10/24/14 New Hematology/Oncology Drug Updates Patrick Medina, - - PDF document

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New Hematology/Oncology Drug Updates

Patrick Medina, PharmD, BCOP The University of Oklahoma College of Pharmacy

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• Dr. Medina has nothing to disclose.

Disclosure

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§ Discuss the pharmacology and indications of medications approved in the year 2013–2014 for the management of patients with cancer or hematologic diseases § Describe recommended monitoring and management of toxicities associated with these agents § Explain the impact of these agents on the advanced practitioner

Learning Objectives

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Newly Marketed Agents: 2013 Through August 1, 2014

Idelalisib (Zydelig)…..……………….. …..July 23, 2014 Belinostat (Beleodaq)………………........July 3, 2014 Ceritinib (Zykadia)...………………………April 29, 2014 Ramucirumab (Cyramza).………………..April 21, 2014 Ibrutinib (Imbruvica)…………………........November 13, 2013 Obinutuzumab (Gazyva)………………….November 1, 2013 Afatinib (Gilotrif)..………………………….July 12, 2013 Dabrafenib (Tafinlar)………………………May 29, 2013 Trametinib (Mekinist)..………………........May 29, 2013 Ado-trastuzumab emtansine (Kadcyla)…February 22, 2013 Pomalidomide (Pomalyst)..……………….February 8, 2013

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• A. Breast
• B. Colon
• C. Lung
• D. Prostate

Ado-trastuzumab emtansine is approved for which of the following cancers?

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HER2-Positive Breast Cancer

§ 20%–25% of invasive breast cancers § Overexpression can activate signaling § Promotes cell proliferation and survival

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§ Trastuzumab and DM1 are covalently linked via a thioether linker § DM1 is a highly potent derivative of antimicrotubule agent maytansine § Ado-trastuzumab emtansine specifically targets HER2+ tumor cells by antibody- dependent cellular cytotoxicity and inhibiting HER2 signaling § A phase I study demonstrated that MTD was 3.6 mg/kg q3wk, and systemic DM1 exposure was low (5 ng/mL maximum plasma levels)

Ado-Trastuzumab Emtansine (T-DM1 )

MTD = maximum tolerated dose 8 ¡

T-DM1: Ado-Trastuzumab Emtansine A New Antibody-Drug Conjugate

Internalization Emtansine release Inhibition of microtubule polymerization

Adapted from LoRusso PM, et al. Clin Cancer Res. 2011;17:6437–6447.

HER2 T-DM1 HER2

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EMILIA Study Design

Centrally confirmed HER2+ LABC or MBC (N = 980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 mo of adjuvant treatment

Ado-trastuzumab emtansine 3.6 mg/kg q3wk IV Capecitabine 1,000 mg/m2 orally bid d1-14, q3wk + Lapatinib 1,250 mg/day orally qd

1:1 ¡

R

Primary endpoints: Independently assessed progression-free survival,

• verall survival, and safety

PD PD

Verma S, et al. N Engl J Med. 2012;367:1783–1791. LABC = locally advanced breast cancer; MBC = metastatic breast cancer.

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Progression-Free Survival, as Assessed by an Independent Review Committee

Verma S, et al. N Engl J Med. 2012;367:1783–1791. 11 ¡

Second Interim Analysis of Overall Survival

Verma S, et al. N Engl J Med. 2012;367:1783–1791. 12 ¡

§ Dose: 3.6 mg/kg IV infusion

• 1st dose over 90 min; subsequent doses over 30 min

§ Indication: The treatment of patients with HER2+ metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination § Warnings: Black box for hepatic, cardiac, and embryo-fetal toxicity

• Also warnings for pulmonary, infusion reactions, hemorrhage,

thrombocytopenia, and neurotoxicity

§ Toxicities

• Frequency > 25% (all grades): Nausea, fatigue, musculoskeletal pain,

thrombocytopenia, increased transaminases, headache, and constipation

• The most common grade ≥ 3 ADRs (frequency > 2%) were

thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue

• Drug-drug interactions: Ado-trastuzumab emtansine is a

CYP3A4 substrate

Ado-Trastuzumab Emtansine

ADR = adverse drug reaction

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Select adverse events (grade ≥ 3) T-DM1 (n = 490) Cape + lap (n = 488) Diarrhea 1.6% 20.7% Hand-foot syndrome 0% 16.4% Vomiting 0.8% 4.5% Nausea 0.8% 2.5% Mucosal inflammation 0.2% 2.3% Increased AST 4.3% 0.8% Increased ALT 2.9% 1.4% Thrombocytopenia 12.8% 0.2%

EMILIA: Adverse Events

Verma S, et al. N Engl J Med. 2012;367:1783–1791. ALT = alanine aminotransferase; AST = aspartate aminotransferase. 14 ¡

Ado-Trastuzumab Emtansine

BOXED WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

Monitor LFTs prior to each dose

Grade 2 (> 1.5 to ≤ 3 × ULN) Grade 3 (> 3 to ≤ 10 × ULN) Grade 4 (> 10 × ULN) Do not administer until total bilirubin recovers to grade ≤ 1, and then treat at same dose level Do not administer until total bilirubin recovers to grade ≤ 1, and then reduce 1 dose level Permanently DC Grade 2 (> 2.5 to ≤ 5 × ULN) Grade 3 (> 5 to ≤ 20 × ULN) Grade 4 (> 20 × ULN) Treat at same dose level Do not administer until AST/ALT recovers to grade ≤ 2, and then reduce 1 dose level Permanently DC

DC = discontinue; LFT = liver function test; ULN = upper limit of normal. 15 ¡

Biomarkers Used in Lung Cancer

Korpanty GJ, et al. Front Oncol. 11 August 2014.

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§ Dose: 750 mg orally once daily (on an empty stomach) § Indication: The treatment of patients with anaplastic lymphoma kinase–positive metastatic NSCLC who have progressed on or who are intolerant to crizotinib § Warnings: Severe or persistent gastrointestinal toxicity, hepatotoxicity, ILD/pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, embryo-fetal toxicity § Toxicities: The most common adverse reactions (incidence ≥ 25%) are diarrhea, nausea, elevated transaminases, vomiting, abdominal pain, fatigue, decreased appetite, and constipation § Drug-drug interactions: Ceritinib is a CYP3A4 substrate as well as an inhibitor of CYP3A4 and CYP2D6

Ceritinib

ILD = interstitial lung disease; NSCLC = non–small cell lung cancer. 17 ¡

Progression-Free Survival

Shaw AT, et al. N Engl J Med. 2014;370:1189–1197. 18 ¡

Adverse ¡Events ¡of ¡Grade ¡3 ¡or ¡4 ¡That ¡Were ¡Suspected ¡to ¡Be ¡Related ¡to ¡Ceri=nib ¡Therapy. ¡

Shaw AT, et al. N Engl J Med. 2014;370:1189–1197.

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§ Dose: 40 mg orally, once daily taken at least 1 hr before or at least 2 hr after a meal § Indication: The first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test § Warnings

• Diarrhea
• Bullous and exfoliative skin disorders
• ILD: Occurs in 1.5% of patients.
• Hepatic toxicity: Monitor with periodic liver testing
• Keratitis

§ Toxicities: Most common adverse reactions (≥ 20%) are diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus § Drug-drug interactions: Pgp substrate

Afatinib

EGFR = epidermal growth factor receptor 20 ¡

EGFR and Mutations Within the TK Domain

Sequist LV, et al. J Clin Oncol. 2007;25:587–595; Shigematsu H, et al. J Natl Cancer Inst. 2005;97:339–346.

3% Codon 719 variants 2% Other variants 46% Exon 19 deletions 40% L858R substitution 9% Exon 20 variants

Ligand L-domain Furin-like domain L-domain Survival Proliferation Extracellular domain Transmembrane domain Intracellular domain TK domain

EGFR

TK = tyrosine kinase 21 ¡

§ T790M known as a major mechanism of acquired resistance § Data suggest that it often is present at a low frequency at baseline and selected for after treatment with EGFR TKI

• EGFR TKIs may kill non–T790M-containing clones preferentially,

enriching for T790M+ population

Secondary Mutations in EGFR (T790M) Lead to Acquired Resistance to EGFR TKIs

Kobayashi S, et al. N Engl J Med. 2005;352:786–792 TKI = tyrosine kinase inhibitor

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LUX LUNG3 Study Design

Sequist LV, et al. J Clin Oncol. 2013;31:3327–3334.

Randomization 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian) Afatinib 40 mg/day Cisplatin + pemetrexed 75 mg/m2 + 500 mg/m2 IV q21d, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review) Secondary endpoints: ORR, DCR, DOR, tumor shrinkage, OS, PRO, safety, PK Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6) EGFR mutation in tumor (central lab testing; Therascreen EGFR29 RGQ PCR)

72% Asian, 65% women, 68% NS 49% del19, 40% L858R, 11% other

AJCC = American Joint Committee on Cancer; DCR = disease control rate; DOR = duration of response; NS = not significant; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; PRO = patient-reported outcomes. 23 ¡

Progression-Free Survival

Sequist LV, et al. J Clin Oncol. 2013;31:3327–3334. 24 ¡

Afatinib (n = 229) Cis/pem (n = 111)

All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%)

Diarrhea 218 (95.2) 33 (14.4) 17 (15.3) Rash/acne 204 (89.1) 37 (16.2) 7 (6.3) Stomatitis/mucositis 165 (72.1) 19 (8.3) 1 (0.4) 17 (15.3) 1 (0.9) Paronychia 130 (56.8) 26 (11.4) Dry skin 67 (29.3) 1 (0.4) 2 (1.8) Nausea 41 (17.9) 2 (0.9) 73 (65.8) 4 (3.6) Decreased appetite 47 (20.5) 7 (3.1) 59 (53.2) 3 (2.7) Fatigue 40 (17.5) 3 (1.3) 52 (46.8) 14 (12.6) Vomiting 39 (17.0) 7 (3.1) 47 (42.3) 3 (2.7) Neutropenia 2 (0.9) 1 (0.4) 35 (31.5) 17 (15.3) 3 (2.7) Anemia 7 (3.1) 1 (0.4) 31 (27.9) 5 (4.5) 2 (1.8)

Most Frequent Related Adverse Events > 20% Difference Between Treatment Arms

Yang JC-H, et al. ASCO 2012, Abstract LBA7500.

† No grade 5 events for the presented adverse events (AEs).

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• A. EGFR inhibitor
• B. VEGF ligand inhibitor
• C. VEGFR-2 inhibitor
• D. HER-2 inhibitor

Which of the following best explains ramucirumab’s mechanism of action?

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§ Dose: 8 mg/kg IV over 60 min every 2 weeks

• Premedicate with diphenhydramine ± dexamethasone
• Check for proteinuria and blood pressure prior to each dose

§ Indication: Advanced gastric cancer or gastroesophageal junction adenocarcinoma, as a single agent after prior fluoropyrimidine- or platinum-containing chemotherapy § Warnings: Black box for hemorrhage; additional warnings for ATEs, hypertension, infusion reactions, GI perforation, impaired wound healing, worsening cirrhosis, posterior leukoencephalopathy § Toxicities: Hypertension and diarrhea are most common § Drug-drug interactions: None reported

Ramucirumab

ATE = arterial thromboembolic event; GI = gastrointestinal. 27 ¡

VEGF-­‑A ¡

VEGF-­‑R1 ¡

(Flt-­‑1) ¡ Migra=on ¡ Invasion ¡ Survival ¡

VEGF-­‑R3 ¡

(Flt-­‑4) ¡ Lymphangio-­‑ ¡ genesis ¡

VEGF-­‑R2 ¡

(KDR/Flk-­‑1) ¡ Prolifera=on ¡ Survival ¡ Permeability ¡

PlGF ¡ VEGF-­‑B ¡ ¡ ¡ VEGF-­‑C, ¡ ¡ VEGF-­‑D ¡

Y ¡

Bevacizumab ¡

Y ¡

Ramucirumab ¡

Aflibercept ¡ ¡ (VEGF ¡Trap) ¡

Large-Molecule VEGF Inhibitors

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REGARD Trial Design

Fuchs CS, et al. Lancet. 2014;383:31–39. 29 ¡

REGARD Trial: Results

Fuchs CS, et al. Lancet. 2014;383:31–39.

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HR (95% CI) = 0.776 (0.603-0.998) Log-rank p value (stratified) =.047

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28 20 40 60 80 100

OS, %

238 117 Number at risk Ramucirumab Placebo 154 66 92 34 49 20 17 7 7 4 3 2 1

Ramucirumab (n = 238) Placebo (n = 117) Censored Time Since Randomization, Months

20

HR (95% CI) = 0.483 (0.376-0.620) Log-rank p value (stratified) <.0001

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 40 60 80 100

PFS, %

238 117 Number at risk Ramucirumab Placebo 213 92 5 2 113 27 65 11 61 7 45 4 30 2 18 2 18 2 11 2 4 1 2 1 1 1 1 1

Time Since Randomization, Months Ramucirumab (n = 238) Placebo (n = 117) Censored

OS PFS

CI = confidence interval; HR = hazard ratio. 30 ¡

§ Several phase III trials show OS benefit in the second-line setting in combination with chemotherapy regimens

• FOLFIRI + ramucirumab in metastatic colon cancer (RAISE study)
• Docetaxel + ramucirumab in metastatic NSCLC (REVEL study)
• Paclitaxel + ramucirumab in gastric cancer (RAINBOW study)

§ Though none of these regimens is FDA approved at this time, submission for regulatory approval is expected

Ramucirumab Future Directions

OS = overall survival; FOLFIRI = leucovorin/5-FU/irinotecan.

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§ Oncogenic mutation of BRAF

• 8% of all solid tumors
• 50% of malignant melanomas
• 40%–70% papillary or

anaplastic thyroid cancers

§ shRNA knock-down experiments support its role in neoplastic behavior § BRAF mutation knock-in mice develop melanoma-like malignancies § Vemurafenib arrests abnormal cell growth in melanoma models

RAS/MEK/ERK Pathway and BRAF Inhibitors

Cohen Y, et al. J Natl Cancer Inst. 2003;95:625–627; Davies H, et al. Nature. 2002;417:949–954; Flaherty KT, et al. N Engl J Med. 2010;363:809–819; Sosman J. Post-ASCO Review 2011. www.vicc.org/2011/onehemrev/presentations/sosman-jeffrey2011.pdf shRNA = short hairpin RNA 32 ¡

§ Inhibits kinase activity of certain mutated forms of BRAF, including BRAF with V600E mutation (present in ~ 50% of melanomas) § Not active against cells with wild-type BRAF

BRAF Kinase Inhibitor

Poulikakos PI, et al. Cancer Cell. 2011;19:11–15. 33 ¡

§ About 50% of nodular melanomas

• Acquired mutation
• RAS/RAF/MEK pathway is constitutively activated driving

proliferation

§ Most common mutation: V600E

• Mutation in DNA causes change in protein amino acid sequence:

Valine at amino acid 600 to glutamine

§ Second most common mutation: V600K

• Same amino acid: valine to lysine

BRAF

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Overall Survival (%) Time (months)

100 80 60 40 20 2 4 6 8 12 10

A: BRAF mutant on inhibitor B: BRAF wild-type C: BRAF mutant no inhibitor Overall P < .001 A v C P < .003 B v C P = .147 A v B P = .027

Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma

Long GV, et al. J Clin Oncol. 2011;29(10):1239–1246. 35 ¡

§ Dose: 150 mg orally twice daily without food § Indication: As a single agent or in combination with trametinib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA- approved test. § Warnings: New primary skin cancers, tumor promotion, hemorrhage, venous thromboembolism, cardiomyopathy, ocular toxicity, febrile reactions, skin toxicity, hypergylcemia, embryo- fetal toxicity, G6-PD deficiency § Toxicities: Most common adverse reactions (≥ 20%) for dabrafenib as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome § Drug-drug interactions

• Substrate of CYP3A4 and CYP2C9
• Induces CYP3A4 and CYP2C9

Dabrafenib

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BRAF Inhibitor: Dabrafenib BREAK-3 Front-Line Study Design

Hauschild A, et al. ASCO 2012, Abstract LBA8500.

Screened N = 733 Dabrafenib 150 mg twice daily n = 187 Dacarbazine 1,000 mg/m2 IV every 3 weeks n = 63 Enrolled n = 250

3:1 randomization

Stratification factors: unresectable stage III, stage IV; M1a + M1b vs. M1c

§ Secondary objectives: OS, ORR in both groups and after crossover, PFS2 (after crossover), duration of response, safety/tolerability, and BRAF mutation assay validation

Crossover allowed at radiologic PD Dabrafenib 150 mg twice daily n = 28 (68% of PD patients)

§ Primary endpoint: Investigator-assessed PFS in BRAF V600E/K patients § > 95% power to detect HR of 0.33

PD = progressive disease

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Dabrafenib, n (%) DTIC, n (%)

AE All Grade 3 Grade 4 All Grade 3 Grade 4

Skin Hyperkeratosis 95 (51) 1 (<1) 1 (<1) – – – Palmar-plantar hyperkeratosis 39 (21) 4 (2) – 1 (2) – – SCC/KA 13 (7) 9 (5) – – – – GI Nausea 18 (10) – – 21 (36) – – Vomiting 8 (4) – – 12 (20) – – Hematologic Neutropenia 2 (1) 1 (<1) – 9 (15) 3 (5) 4 (7) Thrombocytopenia 1 (<1) 1 (<1) – 5 (8) 1 (2) 2 (3) Leukopenia 1 (<1) – – 3 (5) 1 (2) – Other Arthralgia 30 (16) 1 (<1) – – – – Fatigue 32 (17) 2 (1) – 13 (22) – – Headache 32 (17) – – 2 (3) – – Pyrexia 28 (15) 5 (3) – – – – Asthenia 26 (14) – – 7 (12) – –

Treatment-Related AEs: ≥ 5% of Patients

Hauschild A, et al. ASCO 2012, Abstract LBA8500.

Photosensitivity: dabrafenib (3%), DTIC (5%).

KA = keratoacanthoma; SCC = squamous cell carcinoma. 38 ¡ Hauschild A, et al. Lancet. 2012;380(9839):358–365. 39 ¡

§ Dose: 2 mg orally twice daily taken at least 1 hr before or at least 2 hr after a meal

• Approved as a single agent or in combination with dabrafenib
• Confirm the presence of BRAF V600E or V600K mutation
• BRAF V600E mutations result in constitutive activation of the BRAF

pathway which includes MEK1 and MEK2 § Warnings

• Cardiovascular

§ Bleeding; clots; decreased left ventricular ejection fraction (check LVEF before treatment, after 1 month of treatment, then every 2 to 3 mo)

• Retinal pigment epithelial detachment
• Retinal vein occlusion
• ILD
• Serious skin toxicity
• Embryofetal toxicity

§ Toxicities: Most common adverse reactions (≥ 20%) include rash, diarrhea, and lymphedema § Drug-drug interactions: None identified

Trametinib

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40 ¡ Kwong LN, et al. Oncogene. 2013;33:1–9. 41 ¡

§ BRAF mutation status

• Using allele-specific PCR at RGI

§ Stratification factors

• LDH (> ULN vs. < ULN) and
• Prior chemotherapy (yes vs. no)

§ Populations

• ITT (all randomized patients) n = 322
• Primary efficacy (subset of ITT) n = 273

§ Primary endpoint

• PFS in BRAFV600E-positive melanoma

§ Secondary endpoints

• PFS in ITT
• Overall survival, response rate, and

safety

METRIC: Phase 3 Study of MEK Inhibitor Trametinib in Previously Untreated V600E/K Mutation Patients

Robert C, et al. ASCO 2012, Abstract LBA8509.

V600E/K mutation (n = 322) Chemotherapy (n = 108) Trametinib 2 mg qd (n = 214) Trametinib 2 mg qd

PFS FSFV: Dec 2010 LSFV: July 2011 Crossover*

Screened (n = 1,059)

*Allowed after independent confirmation of progression. Chemotherapy = DTIC or paclitaxel; FSFV = first subject first visit; LSFV = last subject first visit; ITT = intent to treat; PCR = polymerase chain reaction; ULN = upper limit of normal. 42 ¡

Progression-Free Survival and Disease Progression or Death According to Subgroup

Flaherty KT, et al. N Engl J Med. 2012;367:107–114.

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Kaplan-Meier Curves for Overall Survival

Flaherty KT, et al. N Engl J Med. 2012;367:107–114. 44 ¡

Adverse Events

Flaherty KT, et al. N Engl J Med. 2012;367:107–114. 45 ¡

*1 patient in the 150/1 group was not evaluable. †p value Dab vs. Dab + Tram 150/1 = .77; Dab vs. Dab + Tram 150/2 = .026.

Combination of Dabrafenib and Trametinib

Flaherty KT, et al. N Engl J Med. 2012;367:1694–1703.

Mono D (N = 54) Combination D + T 150/1 (N = 54)* Combination D + T 150/2 (N = 54) CR 2 (4) 3 (6) 5 (9) PR 27 (50) 24 (44) 36 (67) SD 22 (41) 24 (44) 13 (24) PD 3 (6) 2 (4) Response rate† 29 (54%) 27 (50%) 41 (76%) Duration of response (95% CI) 5.6 mo (4.5–7.4 mo) 9.5 mo (7.4 mo–NA) 10.5 mo (7.4–14.9 mo)

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Hematologic Cancers

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• A. Neutropenia
• B. Congestive heart failure
• C. Diarrhea
• D. Hepatitis B reactivation

Which of the following is a black box warning regarding the use of

• binutuzumab?

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§ Dose: See next slide § Indication: In combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia § Warnings: Black box for hepatitis B virus (HBV) reactivation, and progressive multifocal leukoencephalopathy (PML)

– Additional warnings: Infusion reactions, TLS, neutropenia, thrombocytopenia, immunization

§ Toxicities: Most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder

Obinutuzumab

TLS = tumor lysis syndrome

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§ Premedicate with glucocorticoid, acetaminophen, and antihistamine § Consider withholding antihypertensive treatments for 12 hr prior to and throughout infusion and for the first hour after administration § For patients with high tumor burden and/or high circulating absolute lymphocyte counts (> 25 × 109/L), premedicate and prehydrate for prophylaxis of TLS

50 ¡

Previously untreated CLL patients with comorbidities (CIRS score > 6 and/or CrCl < 70 mL/min) N = 781 Chlorambucil 0.5 mg/kg po on days 1,15 × 6 cycles (n = 118) Obinutuzumab 1,000 mg IV cycle 1 on days 1,8,15; cycles 2–6 on day 1 + chlorambucil 0.5 mg/kg po on days 1,15 × 6 cycles (n = 333) Rituximab 375 mg/m2 IV cycle 1 on day 1; 500 mg/m2 cycles 2–6 on day 1 + chlorambucil 0.5 mg/kg po on days 1,15 × 6 cycles (n = 330) 28-day cycle Patients who progress on chlorambucil alone allowed to crossover to obinutuzumab + chlorambucil arm. Randomized 1:2:2

CLL11 Trial: Obinutuzumab + Chlorambucil

• vs. Rituximab + Chlorambucil

Goede V, et al. N Engl J Med. 2014;370:1101–1110. CIRS = Cumulative Illness Rating Scale; CLL = chronic lymphocytic leukemia; CrCl = creatinine clearance. 51 ¡

Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions

Goede V, et al. N Engl J Med. 2014;370:1101–1110.

100 80 60 40 20 p < .001 p < .001 55.0 22.3 31.4 58.4 7.3 O-Clb (n = 238) Clb (n = 118) R-Clb (n = 233) Patients With a Response (%) Obinutuzumab-Clb CR PR Clb CR PR Rituximab-Clb CR PR

Clb = chlorambucil

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Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions (cont)

Goede V, et al. N Engl J Med. 2014;370:1101–1110.

100 80 60 40 20 100 80 60 40 20 p < .001 20.7 ¡ 57.7 ¡ 7.0 58.1 ¡ Obinutuzumab-Clb (n = 333) Rituximab-Clb (n = 329) Patients With a Response (%) Bone Marrow Blood p < .001 p < .001 19.5 2.6 37.7 3.3

Pts at Risk, n 26/133 3/114 87/231 8/243

Patients With a Negative MRD Test (%) Obinutuzumab-Clb Rituximab-Clb Obinutuzumab-Clb CR PR Rituximab-Clb CR PR

MRD = minimal residual disease. 53 ¡

3 6 9 12 15 18 21 24 27 30 33 36 39 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Probability of PFS Months

CLL11 Trial: PFS Head-to-Head Comparison

Goede V, et al. N Engl J Med. 2014;370:1101–1110.

15.2 26.7 Obinutuzumab-Chlorambucil Rituximab-Chlorambucil Stratified HR, 0.39 (95% CI, 0.31–0.49; p < .0001)

54 ¡

CLL11: Overall Survival

Goede V, et al. N Engl J Med. 2014;370:1101–1110.

1.0 0.8 0.6 0.4 0.2 6 12 18 24 30 36 Months Probability of OS O-Clb Clb Stratified HR for death with O-Clb: 0.41 (95% Cl: 0.23–0.74; p = .002)

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Type I and II Anti-CD20 Monoclonal Antibodies

Cragg MS. Blood. 2011;118:219–220.

Ofatumumab Phospholipid

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Type I vs. Type II Monoclonal Antibodies

Cragg MS. Blood. 2011;118:219–220.

Antibody type I II Lipid rafts Yes No CDC High Low ADCC + + Direct cytotoxicity Weak Strong Binding sites 2 1 Homotypic aggregation Weak Strong

57 ¡

LYN ¡ SYK ¡

BCR ¡

BTK ¡ PLCγ2 PKC ¡ AKT ¡ mTOR ¡ p70s6k ¡ elf4E ¡ GSK-­‑3 ¡ NF-kβ pathway

§ BCR signaling is required for tumor expansion and proliferation § BCR signaling upregulated in B-cell malignancies § New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk

Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies

IbruGnib ¡ AVL-­‑292 ¡

┬ ┬

Idelalisib ¡ IPI-­‑145 ¡ TGR-­‑1202 ¡

┬

FostamaGnib ¡ GS-­‑9973 ¡ PI3K ¡ delta ¡

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§ Dose

• MCL: 560 mg taken orally once daily; CLL: 420 mg taken orally once daily
• Capsules should be taken orally with a glass of water.

§ Indications

• Patients with MCL who have received at least 1 prior therapy
• Patients with CLL who have received at least 1 prior therapy
• Patients with CLL with 17p deletion

§ Warnings

• Hemorrhage, infections, myelosuppression, atrial fibrillation, second primary

malignancies, embryo-fetal toxicity

• Avoid in patients with baseline hepatic impairment

§ Toxicity: The most common adverse reactions (≥ 20%) in patients with CLL were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia § Drug interaction: CYP3A4 substrate

Ibrutinib

MCL = mantle cell lymphoma 59 ¡

§ Forms a specific and irreversible bond with cysteine-481 in BTK § Approved for second-line CLL and MCL § Highly potent BTK inhibition at IC50 = 0.5 nM § Orally administered with once-daily dosing resulting in 24-hr target inhibition § In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation § Inhibits CLL cell migration and adhesion § No cytotoxic effect on T cells or NK cells

Ibrutinib

Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010;107:13075; Herman SEM, et al. Blood. 2011;117:6287–6296; Ponader et al. ASH Abstracts 116:45, 2010.

N ¡ N ¡ N ¡ N ¡ N ¡ H ¡2 ¡ O ¡ N ¡ O ¡

PCI-32765

60 ¡

Warnings and precautions

• Hemorrhage: Monitor for bleeding
• Infections: Monitor patients for fever and infections and evaluate

promptly

• Myelosuppression: Check complete blood counts monthly
• Renal toxicity: Monitor renal function and maintain hydration
• Second primary malignancies: Other malignancies have occurred in

patients, including skin cancers

• CYP3A4 substrate

Ibrutinib

10/24/14 ¡ 21 ¡

61 ¡

Ibrutinib Progression-Free and Overall Survival

Byrd JC, et al. N Engl J Med. 2014;371:213–223. 62 ¡

§ Dose: 150 mg PO twice daily

• Several dose adjustments for hepatic toxicity, pneumonitis, and myelosuppression

§ Indications

• Relapsed CLL, in combination with rituximab
• Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have

received at least 2 prior systemic therapies

• Relapsed small lymphocytic lymphoma (SLL) in patients who have received at

least 2 prior systemic therapies § Warnings: Black box for hepatotoxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation

• Additional warnings: Severe cutaneous reactions, anaphylaxis, neutropenia,

embryo-fetal toxicity § Toxicities: Most common adverse reactions (incidence ≥ 20%) are diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash

• Most common laboratory abnormalities (incidence ≥ 30%) are neutropenia,

hypertriglyceridemia, hyperglycemia, ALT and AST elevations § Drug-drug interactions: CYP3A4 substrate and inhibitor

• Levels decreased by up to 75% with inducers; increased by 1.8-fold with inhibitors; increased

substrate levels by over 5-fold

Idelalisib

63 ¡

LYN ¡ SYK ¡

BCR ¡

BTK ¡ PLCγ2 PKC ¡ AKT ¡ mTOR ¡ p70s6k ¡ elf4E ¡ GSK-­‑3 ¡ NF-kβ pathway

Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies

§ BCR signaling is required for tumor expansion and proliferation § BCR signaling upregulated in B-cell malignancies § New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk

IbruGnib ¡ AVL-­‑292 ¡

┬ ┬

Idelalisib ¡ IPI-­‑145 ¡ TGR-­‑1202 ¡

┬

FostamaGnib ¡ GS-­‑9973 ¡ PI3K ¡ delta ¡

10/24/14 ¡ 22 ¡

64 ¡

Pomalidomide

65 ¡

§ Dose: 4 mg per day taken orally on an empty stomach on days 1–21 of repeated 28-day cycles until disease progression

• Avoid in patients with hepatic or renal dysfunction (serum creatinine

> 3 mg/dL) § Warnings: Black box warning for embryo-fetal toxicity and venous thromboembolism

• Requires anticoagulation prophylaxis

§ Most patients in trials received aspirin § Primarily metabolized by CYP1A2 and CYP3A4; pomalidomide is also a substrate for Pgp § Part of a REMS program

Pomalidomide

REMS = Risk Evaluation and Mitigation Strategies 66 ¡

Pomalidomide

Latif T, et al. Exp Hematol Oncol. 2012,1:27.

Drug Dose Metabolism/ excretion Half-life Dose adjustments Thalidomide 50–100 mg Hepatic/ nonrenal 4–9 hr None Lenalidomide 15–25 mg Renal (mostly unchanged) 3.1–4.5 hr Moderate to severe renal impairment Pomalidomide 1–5 mg Renal (mostly unchanged) 6.2–7.9 hr None

10/24/14 ¡ 23 ¡

67 ¡

IMID Mechanism of Action

Shortt J, et al. Oncogene. 2013;32:4191–4202. 68 ¡

Phase III MM-003 Trial Design

Dimopoulos MA, et al. Proc ASH. 2012, Abstract LBA-6.

Eligibility (n = 455) Primary refractory or relapsed and refractory MM At least 2 prior therapies* Failed LEN and BORT

* Including ≥ 2 consecutive cycles of LEN and BORT, alone or in combination.

† Patients experiencing disease progression on HiDEX could receive POM on

companion MM-003C trial.

POM + LoDEX (n = 302) POM: 4 mg/day, d1–21 LoDEX: 40 mg 20 mg (> 75 yr) d1,8,15,22 (28-day cycle) HiDEX (n = 153)† 40 mg 20 mg (> 75 yr) d1–4,9–12,17–20 (28-day cycle)

R ¡

2:1

MM = multiple myeloma 69 ¡

Primary Endpoint: Progression-Free Survival

Dimopoulos MA, et al. Proc ASH. 2012, Abstract LBA-6.

ITT population

4 8 12 16 0.0 0.2 0.4 0.6 0.8 1.0 Progression-Free Survival (months) Proportion of Patients Median PFS POM + LoDEX (n = 302) 3.6 mo HiDEX (n = 153) 1.8 mo HR = 0.45 p < .001 Proportion of Patients 0.0 0.2 0.4 0.6 0.8 1.0 4 8 12 16 HR = 0.48 p < .001 Progression-Free Survival (months) Median PFS POM + LoDEX (n = 221) 3.2 mo HiDEX (n = 108) 1.7 mo

Patients refractory to LEN and BORT

10/24/14 ¡ 24 ¡

70 ¡

Grade 3/4 AEs POM + LoDEX (n = 300) HiDEX (n = 149) Hematologic Neutropenia Febrile neutropenia Anemia Thrombocytopenia 42% 7% 27% 21% 15% 0% 29% 24% Nonhematologic Infections Hemorrhage 24% 3% 23% 5%

Select Adverse Events

Dimopoulos MA, et al. Proc ASH. 2012, Abstract LBA-6.

Any grade AEs of interest — VTE: POM + LoDEX (3%), HiDEX (2%); peripheral neuropathy: POM + LoDEX (12%), HiDEX (11%)

71 ¡

§ Mechanism of Action: Histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins

• In vitro, caused the accumulation of acetylated histones inducing cell

cycle arrest and/or apoptosis of some tumor cells § Dose: 1,000 mg/m2 administered over 30 min by IV infusion once daily

• n days 1–5 of a 21-day cycle
• Adjust for myelosuppression or known homozygous for

UGT1A1*28 allele § Indication: Relapsed or refractory peripheral T-cell lymphoma § Warnings: Myelosuppression, infection, hepatotoxicity, TLS, embryo- fetal toxicity § Toxicities: The most common adverse reactions (> 25%) are nausea, fatigue, pyrexia, anemia, and vomiting § Drug-drug interactions: UGT1A1 inhibitors and warfarin

Belinostat