Today’s Challenges and Controversies
in Recurrent Ovarian Cancer
Management
Bradley J. Monk, MD, FACS, FACOG
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Chao Family Comprehensive Cancer Center
University of California, Irvine Medical Center
Orange, California
What is Ovarian Cancer?

3 types of cancer
 Epithelial
 Germ cell
 Stromal

Epithelial tumors are of mesodermal origin
 Same as primary peritoneal cancer

Epithelial cancers related to ovulatory events,
which increase mutation frequency
 Reduced by OCPs, pregnancy, or lactation
Newly Diagnosed Advanced Ovarian Cancer
Courtesy of Robert Bristow, Johns Hopkins.
Ovarian Cancer is a Global Disease
International Agency for Research on Cancer (WHO). Courtesy of Dr. Bradley J. Monk.
Ovarian Carcinoma
Incidence and Mortality

Incidence in US women
 21,550 cases in 2009
 9th most common cancer
 2nd most common gynecologic cancer
 1.5% lifetime risk of getting ovarian cancer

Mortality in US women
 14,600 deaths in 2009
 5th most common cause of cancer death
 Most common cause of death due to gynecologic cancer
 1.0% lifetime risk of dying of ovarian cancer
American Cancer Society. Available at: http://www.cancer.org/
Cancer in the United States
With permission from American Cancer Society. Available at: http://www.cancer.org/
FIGO Stage—Outcomes
Stage
Description
Incidence, %
Survival, %
I
Confined to ovaries
20
73
II
Confined to pelvis
5
45
III
Spread IP or nodes
58
21
IV
Distant metastases
17
<5
Abbreviation: IP, Intraperitoneal
Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.
Results of Treatment
Advanced Disease
Parameter
Small Volume
Large Volume
Response, %
95
75
Clinical CR, %
95
50
Pathologic CR, %
50
25
PFS, mo
25
18
Survival, mo
50
36
30–40
15–20
10-y survival, %
Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.
Results of Treatment
Advanced Disease
Parameter, %
Small Volume
Large Volume
1980: 10-y survival
7
0
1990: 10-y survival
20
10
2008: 10-y survival
30–40
15–20
Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.
Ovarian Cancer
Increasing Survival Rates
Proportion Surviving
SEER Data 1973-1997 N=32,845
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
1973-1979
1980-1989
1990-1997
2-Year Survival
5-Year Survival
Barnholtz-Sloan JS, et al. Am J Obstet Gynecol. 2003;189(4):1120-1127.
Approved Drugs in
Ovarian Cancer
1978
2009

1978
Cisplatin

1989
Carboplatin

1990
Altretamine

1992
Paclitaxel

1996
Topotecan

1999
Liposomal doxorubicin (accelerated)

2005
Liposomal doxorubicin (full)

2006
Gemcitabine (with carboplatin)

2009
Trabectedin (with liposomal doxorubicin
EMEA only)
First-line Therapy
Global Standard Treatment
Surgery with maximum
cytoreduction effort
IV Platinum + Taxane Chemotherapy
(Carboplatin + Paclitaxel) x 6
2004 Consensus Statements on the Management of Ovarian Cancer: Final Document of the 3rd International
GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16(suppl 8) viii7–viii12.
Courtesy of Dr. Bradley J. Monk.
Maximal Primary Cytoreduction

Meta-analysis: 53 studies (1989–1998)
 81 cohorts (stage III/IV)
 N = 6885 patients

Results




Expert centers have high optimal rates
Optimal vs not: 11 mo (50% increase)
Each 10%  in cytoreduction = 5.5%  in survival
Platinum intensity = NS
Bristow RE, et al. J Clin Oncol. 2002;20:1248-1259.
Basis for Current Standard
Systemic Therapy
Studies showing paclitaxel/cisplatin superior to
cyclophosphamide/cisplatin
 GOG Protocol 1111
 EORTC-NCIC OV 102
 Studies showing paclitaxel/carboplatin at least
equivalent to paclitaxel/cisplatin in efficacy
 AGO Trial3
 GOG Protocol 1584
1. McGuire WP, et al. N Engl J Med .1996;334:1-6.
2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708.
3. DuBois A, et al. J Natl Cancer Inst. 2003;95:1320-1329.
4. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200.
Standard of Care—2010



Maximum attempt at surgical cytoreduction
Chemotherapy following surgery
Regimen of choice
 Paclitaxel 175 mg/m2/3 h IV +
 Carboplatin AUC 6–7.5 IV
 Repeat every 3 wk for 6 cycles
2004 Consensus Statements on the Management of Ovarian Cancer: Final Document of the 3rd International
GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16(suppl 8) viii7–viii12.
Courtesy of Dr. Bradley J. Monk.
The Role of Antivascular
Agents in the Management of
Recurrent Ovarian Cancer
Robert A. Burger, MD
Professor, Surgical Oncology
Section of Gynecologic Oncology
Director, Women’s Cancer Center
Fox Chase Cancer Center
Philadelphia, Pennsylvania
Angiogenesis in Tumor Progression
With permission from The Angiogenesis Foundation, Inc; www.angio.org.
Angiogenic Balance


Proangiogenic
Antiangiogenic
VEGF
FGF
PGF
TGFs
Angiogenin
Interleukin-8
HGF
GCSGF
PDEGF
Angiopoietin 1
Thrombospondin-1
Angiostatin
Interferon-alpha
Prolactin 16-kd fragment
Metalloproteinase inhibitors
PF-4
Genistein
Placental proliferin-related
protein
TGF-β
Endostatin
Hanahan & Folkman. Cell. 1996;86:353–364.
Rationale for Targeting VEGF in
Treatment of EOC

Human tumors
 VEGF expression and degree of tumor angiogenesis
(microvessel density) associated with



Ascites formation
Malignant progression1-3
Poor prognosis4-7
Abbreviation: EOC, epithelial ovarian cancer.
1. Yoneda J, et al. J Natl Cancer Inst. 1998;90:447-454. 2. Ferrara N. J Mol Med. 1999;77:527-543.
3. Dvorak HF. J Clin Oncol. 2002;20:4368-4380. 4. Gasparini G, et al. Int J Cancer. 1996;69:205-211.
5. Hollingsworth HC, et al. Am J Pathol. 1995;147:33-41. 6. Paley PJ, et al. Cancer. 1997;80:98-106.
7. Alvarez AA, et al. Clin Cancer Res. 1999;5:587-591.
Rationale for Targeting VEGF in
Treatment of EOC

Preclinical models of solid tumors
 Anti-VEGF therapy



Slowing of tumor progression1,2
Resolution of malignant effusions2
Synergy with cytotoxic agents3-5
Abbreviation: EOC, epithelial ovarian cancer.
1. Byrne AT, et al. Clin Cancer Res. 2003;9:5721-5728. 2. Mesiano S et al. Am J Pathol. 1998;153:1249-1256.
3. Gorski DH, et al. Cancer Res. 1999;59:3374-3378. 4. Lee CG, et al. Cancer Res. 2000;60:5565-5570. 5.
Hu L, et al. Am J Pathol. 2002;161:1917-1924.
Direct Anti-VEGF Antitumor Effect?


VEGFRs expressed in multiple solid tumor types:
colon,1 breast,2,3 ovary4
In vitro stimulation of breast carcinoma cells with VEGF3
leads to
 Invasion
 Growth factor signaling

Activation of VEGFR-1 on tumor cells by VEGF3 
 Invasion
 Activation of MAPK
 Cell migration
1. Fan F, et al. Oncogene. 2005;24:2647-2653. 2. Wu Y, et al. AACR 2004. Abstract 3005. 3. Price DJ, et
al. Cell Growth Differ. 2001;12:129-135. 4. Chen H, et al. Gynecol Oncol. 2004;94:630-635.
Classes of Anti-VEGF Agents

Target
 Ligand (VEGF)
 VEGFR

Pharmacology
 Large molecules (monoclonal antibodies, soluble
receptors)
 Small molecule inhibitors (“ibs”)
Classes of Anti-VEGF Agents
Target
Class
Agents
Mab
Bevacizumab1
Soluble decoy receptor
VEGF Trap2,3
Ligand

VEGF-A

VEGF
Receptor

VEGFR2
Mab
Ramucirumab

VEGFR + PDGFR + Raf-K
TKI
Sorafenib

VEGFR + PDGFR
TKI
Sunitinib

VEGFR + PDGFR
TKI
Motesanib

VEGFR + PDGFR + FGF
TKI
Pazopanib

VEGFR + PDGFR + FGF
TKI
Cediranib

VEGFR + PDGFR + FGF
TKI
BIBF-1120
Abbreviations: FGF, fibroblast growth factor; Mab, monoclonal antibody; PDGFR, platelet-derived growth
factor receptor; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
1. Presta G, et al. Cancer Res. 1997;57:4593-4599. 2. Holash J, et al. Proc Natl Acad Sci U S A.
2002;99:11393-11398. 3. Hu L, et al. Clin Cancer Res. 2005;11:6966-6971.
Unique Toxicities of
Anti-VEGF Agents







Proteinuria
Hypertension
Mucosal hemorrhage
Wound healing
Arterial thromboembolism
Reversible posterior leukoencephalopathy
syndrome (RPLS)
GI perforation or fistula
Single-Agent Activity
Single-Agent Anti-VEGF Therapy in
EOC/PPC—Phase II Efficacy Results
Trial
GOG 170-D1
Cannistra et al2*
Tew et al3†
Agent
Bevacizumab
Bevacizumab
VEGF Trap
Enrollment, n
62
44*
162‡
1o platinum DFI <6 mo, %
36
84
47
34/66/0/0
0/52/48/0
0/0/46/46
GOG/ECOG PS (0/1/2), %
73/27/0
59/41/0
60/33/7
RR, n (%)
13 (21)
7 (16)
13(8)
40
28
4
Previous regimens (1/2/3/4), %
6 mo PFS (%)
*Trial terminated prematurely.
†Trial failed to meet primary endpoint.
‡Preliminary analysis.
Abbreviations: EOC, epithelial ovarian cancer; PPC, primary peritoneal cancer.
1. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. 2. Cannistra SA, et al. J Clin Oncol.
2007;25:5180-5186. 3. Tew WP, et al. Paper presented at: 43rd ASCO; June 1-5, 2007.
GOG 170-D
Exploratory Analysis of Prognostic Factors
for PFS (Proportional Hazards)

GOG performance status >0 vs 0
 Hazard ratio 1.491
 Wald P value 0.2466

Platinum sensitivity yes vs no
 Hazard ratio 0.803
 Wald P value 0.4702

Age
 Hazard ratio 1.001
 Wald P value 0.9076

Number of prior regimens 2 vs 1
 Hazard ratio 0.616
 Wald P value 0.1207
Burger RA, et al. J Clin Oncol 2007; 25: 5165-5171.
Single-Agent Anti-VEGF Therapy in
EOC/PPC Toxicities—Phase II Trials
GOG 170-D1
Cannistra et al2*
Tew et al3†
Enrollment, n
62
44*
162‡
≥ G3 GI perforation
0
5 (11%)
2 (1.2%)
≥ G3 arterial TE
0
3§ (7%)
1
≥ G3 HTN
6 (10%)
4§ (9.1%)
18%
≥ G3 CNS
0
1§
1
≥ G3 proteinuria
1
0
7%
Trial
*Trial terminated prematurely.
†Trial failed to meet primary endpoint.
‡Preliminary analysis.
§Event fatal in 1 case.
Abbreviations: EOC, epithelial ovarian cancer; PPC, primary peritoneal cancer.
1. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. 2. Cannistra SA, et al. J Clin Oncol.
2007;25:5180-5186. 3. Tew WP, et al. J Clin Oncol.2007;25 (suppl). Abstract 5508.
Rationale for Combination AntiVEGF and Cytotoxic Regimens


Complementary, independent activity
Synergy in preclinical models1
 Hypothetical mechanisms




Sensitization to apoptosis
Reversal of cytotoxic drug resistance
Increased access of chemotherapeutic—vascular
“normalization”2,3
Positive phase III trials (bevacizumab) in
metastatic colorectal,4,5 breast,6 and lung7
cancers
1. Sweeney CJ, et al. Cancer Res. 2001;61:3369-3372. 2. Jain RK. Science. 2005;307:5706:58-62.
3. Wildiers H, et al. Br J Cancer. 2003;88:1979-1986. 4. Hurwitz H, et al. N Engl J Med. 2004;350:23352243. 5. Giantonio B, et al. J Clin Oncol. 2007;25:1539-1544. 6. Miller K, et al. N Engl J Med.
2007:357:2666-2676. 7. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
Bevacizumab + Metronomic
Cyclophosphamide in Recurrent
Ovarian Cancer—Phase II Results


Toxicity findings similar to
single agent anti-VEGF
phase II trials
N = 70
 GI fistula/perforation:
4 (5.7%)
 CNS ischemia: 2 (2.9%)
 Wound healing impairment: 1
 Pulmonary hypertension:
2 (2.9%)
 Treatment related deaths:
3 (4.3%)
Garcia AA, et al. J Clin Oncol. 2008;26:76-82.

Efficacy
 PFS-6 mo: 56%
 Response rate: 24% (17 PR)
GOG 213
Recurrent ovarian and peritoneal primary cancer
TFI > 6 mo
Surgical candidate?
Yes
No
Randomize
Randomize
Surgery
No surgery
Carboplatin,
paclitaxel
To chemotherapy
randomization
Abbreviation: TFI, treatment-free interval
Slide courtesy of Dr. Robert A. Burger.
ClinicalTrials.gov. NCT00565851 PI: Coleman, Activated 12/07
Carboplatin,
paclitaxel,
bevacizumab
Maintenance
bevacizumab
Primary endpoint: Overall survival
Secondary endpoints: Progression-free
survival, toxicity, quality of life,
translational research
OCEANS—Carboplatin/Gemcitabine ±
Bevacizumab in Ovarian Carcinoma
(Phase III)
Patients with platinumsensitive recurrent
epithelial ovarian, peritoneal,
or fallopian tube carcinoma
(Planned N = 450)


Bevacizumab + Carboplatin +
Gemcitabine
Placebo + Carboplatin +
Gemcitabine
Primary outcome measure: Progression-free survival
Secondary outcome measures: objective response, duration of response,
overall survival, incidence of GI perforation, safety of bevacizumab +
carboplatin/gemcitabine, all adverse events
Slide courtesy of Dr. Robert A. Burger.
ClinicalTrials.gov. NCT00434642
Phase III Frontline Ovarian
Cancer Trials
Trial
Sample size
Arms
GOG 2181
ICON-72
1800
1520
CT
CT
CT + bev
CT + bev  bev
CT + bev  bev
Primary endpoint
PFS (10/08)
PFS
Placebo-controlled
Yes
No
FIGO stage
III/IV
High risk I/IIA, IIB-IV
Secondary endpoints
PFS, TOX, RR, QOL, TR
OS, TOX, RR, QOL, PH-EC
Bev dose/schedule
15 mg/kg every 21 days
7.5 mg/kg every 21 days
Closed 7/09
Activated 4/06
Status
1. ClincialTrials.gov. NCT00262847.
2. ClincialTrials.gov. NCT00483782.
Abbreviations: PFS,progression-free survival; PH-EC,
pharmacoeconomics; QOL, quality of life; RR, response rate;
TOX, toxicity; TR, translational research.
GOG 0218—Frontline CT ± Bev
in Recurrent Ovarian Cancer
(Phase III)
Phase B
Phase A
Arm 1 CT1  CT + plac 2-6
Plac 7-22
Arm 2 CT1  CT + bev 2-6
Plac 7-22
Arm 3 CT1  CT + bev 2-6
Bev 7-22
Cycles
Months
1
1
2
3
2
4
5
3
ClincialTrials.gov. NCT00262847.
6
4
7
5
8
9
6
10 11 12 13 14 15 16 17 18 19 20 21 22
7
8
9
10
11
12
13
14
15
Slide courtesy of Dr. Robert A. Burger.
Multi-Growth Factor Targeting
The Role of the Platelet-Derived
Growth Factor (PDGF) Pathway

PDGF/PDGFR recruitment of pericytes1

PDGFR activation  direct effect on endothelial cells2-5

Implicated in resistance to VEGF pathway inhibition6-9
1. Jain & Booth. J Clin Invest. 2003. 2. Beitz, et al. Proc Natl Acad Sci USA. 1991. 3. Risau, et al. Growth
Factors. 1992. 4. Oikawa, et al. Biol Pharm Bull. 1994 5. Apte, et al. Clin Cancer Res. 2004. 6. Abramsson, et
al. J Clin Invest. 2003; 7. Benjamin. Development. 1998. 8. Bergers, et al. J Clin Invest. 2003. 9. Lu, et al. Am
J Obstet Gynecol. 2008.
The Role of FGF in Angiogenesis
FGF
HGF expression
(VSMC)
VEGF expression
(myocytes, stromal cells, EC)
EC activation
PDGFR expression
(EC, VSMC)
Mural cell recruitment
Angiogenesis
Abbreviations: EC, endothelial cell; FGF, fibroblast growth factor; HGF, hepatocyte growth factor;
PDGFR, platelet-derived growth factor receptor; VSMC, vascular smooth muscle cell.
Slide courtesy of of Dr Robert A. Burger. Murakami and Simons. Curr Opin Hematol. 2008;15:215–220.
Toxicities Associated with Dual
Multi-Pathway Inhibitors





Dermatologic toxicity (ie,
hand-foot skin reaction,
rash/desquamation, skin
discoloration)
GI toxicity (ie, diarrhea,
nausea, abdominal pain,
vomiting, dyspepsia,
constipation, perforation)
Hypertension
Fatigue
Weight loss










Alopecia
Anorexia
Asthenia
Mucositis/stomatitis
Altered taste
Bleeding events
Arterial thrombotic events
Myocardial toxicity
Hypothyroidism
Adrenal toxicity
Phase II Efficacy—MultiTargeted TKI
Trial
GOG 170-F
Agent
Sorafenib
PI
Matei1
N
59
GOG 170-L
Motesanib
Schilder
23*
VEG104450
Pazopanib
Friedlander2
36
PMH-PHL
Cediranib
Hirte3
62
4.8%
?
DFCI-05170
Cediranib
Matulonis4
46
17%
~ 38%
BIBF- 1120
Ledermann5
83**
EUDRACT
RR
3.4%
6-Mo
PFS
24%
Other
CA125 RR 31%
PFS HR .68
* Closed due to toxicity
** Secondary Consolidation, Placebo-Controlled
1. Matei D, et al. J Clin Oncol. 2008;26(suppl). Abstr 5537. 2. Friedlander M, et al. J Clin Oncol. 2007;
25(suppl). Abstr 5561. 3. Hirte HW, et al. J Clin Oncol. 2008;26(suppl). Abstr 5521. 4. Matulonis UA, et al. J
Clin Oncol 2009; 27: 5601-5606. 5. Ledermann JA, et al. J Clin Oncol. 2009;27(suppl). Abstr 5501.
ICON 6 (Second-Line European Trial)
2:3:3 Randomization
Platinum-based chemo
(± taxane)
q 21 days x 6 cycles
+ placebo
Patients with platinumsensitive ovarian cancer
Relapsed >6 mo following
first-line platinum-based
treatment
Measurable disease
Platinum-based chemo
(± taxane)
q 21 days x 6 cycles
+ oral cediranib daily during
chemo, then 18 mo placebo
Platinum-based chemo (± taxane)
q 21 days x 6 cycles
+ oral cediranib during chemo
and until progression or 18 mo
Slide courtesy of Dr. Robert A. Burger.
Planned: phase II (N = 300), phase III (N = 2,000).
Theoretical Pros and Cons of
Multi-Targeting vs Isolating VEGF

Pros
 May more effectively block angiogenesis
 Potentially reduced likelihood of resistance due to
activity of compensatory pathways
 Benefit of oral vs IV route

Cons
 Benefit of IV vs oral
 Increased risk of off-target effects
Vascular Disrupting Agents
Unlike anti-angiogenesis agents, which inhibit
the formation of new blood vessels, vascular
disrupting agents destroy the existing vascular
structure in a tumor
 Small molecule flavonoids: DMXAA
 Microtubulin-destabilizing agents:
combretastatin (CA4P, AVE8062)
Lippert JW III. Bioorg Med Chem. 2007;15: 605-615. Cai SX. Recent Pat Anticancer Drug Discov.2007;2:79101. Delmonte A, Sessa C. Expert Opin Investig Drugs. 2009;18:1541-1548.
Summary



Rationale for antiangiogenic ovarian cancer therapy
Multiple pathways and targets
Anti-VEGF drugs
 Single-agent activity
 Unique toxicity profile

Multi-targeted inhibitors
 Single-agent activity
 Expanded toxicity profile


Role of vascular disrupting agents
Many unanswered questions
The Role of Other
Nonvascular Targeted
Therapies in the Management
of Recurrent Ovarian Cancer
Bradley J. Monk, MD, FACS, FACOG
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Chao Family Comprehensive Cancer Center
University of California, Irvine Medical Center
Orange, California
Active Nonvascular Targeted Agents
in Ovarian Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors
 Olaparib

Antifolates
 Pemetrexed
 Farletuzumab (MORAb-003)

Mammalian target of rapamycin (mTOR) inhibitors
 Everolimus

Human epidermal growth factor receptor 2 (HER2)
inhibitors
 Trastuzumab
 Pertuzumab
PARP Inhibitors
Targeting DNA Repair
in Oncology—Rationale
DNA damage frequently occurs in all cells
Why is DNA
repair a good
target?
DNA repair defects lead to increased
cancer susceptibility and increased
sensitivity to DNA-damaging agents
Normal cells have multiple DNA repair
pathways but some are lost in cancer cells
Inhibiting DNA repair in cancer cells that have
impaired repair pathways leads to selective
cell killing and an increased therapeutic ratio
Novel targeted therapeutic approach
Kennedy RD, D’Andrea AD. J Clin Oncol. 2006;24:3799-3808. Courtesy of Dr. Bradley J. Monk.
Types of DNA Damage and Repair
Type of
damage
Repair
pathway
Bulky
adducts
Singlestrand
breaks
Doublestrand
breaks
Base Recombinational
repair
excision
repair
HR
Repair
enzymes
O6alkylguanine
Insertions
and deletions
Nucleotideexcision Mismatch Direct
reversal
repair
repair
NHEJ
PARP ATM DNA-PK
XP,
MSH2,
poly-merases MLH1
AGT
Hoeijmakers JHJ. Nature.2001;411:366-374. Khanna KK, Jackson SP Nat Genet. 2001;27:247-254.
Sanchez-Perez I. Clbl. Transl Oncol. 2006;8:642-646. Courtesy of Dr. Bradley J. Monk
Targeted Killing of Cancer Cells with
Defective DNA-Repair Mechanisms
Double-stranded break
Cancer cell with
defective repair
Normal cell
Repair by HR
pathway
BRCA deficient or
deficiency of other
HR proteins
No repair
(no HR pathway)
Survival
Cell death
Exploits inherent weakness of cancer cells that have
defective DNA repair
Abbreviation: HR, homologous recombination.
Martin SA, et al. Curr Opin Genet Develop.2008;18:80-86. Courtesy of Dr. Bradley J. Monk.
DNA Repair Inhibitors in Cancer Cells
Two Modes of Action

Potentiation
 Inhibition of DNA repair following DNA-damaging
agents
 Original hypothesis

Synthetic lethality
 Selected cancer cells lose DNA repair pathways,
whereas normal cells remain unaffected
 Targeting these defective cells may cause selective
cell kill with an increased therapeutic ratio
 May allow for a novel targeted approach to cancer
treatment
Bentle MS, et al. J Mol Histol. 2006;37:203-218.
Olaparib (AZD 2281) Development


Oral small molecule PARP inhibitor (low nM)
Escalation phase (N = 46)
 All tumors
 BRCA mutation not required (11 BRCA ovarian cancers)
 10 dose levels; administration 2 of 3 weeks up to BID
continuously




PK and PD determined
DLT: Myelosuppression, N/V, CNS (mood changes)
MTD: 400 mg BID
Expansion phase (N = 52)
 All confirmed BRCA mutation carriers (39 ovarian cancers)
 DLT: Fatigue, thrombocytopenia, somnolence
 Administration 200 mg BID continuously
Yap TA, et al. J Clin Oncol. 2007;25(suppl). Abstr 3529.
Fong PC, et al. J Clin Oncol. 2008;26(suppl). Abstr 5510.
Phase I—Olaparib (AZD 2281) Updated
Expanded BRCA Cohort
Characteristic
Mutation
– BRCA1
– BRCA2
– Family history
Age mean (range)
PS (0–1)
Time from Dx to Rx
Platinum status
– Sensitive
– Resistant
– Refractory
Number of priors (range)
Number
15
1
1
54.8 years (19–82)
55
4.7 years (0.5–16)
10 (20%)
27 (54%)
13 (26%)
3 (1–8)
Fong PC, et al. N Engl J Med. 2009;361:123-134. Fong PC, et al. J Clin Oncol.2008;26(suppl). Abstr
5510. Courtesy of Dr. Bradley J. Monk.
Phase I—Olaparib (AZD 2281)
Clinical Activity—RECIST + GCIG
Total
Platinum
Sensitive
Platinum
Resistant
Platinum
Refractory
46
10
25
11
Responders by RECIST
13 (28%)
5 (50%)
8 (32%)
0 (0%)
Responders by GCIG
CA125
18 (39%)
8 (80%)
8 (32%)
2 (18%)
Responders by either
RECIST or GCIG criteria
21 (46%)
8 (80%)
11 (44%)
2 (18%)
SD (>4 cycles)
6 (13%)
1 (10%)
4 (16%)
1 (95)
Median duration of
response in weeks (range)
24 (10–
77)
23 (16–77)
24 (10–65)
26 (20–32)
No. of evaluable patients
Abbreviations: GCIG, Gynecologic Intergroup ;RECIST, Response Evaluation Criteria in Solid Tumors.
Fong PC, et al. N Engl J Med. 2009;361:123-134. Fong PC, et al. J Clin Oncol.2008;26 (Suppl). Abstr
5510. Courtesy of Dr. Bradley J. Monk.
Phase II Trial of the PARP Inhibitor Olaparib (AZD 2281)
in BRCA-Deficient Advanced Ovarian Cancer—Efficacy
Patients with confirmed mutation, recurrent (stage IIIB/IIIC/IV) ovarian
cancer after failure of ≥1 platinum-based chemotherapy
Olaparib 400 mg BID
(n = 33)
Olaparib 100 mg BID
(n = 24)
Response by RECIST
11 (33%)
3 (13%)
 Platinum sensitive
1/7 (14%)
2/8 (25%)
 Platinum resistant
10/26 (38%)
1/16 (6%)
20 (61%)
4 (17%)
290 days (126–513)
269 days (169–288)
5.8 months
1.9 months
(n = 33)
(n = 24)
 Nausea
2 (6%)
3 (13%)
 Vomiting
2 (6%)
2 (8%)
Discontinuation due to AEs
4 (12%)
1 (4%)
Dose interruption due to AEs
12 (36%)
4 (17%)
Response by RECIST and/or GCIG
Median DOR (range)
Median PFS
Grade 3/4 AEs
Audeh MW, et al. Presented at 45th Annual ASCO; May 29-June 2, 2009.
All Patients—Who Will Benefit From
PARP Treatment?
Sporadic tumors
with intact BRCA
function
Abbreviation: Nl, Normal lymphocytes.
Prevention?
Courtesy of Dr. Robert Coleman.
Coleman RL. Curr Oncol Rep. 2009;11:414-416.
Olaparib (AZD 2281) Maintenance Trial



Histologically or cytologically
confirmed serous epithelial
ovarian cancer
CR/PR to 2nd- or 3rd-line
platinum-based
chemotherapy (penultimate
treatment-free interval
>6 months)
BRCA mutation not required
R
A
N
D
O
M
I
Z
E
Olaparib PO 400 mg BID
until disease progression
Placebo
until disease progression
Primary end point = PFS
N = 250
Recruitment complete (results expected late 2010)
ClinicalTrials.gov Identifier: NCT00753545. Courtesy of Bradley J. Monk.
Key Issue for Future
Developments of PARP Inhibitors

Is single-agent PARP inhibitor or combination preferable?
 Single-agent treatment utilizes selective synthetic lethality with limited
toxicity
 Combination with DNA-damaging agents (temozolamide or platinum)
reverses resistance in experimental models
 More myelotoxicity (BSI-201 exception)

What determines resistance to PARP?


Return of BRCA function through intragenic deletion1
Will PARP exposure impact response to further chemotherapy?
1. Edwards SL, et al. Nature. 2008;451:1111-1115.
PARP Inhibitors—Summary




Active in those with BRCA germ line mutations
Potential activity in those with BRCA dysfunction
Synthetic lethality represents new paradigm in
therapeutic oncology
Combinations of PARP inhibitors and
chemotherapy ongoing
Antifolates
Pemetrexed
O
O
N
H

OH
 Approved in malignant mesothelioma
and nonsquamous NSCLC1
 Enters via reduced folate carrier and
a selective high capacity transporter
 Active against DHFR, TS, GARFT
O
O
OH

N
N
H
GOG 126-Q
 21% RR2
HN
H2N
Antifolate

Combination3
N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7Hpyrrolo[2,3-d]pyrimidin-5yl)ethyl]benzoyl]-L-glutamic acid
Pemetrexed
1. Alimta® PI, Eli Lilly and Company Indianapolis, IN, 2009.
2. Miller DS, et al. J Clin Oncol. 2009;27:2686-2691.
3. Horowitz NS, et al. J Clin Oncol. 2008;26(suppl). Abstr 5523.
Abbreviations: DHFR, dihydrofolate reductase;
GARFT, glycinamide formyltransferase; TS,
thymidylate synthase.
Targeting the Folate Receptor—
Farletuzumab (MORAb-003)



Humanzied MoAb to folate receptor-a (FR-a)
Induces complement-dependent cytotoxicity
(CDC) and antibody-dependent cell-mediated
cytotoxicity (ADCC)
Blocks Lyn kinase-(P)
Farletuzumab (MORAb-003)—Phase II
EOC in first relapse
platinum-sensitive (>6 mo)
Increased CA-125;
Measurable or CA-125
No symptoms of disease
Arm A
Single-agent farletuzumab
Until progression or symptoms
Increased CA-125;
Measurable or CA-125
Needing chemotherapy
Symptoms
Arm B
Front-line CT regimen
Farletuzumab (6 cycles)
Arm C
Maintenance
Farletuzumab
Armstrong DK, et al. Presented at 44th Annual ASCO; May 30-June 3, 2008. Courtesy of Dr. Bradley J. Monk.
Farletuzumab (MORAb-003)—
Phase II
Response: CA-125 criteria

41 evaluable
 37 (90%) normalized CA-125
 34 still on study


12 on study longer than TFI1
– 6 (50%) have TFI2 > TFI1
22 in follow-up
– 15 in remission
– 7 relapsed
Response: RECIST

Independent review (early)





CR: 7%
PR: 63%
SD: 26%
PD: 4%
RR: 70%
Abbreviations: TFI1, first tumor-free interval; TFI2, second tumor-free interval.
Armstrong DK, et al. Presented at 44th Annual ASCO; May 30-June 3, 2008.
Farletuzumab (MORAb-003)—
Phase II
Safety




Infrequent infusion reactions
No additive toxicity with carboplatin/taxane
Grade 3 (single agent): Headache
Grade 3 (combination): Neutropenia, diarrhea
Armstrong DK, et al. Presented at 44th Annul ASCO; May 30-June 3, 2008.
Farletuzumab (MORAb-003)—
Phase III





Histologically or cytologically
confirmed nonmucinous
epithelial ovarian cancer
including primary peritoneal or
fallopian tube malignancies
Measurable disease by CT or
MRI scan
Relapse within ≥6 and <24 mo
after first-line platinum/taxane
chemotherapy
Candidate for repeat
carboplatin/taxane therapy
Neurologic function: Neuropathy
(sensory and motor) ≤CTCAE
Grade 1
R
A
N
D
O
M
I
Z
E
Carboplatin and taxane
with placebo
Carboplatin and taxane
with MORAb-003 1.25 mg/kg
Carboplatin and taxane
with MORAb-003 2.5 mg/kg
Primary end point = PFS
N = 900
Abbreviation: CTCAE, common terminology criteria for adverse events.
US NIH. 2009.
Courtesy of Dr. Bradley J. Monk.
mTOR Inhibitors
The PI3K/Akt/mTOR Pathway
Growth factors
and other mitogens
PI3K
Ras
Akt
Raf
mTOR
MEK
Raptor
Rheb
GTP
Nutrients, ATP
AMPK
Rheb
GDP
Phosphatases
ERK
4E-BP1
Mnk-1
TSC1
TSC2
Rictor
p38
LKB1
PTEN
S6K
pdcd4
eIF4E
S6
eIF4B
Translation, ribosome biogenesis, metabolism, cell growth, angiogenesis, ↓ autophagy
Meric-Bernstam F, Gonzales-Angulo AM. J Clin Oncol. 2009;27:2278-2287.
Courtesy of Dr. Bradley J. Monk.
GOG Future Directions
Randomized Phase II Ovarian Cancer—
GOG 186G mTOR Inhibitor, Everolimus
Regimen I:
Ovarian, fallopian
tube or primary
peritoneal cancer
1-3 priors
Bevacizumab 10 mg/kg IV q2 wks
Plus
Everolimus 10 mg orally daily
Regimen II:
Bevacizumab 10 mg/kg IV q2 wks
Plus
Matched placebo
*Primary endpoint PFS
ClinicalTrials.gov NCT00886691. Courtesy of Dr. Bradley J. Monk.
HER2 Inhibitors
Trastuzumab and Pertuzumab Bind
Distinct Epitopes on HER2


Trastuzumab requires HER2 overexpression for
activity; pertuzumab does not require
overexpression
Pertuzumab specifically binds HER2’s
dimerization domain, which inhibits downstream
signaling
Trastuzumab in Ovarian Cancer



HER2 expression occurs at low levels in advanced,
recurrent ovarian cancer (6.7%–11.7%)1,2
Single-agent trastuzumab resulted in response rate of
only 7.3% in HER2+ patients1
Trastuzumab in combination with paclitaxel and
carboplatin was tested in 321 patients with advanced
ovarian cancer2,3
 Only 22 were HER2+, only 7 met the eligibility criteria of the trial
 3/7 had complete responses lasting 6,7+, and 24+ months
 2/7 had stable disease
1. Bookman MA, et al. J Clin Oncol. 2003;21:283-290; 2. Guastalla JP, et al. J Clin Oncol. 2007;25 (suppl).
Abstr 5559. 3. Ray-Coquard I, et al. Clin Ovarian Cancer. 2008:1:54-59..
Gemcitabine ± Pertuzumab
Study Schema for TOC3258g
Platinum-Resistant Ovarian Cancer, N=130
1:1 randomization

Gemcitabine + Placeboa, n = 65

Disease Progression

Discontinue Study Treatment,
Cross-Over Allowed
aUp
to 17 cycles
Makhija S, et al. J Clin Oncol. 2010;28;1215-1223.

Gemcitabine + Pertuzumaba, n = 65

Disease Progression

Discontinue Study Treatment
HER3 mRNA Biomarker Analysis

mRNA expression analysis of archival formalin-fixed
paraffin-embedded tissue (FFPET) samples that
focused on selected HER receptors and their ligands
(EGFR, HER2, HER3, amphiregulin, and betacellulin)
was performed on 122/130 (94%) of patients’ tumors;
the results were correlated with clinical outcomes

For these 5 markers, only HER3 expression levels
correlated with differential treatment benefit between
gemcitabine + pertuzumab and gemcitabine +
placebo
Makhija S, et al. J Clin Oncol. 2010;28;1215-1223.
Gemcitabine + Pertuzumab
Response Rate
Gem
Gem + Pertuzumab
3/65 (4.6%)
9/65 (13.8%)
2.4%
16.7%
Low HER3 (<median)
0
6
High HER3 (≥median)
3
3
All patients
1 prior platinum-based Tx only
(n = 90)
Makhija S, et al. J Clin Oncol. 2010;28:1215-1223.
Progression-Free Survival (PFS)
by HER3
Median (Mo)
a
Gem
Gem + Pertub
HR
P Value

All patients
2.6
2.9
0.66
.07

Low HER3a
1.4
6.6
0.16
.0002

High HER3b
5.5
2.8
1.68
.0844
<50th percentile
percentile
b >50th
Makhija S, et al. J Clin Oncol. 2010;28:1215-1223.
Overall Survival by HER3
Median (Mo)
a
b
Gem
Gem + Pertub
HR
P Value

All patients
13.1
13.0
0.91
.65

Low HER3a
8.4
12.5
0.61
.1026

High HER3b
18.2
15.1
1.59
.1943
<50th percentile
>50th percentile
Makhija S, et al. J Clin Oncol. 2010;28:1215-1223.
Synopsis



Experimental data demonstrate that HER3-HER2
signaling leads to the downregulation of HER3 mRNA
in model systems
The impetus to study this attenuation mechanism was
driven by the analysis of HER3 mRNA levels in the
TOC3258g trial
This mechanism may explain pertuzumab’s
activity in Pt-resistant ovarian cancer patients whose
tumors express low levels of HER3 mRNA
Key Takeaways

Agents other than antiangiogenesis molecules
active in ovarian cancer
 Understanding tumor biology key
 Rationale clinical design critical

Major challenges remain
 Patient selection
 Strategic combinations
 Faster and cheaper development
Off-Target Effects of
“Targeted” Therapy
Robert L. Coleman, MD
Professor and Director, Clinical Research
Department of Gynecologic Oncology
M. D. Anderson Cancer Center
Houston, Texas
Targeted Agents
Monoclonal Abs
Tyrosine Kinase Inhibitors
Long t1/2
Short t1/2
Targeted
Promiscuous
IV (SQ)
PO (IV)
Few drug-drug interactions
Many drug-drug interactions
Toxicity to On- and Off-Target
Constituents
On-Target AE’s
 Hypertension
 CNS


Proteinuria
GI toxicity
 Thyroid

 Perforation, fistula

Hemorrhage

Cardiac


Off-Target AE’s
 Endocrine
 Low: Mg++, Ca++,
phosphate, sodium
 High: glucose, alkaline
phosphatase, bilirubin,
transaminases
 Pulmonary
 Bleeding
 Congestive heart failure,
conduction abnormalities
Thyroid
VTE
 Arterial and venous
Abbreviation: VTE, venous thromboembolism.
Electrolyte

Dermatologic
 Rash
 Wound disruption
Anti-Vascular Endothelial Growth Factor
(VEGF)-Induced Hypertension

Sorafenib: all grade hypertension ranges 16.2%–42.6%
(mean: 23.4%)1

Sunitinib malate: all grade hypertension incidence 30%2

Bevacizumab: the need for antihypertensive drug therapy
occurs in 10%–20% of patients (10 mg/kg) 3-5
 Dose-effect: 3%–32% in low (3-7.5 mg/kg) vs 18-36% in high
dose (10-15 mg/kg)6
1. Wu S, et al. Lancet Oncology. 2008;9:117-123.
2. Sunitinib PI. Pfizer, New York, NY, 2008.
3. Hurwitz H, et al. N Engl J Med. 2004; 350:2335-2342.
4. Ranpura V, et al. Am J Hypertens.2010; epub ahead of print.
5. Chowdhury S, et al. Targeted Oncology. 2006;1:104-108.
6. Gressett S, et al. Ann Pharmacother. 2009;43:490-501.
Possible Mechanisms



The mechanism of action by which VEGF
inhibitors cause hypertension is uncertain
VEGF is a stimulator of nitric oxide, and the
inhibition of VEGF may cause increased
systemic vascular resistance1
It has been suggested that hypertension is a
biomarker for activity
1. Hood JD, et al. Am J Physiol Heart Circ Physiol. 1998;274:1054-1058.
Anti-VEGF-Induced Hypertension


The characteristics of hypertension caused by
sorafenib was investigated in patients who
sustained a systolic blood pressure elevation of
≥20 mm Hg 3 weeks after therapy initiation
Pulse wave velocities and aortic augmentation
indices were increased, indicating increased
vascular stiffness
Veronese ML, et al. J Clin Oncol. 2006;24:1363-1369.
Essential Hypertension
(BP >140/90)




Thiazide-(like) diuretics
Angiotensin converting enzyme inhibitors/
angiotensin receptor blockers
Calcium channel blockers
Beta blockers
Essential Hypertension



Each of these categories is roughly equally
effective (works in 30–50% of cases)
Start with single agent if blood pressure <20/10
above goal
African Americans/elderly do better with diuretic/
calcium channel blocker
Essential Hypertension


Thiazide-like diuretics: hypokalemia, glucose
intolerance, hyperuricemia, lower urinary calcium
excretion
Dihydropyridine calcium channel blockers: pedal
edema
 10% of patients on amlodipine at 10 mg develop edema1

Angiotensin converting enzyme inhibitors: cough,
increased potassium levels, hyperkalemia, renal
insufficiency, angioedema (↑in African-American
women2)
 18% of patients discontinued for toxicity,3 including 3%–11%
for cough2

Beta blockers: may be associated with a small
absolute increase in stroke risk
1. Amlodipine PI. Pfizer, New York, NY. January 2010. 2. Elliott WJ. Clin Pharmacol Therapeutics. 1996;60:582588. 3. Lau E. COMPETE III team. Proc CAPT, May 27-30, 2007.
Essential Hypertension

If first agent does not succeed, options include
 Increasing dose to maximum
 Switching agents
 Adding a 2nd agent

Most patients with blood pressure more than
20/10 above goal will require 2 agents
Essential Hypertension

Useful combinations
 ACE inhibitors with diuretic or CCB (decreases pedal
edema)

Less useful
 CCB with diuretic
Abbreviations: ACE, angiotensin converting enzyme; CCB, calcium channel blockers.
Antihypertensive Therapy

Non-dihydropyridine CCBs interact (inhibit)
with CYP3A41, which metabolizes sorafenib2
and sunitinib3
 Therefore verapamil and diltiazem (inhibitors)
should be used cautiously1,4

1.
2.
3.
4.
Most dihydropyridine CCBs (eg, amlodipine,
nifedipine) are CYP2A4 substrates, but not
inhibitors
Lim GE, et al. Exp Clin Cardiol. 2003;8:99-107.
Sorafenib PI. Bayer Healthcare Pharmaceuticals; Wayne, NJ. 2009.
Sunitinib PI. Pfizer, Inc.; New York, NY. 2008.
Bailey DG, et al. Br J Clin Pharmacol. 1998;46:101-110.
Reversible Posterior
Leukoencephalopathy Syndrome
Courtesy of Dr. Carolyn Muller, University of New Mexico.
Reversible Posterior Leukoencephalopathy
Syndrome




Presents with headache, seizure, lethargy,
confusion, blindness
Mild to severe hypertension may be present, but
is not necessary for diagnosis
Diagnosis is confirmed with MRI; white matter
abnormalities suggestive of edema as seen in
posterior parieto-occipital regions
Most patients recover
Bevacizumab—Clotting


Arterial thrombotic events including
myocardial infarction, cerebral vascular
accident, arterial thromboembolic event
8.5% of patients age >65 years and 2.1% of
patients age <65 years experienced arterial
thromboembolic event1
1. Bevacizumab PI. Genentech, Inc., South San Francisco, CA. 2009.
Bevacizumab—Bleeding




Delays wound healing
T1/2 ~20 days1
Minor nose bleeds common
≥5% of lung cancer patients have developed
serious/fatal hemoptysis;2,3 limited data in
ovarian patients
1. Bevacizumab PI. Genentech; South San Francisco, CA. 2009. 2. Johnson DH, et al. J Clin Oncol. 2004;
22:2184-2191. 3. Sandler A, et al . N Engl J Med. 2006;355:2542-2550.
Fistula
Management strategies
• Stop agent
• Conservative: Isolation (ostomy bag), NPO, TPN, octreotide (if high output)
• Refractory or nonhealing: Surgery (wait 2–4 half-lives for washout)
Abbreviations: NPO, nothing by mouth; TNP, total parenteral nutrition.
Courtesy of Dr. Robert L. Coleman.
Proteinuria



Incidence of proteinuria in the bevacizumab
trials for colorectal cancer has been reported as
23%–38%, compared with an incidence of
11%–22% in control groups treated with
chemotherapy alone1
Incidence in ovarian cancer unknown but likely
to be similar to that in colorectal cancer
Development of proteinuria is associated with
hypertension
1. Gordon MS, Cunningham D. Oncology. 2005;69(suppl 3):25-33.
Courtesy of Dr. Robert L. Coleman.
Cutaneous Toxicities of
EGFR/VEGFR Inhibitors


Produced by EGFR TKIs (eg,
erlotinib) and MoAbs (eg,
cetuximab) and VEGFR TKIs (eg,
sorafenib, sunitinib, cediranib, etc)
Include




Acneiform rash (face, upper back)
Dry itchy skin, dry mucosa
Trichomegaly (long curly eyelashes)
Paronychia
Abbreviations: EGFR, epidermal growth factor receptor ; MoAbs, monoclonal antibodies; TKIs, tyrosine kinase
inhibitors; VEGFR, vascular endothelial growth factor receptor.
Courtesy of Dr. Robert L. Coleman.
Cutaneous Toxicities of
EGFR Inhibitors

Treatment of rash
 Topical agents (eg, clindamycin 1% gel)
 Systemic antibiotics (eg, tetracycline or minocycline)

Treatment of paronychia




Difficult
Wide shoes, good nail hygiene
Local antibiotics (preventive)
Systemic antibiotics (if impetiginization occurs)
Sorafenib Rash



Less common than and different in appearance
from EGFR rashes
May disappear spontaneously after several
weeks of treatment
Should be differentiated from classic
erythrodermic allergic reactions (which may also
occur with sorafenib and sunitinib)
Sorafenib Rash
Slide courtesy of Beth Manchen, University of Chicago.
Treatment of Anti-VEGFR TKI HandFoot Syndrome




Drug holiday or dose reduction
Cotton socks, soft padded shoes
Moisturizers
Urea and/or salicylate-containing creams for
calloused areas (under socks and gloves
overnight)
Sunitinib—Hypothyroidism




3%–4% of patients on placebo-controlled GIST
trial developed hypothyroidism1
In 1 study, 85% of patients treated with sunitinib
developed at least 1 laboratory abnormality c/w
hypothyroidism2
Less common with sorafenib
Unclear how much this contributes to fatigue
1. Sunitinib PI. Pfizer Labs. New York, NY 2010. 2. Rini BI. J Natl Cancer Inst. 2007;99:81-83.
Laboratory Abnormalities



13% of patients on sorafenib developed grade 3
hypophosphatemia1
Sunitinib may cause hyperbilirubinemia2
Cetuximab/panitumumab can cause severe
hypomagnesemia3,4
1. Sorafenib PI. Bayer Healthcare Pharmaceuticals Inc; Wayne, NJ. 2009.
2. Sunitinib PI. Pfizer, Inc; New York, NY 2008.
3. Cetuximab PI. ImClone Systems & Bristol-Myers Squibb; Branchburg, NJ. 2010.
4. Panitumumab PI. Amgen; Thousand Oaks, CA. 2009.
QT Prolongation


Most common cause of delays in drug
development, nonapprovals, postmarketing
withdrawals by FDA
Risk of malignant cardiac arrhythmia with
torsades de pointes and sudden cardiac death
QT Prolongation



Ion channel malfunction
results in excess positive
intracellular change
This extends ventricular
repolarization and results
in a prolonged QT interval
Upper limit of normal for
QTc is 450 ms in men,
460 ms in women
QT Prolongation—Targeted
Oncology Agents




Depsipeptide (HDAC inhibitor)
Sunitinib (uncertain significance)
Dasatinib (Src/bcr-abl/kit kinase inhibitor)
Vandetanib (VEGFR/EGFR inhibitor)
Torsades de Pointes
http://www.aic.cuhk.edu.hk/web8/Hi%20res/torsades1.jpg
Torsade de Pointes


Lists of medications implicated in QT
prolongation are maintained on internet by
University of Arizona
(www.torsades.org)
CYP3A4 inhibitors may prolong t1/2 of QT
prolonging drugs
Grapefruit Juice



Potent intestinal CYP3A4,1,2,3 CYP1A2 and CYP2A6
inhibitor
Small bowel enterocyte CYP3A4 protein levels
decrease 62% after 5 days of grapefruit juice2
Seville oranges have similar effect2,3
 Furanocoumarins may be responsible)

Absorption of drugs is therefore increased
 Cmax of drugs, such as rapamycin, is increased 150%–250%4
1.Yoshida M, et al. Pharmacoepidemiol Drug Safety. 2008;17:70-75. 2. Bailey DH, et al. Br. J Clin Pharmacol.
1998;46:101-110. 3. Lim GE, et al. Exp Clin Cardiol. 2003;8:99-104. 4. Cohen E, et al. Paper presented at: 100th
Annual AACR; April 18-22, 2009.
Adverse Events Associated with Emerging
Agents in Ovarian Cancer

PARP-1 inhibitor
 Olaparib 400 mg BID (N = 60)1


Grades 3 and 4 in >10% of patients: lymphopenia; nausea/vomiting;
dizziness
Folate inhibitors
 Pemetrexed 900 mg/m2 q21d (N = 51)2

Grades 3 and 4: neutropenia (42%); leukopenia (25%), anemia (15%);
constitutional (15%)
 Farletuzumab 100 mg/m2 weekly (N = 28)3



Grade 3 headache as part of infusion
DLT: Not reached at 400 mg/m2 the highest dose tested
mTOR inhibitor
 Everolimus (in endometrial cancer)4

Grades 3 and 4 in >10%: fatigue; nausea; anemia; lymphopenia;
electrolyte abnormalities
1. Fong PC, et al. N Engl J Med. 2009;361:123-134. 2. Miller DS, et al. J Clin Oncol. 2009;27:2686-2691. 3.
Armstrong DK, et al. Presented at: 44th Annual ASCO; May 30-June 3, 2008. 4. Slomovitz BM, et al. Presented
at 44th Annual ASCO; May 30-June 3, 2008.
Conclusions





Targeted therapies are not nontoxic
Many toxicities are dose-dependent
Not all toxicities are known
Particularly as antiangiogenic drugs are used in
earlier stage disease, careful blood pressure
monitoring is essential
With oral agents, drug-drug interactions are
common