 33 7) 21/57 (36 8%, 24 4 50 7) 13/50 (26 0%, 14 6 40 3) 3/51 (5 9%, 1 2 16 2) 8/46 (17 4%, 7 8 31 4) 36/57 (63 2%, 49 3 75 6) 15/55 (27 3%, 16 1 41 0) 15/50 (30 0%, 17 9 44 6) 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):25-32..
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):791-800.
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. 2017 Feb;79(2):353-361.
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. 2017 Feb;79(2):353-361.
Thank You Chris Vaklavas, M.D. Assistant Professor Department of Medicine, Division of Hematology/Oncology University of Alabama at Birmingham NP2540M 1802 6th Avenue South Birmingham, AL 35294-3300 Office 205 934 5677 cvaklavas@uabmc.edu Assistant: Jacqueline Jones 205 975 2914 Fax 205 975 3910