today’s challenges and controversies in recurrent ovarian cancer management bradley j. monk, md,...
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Today’s Challenges and Controversies in Recurrent Ovarian Cancer
Management
Bradley J. Monk, MD, FACS, FACOGDivision of Gynecologic Oncology
Department of Obstetrics and GynecologyChao Family Comprehensive Cancer CenterUniversity 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 CarcinomaIncidence 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 TreatmentAdvanced Disease
Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.
Parameter Small Volume Large Volume
Response, % 95 75
Clinical CR, % 95 50
Pathologic CR, % 50 25
PFS, mo 25 18
Survival, mo 50 36
10-y survival, % 30–40 15–20
Results of TreatmentAdvanced 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.
SEER Data 1973-1997 N=32,845
0.000.050.100.150.200.250.300.350.400.450.500.550.600.650.700.75
2-Year Survival 5-Year Survival
Proportion Surviving
1973-19791980-19891990-1997
Ovarian Cancer Increasing Survival Rates
Barnholtz-Sloan JS, et al. Am J Obstet Gynecol. 2003;189(4):1120-1127.
Approved Drugs inOvarian Cancer
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)
1978
2009
First-line TherapyGlobal Standard Treatment
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.
Surgery with maximum cytoreduction effort
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.
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.
Basis for Current StandardSystemic 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
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 AntivascularAgents in the Management of
Recurrent Ovarian CancerRobert A. Burger, MD
Professor, Surgical OncologySection of Gynecologic OncologyDirector, Women’s Cancer Center
Fox Chase Cancer CenterPhiladelphia, Pennsylvania
Angiogenesis in Tumor Progression
With permission from The Angiogenesis Foundation, Inc; www.angio.org.
Hanahan & Folkman. Cell. 1996;86:353–364.
ProangiogenicVEGFFGFPGFTGFs
AngiogeninInterleukin-8
HGFGCSGFPDEGF
Angiopoietin 1
AntiangiogenicThrombospondin-1
AngiostatinInterferon-alpha
Prolactin 16-kd fragmentMetalloproteinase inhibitors
PF-4Genistein
Placental proliferin-related protein
TGF-β Endostatin
Angiogenic Balance
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
Human tumors VEGF expression and degree of tumor angiogenesis
(microvessel density) associated with Ascites formation Malignant progression1-3
Poor prognosis4-7
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.
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. 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.
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
Classes of Anti-VEGF Agents
Target Ligand (VEGF) VEGFR
Pharmacology Large molecules (monoclonal antibodies, soluble
receptors) Small molecule inhibitors (“ibs”)
Target Class Agents
Ligand
VEGF-A Mab Bevacizumab1
VEGF Soluble decoy receptor VEGF Trap2,3
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
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.
Abbreviations: FGF, fibroblast growth factor; Mab, monoclonal antibody; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
Classes of Anti-VEGF Agents
Unique Toxicities ofAnti-VEGF Agents
Proteinuria Hypertension Mucosal hemorrhage Wound healing Arterial thromboembolism Reversible posterior leukoencephalopathy
syndrome (RPLS) GI perforation or fistula
Single-Agent Activity
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
Previous regimens (1/2/3/4), % 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)
6 mo PFS (%) 40 28 4
*Trial terminated prematurely. †Trial failed to meet primary endpoint.
‡Preliminary analysis.
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.
Single-Agent Anti-VEGF Therapy in EOC/PPC—Phase II Efficacy Results
Abbreviations: EOC, epithelial ovarian cancer; PPC, primary peritoneal cancer.
GOG 170-DExploratory 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.
Trial 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 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.
Single-Agent Anti-VEGF Therapy in EOC/PPC Toxicities—Phase II Trials
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;350:2335-2243. 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.
Rationale for Combination Anti-VEGF 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
Garcia AA, et al. J Clin Oncol. 2008;26:76-82.
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%)
Efficacy PFS-6 mo: 56% Response rate: 24% (17 PR)
ClinicalTrials.gov. NCT00565851 PI: Coleman, Activated 12/07
Surgical candidate?
Recurrent ovarian and peritoneal primary cancerTFI > 6 mo
Carboplatin,paclitaxel
Maintenancebevacizumab
Carboplatin,paclitaxel,
bevacizumab
No
Randomize
Surgery No surgery
To chemotherapyrandomization
Randomize
Yes
Primary endpoint: Overall survivalSecondary endpoints: Progression-free survival, toxicity, quality of life, translational research
GOG 213
Abbreviation: TFI, treatment-free intervalSlide courtesy of Dr. Robert A. Burger.
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
Bevacizumab + Carboplatin + Gemcitabine
Placebo + Carboplatin + Gemcitabine (Planned N = 450)
ClinicalTrials.gov. NCT00434642
OCEANS—Carboplatin/Gemcitabine ± Bevacizumab in Ovarian Carcinoma
(Phase III)
Patients with platinum-sensitive recurrent
epithelial ovarian, peritoneal, or fallopian tube carcinoma
Slide courtesy of Dr. Robert A. Burger.
Trial GOG 2181 ICON-72
Sample size 1800 1520
Arms 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
Status Closed 7/09 Activated 4/06
1. ClincialTrials.gov. NCT00262847.2. ClincialTrials.gov. NCT00483782.
Phase III Frontline OvarianCancer Trials
Abbreviations: PFS,progression-free survival; PH-EC, pharmacoeconomics; QOL, quality of life; RR, response rate; TOX, toxicity; TR, translational research.
Months
Cycles
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Phase A Phase B
Arm 1
Arm 2
Arm 3
CT1 CT + plac 2-6
CT1 CT + bev 2-6
CT1 CT + bev 2-6
Plac 7-22
Plac 7-22
Bev 7-22
ClincialTrials.gov. NCT00262847.
GOG 0218—Frontline CT ± Bev in Recurrent Ovarian Cancer
(Phase III)
Slide courtesy of Dr. Robert A. Burger.
Multi-Growth Factor Targeting
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 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
FGF
HGF expression(VSMC)
VEGF expression(myocytes, stromal cells, EC)
EC activation Mural cell recruitment
Angiogenesis
PDGFR expression(EC, VSMC)
Slide courtesy of of Dr Robert A. Burger. Murakami and Simons. Curr Opin Hematol. 2008;15:215–220.
The Role of FGF in Angiogenesis
Abbreviations: EC, endothelial cell; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; PDGFR, platelet-derived growth factor receptor; VSMC, vascular smooth muscle cell.
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
Trial Agent PI N RR6-Mo PFS Other
GOG 170-F Sorafenib Matei1 59 3.4% 24%
GOG 170-L Motesanib Schilder 23*
VEG104450 Pazopanib Friedlander2 36 CA125 RR 31%
PMH-PHL Cediranib Hirte3 62 4.8% ?
DFCI-05170 Cediranib Matulonis4 46 17% ~ 38%
EUDRACT BIBF- 1120 Ledermann5 83** PFS HR .68
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.
* Closed due to toxicity** Secondary Consolidation, Placebo-Controlled
Phase II Efficacy—Multi-Targeted TKI
Planned: phase II (N = 300), phase III (N = 2,000).
Patients with platinum-sensitive ovarian cancer
Relapsed >6 mo following first-line platinum-based
treatment
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+ placebo
Platinum-based chemo (± taxane)q 21 days x 6 cycles
+ oral cediranib during chemoand until progression or 18 mo
2:3:3 Randomization
ICON 6 (Second-Line European Trial)
Measurable disease
Slide courtesy of Dr. Robert A. Burger.
Theoretical Pros and Cons ofMulti-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;2:79-101. 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 OtherNonvascular Targeted
Therapies in the Managementof Recurrent Ovarian Cancer
Bradley J. Monk, MD, FACS, FACOGDivision of Gynecologic Oncology
Department of Obstetrics and GynecologyChao Family Comprehensive Cancer CenterUniversity 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
DNA repair defects lead to increased cancer susceptibility and increased sensitivity to DNA-damaging agents
Novel targeted therapeutic approach
Normal cells have multiple DNA repairpathways but some are lost in cancer cells
DNA damage frequently occurs in all cells
Inhibiting DNA repair in cancer cells that have impaired repair pathways leads to selective cell killing and an increased therapeutic ratio
Why is DNA repair a good
target?
Targeting DNA Repair in Oncology—Rationale
Kennedy RD, D’Andrea AD. J Clin Oncol. 2006;24:3799-3808. Courtesy of Dr. Bradley J. Monk.
Base excision
repair
Type of damage
Bulky adducts
Insertionsand deletions
O6-alkylguanine
Repairpathway
Nucleotide-excision
repair
Mismatch repair
Directreversal
Repairenzymes
Double-strandbreaks
Single-strand breaks
PARP
Recombinationalrepair
ATM DNA-PK
HR NHEJ
XP, poly-merases
MSH2,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
Types of DNA Damage and Repair
Survival
Normal cell
Repair by HR pathway
Exploits inherent weakness of cancer cells that have defective DNA repair
Double-stranded break
BRCA deficient ordeficiency of other
HR proteins
No repair(no HR pathway)
Cell death
Cancer cell with defective repair
Targeted Killing of Cancer Cells with Defective DNA-Repair Mechanisms
Martin SA, et al. Curr Opin Genet Develop.2008;18:80-86. Courtesy of Dr. Bradley J. Monk.
Abbreviation: HR, homologous recombination.
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.
Yap TA, et al. J Clin Oncol. 2007;25(suppl). Abstr 3529.Fong PC, et al. J Clin Oncol. 2008;26(suppl). Abstr 5510.
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
Phase I—Olaparib (AZD 2281) Updated Expanded BRCA Cohort
Characteristic Number
Mutation– BRCA1– BRCA2– Family history
1511
Age mean (range) 54.8 years (19–82)
PS (0–1) 55
Time from Dx to Rx 4.7 years (0.5–16)
Platinum status– Sensitive– Resistant– Refractory
10 (20%)27 (54%)13 (26%)
Number of priors (range) 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
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.
Abbreviations: GCIG, Gynecologic Intergroup ;RECIST, Response Evaluation Criteria in Solid Tumors.
Total Platinum Sensitive
Platinum Resistant
Platinum Refractory
No. of evaluable patients 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)
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
Audeh MW, et al. Presented at 45th Annual ASCO; May 29-June 2, 2009.
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%)
Response by RECIST and/or GCIG 20 (61%) 4 (17%)
Median DOR (range) 290 days (126–513) 269 days (169–288)
Median PFS 5.8 months 1.9 months
Grade 3/4 AEs (n = 33) (n = 24)
Nausea
Vomiting
2 (6%)
2 (6%)
3 (13%)
2 (8%)
Discontinuation due to AEs 4 (12%) 1 (4%)
Dose interruption due to AEs 12 (36%) 4 (17%)
All Patients—Who Will Benefit From PARP Treatment?
GermlineSomaticHypermethylatedAlt PathsNl BRCA Fnct
Sporadic tumors with intact BRCA
function
Prevention?Courtesy of Dr. Robert Coleman.Coleman RL. Curr Oncol Rep. 2009;11:414-416.
Abbreviation: Nl, Normal lymphocytes.
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
Primary end point = PFSN = 250Recruitment complete (results expected late 2010)
Placebountil disease progression
Olaparib PO 400 mg BIDuntil disease progression
RANDOMIZE
ClinicalTrials.gov Identifier: NCT00753545. Courtesy of Bradley J. Monk.
Key Issue for FutureDevelopments 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
Antifolate Approved in malignant mesothelioma
and nonsquamous NSCLC1
Enters via reduced folate carrier and a selective high capacity transporter
Active against DHFR, TS, GARFT GOG 126-Q
21% RR2 Combination3
N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-
yl)ethyl]benzoyl]-L-glutamic acid
Pemetrexed
NH
N N
O
NH2
N
OHO
OH
O
O
H
H
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 relapseplatinum-sensitive (>6 mo)
Increased CA-125; Measurable or CA-125No symptoms of disease
Increased CA-125; Measurable or CA-125Needing chemotherapySymptoms
Arm ASingle-agent farletuzumab
Until progression or symptoms
Arm BFront-line CT regimen
Farletuzumab (6 cycles)
Arm CMaintenance 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
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
Independent review (early) CR: 7% PR: 63% SD: 26% PD: 4%
RR: 70%
Response: CA-125 criteriaResponse: RECIST
Armstrong DK, et al. Presented at 44th Annual ASCO; May 30-June 3, 2008.
Abbreviations: TFI1, first tumor-free interval; TFI2, second tumor-free interval.
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
Primary end point = PFSN = 900
Carboplatin and taxanewith MORAb-003 1.25 mg/kg
Carboplatin and taxanewith MORAb-003 2.5 mg/kg
Carboplatin and taxanewith placebo R
ANDOMIZE
Abbreviation: CTCAE, common terminology criteria for adverse events.US NIH. 2009.Courtesy of Dr. Bradley J. Monk.
mTOR Inhibitors
4E-BP1
eIF4E
PI3K
S6K
S6
Translation, ribosome biogenesis, metabolism, cell growth, angiogenesis, ↓ autophagy
Raptor
Growth factorsand other mitogens
Akt
mTOR
Ras
Raf
MEK
ERK
Mnk-1
p38
Nutrients, ATPPTENLKB1
AMPK
Phosphatases
eIF4B
Rheb RhebGTP GDP
TSC1
TSC2Rictor
pdcd4
The PI3K/Akt/mTOR Pathway
Meric-Bernstam F, Gonzales-Angulo AM. J Clin Oncol. 2009;27:2278-2287. Courtesy of Dr. Bradley J. Monk.
GOG Future DirectionsRandomized Phase II Ovarian Cancer—GOG 186G mTOR Inhibitor, Everolimus
Ovarian, fallopian tube or primary peritoneal cancer1-3 priors
Regimen I:Bevacizumab 10 mg/kg IV q2 wksPlusEverolimus 10 mg orally daily
Regimen II:Bevacizumab 10 mg/kg IV q2 wksPlusMatched 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..
1:1 randomization
Gemcitabine + Placeboa, n = 65 Gemcitabine + Pertuzumaba, n = 65
Disease Progression Disease Progression
Discontinue Study Treatment, Discontinue Study Treatment
Cross-Over Allowed
aUp to 17 cycles
Makhija S, et al. J Clin Oncol. 2010;28;1215-1223.
Gemcitabine ± PertuzumabStudy Schema for TOC3258g
Platinum-Resistant Ovarian Cancer, N=130
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 + PertuzumabResponse Rate
Makhija S, et al. J Clin Oncol. 2010;28:1215-1223.
Gem Gem + Pertuzumab
All patients 3/65 (4.6%) 9/65 (13.8%)
1 prior platinum-based Tx only(n = 90)
2.4% 16.7%
Low HER3 (<median) 0 6
High HER3 (≥median) 3 3
Progression-Free Survival (PFS) by HER3
a <50th percentileb >50th percentile
Makhija S, et al. J Clin Oncol. 2010;28:1215-1223.
Median (Mo)
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
Overall Survival by HER3
a <50th percentileb >50th percentile
Makhija S, et al. J Clin Oncol. 2010;28:1215-1223.
Median (Mo)
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
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
Perforation, fistula Hemorrhage
Pulmonary Bleeding
Cardiac Congestive heart failure,
conduction abnormalities Thyroid VTE
Arterial and venous
Off-Target AE’s Endocrine
Thyroid Electrolyte
Low: Mg++, Ca++, phosphate, sodium
High: glucose, alkaline phosphatase, bilirubin, transaminases
Dermatologic Rash Wound disruption
Abbreviation: VTE, venous thromboembolism.
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.
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. Hood JD, et al. Am J Physiol Heart Circ Physiol. 1998;274:1054-1058.
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
Veronese ML, et al. J Clin Oncol. 2006;24:1363-1369.
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
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;60:582-588. 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
Most dihydropyridine CCBs (eg, amlodipine, nifedipine) are CYP2A4 substrates, but not inhibitors
1. Lim GE, et al. Exp Clin Cardiol. 2003;8:99-107.2. Sorafenib PI. Bayer Healthcare Pharmaceuticals; Wayne, NJ. 2009.3. Sunitinib PI. Pfizer, Inc.; New York, NY. 2008.4. Bailey DG, et al. Br J Clin Pharmacol. 1998;46:101-110.
Courtesy of Dr. Carolyn Muller, University of New Mexico.
Reversible Posterior Leukoencephalopathy Syndrome
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)
Courtesy of Dr. Robert L. Coleman.
Abbreviations: NPO, nothing by mouth; TNP, total parenteral nutrition.
1. Gordon MS, Cunningham D. Oncology. 2005;69(suppl 3):25-33.
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
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 ofEGFR 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 Hand-Foot 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.
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.
Laboratory Abnormalities
13% of patients on sorafenib developed grade 3 hypophosphatemia1
Sunitinib may cause hyperbilirubinemia2
Cetuximab/panitumumab can cause severe hypomagnesemia3,4
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)
http://www.aic.cuhk.edu.hk/web8/Hi%20res/torsades1.jpg
Torsades de Pointes
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