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

KRAS

PIP3 AKT BTK

PI3Kδ BRAF

MEK ERK

Proliferation and Survival

Tyrosine Kinase Domain (EGFR, VEGF, HER2)

Dabrafenib Vemurafeni b Trametinib Cobimetinib Binimetinib Idelalisib Ibrutinib

mTOR

Everolimus

PD‐L1

MHC‐1

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 (3rd deadliest)

American Cancer Society: Cancer Facts and Figures 2016. Atlanta, GA. Colon Cancer. NCCN Guidelines Version 2.2016.

LV, leucovorin *in most instances Colon Cancer. NCCN Guidelines Version 2.2016. see this reference for more detailed algorithm

THIRD LINE (AND BEYOND)

EGFR‐ DIRECTED THERAPY REGORAFENIB TRIFLURIDINE‐ TIPIRACIL FOLFOX

SECOND LINE

FOLFIRI FOLFOX IRINOTECAN EGFR‐ DIRECTED THERAPY

FIRST LINE

FOLFOX FOLFIRI 5‐FU/LV FOLFOXIRI

+/‐VEGF or EGFR‐ DIRECTED THERAPY* +/‐VEGF or EGFR‐ DIRECTED THERAPY*

 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/m2 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.

Adapted from: Lenz HJ, et al. Cancer Treat Rev 2015;41(9): 777‐83. TPI

Hepatic FTD degradation

FTD F3dTMP TK TS

dTTP depletion due to inhibition of TS DNA incorporation DNA damage

F3dTTP

Antiangiogenic effects

• FTD, trifluridine
• TPI, triphosphate
• TK, thymidine kinase
• F3dTMP, trifluoromethyl

deoxyuridine 5’‐monophosphate

• F3dTTP, trifluoromethyl

deoxyuridine 5’‐triphosphate

• TS, thymidylate synthase

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.

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

Atezolizumab

• 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.

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.

Test Baseline Prior to each cycle CBC differential X X CMP (Creatinine, Na, K, Ca, LFTs) X X 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 A/B/C, CMV, HIV, EBV (x) (x) ACTH (x) (x)

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

• therwise 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

 1‐4 mg/kg/d prednisone or equivalent  Tapered over > 4 weeks

• Generally decrease dose by 10 mg q5‐7 days
• Average patient ends up needing much longer taper
• Consider providing schedule/calendar
• PCP prophylaxis: bactrim DS, dapsone (G6PD

proficient), pentamidine, atovaquone

 IV steroids may be switched to equivalent dose

• ral CS at start of tapering or earlier, once

sustained clinical improvement

Weber JS, D'Angelo SP, Minor D, et al. Lancet Oncol. 2015. doi:10.1016/S1470‐2045(15)70076‐8. NCCN Clinical Practice Guidelines. Prevention and Treatment of Cancer‐Related Infections. V1.2016.

 Which of the following is correct regarding

atezolizumab?

• A. Requires renal dose adjustments
• B. Dosing is weight‐based
• C. Side effects are mainly immune‐mediated

and include neurological side effects

• D. Is approved for first‐line treatment of

urothelial carcinoma

VENETOCLAX

 Average age at diagnosis is 71 years old  19,000 new cases in the US in 2016

• 1/4 of all leukemia cases

 4,600 deaths projected in US in 2016

• 1/5 of all leukemia‐related deaths

American Cancer Society: Cancer Facts and Figures 2016. Atlanta, GA.

 Relapsed or refractory CLL with 17p deletion  Potent, selective BCL‐2 inhibitor  Venetoclax dose‐escalation (to minimize TLS)

• Week 1: 20 mg once daily
• Week 2: 50 mg once daily
• Week 3: 100 mg once daily
• Week 4: 200 mg once daily
• Thereafter: 400 mg once daily
• Doses taken with meals

Venclexta™ [prescribing information]. North Chicago, IL: AbbVie Inc., 2016.

 Phase II, single‐arm, multicenter  N= 106, relapsed/refractory CLL with del 17p  Median age = 67  Median of 2 prior regimens  73% received fludarabine  Patients with CrCl < 50 ml/min excluded from

trials

Stilgenbauer S, et al. ASH LBA‐6.

 ORR = 79%  7.5% CR/CRi; 2.5% nodular PR  85% maintained response at 12 months;

100% with CR/CRi/nPR

 Median duration of response, PFS, and OS

not reached (median follow‐up not reported)

 17% were MRD‐negative

Stilgenbauer S, et al. ASH LBA‐6.

Tumor Burden Hydrationa Medical TLS prophylaxis Setting and frequency of assessments

Low All LN <5 cm AND ALC <25 x 109/L Oral (1.5–2 L) Allopurinolb

Outpatient

 Pre‐dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg  Pre‐dose at subsequent ramp‐up doses

Medium Any LN 5 cm to <10 cm OR ALC > 25 x 109/L Oral (1.5‐2 L) Allopurinolb

Outpatient

 Pre‐dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg  Pre‐dose at subsequent ramp‐up doses  Consider hospitalization for patients with CrCl <80 ml/min at first dose

• f 20 mg and 50 mg;

treat as below

Venclexta™ [prescribing information]. North Chicago, IL: AbbVie Inc., 2016.

Tumor Burden Hydrationa Medical TLS prophylaxis Setting and frequency of assessments

High Any LN > 10 cm OR ALC > 25x109/L AND any LN > 5 cm Oral (1.5‐2 L) and intravenous (150‐ 200 mL/hr as tolerated) Allopurinolb; consider rasburicase if baseline uric acid elevated In hospital at first dose of 20 mg and 50 mg

 Pre‐dose, 4, 8, 12, 24 hours

Outpatient at subsequent ramp‐up doses

 Pre‐dose, 6 to 8 hours, 24 hours

Venclexta™ [prescribing information]. North Chicago, IL: AbbVie Inc., 2016.

Grade 3/4

 Neutropenia (40%)  Anemia (18%)  Thrombocytopenia (15%)  Infection (20%)

Other previously reported:

 <5%: fatigue, diarrhea, upper respiratory tract

infection, nausea, vomiting, fever, headache, constipation, arthralgia

Venclexta™ [prescribing information]. North Chicago, IL: AbbVie Inc., 2016.

Inhibitors Inhibitor examples Initiation and ramp‐up phase Steady Daily Dose (after ramp‐up phase) Strong CYP3A inhibitor Posaconazole, voriconazole, protease inhibitors Contraindicated Avoid or reduce venetoclax dose by at least 75% Moderate CYP3A inhibitor Fluconazole, ciprofloxacin, diltiazem, verapamil Avoid inhibitor use or reduce the venetoclax dose by at least 50% P‐gp inhibitor Amiodarone, azithromycin, carvedilol, cyclosporine

Venclexta™ [prescribing information]. North Chicago, IL: AbbVie Inc., 2016.

 Avoid: CYP3A inducers (phenytoin,

carbamazepine, modafinil, St. John’s wort); food interactions (grapefruit products, Seville

• ranges)

 Monitor: warfarin (venetoclax increases warfarin

exposure), more frequent INR monitoring necessary

 P‐gp substrates with narrow therapeutic window

(dixogin, everolimus, sirlimus) should be avoided

• r given at least 6 hours prior to venetoclax

doses

Venclexta™ [prescribing information]. North Chicago, IL: AbbVie Inc., 2016.

 Patient LM is 86‐year‐old female whose physician

would like to start venetoclax for her refractory 17p‐ deletion CLL (largest LN is 11 cm). She has a PMHx significant for hyperlipidemia and CHF, for which she takes pravastatin, carvedilol, and furosemide. Which

• f the following concerns you?

A.

She is at higher risk of TLS, given tumor burden and should be hospitalized for the first 2 doses.

B.

Carvedilol interacts with venetoclax and requires venetoclax dose adjustment

C.

Her creatinine is unknown but is expected to be elevated given her age and patients with CrCl <50 ml/min were excluded from trials.

D.

All of the above

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