Britny Rogala, PharmD, BCOP Pharmacist Clinician, Oncology 28 October - PowerPoint PPT Presentation

Britny Rogala, PharmD, BCOP Pharmacist Clinician, Oncology 28 October 2016

For each therapy discussed:  Discuss newly approved anticancer agents and their place in therapy  Describe the mechanism of action  Identify pertinent adverse effects, drug interactions, and administration points  Provide appropriate strategies for side effect monitoring and management

Tyrosine Kinase Domain (EGFR, VEGF, HER2) PD ‐ L1 KRAS MHC ‐ 1 PI3K δ Dabrafenib BRAF PIP3 Vemurafeni b Idelalisib AKT Trametinib MEK BTK Cobimetinib Binimetinib Ibrutinib Everolimus mTOR ERK Proliferation and Survival

TRIFLURIDINE ‐ TIPIRACIL

 Third most common cancer in both men and women  134,490 estimated new cases in 2016  Localized disease 5 ‐ year survival: 90%; only 39% of patients  50 ‐ 60% of patients develop metastases  49,190 estimated deaths in 2016 (3 rd deadliest) American Cancer Society: Cancer Facts and Figures 2016. Atlanta, GA. Colon Cancer. NCCN Guidelines Version 2.2016.

+/ ‐ VEGF or EGFR ‐ FIRST LINE DIRECTED FOLFOX FOLFIRI 5 ‐ FU/LV FOLFOXIRI THERAPY* +/ ‐ VEGF or EGFR ‐ SECOND LINE DIRECTED EGFR ‐ FOLFIRI FOLFOX IRINOTECAN DIRECTED THERAPY* THERAPY THIRD LINE (AND BEYOND) EGFR ‐ TRIFLURIDINE ‐ DIRECTED REGORAFENIB FOLFOX TIPIRACIL THERAPY LV, leucovorin *in most instances Colon Cancer. NCCN Guidelines Version 2.2016. see this reference for more detailed algorithm

 Previous treatment with fluoropyrimidine, oxaliplatin, and irinotecan ‐ based chemotherapy, anti ‐ VEGF therapy and, if RAS wild ‐ type, an anti ‐ EGFR therapy  Long story short: regorafenib or trifluridine ‐ tipiracil as last ‐ line therapy?  Consider: site of metastases, organ dysfunction  Dosing: it’s complicated Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc.; 2015.

 35 mg/m 2 PO BID on days 1 ‐ 5 and 8 ‐ 12 of a 28 ‐ day cycle within 1 hour of completion of morning and evening meals  Maximum dose = 80 mg/d  Preparations:  15 ‐ 6.14 mg  20 ‐ 8.19 mg  mg dose based on trifluridine component – often requires multiple tablet strengths  Cost per cycle: approximately $8,000 to $15,000 Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc.; 2015.

TREATMENT DAY 1 2 3 4 5 6 7 X X X X X 8 9 10 11 12 13 14 X X X X X 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc.; 2015.

Hepatic FTD FTD TPI Antiangiogenic effects degradation TK F 3 dTMP • FTD, trifluridine • TPI, triphosphate • TK, thymidine kinase TS • F3dTMP, trifluoromethyl F 3 dTTP deoxyuridine 5’ ‐ monophosphate • F3dTTP, trifluoromethyl deoxyuridine 5’ ‐ triphosphate dTTP depletion due to • TS, thymidylate synthase inhibition of TS DNA incorporation DNA damage Adapted from: Lenz HJ, et al. Cancer Treat Rev 2015;41(9): 777 ‐ 83.

Versus placebo: 2 month increase in overall survival (7.1 months versus 5.3 months; HR 0.68; 95% CI 0.58 ‐ 0.81; P<0.001) Longer maintenance of performance status (Time to ECOG > 2: 5.7 months versus 4.0 months; HR 0.68; 95% CI, 0.56 ‐ 0.78; P<0.001) Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS ‐ 102 for refractory metastatic colorectal cancer. N Engl J Med 2015;372:1909 ‐ 19.

Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS ‐ 102 for refractory metastatic colorectal cancer. N Engl J Med 2015;372:1909 ‐ 19.

 Prior to each cycle:  Serum creatinine  CBC with differential  Day 15: CBC with differential  Consider ECG monitoring in high risk patients ECG, electrocardiogram. Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc.; 2015.

 Take within 1 hour after completion of morning and evening meals  Use a calendar to keep track of your doses, follow dose on prescription label  Report any signs of infection, abdominal pain  Side effect management: nausea, vomiting, diarrhea, decreased appetite, fatigue  Contraception / breastfeeding  Safe handling, storage, adherence Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc.; 2015.

 Which of the following is NOT true with regard to how trifluridine ‐ tipiracil should be taken? A. Each dose may require more than one tablet strength B. Doses should be taken on an empty stomach C. Take on days 1 ‐ 5 and 8 ‐ 12 of a 28 ‐ day cycle D. The maximum dose is 80 mg

Atezolizumab

 Accounts for about 5% of new cases each year  ~77,000 new cases projected in the US in 2016  3:1 male to female ratio (fourth most common in men)  16,000 deaths projected in the US in 2016 American Cancer Society: Cancer Facts and Figures 2016. Atlanta, GA.

Locally advanced or metastatic urothelial carcinoma:  Disease progression following or during platinum ‐ containing chemotherapy  Disease progression within 12 months of neoadjuvant or adjuvant platinum ‐ containing therapy Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2016.

 The immune system is critical to controlling and eliminating cancer  The programmed cell death protein 1 (PD ‐ 1) is expressed on activated T cells  Programmed cell death ligands (PD ‐ L1 and PD ‐ L2) help T cells to identify self versus non ‐ self  Cancer cells can upregulate PD ‐ L1 and PD ‐ L2 to evade cytotoxic T cell attack and immune surveillance  Decreased T cell proliferation, cytokine production  Atezolizumab blocks interaction between PD ‐ L1 and PD ‐ 1/B7.1 Zibelman M et al. J Natl Compr Canc Netw 2014;12:S1 ‐ S5.

Atezolizumab Zibelman M et al. J Natl Compr Canc Netw 2014;12:S1 ‐ S5.

• IgG1, humanized, monoclonal antibody that binds the PD ‐ 1 receptor on T cells • 1200 mg IV over 60 minutes every 3 weeks • Immune ‐ mediated adverse effects • No dose reductions Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2016.

 Multicenter, single ‐ arm, phase 2 trial  Inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after prior platinum ‐ based therapy  N=310  Primary endpoint: objective response rate  Compared to historical control of 10% Rosenberg JE, et al. Lancet: 387: 1909 ‐ 1920.

Rosenberg JE, et al. Lancet: 387: 1909 ‐ 1920.

Test Baseline Prior to each cycle CBC differential X X CMP (Creatinine, Na, K, Ca, X X LFTs) LDH X (x) TSH (x) (x) C ‐ reactive protein (x) (x) Lipase, Amylase (x) (x) fT3 and fT4 (x) (x) Cortisol (x) (x) Serologic tests: Hepatitis (x) (x) A/B/C, CMV, HIV, EBV ACTH (x) (x) X: test recommended; (x): test optional EigentlerTK, et al. Cancer Treat Rev 2016;45:7 ‐ 18. Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2016.

Michot JM, et al. Eur J Cancer 2016;54:139 ‐ 48.

Michot JM, et al. Eur J Cancer 2016;54:139 ‐ 48.

Report signs of immune ‐ mediated reactions immediately  Skin: any rash  Hepatitis: abdominal pain, light colored stool, dark urine, jaundice  Hypophysitis/hypothyroidism: headache, fatigue, vision changes, confusion, change in menses, weight loss, chills  Colitis: diarrhea, blood or mucus in stool, abdominal cramping  Pneumonitis: shortness of breath, chest pain, new or worse cough  Ocular toxicity: blurry vision, diplopia, eye pain or redness  Neurologic abnormalities: severe muscle weakness, neuropathy, fever, confusion, changes in mood or behavior, extreme sensitivity to light, neck stiffness  Infection Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2016.

 Headaches that will not go away or that are unusual  Extreme weakness  Fatigue  Dizziness or fainting  Vision changes  Weight gain or weight loss  Rapid heartbeat, increased sweating, hair loss, feeling cold, constipation  Deepened voice  Muscle aches  Increased hunger or thirst  More frequent urination  Adrenal crisis: dehydration, hypotonia, signs of shock Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2016. EigentlerTK, et al. Cancer Treat Rev 2016;45:7 ‐ 18.

 Common side effects:  Fatigue  Decreased appetite  Nausea  Urinary tract infection  Fever  Constipation  Contraception during treatment and for 5 months thereafter Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2016.

 Treatment with corticosteroids 1 ‐ 2 mg/kg/day prednisone or equivalent tapered over > 4 weeks unless otherwise indicated (HD CS)  Taper < 10 mg every > 5 days (consider every 7 days in patients who have difficulty with instructions or provide calendar)  Therapy should be held until < grade 1 irAE and prednisone equivalent < 10 mg or less  Permanently discontinue therapy if unable to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks  Patients receiving CS for > 4 weeks should be initiated on PCP prophylaxis HD CS, high dose corticosteroids. . EigentlerTK, et al. Cancer Treat Rev 2016;45:7 ‐ 18. Spain L, Diem S, Larkin J. Cancer Treat Rev 2016;44:51 ‐ 60. Postow MA. Am Soc Clin Oncol Educ Book 2015:76 ‐ 83