Download Updates in Oncology JM.ONS.2017

PHARMACOLOGY UPDATE - ONCOLOGY
JANELLE MANN, PHARMD, BCOP
CLINICAL ONCOLOGY PHARMACIST, INVESTIGATIONAL DRUG SERVICES
OBJECTIVES
 Describe new drug therapies approved in oncology during the past year
 Summarize the clinical data surrounding newly approved oncology agents and their place in treatment
 Determine appropriate adverse effect monitoring, treatment of events and patient education for newly approved
oncology therapies
 Describe the future of the oncology drug pipeline and its impact on patient care
ONCOLOGY DRUGS APPROVED IN 2016
Brand
Generic
Indication
Lartruvo ®
Olaratumab
Oct. 2016: soft tissue sarcoma (STS) not amenable to curative
treatment with radiotherapy or surgery and with histologic subtype for
which anthracycline-containing regimen is appropriate
Tecentriq ®
Atezolizumab
Oct. 2016: Met. NSCLC progressed during or following platinumcontaining chemotherapy.
• EGFR or ALK genomic tumor alterations should have disease
progression on FDA-approved therapy prior to atezolizumab
May 2016: locally advanced or met. Urothelial carcinoma (UC)
progressed during or following platinum-containing chemotherapy or
progressed within 12 months of neoadjuvant or adjuvant treatment
with platinum-containing chemotherapy
Cabometyx ®
Cabozantinib
April 2016: Advanced renal cell carcinoma (RCC) in patients who have
received prior anti-angiogenic therapy
Venclexta ®
Venetoclax
April 2016: Chronic lymphocytic leukemia (CLL) with 17p deletion
who have received at least one prior therapy
ONCOLOGY DRUGS APPROVED IN 2016 - 2017
Brand
Generic
Indication
Rubraca ®
Rucaparib
December 2016: Advanced ovarian cancer with deleterious BRCA
mutation (germline and/or somatic) who have received two or more
chemotherapies
Zejula ®
Niraparib
March 2017: Recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer as maintenance treatment who are in complete or
partial response to platinum-based chemotherapy
Bavencio ®
Avelumab
March 2017: adult and pediatric patients with met. Merkel cell
carcinoma (MCC)
Kisqali ®
Ribociclib
March 2017: Initial therapy in combination with an aromatase
inhibitor for advanced or met. Hormone receptor positive, HER2
negative, postmenopausal women with breast cancer
SUPPORTIVE CARE DRUGS APPROVED IN 2016
Brand
Generic
Indication
Defitelio ®
Defibrotide
March 2016: adult and pediatric patients with hepatic veno-occlusive
disease (VOD)/ sinusoidal obstructive syndrome (SOS), with renal or
pulmonary dysfunction following hematopoietic stem-cell
transplantation (HSCT)
EXPANDED INDICATIONS
Brand
Generic
Indications
Darzalex ®
Daratumumab
2nd line for multiple myeloma in combination with lenalidomide and
dexamethasone, or bortezomib and dexamethasone
Opdivo ®
Nivolumab
• Recurrent or met. Squamous cell carcinoma of the head and neck with
disease progression on or after a plantinum-based therapy (3 mg/kg)
• In RCC, melanoma, and NSCLC – dose modification to 240 mg IV every 2
weeks
• Negative data in first-line NSCLC (CheckMate 026 trial)
• Classical Hodgkin Lymphoma (cHL) relapsed or progressed after autologous
HSCT and post-transplantation brentuximab vedotin
Keytruda ®
Pembrolizumab
• Refractory cHL or those who have relapsed after 3 or more prior lines of
threapy
• Met. NSCLC whose tumors express PD-L1 as determined by FDA-approved
test
• Recurrent or me HNSCC with disease progression on or after plantinumcontaining chemotherapy
EXPANDED INDICATIONS (CONTINUED)
Brand
Generic
Indications
Tarceva ®
Erlotinib
NSCLC to limit use to patients whose tumors have specific EGFR mutation
Lenvima ®
Lenvatinib
Advanced RCC (with everolimus) following one prior anti-angiogenic therapy
Xalkori ®
Crizotinib
Met. ROS1-positive NSCLC
Afinitor ®
Everolimus
Progressive, well-differentiated non-functional, neuroendocrine tumors (NET)
of GI or lung origin with unresectable, locally advanced or metastatic disease
Gazyva ®
Obinutuzumab
Follicular lymphoma relapsed after or refractory to rituximab-containing
regimen. Given with bendamustine, followed by obinutuzumab monotherapy
Ibrance ®
Palbociclib
HR positive, HER2 negative, advanced or met. Breast cancer with disease
progression following endocrine therapy. Given in combination with fulvestrant
Halaven ®
Eribulin
Unresectable or met. Liposarcoma who have received a prior anthracyclinecontaining regimen
Arzerra ®
Ofatumumab
Extended treatment in patients with progressive CLL who are in CR or PR
after at least two lines of therapy
NEW DRUG UPDATE
THE INS AND OUTS OF NEW THERAPY
ATEZOLIZUMAB (MPDL3280A, TECENTRIQ ®)
 First anti-PD-L1 monoclonal antibody approved in US

Locally advanced or metastatic urothelial carcinoma

Metastatic NSCLC
t
 Indications:
 NCCN Category: 2 A
Tecentriq [package insert]. San Francisco, CA: Genetech; 2016.
ANTI-PD-1 MABS – MECHANISM OF ACTION
 PD-1 is expressed on several
different cell types
 PD-1 interacts with ligands (PD-
L1/PD-L2) to induce
downstream signaling inhibiting
T-cell proliferation, cytokine
release, and cytotoxicity
 Many tumors suppress cytotoxic
T-cell activity by expressing PD-1
ligand (PD-L1) on the cell
surface
 Anti-PD-1 antibodies block the
binding of PD-L1/L2 to PD-1 and
reverse T-cell suppression
Okazaki, T, et al (2013). Nat Immunol, 14: 1212-18.
ATEZOLIZUMAB: CLINICAL TRIALS
 OAK Study: 1225 NSCLC pts stratified by PD-L1 status, prior chemo, and histology

Atezolizumab 1200 mg every 3 weeks or docetaxel 75 mg/m2 every 3 weeks

Median OS 13.8 months vs. 9.6 months on docetaxel (HR 0.73; p= 0.0003)

Median OS 20.5 months in patients with highest levels of PD-L1 expression (TC3 group) (HR 0.41; p<0.0001)
 POPLAR study: similar study to OAK study (smaller, phase II) demonstrated same pattern of survival benefit
observed with prior approved PD1 inhibitors

Higher PD-L1 expression (on tumor cells and/or immune cells) correlates with greater benefit from atezolizumab

No benefit with atezolizumab in 32% of pts with negative PD-L1 expression on tumor cells or immune cells
Tecentriq [package insert]. San Francisco, CA: Genetech; 2016.
ATEZOLIZUMAB: CLINICAL TRIALS
 IMvigor210 study: 310 patients with locally advanced or metastatic urothelial carcinoma (UC)
 Treatment: atezolizumab 1200 mg every 3 weeks until loss of clinical benefit
 Looked at effects based on “positive” vs. “negative” expression of PD-L1 protein on patients tumor-infiltrating
immune cells (IC)
 ORR: 14.8% experienced tumor shrinkage, lasting from about 2.1 months to 13.8 months
 In patients classified as “positive” for PD-L1 expression, 26% experienced tumor response (compared to 9.5%
who were classified as “negative”)
Tecentriq [package insert]. San Francisco, CA: Genetech; 2016.
ATEZOLIZUMAB
 1200 mg IV every 3 weeks until disease progression
 Infuse cycle 1 (dose 1) over 60 minutes, and if no reactions, subsequent doses can be administered over 30
minutes
 No routine prophylaxis
 Dose adjustments:

None recommended
Tecentriq [package insert]. San Francisco, CA: Genetech; 2016.
ATEZOLIZUMAB
 Immune-mediated pneumonitis (2.6%), colitis (19%), and hepatitis (1.7%)

Hold for select Grade 2 or 3 immune-mediated toxicities

High-dose methylprednisolone followed by oral prednisone taper

After recovery to Grade 0 or 1, reinitiation at prescriber discretion
 Infusion reactions 1.7%

Grade 1 or 2 – may treat and rechallenge

Grade 3 or 4 – permanently discontinue drug
Tecentriq [package insert]. San Francisco, CA: Genetech; 2016.
ATEZOLIZUMAB: ADVERSE EFFECTS
Common Adverse Effects: >/= 10%
Adverse Effects </= 10%
 General: fatigue, musculoskeletal pain
 2% severe infusion reactions
 GI: decreased appetite, nausea, constipation
 3.7% immune-mediated pneumonitis
 Lung: dyspnea, cough
 Laboratory: hyponatremia, hypoalbuminemia,
elevated transaminases, hypokalemia, hypercalcemia,
hyperbilirubinemia
Tecentriq [package insert]. San Francisco, CA: Genetech; 2016.
AUDIENCE RESPONSE QUESTION
 EM is a 55 yo male with Stage IV NSCLC. He is found to have new onset dry cough and mild shortness of breath
which he attributes to his lung cancer. He is currently receiving atezolizumab for his lung cancer which is PD-L1
positive. He has received 5 cycles.
 Which of the following would you recommend?

Tell the patient to initiate loratadine daily for what sounds like possible allergies

Notify the provider and consider obtaining chest x-ray

The patient should go to the ER for work up for pulmonary embolism

Recommend asking his PCP for an antibiotic for possible pneumonia
AVELUMAB (BAVENCIO ®)
 Indication: adult and pediatric patients 12 yrs and older with metastatic
merkle cell carcinoma (MCC)
 Mechanism of Action: PD-L1 blocking human IgG1 lambda monoclonal
antibody
 NCCN Category: TBD
 First FDA approved product to treat this type of cancer
Avelumab [package insert]. Roackland, MA; Pfizer; 2017.
AVELUMAB: CLINICAL TRIAL
 JAVELIN Merkel 200 trial:
 Open-label, single-arm, multi-center clinical trial

All patients has histologically confirmed metastatic MCC with disease progression on or after chemotherapy
 Avelumab 10 mg/kg IV over 60 minutes every 2 weeks
 Results:

ORR: 33% (11% complete and 22% partial response rates)


RR: 2.8 months to 23.3+ months (86% of responses durable for 6 months or longer)
Responses observed regardless of PD-L1 tumor expression or presence of Merkel cell polyomavirus
Avelumab [package insert]. Roackland, MA; Pfizer; 2017.
AVELUMAB
 Most common Adverse Effects:
 Serious adverse effects:

Fatigue

Immune-mediated toxicities

Musculoskeletal pain

Life-threatening infusion reactions

Diarrhea

Kidney injury

Nausea

Abdominal pain

Infusion-related reactions

Ileus

Cellulitis

Premedicate with APAP and Diphenhydramine for the first 4
infusions and subsequently as needed

Rash

Peripheral edema
Avelumab [package insert]. Roackland, MA; Pfizer; 2017.
IMMUNOTHERAPY
 Toxicities:
 Immune-Mediated
 Fatigue
 Rash
 Pruritus
 Constipation
 Decreased appetite
 Cough
 Hyponatremia/ hyperkalemia
SERIOUS IMMUNE-MEDIATED TOXICITIES
 Hepatitis
 Colitis
 Nephritis
 Pneumonitis (More commonly in NSCLC)
 Thyroid dysfunction
**Treatment of Serious Immune-mediated toxicities:

High dose steroids and prolonged tapers

Use of infliximab, mycophenolate mofetil etc. have been utilized when steroid refractory
CONTRAINDICATIONS TO IMMUNOTHERAPY
 History of autoimmune disorder:

Rheumatoid arthritis

Ulcerative colitis

Lupus
 Require chronic steroids (Prednisone dose ≥ 10 mg equivalent daily)
CABOZANTINIB (CABOMETYX ®)
 Recommended dose: 60 mg tablet PO daily
 Indication: advanced renal cell carcinoma after having
received prior anti-angiogenic therapy
 NCCN: 2A

Do not eat least 2 hours before or at least 1 hour after
taking
 Cabzantinib capsules may NOT be substituted
for cabozantinib tablets
Cabometyx [package insert]. San Francisco, CA; Exelixis; 2016.
CABOZANTINIB
 Mechanism: small tyrosine kinase inhibit which
inhibits activity of MET,VEGFR-1, -2, -3, and several
other kinases
 These receptors are involved in both normal cellular
function and processes involving oncogenesis,
metastasis, tumor angiogenesis, drug resistance, and
maintenance of the tumor microenvironment
Cabometyx [package insert]. San Francisco, CA; Exelixis; 2016.
CABOZANTINIB
 Randomized, Open-Label, Phase 3 trial
 N= 658 patients
 Patients were randomized 1:1 to receive

Cabozantinib 60 mg PO daily (N= 330)

Everolimus 10 mg PO daily (N= 328)
 Results (first 375 patients):

Median PFS 7.4 vs 3.8 months in the cabozantinib and
everolimus arms

Median OS in ITT was 21.4 and 16.5 months in the
cabozantinib and everolimus arms

HR 0.66, P = 0.0003
CABOZANTINIB ADVERSE EFFECTS
Greater than 25%
Serious Adverse Effects
 Diarrhea
 Reported in 40% of patients
 Fatigue
 Most common:

Abdominal pain

Pleural effusions
 Decreased appetite

Diarrhea
 Palmar-plantar erythrodysesthesia syndrome

Nausea
 Nausea (minimal to low emetic potential per
NCCN)
 Hypertension
** 60% of patients treated with cabozantinib had at least one dose reduction while on study**
Cabometyx [package insert]. San Francisco, CA; Exelixis; 2016.
CABOZANTINIB
 Special Considerations:

Reduce the dose in patients with mild to moderate hepatic impairment

Avoid breastfeeding while taking cabozantinb

Consider dose adjustments if patients require concomitant therapy with CYP3A4 inhibitors or inducers
Cabometyx [package insert]. San Francisco, CA; Exelixis; 2016.
AUDIENCE RESPONSE QUESTION
 Which of the following is a target of cabozatinib?

BCR-ABL

EGFR

VEGFR

mTOR
OLARATUMAB (LY3012207, IMC-3G3, LARTRUVO ®)
 First anti-PDGFRα monoclonal antibody approved in the US
 Indication: Soft tissue sarcoma (STS) not amendable to curative treatment with radiotherapy or surgery and with
histologic subtype for which an anthracycline-containing regimen is appropriate
 NCCN category: 2A
Lartruvo [package insert]. Indianapolis, IN; Lilly; 2016.
OLARATUMAB
 Human IgG1 monoclonal antibody that binds to human platelet-derived growth factor receptor alpha (PDGFRα)
and blocks the PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding receptor
 Signaling through PDGFR plays a role in cell growth, chemotaxis, and stem cell differentiation
 This receptor is also seen on some tumor cells where signaling can play a role in cancer cell proliferation,
metastasis, and maintenance
 Actual mechanism of action not well understood
Lartruvo [package insert]. Indianapolis, IN; Lilly; 2016.
OLARATUMAB: CLINICAL TRIALS
 Phase II: Olaratumab plus doxorubicin vs.
doxorubicin alone in STS
 Open-label, multicenter, randomized phase
Ib/II trial
 Patients aged 18 yo or older with unresectable
Olaratumab 15 mg/kg
IV days 1, 8
Doxorubicin 75 mg/m2
IV day 1
Every 21 days x 8
cycles
• Continue olaratumab
until disease progression
or metastatic STS

N=133
 Patients received dexrazoxane 750 mg/m2 IV
at investigator discretion on Day 1 of cycles 58 to prevent cardiotoxicity
 Primary endpoint: PFS
Doxorubicin 75 mg/m2
IV on day 1
Every 21 days x 8
cycles
• Optional – olaratumab
after progression
OLARATUMAB: CLINICAL TRIALS
 Results:
 Observations:

Median OS: 26.5 months vs. 14.7 months (HR 0.46; P =
0.0003)

Large difference between OS vs. PFS benefit (11.8
months vs. 2.5 months)

Median PFS: 6.6 months vs. 4.1 months (HR 0.67; P =
0.0615)

Trial used cumulative 600 mg/m2 doxorubicin (vs. 450
mg/m2 standard of care)

Objective Response Rate: 18% vs. 8% (P = 0.3421)

Post-study treatment variability
 Larger confirmatory trial needed:

Ongoing phase III ANNOUNCE trial
Lartruvo [package insert]. Indianapolis, IN; Lilly; 2016.
OLARATUMAB
 Cycles 1-4 (21 day cycles):

Olaratumab 15 mg/kg IV on days 1 and 8, infuse

Doxorubicin 75 mg/m2 IV on day 1

Premedication:

Diphenhydramine & Dexamethasone prior to cycle 1, dose 1 only.

[Do not duplicate dexamethasone in CINV prophylaxis]
 Cycles 5- 8: add dexrazoxane 750 mg/m2
 Cycles 9 onwards: olaratumab alone
Lartruvo [package insert]. Indianapolis, IN; Lilly; 2016.
OLARATUMAB
 Permanently discontinue olaratumab for any of the following:

Grade 3 or 4 infusion-related reactions

Neutropenic fever/infection or grade 4 neutropenia lasting longer than 1 week
 Restart olaratumab after ANC is >/= 1000 and permanently reduce dose to 12mg/kg
 Interrupt olaratumab infusion for grade 1 or 2 infusion-related reactions

After resolution, resume infusion at 50% of the initial infusion rate
Lartruvo [package insert]. Indianapolis, IN; Lilly; 2016.
OLARATUMAB
 Special Populations:

Pregnancy – olaratumab can cause fetal harm when administered to a pregnant woman

Nursing mothers – advise mothers not to breastfeed during treatment with olaratumab and for 3 months after final dose

Patients of reproductive potential – females of childbearing potential should use effective contraception during treatment,
and for 3 months after final dose
Lartruvo [package insert]. Indianapolis, IN; Lilly; 2016.
AUDIENCE RESPONSE QUESTION
 You have a patient who is starting on olaratumab for STS. What are some supportive care considerations you
should be looking for when assessing orders?

CINV risk


Doxorubicin: high CINV risk
Premedication for infusion reactions with olaratumab

Dexamethasone and diphenhydramine

Neutropenic Risk

Cardiac Toxicities

Dexrazoxane starting with cycle 5
RIBOCICLIB (KISQALI ®)
 Indication: Initial therapy for hormone receptor positive,
HER2 negative, advanced or metastatic breast cancer in
combination with an aromatase inhibitor for
postmenopausal women
 NCCN Category: TBD
 MOA: cyclin-dependent 4/6 inhibitor
Kisqali [package insert]. East Hanover, NJ: Novartis; 2017.
RIBOCICLIB: CLINICAL TRIAL
 MONALEESA-2: Randomized, double-blind, placebo-controlled, international clinical trial
 N = 668
 Randomized to receive:

Ribociclib 600 mg (three 200 mg tablets) PO daily for 21 days, followed by 7 days off plus letrozole 2.5 mg PO daily(334)

Placebo plus letrozole (334)
 Treatment continued until disease progression or unacceptable toxicity
 Median PFS: ribociclib arm not yet reached vs. 14.7 months in the placebo containing arm (HR: 0.556, P < 0.0001)
 ORR was 52.7% in ribociclib arm compared to 37.1 % in placebo arm
Kisqali [package insert]. East Hanover, NJ: Novartis; 2017.
RIBOCICLIB: ADVERSE EFFECTS
Greater than 20% incidence:
Grade 3 or 4 (> 2% incidence)
 Neutropenia
 Constipation
 Neutropenia
 Nausea
 Headache
 Leukopenia
 Fatigue
 Back pain
 Abnormal liver functions tests
 Diarrhea
 Lymphopenia
 Leukpenia
 Vomiting
 Alopecia
 Vomiting
**Prolonged QT interval has been observed and is concentration-dependent**
Kisqali [package insert]. East Hanover, NJ: Novartis; 2017.
RIBOCICLIB
 Special Considerations:
 Dose adjustments or avoidance may be needed for CYP3A4 inhibitors, inducers, or substrates
 QT prolongation – avoid concomitant use of drugs known to prolong QT interval
 Monitor:

CBC baseline then every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically
indicated

QT interval prior to initiation, repeat at day 14 of the first cycle and at the beginning of the second cycle

Monitor electrolytes at the beginning of each cycle for 6 cycles
Kisqali [package insert]. East Hanover, NJ: Novartis; 2017.
AUDIENCE RESPONSE QUESTION
 What would be one counseling point for a patient who is starting ribociclib with letrozole for treatment of her
breast cancer?
 What monitoring is recommended 14 days after starting therapy?

Pulmonary function test

ECHO

EKG

Renal function
RUCAPARIB (RUBRACA ®)
 Indication: advanced ovarian cancer with deleterious BRCA mutation (germline and/or somatic) who have received
2 or more chemotherapies
 NCCN Category: TBD
 Approved in conjunction with CDxBRCA test – detects alterations in BRCA 1 and BRCA 2 genes in tumor tissue
Rubraca [package insert].Boulder, CO: Clovis Oncology; 2016.
RUCAPARIB
 Mechanism of action: PARP Inhibitor
 PARP and BRCA 1/2 normally function to repair daily
 If BCRA1/2 is damaged or not working, the cell is
 Allows cells to grow in a healthy way
 PARP inhibitors prevent DNA repair in cancer cells
DNA damage
 Too much DNA damage  cell death
dependent on PARP for ALL DNA repair

May increase cancer cell death

May help chemotherapy and radiation work better
Rubraca [package insert].Boulder, CO: Clovis Oncology; 2016.
RUCAPARIB: CLINICAL TRIALS
 Approval was based on two multicenter, single-arm, open label clinical trials (ARIEL2)
 N=106
 All patients received rucaparib 600 mg PO BID until disease progression or unacceptable toxicity
 Groups were stratified based on mutations: (1) BRCA-mutant (2) BRCA wild-type with high LOH (3) BRCA wild-
type with low LOH
 Results:

BRCA-mutant group: median PFS of 12.8 months and response rate of 80%
Rubraca [package insert].Boulder, CO: Clovis Oncology; 2016.
RUCAPARIB
 Recommended starting dose:

Rucaparib 600 mg (two 300 mg tablets) PO BID with or without food
 Dose reductions occur by 100 mg BID
 May increase myelosuppressive effects of other medications
 Primary metabolism via CYP2D6; CYP1A2, CYP3A4 to a lesser degree
Rubraca [package insert].Boulder, CO: Clovis Oncology; 2016.
RUCAPARIB: ADVERSE EFFECTS
 377 patients were evaluated:
 Most common adverse effects (>20% incidence)

Nausea (Moderate to High emetogenic risk)

Abodminal pain

Fatigue

Dyspgeusia

Vomiting

Constipation

Anemia

Thrombocytopenia

Dyspnea

Rare: MDS/AML and AML
Adverse reactions lead to dose discontinuation in 10% of patients (2% fatigue/asthenia)
Rubraca [package insert].Boulder, CO: Clovis Oncology; 2016.
NIRAPARIB (ZEJULA ®)
 Indication: Maintenance treatment in recurrent epithelial ovaria, fallopian tube, or primary peritoneal cancer who
are in complete or partial response to platinum-based chemotherapy
 NCCN Category: TBD
 Randomizied trial (NOVA) of 553 patients

Niraparib 300 mg PO daily vs. placebo
 Results:

Median PFS (germline BRCA mutation) 21 months compared to 5.5 months (HR= 0.26; P < 0.0001)

Median PFS (non-germline BRCA mutation) 9.3 months compared to 3.9 months (HR= 0.45; P < 0.0001)
 Most common adverse effects:

Thrombocytopenia, anemia, neutropenia, palpitations, nausea, constipation, mucositis,, fatigue, abdominal pain,
Zejula [package insert]. Waltham, MA:Tesaro; 2017.
NIRAPARIB
 Special Considerations:
Lactation: avoid breast feeding during treatment and for 1 month following final dose
 Monitoring:

CBC weekly for first month, monthly for next 11 months

Blood pressure (hypertension occurred in 9% of patients)
 Warnings/Precautions:

MDS/AML and AML has been observed while taking therapy (1.4% incidence)
Zejula [package insert]. Waltham, MA:Tesaro; 2017.
VENETOCLAX (VENCLEXTA ®)
 Indication: relapsed/refactory chronic
lymphocytic leukemia (CLL) with 17p deletion
(at least 1 prior therapy)
 NCCN Compendia: 2A
Venclexta [package insert]. Chicago, IL: AbbVie; 2016.
VENETOCLAX
 Small molecule selective inhibitor of BCL-2, an anti-
apoptotic protein which is overexpressed in CLL
cells
 BCL-2 mediates tumor cell survival and has been
associated with chemo resistance
 Inhibition of BCL-2 helps to restore apoptosis
Venclexta [package insert]. Chicago, IL: AbbVie; 2016.
VENETOCLAX
 Open-label, phase II single arm, multicenter study:
106 patients with previously treated CLL with 17p
deletion (confirmed thru FISH)
 Target dose 400 mg PO daily

 Results:

ORR 80%, including 8% CR and 2% Cri

Median duration of response not reached; 12 months
median follow-up
Dosing:

Week 1 – 20 mg PO daily

Week 2 – 50 mg PO daily

Week 3 – 100 mg PO daily

Week 4 – 200 mg PO daily

1.5 to 2 liters of oral hydration daily

Week 5 and beyond: 400 mg PO daily

Allopurinol beginning 2-3 days before starting venetoclax

 Special considerations:

TLS prophylaxis – hydration and allopurinol
Continue until disease progression or unacceptable toxicity
Venclexta [package insert]. Chicago, IL: AbbVie; 2016.
VENETOCLAX

 Many potential drug-drug and drug-food interactions:


Venetoclax is a major CYP 3A4 substrate and Pglycoprotein substrate
Consult specialized drug information resources
Do NOT co-administer with:

BCG

Bitter Orange

Conivaptan

Deferiprone

Dipyrone

Idelalisib

Grapefruit juice

Star fruit

Live vaccines

Shingles, MMR, rotavirus, influenza (Nasal spray)
Venclexta [package insert]. Chicago, IL: AbbVie; 2016.
Venclexta [package insert]. Chicago, IL: AbbVie; 2016.
SUPPORTIVE CARE ADVANCES
DEFIBROTIDE (DEFITELIO ®)
 First FDA-approved treatment for severe hepatic veno-occlusive disease (VOD) aka sinusoidal obstruction
syndrome (SOS)
 Indication:VOD with renal or pulmonary dysfunction after HSCT
Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2016.
DEFIBROTIDE
 Safety:


Hemorrhage (any)

Hold and treat hemorrhage

Resume only when bleeding stopped and hemodynamically stable
Hypersensitivity reactions


If severe: permanently discontinue
Hypotension
Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2016.
DEFIBROTIDE
 Recommendations:


Establish “unequivocal” diagnostic criteria for VOD, for example:

Baltimore criteria

Multi-organ failure (MOF)

Abdominal ultrasound

Liver biopsy
Plan criteria for when prophylaxis gets approved
Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2016.
DEFIBROTIDE: CLINICAL TRIAL
 Efficacy of defibrotide: two prospective clinical trials and an expanded access study
 N= 528
 Defibrotide 6.25 mg/kg IV every 6 hours until resolution of VOD
 Results:

Survival at day +100 after HSCT

38% (Study 1), 44% (Study 2), 45% (Study 3)

21 – 31% of patients with hepatic VOD with renal or pulmonary dysfunction
Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2016.
DEFIBROTIDE
 MOA: profibrinolytic activity

Contraindicated in patients being treated concurrently
with anticoagulants or fibrinolytic therapies
 Dosing:

6.25 mg/kg IV every 6 hours

Initiate as soon as possible following diagnosis

Treatment duration: 21 – 60 days
 Adverse effects:

Hypotension

Diarrhea

Vomiting

Nausea

Epistaxis
Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2016.
DRUG DEVELOPMENT PIPELINE
FUTURE DIRECTIONS
DRUGS TO EXPECT DOWN THE ROAD FOR CANCER TREATMENT
 PARP inhibitors:

2 approved in 6 months  combination studies with multiples agents and pathways coming

Multiple agents under investigation in many diseases, include breast cancer, prostate, lung, and GBM

Olaparib, Rucaparib, Niraparib, Talazoparib, Veliparib
 Cyclin Dependent Kinases: (CDK 4/6 inhibitors)

Indications outside of breast cancer,

Multiple combinations
 Role of Tumor Suppressor Proteins in cell cycle regulation (XPO1)
 PI3K/AKT/mTOR Pathway agents

Over 30 agents under investigation in a variety of trials

Clinical development of these inhiitors has proven challenging due to toxicity of pan-inhibitors

Dual combination PI3K/mTOR is in the clinic and showing significant promise
STRATEGIES TO REDUCE DRUG RESISTANCE
 Combination therapy to slow and shut down escape pathways
 Epigenetic therapy
 Bromodomain Inhibitors (BET inhibitors)
 Induced protein degradation (PROTACs)
CITATIONS
 The state of cancer care in America, 2016: A Report by the American Society of Clinical Oncology. Journal of
Oncology Practice 12,no.4 (April 2016) 339-383.
 Mullar A. 2015 FDA drug approvals. Nature Reviews Drug Discovery.15, (2016) 73-76.
 Lu D., Lu T., et al. A survey of new oncology drug approvals in the USA from 2010 to 2015: A focus on optimal
dose and related postmarketing activities. Cancer Chemother Pharmacol. (2016) 77: 459-476.
 Capasso A., Eckhardt SG. The changing landscape of phase I trials in oncology. Nature Reviews Clinical Oncology. 13,
(2016) 106-177.
 Hematology/Oncology (Cancer) Approvals & Safety Notifications.
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed 3-27-17
QUESTIONS?