10/24/14

New Hematology/Oncology Drug Updates

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

Disclosure

Dr. Medina has nothing to disclose.

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Learning Objectives

§ 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

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

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

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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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Ado-Trastuzumab Emtansine (T-DM1 )

§ 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)

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MTD = maximum tolerated dose

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

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

T-DM1 HER2

Emtansine HER2 release

Inhibition of microtubule polymerization Internalization

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EMILIA Study Design

Ado-trastuzumab emtansine PD Centrally confirmed HER2+ 3.6 mg/kg q3wk IV LABC or MBC (N = 980)

Prior taxane and 1:1 trastuzumab R

Progression on metastatic Capecitabine treatment or within 6 mo of 1,000 mg/m2 orally bid adjuvant treatment d1-14, q3wk + PD Lapatinib 1,250 mg/day orally qd Primary endpoints: Independently assessed progression-free survival, overall survival, and safety

LABC = locally advanced breast cancer;9 MBC = metastatic breast cancer. Verma S, et al. N Engl J Med. 2012;367:1783–1791.

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

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

Second Interim Analysis of Overall Survival

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

Ado-Trastuzumab Emtansine § 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

12 ADR = adverse drug reaction

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EMILIA: Adverse Events

T-DM1 Cape + lap Select adverse events (grade ≥ 3) (n = 490) (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%

ALT = alanine aminotransferase; AST =13 aspartate aminotransferase. Verma S, et al. N Engl J Med. 2012;367:1783–1791.

Ado-Trastuzumab Emtansine

Grade 2 Grade 3 Grade 4 (> 1.5 to ≤ 3 × ULN) (> 3 to ≤ 10 × ULN) (> 10 × ULN) Do not administer Do not administer Permanently until total bilirubin until total bilirubin DC BOXED WARNINGS: recovers to grade ≤ 1, recovers to grade ≤ 1, and then treat at and then reduce 1 HEPATOTOXICITY, same dose level dose level CARDIAC TOXICITY, EMBRYO-FETAL Grade 2 Grade 3 Grade 4 TOXICITY (> 2.5 to ≤ 5 × ULN) (> 5 to ≤ 20 × ULN) (> 20 × ULN) Monitor LFTs prior to Treat at same dose Do not administer Permanently each dose level until AST/ALT DC recovers to grade ≤ 2, and then reduce 1 dose level

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

Biomarkers Used in Lung Cancer

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

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Ceritinib

§ 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

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

Progression-Free Survival

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

Adverse Events of Grade 3 or 4 That Were Suspected to Be Related to Cerinib Therapy.

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

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Afatinib

§ 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 19 EGFR = epidermal growth factor receptor

EGFR and Mutations Within the TK Domain

Ligand 3% Codon 719 9% variants 2% L-domain Exon 20 Other Furin-like domain variants variants Extracellular domain L-domain Transmembrane domain Intracellular domain

TK domain Survival

Proliferation 40% L858R 46% substitution Exon 19 EGFR deletions

TK = tyrosine kinase 20 Sequist LV, et al. J Clin Oncol. 2007;25:587–595; Shigematsu H, et al. J Natl Cancer Inst. 2005;97:339–346.

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

§ 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

TKI = tyrosine kinase inhibitor 21 Kobayashi S, et al. N Engl J Med. 2005;352:786–792

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LUX LUNG3 Study Design

Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)

EGFR mutation in tumor (central lab testing; Therascreen EGFR29 RGQ PCR)

Randomization 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian)

Cisplatin + pemetrexed Afatinib 40 mg/day 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

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;22 PRO = patient-reported outcomes. Sequist LV, et al. J Clin Oncol. 2013;31:3327–3334.

Progression-Free Survival

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

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

Afatinib Cis/pem (n = 229) (n = 111) All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%) Diarrhea 218 (95.2) 33 (14.4) 0 17 (15.3) 0 0 Rash/acne 204 (89.1) 37 (16.2) 0 7 (6.3) 0 0 Stomatitis/mucositis 165 (72.1) 19 (8.3) 1 (0.4) 17 (15.3) 1 (0.9) 0 Paronychia 130 (56.8) 26 (11.4) 0 0 0 0 Dry skin 67 (29.3) 1 (0.4) 0 2 (1.8) 0 0

Nausea 41 (17.9) 2 (0.9) 0 73 (65.8) 4 (3.6) 0 Decreased appetite 47 (20.5) 7 (3.1) 0 59 (53.2) 3 (2.7) 0 Fatigue 40 (17.5) 3 (1.3) 0 52 (46.8) 14 (12.6) 0 Vomiting 39 (17.0) 7 (3.1) 0 47 (42.3) 3 (2.7) 0 Neutropenia 2 (0.9) 1 (0.4) 0 35 (31.5) 17 (15.3) 3 (2.7) Anemia 7 (3.1) 1 (0.4) 0 31 (27.9) 5 (4.5) 2 (1.8)

† No grade 5 events for the presented adverse events (AEs). 24 Yang JC-H, et al. ASCO 2012, Abstract LBA7500.

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

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

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Ramucirumab

§ 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

26 ATE = arterial thromboembolic event; GI = gastrointestinal.

Large-Molecule VEGF Inhibitors

PlGF VEGF-A VEGF-C, Y

VEGF-B Bevacizumab VEGF-D RamucirumabY

Aflibercept (VEGF Trap)

VEGF-R1 VEGF-R2 VEGF-R3 (Flt-1) (KDR/Flk-1) (Flt-4) Migraon Proliferaon Lymphangio- Invasion Survival genesis Survival 27 Permeability

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REGARD Trial Design

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

REGARD Trial: Results

OS PFS 100 100

Ramucirumab (n = 238) 80 Ramucirumab (n = 238) 80 Placebo (n = 117) Placebo (n = 117) Censored Censored 60 60 HR (95% CI) = 0.483 (0.376-0.620) HR (95% CI) = 0.776 (0.603-0.998) Log-rank p value (stratified) <.0001 Log-rank p value (stratified) =.047 40 PFS, % PFS,

OS, % OS, 40

20 20

0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time Since Randomization, Months Number at risk Time Since Randomization, Months Number at risk Ramucirumab 238 154 92 49 17 7 3 0 0 Ramucirumab 238 213 113 65 61 45 30 18 18 11 5 4 2 1 1 1 1 0 Placebo 117 66 34 20 7 4 2 1 0 Placebo 117 92 27 11 7 4 2 2 2 2 2 1 1 0 0 0 0 0

CI = confidence interval; HR = hazard29 ratio. Fuchs CS, et al. Lancet. 2014;383:31–39.

Ramucirumab Future Directions

§ 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

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

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RAS/MEK/ERK Pathway and BRAF Inhibitors § 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 shRNA = short hairpin RNA cell growth in melanoma models

Cohen Y, et al. J Natl Cancer Inst. 2003;95:625–627;31 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

BRAF Kinase Inhibitor

§ 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

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

BRAF

§ 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

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11 Long et al

Correlates of mutant BRAF in the antecedent primary mela- 100 A A: BRAF mutant on inhibitor noma were site (trunk), earlier age of onset, lack of CSD, and nodular B: BRAF wild-type and superficial spreading histopathologic subtypes, consistent with C: BRAF mutant no inhibitor 80 the findings of studies in early disease.2,4-6,14,15 However, an additional novel finding was the correlation of mutant BRAF with the presence of 10/24/14 60 mitoses in the antecedent primary melanoma. Conversely, in a large study of primary, as opposed to metastatic, melanoma, the presence of 40 mitoses was associated with wild-type BRAF4 and mutant NRAS.27 Nevertheless, these findings support the concept that mutant BRAF Overall P < .001 Overall Survival (%) 20 A v C P < .003 melanoma is biologically heterogeneous or at least acts in concert with B v C P = .006 other genetic alterations to produce a particular phenotype. We also A v B P = .138 observed an association of wild-type BRAF with a history of multiple 0 1 2 3 4 5 cutaneous primary melanomas. This finding is important given the Time (years) recent report that a history of multiple cutaneous primary melanomas No.Prognostic at risk and Clinicopathologic is an independent good prognostic factor for overall survival from BRAF mutant on diagnosis of distant metastases.28 Associationsinhibitor 38 of 18 Oncogenic 7 5 BRAF 3 in 3 BRAF wild-type 102 46 18 17 11 11 The presence of an activating mutation in the BRAF oncogene BRAF mutant no Metastaticinhibitor 57 Melanoma 17 9 6 6 6 had no impact on time to distant or unresectable metastasis (DFI) but was associated with a worse outcome thereafter. This was previously B 100 reported in colorectal cancer29,30 and a small study in melanoma.3 BRAF mutations are present in 80% to 90% of benign nevi,31 and it 80 may seem paradoxical that such an apparently early event would influence tumor prognosis only after metastasis. However, nevi are 60 not obligatory precursors to melanoma, because many melanomas develop in normal skin,32 and 53% to 67% of primary cutaneous 40 melanomas do not carry BRAF mutations.1-6 Furthermore, factors such as host response or other genetic alterations that arise with tumor Overall P < .001 Overall Survival (%) 20 A v C P < .003 A: BRAF mutant on inhibitor metastasis may differentially impact prognosis only at a late stage. Two B v C P = .147 B: BRAF wild-type studies of gene expression in melanoma support the hypothesis that A v B P = .027 C: BRAF mutant no inhibitor additional factors act in concert with the BRAF mutation to produce a 0 2 4 6 8 10 12 prognostic phenotype.33,34 Time (months) The survival analysis after diagnosis of distant metastases was No. at risk confounded by the subset of BRAF-mutant patients who received a 34 BRAF mutant on Long GV, et al.inhibitor J Clin Oncol . 2011;29(10):1239–1246. 19 19 19 19 13 9 BRAF inhibitor for two reasons. First, treatment with a BRAF BRAF wild-type 44 40 32 22 15 9 inhibitor may extend overall survival; BRAF inhibitors are active BRAF mutant no 19-21,23 inhibitor 30 27 21 12 6 6 against metastatic melanoma in phase I trials, and the me- dian progression-free survival for RG7204 in a phase I to II trial is Fig 2. Overall survival from diagnosis of metastatic melanoma according to more than 6 months.22,23 Second, patients selected to participate in BRAF mutation status, and treatment with a BRAF inhibitor at some point after diagnosis of metastatic melanoma in (A) the total cohort of patients and (B) clinical trials may have better prognostic factors, including better patients with newly diagnosed metastatic melanoma during study period. performance status, absence of symptomatic brain metastases, and other nonmeasurable factors (social, psychological, and eco- nomic). The poorer outcome of BRAF-mutant versus BRAF wild- The frequency of non-V600E oncogenic mutations was higher type metastatic melanoma warrants confirmation in a historic than previously reported, with an incidence of V600K occurring in cohort of patients before the use of BRAF inhibitors. 20%Dabrafenib of tumors. Similar rates were reported in two studies that exam- A trend to poorer outcome in patients with mutant BRAF ined the whole of exon 15 in the BRAF gene,6,10 and more limited melanoma was observed in two smaller series7,12 but not in other § Dose: 150 mg orally twice daily without food methods of BRAF testing may underestimate the frequency of non- retrospective studies.7,11,12,14 These studies were limited by small size, V600E§ Indication: mutations in As melanoma. a single Theagent implications or in combination for clinical with practice trametinibheterogeneous composition (early and distant metastatic disease), and for the treatment of patients with unresectable or metastatic are important because there is evidence of activity of GSK2118436 in selection bias based on the availability of melanoma tissue. melanoma with BRAF V600E mutation as detected by an FDA- non-V600E BRAF-mutant melanoma, including V600K,19-21 and a If our observation is real, that a BRAF mutation has no effect on approved test. case report of activity of RG720425 in a patient with V600K-mutant the DFI yet impacts survival after diagnosis of distant metastases, it metastatic§ Warnings: melanoma. New Non-V600E primary skinBRAF cancers,-mutant tumor patients promotion, were in- suggests that the presence of a BRAF mutation provides an essential cludedhemorrhage, in the phase I venous and II trials thromboembolism, of GSK2118436 and cardiomyopathy, were excluded oculargenetic background for more rapid evolution of the metastatic pheno- from phasetoxicity, I, II, febrile and III reactions, trials of RG7204. skin toxicity,22,23,26 hypergylcemia, embryo-type once early metastatic events occur. fetal toxicity, G6-PD deficiency Patients with metastatic melanoma who had the BRAF mutation Finally, we observed for the first time, to our knowledge, a possi- were§ youngerToxicities: and hadMost a poorercommon survival adverse unless reactions treated with(≥ 20%) a BRAF for ble positive effect of treatment with a BRAF inhibitor on outcome, inhibitor.dabrafenib There were as noa single specific agent clinical are features hyperkeratosis, of metastatic headache, disease which remained significant with every subgroup analysis performed that correlatedpyrexia, witharthralgia,BRAF mutation papilloma, status. alopecia, and palmar-plantar to limit bias (eg, ECOG performance status 0 or 1 or new patients erythrodysesthesia syndrome

6 §© 2011Drug-drug by American interactions Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY • Substrate of CYP3A4 and CYP2C9

• Induces CYP3A435 and CYP2C9

BRAF Inhibitor: Dabrafenib BREAK-3 Front-Line Study Design § Primary endpoint: Investigator-assessed PFS in BRAF V600E/K patients § > 95% power to detect HR of 0.33

Screened N = 733 Dabrafenib 150 mg twice daily n = 187

3:1 randomization Enrolled n = 250 Stratification factors: unresectable stage III, stage IV; M1a + M1b vs. M1c

Crossover

allowed at Dacarbazine Dabrafenib 2 radiologic PD 1,000 mg/m IV 150 mg twice daily every 3 weeks n = 28 n = 63 (68% of PD patients)

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

PD = progressive disease 36 Hauschild A, et al. ASCO 2012, Abstract LBA8500.

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Treatment-Related AEs: ≥ 5% of Patients

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) – –

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

KA = keratoacanthoma; SCC = squamous37 cell carcinoma.

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

38 Hauschild A, et al. Lancet. 2012;380(9839):358–365.

Trametinib

§ 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:39 None identified

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

METRIC: Phase 3 Study of MEK Inhibitor Trametinib in Previously Untreated V600E/K Mutation Patients § BRAF mutation status Screened • Using allele-specific PCR at RGI (n = 1,059) § Stratification factors • LDH (> ULN vs. < ULN) and V600E/K • Prior chemotherapy (yes vs. no) mutation § Populations (n = 322) • ITT (all randomized patients) n = 322 Trametinib • Primary efficacy (subset of ITT) n = 273 Chemotherapy 2 mg qd § Primary endpoint (n = 108) (n = 214) • PFS in BRAFV600E-positive melanoma Crossover* § Secondary endpoints PFS • PFS in ITT • Overall survival, response rate, and FSFV: Dec 2010 Trametinib LSFV: July 2011 safety 2 mg qd

*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; 41 ULN = upper limit of normal. Robert C, et al. ASCO 2012, Abstract LBA8509.

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

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

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Kaplan-Meier Curves for Overall Survival

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

Adverse Events

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

Combination of Dabrafenib and Trametinib

Combination D + T Combination D + T Mono D 150/1 150/2 (N = 54) (N = 54)* (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) 0

Response rate† 29 (54%) 27 (50%) 41 (76%)

Duration of response 5.6 mo 9.5 mo 10.5 mo (95% CI) (4.5–7.4 mo) (7.4 mo–NA) (7.4–14.9 mo)

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

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Hematologic Cancers

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

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

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Obinutuzumab

§ 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

48 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

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CLL11 Trial: Obinutuzumab + Chlorambucil vs. Rituximab + Chlorambucil

Randomized 1:2:2 28-day cycle

Chlorambucil 0.5 mg/kg po on days 1,15 × 6 cycles (n = 118)

Previously untreated CLL patients with comorbidities 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 (CIRS score > 6 and/or (n = 333) CrCl < 70 mL/min) N = 781

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)

Patients who progress on chlorambucil alone allowed to crossover to obinutuzumab + chlorambucil arm.

CIRS = Cumulative Illness Rating Scale; CLL = chronic lymphocytic leukemia; CrCl = creatinine clearance. 50 Goede V, et al. N Engl J Med. 2014;370:1101–1110.

Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions

100 p < .001 p < .001 Obinutuzumab-Clb 80 CR PR 22.3 60 7.3 58.4 Clb 55.0 CR 40 PR

31.4 20 Rituximab-Clb CR

PatientsaResponseWith (%) PR 0 O-Clb Clb R-Clb (n = 238) (n = 118) (n = 233)

Clb = chlorambucil 51 Goede V, et al. N Engl J Med. 2014;370:1101–1110.

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

p < .001 Obinutuzumab-Clb 100 100 Rituximab-Clb 80 80 20.7 7.0 p < .001 p < .001 60 60 40 57.7 58.1 40 37.7

MRD Test (%) Test MRD 19.5

Response(%) 20 20 Patientsa With 2.6 3.3 0

PatientsaNegativeWith 0 Obinutuzumab-Clb Rituximab-Clb Pts at Bone Marrow Blood (n = 333) (n = 329) Risk, n 26/133 3/114 87/231 8/243 Obinutuzumab-Clb Rituximab-Clb CR CR PR PR

MRD = minimal residual disease. 52 Goede V, et al. N Engl J Med. 2014;370:1101–1110.

CLL11 Trial: PFS Head-to-Head Comparison

Obinutuzumab-Chlorambucil Rituximab-Chlorambucil 1.0 0.9 Stratified HR, 0.39 (95% CI, 0.31–0.49; 0.8 p < .0001) 0.7 0.6 0.5 0.4 0.3 Probability PFS of 0.2 0.1 15.2 26.7 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months

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

CLL11: Overall Survival

1.0 O-Clb 0.8

0.6 Clb

0.4 Stratified HR for death with O-Clb: 0.41

Probability OS of (95% Cl: 0.23–0.74; 0.2 p = .002)

0 0 6 12 18 24 30 36 Months

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

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Type I and II Anti-CD20 Monoclonal Antibodies

Ofatumumab

Phospholipid

55 Cragg MS. Blood. 2011;118:219–220.

Type I vs. Type II Monoclonal Antibodies

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

56 Cragg MS. Blood. 2011;118:219–220.

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

BCR § BCR signaling is required for tumor expansion and proliferation § BCR signaling upregulated in

LYN Fostamanib B-cell malignancies

┬ GS-9973 SYK § New inhibitors are targeting

Idelalisib multiple components of BCR

┬ IPI-145 signaling including PI3K Ibrunib ┬ PI3K TGR-1202 BTK AVL-292 delta delta, BTK, and Syk

PLCγ2 AKT NF-kβ GSK-3 PKC mTOR pathway

p70s6k elf4E 57

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Ibrutinib § 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

58 MCL = mantle cell lymphoma

Ibrutinib

§ Forms a specific and irreversible bond with cysteine-481 in BTK

O § Approved for second-line CLL and MCL

§ Highly potent BTK inhibition at IC50 = 0.5 nM

N H 2 § Orally administered with once-daily dosing resulting in 24-hr target inhibition N N § In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA N N binding, CpG mediated proliferation

N § Inhibits CLL cell migration and adhesion

O § No cytotoxic effect on T cells or NK cells PCI-32765

59 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.

Ibrutinib

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

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Ibrutinib Progression-Free and Overall Survival

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

Idelalisib

§ 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

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

BCR § BCR signaling is required for tumor expansion and proliferation § BCR signaling upregulated in

B-cell malignancies

LYN Fostamanib

┬ GS-9973 § New inhibitors are targeting SYK

Idelalisib multiple components of BCR

┬ IPI-145 signaling including PI3K delta, Ibrunib ┬ PI3K TGR-1202 BTK AVL-292 delta BTK, and Syk

PLCγ2 AKT NF-kβ GSK-3 PKC mTOR pathway

p70s6k elf4E 63

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Pomalidomide

64

Pomalidomide

§ 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

65 REMS = Risk Evaluation and Mitigation Strategies

Pomalidomide

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

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

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IMID Mechanism of Action

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

Phase III MM-003 Trial Design

POM + LoDEX (n = 302) POM: 4 mg/day, d1–21 Eligibility (n = 455) LoDEX: 40 mg 20 mg (> 75 yr) Primary refractory or relapsed 2:1 d1,8,15,22 (28-day cycle) and refractory MM R At least 2 prior therapies* HiDEX (n = 153)† Failed LEN and BORT 40 mg 20 mg (> 75 yr) d1–4,9–12,17–20 (28-day cycle)

* 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.

MM = multiple myeloma 68 Dimopoulos MA, et al. Proc ASH. 2012, Abstract LBA-6.

Primary Endpoint: Progression-Free Survival ITT population Patients refractory to LEN and BORT

Median PFS Median PFS

POM + LoDEX (n = 302) 3.6 mo POM + LoDEX (n = 221) 3.2 mo

HiDEX (n = 153) 1.8 mo HiDEX (n = 108) 1.7 mo 1.0 1.0

0.8 0.8 HR = 0.45 HR = 0.48 0.6 p < .001 0.6 p < .001

0.4 0.4

0.2 0.2 Proportion of Patients of Proportion Proportion of Patients of Proportion 0.0 0.0 0 4 8 12 16 0 4 8 12 16

Progression-Free Survival (months) Progression-Free Survival (months)

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

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Select Adverse Events

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

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

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

Belinostat § 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 on 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

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