Ibrance® - Palbociclib Manufacturer: Pfizer FDA Approval Date: February 3, 2015

Ibrance® - Palbociclib Clinical Application Indications: Treatment of post-menopausal women with estrogen positive, human epidermal growth factor negative advanced breast cancer Place in therapy: Only non hormonal therapy for advanced ER+ breast cancer

Ibrance® - Palbociclib Clinical Application Contraindications: none Warnings and Precautions: Neutropenia Infections Pulmonary embolism Embryo-Fetal toxicity

Ibrance® - Palbociclib Clinical Application Pregnancy: Category not currently assigned (likely X) Adverse events observed in animal reproduction studies Lactation: Excretion in breast milk not known Not recommended

Ibrance® - Palbociclib Drug Facts Pharmacology: Inhibitor of cyclin-dependent kinase (CDK) 4 and 6 Reduces cellular proliferation by blocking progression of the cell from G1 into S phase of cell cycle

Brand®or™ - Generic Drug Facts Pharmacokinetics: A Bioavialibility: 46%. Cmax: 6-12 hours D 85% protein bound with mean Vd of 2583 L M Extensive hepatic metabolism predominately via CYP3A4 and SULT2A1 E Feces (74% as metabolites); Urine (17.5% as metabolites); mean plasma half-life of 29 +/- 5 hrs.

Ibrance® - Palbociclib Drug Interactions Drug Interactions – Object Drugs: Weak CYP3A4 inhibitor  levels of CYP3A4 substrates Dose adjustment may be required for agents with narrow therapeutic indices

Ibrance® - Palbociclib Drug Interactions Drug Interactions – Precipitant Drugs: Strong CYP3A4 inhibitors  concentration of Ibrance (palbociclib) Strong CYP3A4 inducers: ↓ concentration of Ibrance (palbociclib)

Ibrance® - Palbociclib Monitoring Parameters Efficacy Monitoring: Signs of clinical improvement Absence of disease progression Toxicity Monitoring: CBC with differential prior to treatment, every 2 weeks for first 2 cycles, then prior to each cycle Monitor for s/sx of infection and pulmonary embolism

Ibrance® - Palbociclib Prescription Information Dosing: 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles Should be taken with food and in combination with letrozole 2.5 mg once daily continuously.

Ibrance® - Palbociclib Prescription Information Cost: 125 mg, 100 mg and 75 mg $11,820.00 for one month supply (21 capsules) Lexi-Comp via UpToDate; Accessed 3/6/2015

Ibrance® - Palbociclib Literature Review Study Design (PALOMA-1/TRIO-18) Phase 2, randomized, open label trial 50 sites in 12 countries (North America, Latin American and Europe) Interventions Palbociclib 125 mg daily (3 wks on/1 wk off) + Letrozole 2.5 mg daily Letrozole 2.5 mg daily Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Ibrance® - Palbociclib Literature Review Primary Endpoint: Progression free survival Secondary Endpoints: Objective response, clinical benefit, duration of response, overall survival Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Ibrance® - Palbociclib Literature Review Inclusion criteria Exclusion criteria Post-menopausal Received treatment with Letrozole within past 12 months Locally recurrent disease not amenable to surgery or metastatic disease Any previous treatment for advanced breast cancer No previous treatment for advanced disease Brain metastasis ER+/Her2- Any previous treatment with CDK inhibitor ECOG performance status of 0 or 1 Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Ibrance® - Palbociclib Literature Review Significant Adverse Events: (>20%) Event Palbociclib+Letrozole (n=83) Letrozole (n=77) URI 31 18 Neutropenia 75 5 Leukopenia 43 3 Anemia 35 7 Stomatitis 25 Nausea 13 Diarrhea 21 10 Alopecia 22 Fatigue 41 23 Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Ibrance® - Palbociclib Literature Review Efficacy Results: Investigator assessment PFS Intent to Treat Population Progression Free Survival Palbociclib + Letrozole (n=84) Letrozole (n=81) Number of PFS Events (%) 41 (48.8%) 59 (72.8%) Hazard Ratio (95% CI) 0.488 (0.319, 0.748) Median PFS [months] (95%CI) 20.2 (13.8, 27.5) 10.2 (5.7, 12.6) Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Ibrance® - Palbociclib Literature Review PALOMA-1/TRIO-18 Conclusions Addition of palbociclib to letrozole significantly improved progression free survival in women with advanced ER+ and HER2- breast cancer Phase 3 trial currently underway Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Ibrance® - Palbociclib Summary Only non-hormonal targeted therapy approved for use in ER-positive, HER-2 negative advanced breast cancer First CDK inhibitor approved for use in oncology Used in combination with letrozole Side effects: neutropenia / leukopenia Dose reduction is suggested as 1st step in tx

Ibrance® - Palbociclib References http://www.Ibrance.com Ibrance full prescribing infromation. Pfizer. Feb. 2015 Palbociclib. Drug information. Lexicomp Drug Information. Accessed through UpToDate. Accessed on February 15, 2015. Finn et al., The cyclin dependent kinase 4/6 inhibitor palbociclib in combination with letrozole vs letrozole alone as first linetreatment of estrogen receptor- positive HER2 negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomized phase 2 study. Lancet Oncol. 2015;16: 25-35