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Pharmacology Update

Rowena Schwartz, PharmD, BCOP Key Session Takeaways Associate Professor 1. Over the last year there has been both the approval of University of Cincinnati new drugs for cancer and the approval of new indica- [email protected] tions of many marketed agents for cancer care. As the use of an agent(s) evolves it is important that the health- care team determine optimal strategies for care for clinical practice. 2. The dysregulation of apoptosis via overexpression of BCL-2 has been a target for drug therapy for many years. , a drug currently indicated for treatment of patients with chronic lymphocytic leukemia, has a po- tential for broader use. 3. The results from clinical trials provide the evidence and basis for the approval of new drugs and strategies in the management of cancer. The knowledge practitioners gain from practice should be shared broadly to optimize the benefits and minimize toxicities of these agents.

Oncology Nursing Society 42nd Annual Congress Power May 4–7, 2017 • Denver, CO 1 ONS 42nd Annual Congress

Pharmacology Update in Oncology: 2017

Rowena (Moe) Schwartz, PharmD, BCOP University of Cincinnati James L. Winkle College of Pharmacy

Progress in Oncology Drug Therapy

• Approval of new medications

• Optimizing the clinical applications of medications – Patient and/or population selection – Clarifying the place in therapy – Mitigation and management of toxicities

• Integration of drug therapy into cancer care

Drug Approvals from the FDA (2016 – 2017) New Drugs: • Defibrotide sodium (Defitelio®) on March 30, 2016 • Venetoclax (Venclexta®) on April 11, 2016 • (Tecentriq®) on May 18, 2016 • (Lartruvo®) on October 19, 2016 • Rucaparib (Rubraca®) on December 19, 2016

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Indication(s) Approvals from the FDA (Jan –Feb 2016) Expanding Clinical Applications: • (Arzerra®)→ extended treatment of pt who are in CR or PR after at least two LOT for recurrent or progressive CLL • (Halaven®)→ treatment of pts with unresectable or metastatic liposarcoma who have received prior ‐containing regimens • (Ibrance®)→ in combinaon with fulvestrant for the treatment of women with HR+, HER2‐ advanced or metastatic breast cancer with disease progression following endocrine therapy • (Gazyva®)→in combinaon with followed by obinutuzumab monotherapy for treatment of pts with who relapsed after, or are refractory to, a ‐ containing therapy. • (Affinitor®)→ treatment of adults with progressive, well‐ differentiated non‐functional, neuroendocrine tumors of gastrointestinal of lung origin with unresectable, locally advanced or metastatic disease.

Pt = patient HR = hormone receptor CR = complete response HER2 = epidermal growth factor receptor 2 PR = partial response LOT = line of therapy

Indication Approvals from the FDA (March ‐ May 2016)

Expanding Clinical Applications: • (Xalkori®)→ treatment of pts with metastatic NSCLC whose tumors are ROS1‐positive • (Cabometyx®)→ treatment of advanced RCC in patients who have received prior anti‐angiogenic therapy • (Lenvima®)→ in combinaon with everolimus for the treatment of advanced RCC following one prior anti‐ angiogenic therapy. • (Opdivo®)→treatment of paents with classical Hodgkin lymphoma that has relapsed or progressed after autologous HSCT and post transplant

NSCLC = non small cell lung cancer RCC = renal cell cancer HSCT = hematopoietic stem cell transplantation

Indication Approvals and Modifications from the FDA (June ‐ Sept 2016)

Expanding Clinical Applications: • (Keytruda®)→ treatment of patients with recurrent of metastatic head and neck squamous cell cancer with disease progression on or after platinum‐containing . • Nivolumab → modified dosage regimen for the currently approved indications for RCC, metastatic , NSCLC to flat dose of 240 mg IV q 2 weeks.

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Indication Approvals from the FDA (October ‐ December 2016)

Expanding Clinical Applications: • (Tarceva®)→ treatment of NSCLC whose tumors have specific EGFR mutations. • Atezolizumab → treatment of pts with metastatic NSCLC whose disease has progressed during or following platinum‐containing chemotherapy. Pts with EGFR or ALK genomic tumor aberrations should have disease progression on FDA‐approved therapy for these aberrations. • Pembrolizumab → treatment of paents with metastatic NSCLC whose tumors express PD‐L1 as determined by FDA‐approved test. • Nivolumab → treatment of pts with recurrent or metastatic SCCHN with disease progression on or after a platinum‐containing chemotherapy. • Daratumumab (Darzalex®)→ in combination with and , or and dexamethasone, for the treatment of patients with who have received at least one prior therapy.

SCCHN = squamous cell carcinoma of the head and neck

Target: BCL‐2 Venetoclax

Venetoclax Target: BCL‐2

Lampson BL, et al. Current Hematol Malig Rep. 2017

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Target: BCL‐2

• BCL‐2 gene was first clone in a lymphoid cell line • BCL‐2 is a family of proteins that coordinate pro‐apoptotic signals and anti‐ apoptotic signals within the cell – Reside on the outer surface of the mitochondrial membrane – Direct protein to protein interaction – BCL‐2 is a protein that encodes anti‐apoptotic proteins • Strategies to manipulate BCL‐2 – – antisense oligodeoxynucleoside targeting BCL‐2 mRNA – Gossypol –direct interactions with BCL‐XL – Obatoclax –small molecule that disrupts protein‐protein interaction of BCL‐2 family – Navitoclax –small molecule that blocks BH3‐binding domain of BCL‐XL – Venetoclax – reverse engineered navitoclax to increase BCL‐2 selectivity

Lampson BL, et al. Curr Hematol Malig Rep 2017 (published online)

Venetoclax: Relapsed CLL / SLL

Rationale: • Phase I dose‐escalation study of daily oral venetoclax in patients with relapsed or refractory chronic lymphocytic lymphoma (CLL) or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile and efficacy. • Methods: • Open‐label, multicenter, dose‐escalation trial in patients with relapsed or refractory CLL or SLL or NHL. (Note: publication only reports on CLL and SLL) • Patients received treatment in one of eight doses (n=56) from 6/2011 to 12/2012 – ‐ Dose range from 150 mg → 1200 mg po per day • Expansion cohort: patients treated with a weekly stepwise ramp‐up in doses (n = 60) from 6/2013 to 12/2014 – ‐ Dose ramped up → 1200 mg

Roberts AW, et al. NEJM 2016;374: 311‐ 322

Venetoclax: Relapsed CLL / SLL

Eligibility: • Patients with CLL or SLL with relapsed or refractory disease requiring therapy per standard criteria • Performance status 0 ‐1 (ECOG) • Adequate bone marrow function (defined changed in expansion arm) • Adequate organ function (CrCl ≥ 50 ml/min)

Exclusion: • Previous allogeneic or autologous SCT • Major organ dysfunction • Active infection • Autoimmune cytopenia • Other cancer

Roberts AW, et al. NEJM 2016;374: 311‐ 322

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Venetoclax: Relapsed CLL / SLL

Result: • TLS seen after initial dose of 100 or 200 mg in all 3 paents in inial group → strategy changed to include a dose of 50 mg or 20 mg and then dose escalated. • Continuation of therapy in 44% of patients at publication cut‐off (21 month) • Reason for discontinuation: – Progressive disease (35%) – Toxicity (11%) – Eligibility for alloSCT (6%)

Roberts AW, et al. NEJM 2016;374: 311‐ 322

Venetoclax: Relapsed CLL / SLL Safety: • Tumor lysis syndrome occurred in 18% of patients • Common adverse effects were usually grade 1 or 2 • Neutropenia – Most common grade 4 toxicity (28%) – Increased risk in those patients with low ANC prior to therapy – WBC GF allowed – Febrile neutropenia (6%)

MTD was not identified.

Roberts AW, et al. NEJM 2016;374: 311‐ 322

Venetoclax in Relapsed CLL / SLL : Adverse Effects Adverse Event Any Grade (%) Grade 3 or 4 (%) Diarrhea 52% 2% Upper respiratory tract infection 48% 1% Nausea / Vomiting 47% / 18% 2%/ 2% Neutropenia 45% 41% Fatigue 40% 3% Cough 30% 0 Pyrexia 26% 1% Anemia 29% 12% Headache 24% 1% Constipation 21% 1% Thrombocytopenia 21% 12% Arthralgia 18% 1% Peripheral edema 16% 0 Hyperglycemia 15% 9%

Roberts AW, et al. NEJM 2016;374: 311‐ 322

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Venetoclax in Relapsed CLL / SLL : Serious Adverse Effects Serious Adverse Event Any Grade (%)

Febrile neutropenia 6% Pneumonia 4% Upper respiratory tract infection 3% Immune thrombocytopenia 3% Tumor lysis syndrome 3% Diarrhea 2% Fluid overload 2% Hyperglycemia 2% Prostate cancer 2% Pyrexia 2%

Roberts AW, et al. NEJM 2016;374: 311‐ 322

Venetoclax in Relapsed CLL / SLL : Efficacy

Variable No. of Pts CR rates (% )ORR (%) All patients 116 20% 79% resistance Yes 70 16% 79% No 44 27% 82% Chromosome 17p deletion Yes 31 16% 71% No 60 18% 80% Chromosome 11q deletion Yes 28 11% 82% No 62 21% 76% IGHV status Unmutated 46 17% 76% Mutated 17 29% 94%

ORR was not different on basis of age or number of previous therapies. Roberts AW, et al. NEJM 2016;374: 311‐ 322

Venetoclax: 17p deleted CLL

Phase II • Single‐arm, open‐label, multicenter study in patients with relapsed, refractory, 17p‐deleted CLL. • Dose: venetoclax 400 mg po daily (stepwise ramp‐up dosing) • Results (median follow up 12 months) ‐ ORR 79% ‐ CR 8% Stilgenbauer S, et al. Lancet Oncol 2016;17:768‐78.

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Venetoclax : 17p deleted CLL

Efficacy Outcomes Venetoclax (n=107) Overall Response Rate, % 79.4 Deep Response Rate (CR+Cri+nPR), % 10 Median Time to First Response, mo 0.8

Median Duration of Response, mo Not yet reached Progression-Free Survival (12-mo), % 72

Stilgenbauer S. Lancet Oncol. 2016

Venetoclax: Clinical Trials in CLL

Venetoclax Combinations (investigation) Phase Rituximab 1b

Bendamustine, obinutuzumab 1b

Bendamustine, rituximab 1b

Obinutuzumab 1b, 3

Ibrutinib 3

Ibrutinib, obinutuzumab 1b, 2

Lampson BL, et al. Curr Hematol Malig Rep 2017 (published online)

Venetoclax (VenclextaTM)

FDA Indication: • CLL with del 17p who have received one prior treatment Dosing ramp up schedule.

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Venetoclax :

Week Ramp-Up Dosing

1 20 mg

2 50 mg

3 100 mg

4 200 mg

5 400 mg once daily Continue until disease progression or toxicity

Venclexta [package insert]. 2017

Venetoclax : Warnings

• Tumor lysis syndrome (TLS) – Somewhat mediated by the ramp‐up dosing schedule – May see as early as 6 –8 hours after the first dose and at each dose increase • Neutropenia – Grade 3/4 = 41% • Live attenuated vaccines – Do not administer prior to, during or after treatment with Venetoclax™ until B cell recovery • Embryo‐fetal toxicity – Advise patients to use effective contraception during treatment and for 30 days after the last dose Venclexta [package insert]. 2017

BCL‐2 Inhibition: Determining Scope

• Non‐Hodgkin Lymphoma (NHL) – BCL‐2 gene is hallmark of follicular lymphoma – Overexpressed in ≈ 30% of diffuse large B‐cell lymphoma – Amplication of chromosome region is found in

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The Evolution of Venetoclax: Non‐Hodgkin Lymphoma (NHL) in M12‐175

• Study Overview • Phase I cohort in NHL → safety, pharmacokinecs and efficacy • Patient with relapsed or refractory NHL • Doses venetoclax 200 to 1200 mg po daily until disease progression or unacceptable toxicity • Response in NHL (including MCL, FL, DLBCL, Waldenstrom macroglobulinemia, marginal zone lymphoma) – 44% ORR (n=106)

Davids MS, et al. J Clin Oncol 2017:35

Target: PD‐L1 Atezolizumab

Programmed Death‐Ligand 1

• Programmed death ligand‐1 – B7‐H1 – CD274 • PD‐L1 is expressed on tumor cells (TC) and tumor‐infiltrating immune cells (IC) in the tumor microenvironment • PD‐L1 negatively regulates T‐cell proliferation and funcon→ tumors evade immune surveillance and eradication

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Programmed Death‐Ligand 1 • Programmed death ligand‐1 – B7‐H1 – CD274 • PD‐L1 is expressed on tumor cells (TC) and tumor‐infiltrating immune cells (IC) in the tumor microenvironment • PD‐L1 negatively regulates T‐cell proliferation and funcon→ tumors evade immune surveillance and eradication

Inhibition of PD‐L1 signaling has been shown to have activity in wide variety of solid tumors.

Atezolizumab: Imvigor 210

Methods: • Open label, multicenter single arm Phase II study that evaluated safety + efficacy of atezolizumab in patients with locally advanced metastatic uretholial cancer (regardless of PD‐L1 expression) with disease progressed during or following previous treatment with platinum based chemotherapy

Treatment: • atezolizumab 1200 mg IV on D1 q 21 cycles until loss of clinical benefit

Outcomes: • Primary endpoint: ORR by IRF using RECIST v1.1 • Secondary endpoints: DOR, OS, PFS, safety

Results: • Updated analysis of 11.1 months of median follow up • ORR 15% (95% CI:11,19) • ORR 26% (95% CI:18,36) in pts with medium and high level PD‐L1 expression (n=100)

Rosenberg JE, et al. Lancet. 2016.

Atezolizumab: Advanced Bladder Cancer

Outcome All Patients (ITT) Any PD‐L1 Medium and High n= 310 Expression PD‐L1 Expression N = 207 N=100

ORR, % 15 18 26 (p=0.0058) (p=0.0004) (p<0.0001)

CR, %5611

OS (months) 7.9 8.8 11.4

OS (12 months), %363948

Rosenberg JE, et al. Lancet. 2016

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Atezolizumab: Anti‐PD‐L1 Antibody

• Purpose: • Determine safety and clinical activity in renal cell carcinoma (RCC) • Evaluate biomarkers ↔ association with outcomes • Methods: • RCC cohort was part of an ongoing phase 1a multicenter, dose‐escalation and dose‐expansion trial of atezolizumab • Patients initially enrolled regardless of PD‐L1 status → enrollment was limited to patients whose tumors expressed PD‐L1 IC2 or IC3 (≥ 5% of ICs stained positive for PD‐L1)

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

Atezolizumab: Anti‐PD‐L1 Antibody

Methods: • Patients with either metastatic clear‐cell RCC or non‐clear cell histology • Prior treatment allowed if treatments completed 3 weeks prior to starting (6 wks for interleukin‐2) – VEGF tyrosine kinase inhibitors (TKI) – – mTOR inhibitors – Interleukin‐2

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

Atezolizumab: Renal Cell Carcinoma

Methods: • Immunohistochemistry: PD‐L1 expression on tumor tissue and infiltrating immune cells (IC) • Score per IC per tumor area stained positive: – IC0 if < 1% – IC1 if 1% ‐ 5% – IC2 if 5‐10% – IC3 if > 10%

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

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Atezolizumab: Renal Cell Carcinoma

Methods: • Primary endpoints: – Safety and toxicity – Secondary endpoints: ORR, time‐to‐event endpoints • Safety: – adverse events severity was graded by NCI Common Terminology Criteria for Adverse Events (v 4.0) • Antitumor activity: evaluated in all patients treated with 3 mg/kg or more of atezolizumab – RECIST – irRC

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

Atezolizumab: Renal Cell Carcinoma

Patient Characteristics Characteristics Age, years Median: 61 years Range: 33 –81 Gender Males: 77% Females: 33% Performance status (ECOG) PS 0: 57% PS 1: 43% PD‐L1 IC Score 0 : 33% 1 : 23% 2 : 17% 3 : 16% Histologic subtypes of disease Clear cell: 90% Non‐clear cell: 10% Prior regimens Median: 2 (range 0‐7) no prior 13%, 1 prior 30%, ≥ 2 prior 57%

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

Atezolizumab: Renal Cell Cancer

Treatment‐Related AE Any Grade (%) Grade 3‐4 (%) All 84% 17% Fatigue 29% 4% Decreased appetite 16% 0 Arthralgia 14% 0 Rash 14% 0 Nausea 13% 0 Anemia 11% 4% Chills 11% 0 Diarrhea 11% 0 Influenza‐like 11% 0 Pruritis 11% 0 Pyrexia 11% 0

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

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Atezolizumab: Renal Cell Cancer

Treatment‐Related AE Any Grade (%) Grade 3‐4 (%)

All 84% 17%

rash 14% 0

hypothyroidism 9% 0

pneumonitis 3% 0

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

Atezolizumab: Published Results

• 63 patients with clear cell Renal Cell Cancer were evaluable for response – Median OS was 28.9 mo (95% CI, 20 mo –not reached) – Median PFS was 5.6 mo (95% CI, 3.9 –8.2 months) • 62 patients were evaluable for overall response – ORR: 15% (95% CI, 7% to 26%) • Decrease in circulating plasma markers, acute‐ phase proteins and increase baseline T‐cell to regulatory T‐cell gene expression ratio correlated with response to treatment

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

Atezolizumab: Published Results

• Maximum tolerated dose was not reached • No dose limiting toxicities were observed – 84% experienced a treatment‐related AE – Majority of adverse events where low grade (1,2) – Immune‐mediated adverse events were reported in 43% – Adverse events led to discontinuation in 3 patients • Grade 2 gaze palsy → resolved with corcosteroids • Sudden death • Suicide attempt

McDermott DF, et al. J Clin Oncol 2016;34:833‐42.

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Durvalumab(MEDI‐4736)

• PD‐L1 • Clinical trials as monotherapy + combination therapy with other agents for non‐small cell lung cancer – Interim result presented at ASCO 2015 in cohort of patients with NSCLC with ORR 14% with durable responses in 76% of patients for up to 35 weeks. – Note: ORR was higher in patients with squamous histology (21%) vs nonsquamous NSCLC (10%)

Rizvi NA, et al. ASCO 2015 (abstract 8032)

Target: Platelet‐Derived Growth Factor Olaratumab

Olaratumab Target: Platelet‐Derived Growth Factor (?) • Platelet‐derived growth factor (PDGF) + PDGF receptor – signaling in mesenchymal biology • Mesenchymal stem cell differentiation and growth • Angiogenesis – aberrant cellular signaling – modulating tumor or stromal microenvironment • Olaratumab binds PDGFRα blocking PDGF‐AA, PDGF‐BB and PDGF‐CC binding and receptor activation • True mechanism of action for tumor activity?

(Judson I, et al. Nature Rev Clin Oncol 2016)

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Olaratumab: Phase I trials • Phase I trial evaluating safety, MTD, recommended dose for phase II studies, and antitumor activity in solid tumors. (n=19) • 5 dose‐escalating cohorts of 3‐6 patients

Cohort Dose Regimen 14 mg/kg IV weekly 28 mg/kg IV weekly 316 mg/kg IV weekly 415 mg/kg IV q 2 weeks 520 mg/kg IV q 2 weeks

No dose limiting toxicities. The MTD was not identified

Chiorean EG, et al. Cancer Chemother Pharmacol 2014;73:595‐604

Olaratumab: Phase I trials

Phase I: Single‐center, dose‐escalation trial of olaratumab in patients with advanced or refractory solid tumors.

Cohort Dose Regimen 1Olaratumab10 mg/kg IV on day 1 and 8 q 3 wks 2Olaratumab20 mg/kg IV q 2 weeks 3Olaratumab15mg/kgIV on day 1 and 8 q 3 wks

No dose limiting toxicities. The MTD was not identified

Doi T, et al. Cancer Sci 2014;105:862‐9.

Soft Tissue Sarcoma: Olaratumab + vs. Doxorubicin Rationale: • Doxorubicin is standard of care for patients with metastatic soft‐tissue sarcoma • Olaratumab has demonstrated antitumor activity in human sarcoma xenografts Strategy: • Open‐label phase 1b and randomized phase 2trial comparing combination of olaratumab + doxorubicin to doxorubicin • 16 sites in US

Tap WD, et al. Lancet 2016;388:488‐97.

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Soft Tissue Sarcoma: Olaratumab + Doxorubicin vs. Doxorubicin

Eligibility Exclusion • Age ≥ 18 years of age • Untreated CNS metastases • Advanced or metastatic • Prior therapy with anthracycline or soft‐tissue sarcoma not anthracenedione previously treated with • Prior therapy with drug that anthracycline targets PDGF or PDGFr • PS 0‐2 (ECOG) • Prior RT to mediastinal or • Available tumor tissue pericardial area • (PDGFRα) Concurrent anticancer therapy • Unstable cardiac • HIV

Tap WD, et al. Lancet 2016;388:488‐97.

Soft Tissue Sarcoma: Olaratumab + Doxorubicin vs. Doxorubicin Phase 1b: Phase 2: • Olaratumab 1mg/kg IV • Patient randomized to day 1 and 8 + doxorubicin combination vs 75 mg/m2 every 21 days doxorubicin for up to 8 for up to 8 cycles cycles • Olaratumab could be • After 8 cycles pts in continued as combination arm could monotherapy. continue olaratumab • During cycles 5‐8 monotherapy dexrazoxane was allowed to reduce cardiotoxicity

Tumor response was assessed every 6 weeks (RECIST)

Tap WD, et al. Lancet 2016;388:488‐97.

Soft Tissue Sarcoma: Olaratumab + Doxorubicin vs. Doxorubicin • Efficacy: Olaratumab + Doxorubicin Doxorubicin

Median PFS 6 months 4.1 months

HR 0.67; 0.44 – 1.02; p= 0.0615

Median OS 26.5 months 14.7 months

HR 0.46; 0.30 – 0.71; p= 0.0003

ORR 18.2% 11.9%

p= 0.3421

Tap WD, et al. Lancet 2016;388:488‐97.

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Soft Tissue Sarcoma: Olaratumab + Doxorubicin vs. Doxorubicin • Adverse effects where more common with the combination therapy. • Toxicities: – Neutropenia – Mucositis – Nausea/ vomiting – Diarrhea

Tap WD, et al. Lancet 2016;388:488‐97.

Olaratumab in Practice (Feb 2017)

Indication (per package insert): • Olaratumab is indicated in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma with a histologic subtype for which an anthracycline‐containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. (accelerated approval) Dose: • 15 mg/kg administered as an IV infusion over 60 minutes on day 1 and 8 of each 21 day cycle until disease progression or unacceptable toxicity (administered with doxorubicin for first 8 cycles) • Premedication: diphenhydramine IV + dexamethasone IV prior to olaratumab on day 1 of cycle 1.

Target: Poly (ADP‐ribose) polymerase inhibitor Rucaparib

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Poly (ADP‐ribose) polymerase (PARP)

• Synthec lethality → selecvely targets cells deficient in tumor suppressor genes BRCA1 and BRCA2

• Synthetic lethality occurs when a genetic or defective protein is compatible with cell viability …… but when combined with another defect it is not.

• Synthetic sick occurs when a genetic or defective protein is compatible with cell viability …… and when combined with another defect there is non‐lethal growth impairment.

Liu FW, et al. Curr Treat Options in Oncol 2016;17:12.

Rucaparib: Advanced Ovarian and Breast Cancer* Method: • Phase II, open‐label, multicenter of rucaparib in individuals with BRCA mutation carriers with advanced breast and colon cancer. • Initial dose escalation phase (stage I) • Proof of principle phase (stage 2) – Patients stratified into four groups to asses response based on BRCA mutation status (1 or 2) and tumor type (breast or ) – In stage 1 paents recruited into the original cohort → recruited to subsequent cohorts provided there were not dose‐limiting toxicities at the previous dose level

*Germline BRCA mutation carriers Drew Y, et al. Br J Cancer 2016;114:723‐30.

Rucaparib: Advanced Ovarian and Breast Cancer* Methods: • Intravenous → oral rucaparib assessed using a range of dosing schedules • Evaluation of safety and tolerability, dose‐ limiting toxicities, pharmacokinetic and pharmacodynamics profiles.

*Germline BRCA mutation carriers Drew Y, et al. Br J Cancer 2016;114:723‐30.

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Rucaparib: Advanced Ovarian and Breast Cancer* Efficacy Results • Rucaparib was well tolerated up to doses of 480 mg po per day • PARP inhibition was sustained for ≥ 24 hrs after a single dose • IV rucaparib (intermittent dose schedule) ORR 2% – ‐ Stable disease in 41% of patients for ≥ 12 weeks • PO rucaparib (six dose levels) ORR 15% – ‐ Ovarian cancer : 12 of 13 achieved CR or PR or SD ≥ 12 weeks with median response of 179 days (range 84 – 567 days) *Germline BRCA mutation carriers Drew Y, et al. Br J Cancer 2016;114:723‐30.

Rucaparib: Advanced Ovarian and Breast Cancer* Toxicity Results: • Rucaparib was well tolerated up to doses of 480 mg po daily. • DLT was fatigue – Fatigue 51% (all grades) • Nausea was seen in 36% of patients (all grades) • No reported grade 4 or 5 adverse effects • No treatment related deaths

*Germline BRCA mutation carriers Drew Y, et al. Br J Cancer 2016;114:723‐30.

Rucaparib: Advanced Ovarian and Breast Cancer* Pharmacodynamics: • Inhibition of PARP enzyme activity was maintained ≥ 24 hours after a single dose of rucaparib po

*Germline BRCA mutation carriers Drew Y, et al. Br J Cancer 2016;114:723‐30.

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Rucaparib: Ovarian Cancer (ARIEL2)

• ARIEL2 is an international, multi‐center, phase 2 open – label study to assess the ability of tumor genomic LOH to predict response to rucaparib in women with ovarian cancer. • Part I: Patients with recurrent, platinum‐sensitive, high‐grade ovarian cancer were classified into three predefined groups based on tumor mutational analysis ‐ BRCA mutant (deleterious germline or somatic) ‐ BRCA WT and LOH high ‐ BRCA WT and LOH low • Treatment: rucaparib 600 mg po BID x 28 days until disease progression or drug discontinuation

Swisher EM, et al. Lancet 2017;18.

Rucaparib: Ovarian Cancer (ARIEL2)

Confirmed objective Objective responses response (RECIST and CA‐125) (RECIST) BRCA mutant (n=40) 32 (80%) 34 (85%)

BRCA WT LOH high (n=82) 24 (29%) 36 (44%)

BRCA WT LOH low (n=70) 7 (10%) 14 (20%)

BRCA WT LOH not classified 4 (33%) 7 (58%) (n=12)

Swisher EM, et al. Lancet 2017;18.

Rucaparib: Ovarian Cancer (ARIEL2)

• Most common toxicities (≥ gr 3): anemia (22%), increase LFT (12%) • Serious adverse events reported included: – Small bowel obstruction (5% of patients) – Disease progression

Swisher EM, et al. Lancet 2017;18.

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Rucaparib in Practice (Feb 2017)

Current indication (per package insert): • Rucaparib is indicated for monotherapy for the treatment of patients with deleterious BRCA mutation (germline/somatic) associated ovarian cancer who have been treated with two or more chemotherapy. Dose: 600 mg (2 x 300 mg tablets) po BID with or without food Administration: ‐ With or without food ‐ Do not make up missed doses (nor doses vomited)

Rucaparib in Practice (Feb 2017)

Warning: Adverse events: (>20%) • MDS • Nausea and vomiting • AML • Constipation • Embro‐fetal toxicity • Diarrhea • Asthenia • Anemia • Thrombocytopenia • Dysgeusia • Dyspnea • Decrease appetite

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