New chemotherapyto overcomeplatinumresistance · 2016-05-30 · Angiogenesis as a Target in Ovarian Cancer: Anti-VEGF-VEGFR Pathway •Anti-vascular endothelial growth factor (VEGF)

New chemotherapy to overcome platinum resistance

Laura Cortesi Laura Cortesi

Dipartimento di Oncologia ed Ematologia

Azienda Ospedaliera Policlinico Modena

Selection of chemotherapy:defining platinum-resistant

1 Blackledge et al, Br J Canc, 19892 Gore et al., Gynec Oncol, 19903 Marckman et al., JCO 1991

Refractory

PRI

MAR

0 3 6 12 18 24

Months

Ovarian Cancer at First RelapseDefinition of Sensitivity

RY

TREATMENT

Resistant

Partial Sensitive

“Very Sensitive”

Defined as measurable recurrence, not biochemical (CA-125) recurrence

Treatment choices in platinum-resistantrelapse

Treatment choices in platinum-resistantrelapse

Enrollment

• Recurrent epithelialovarian cancer

• 474 patients

RAN

Recurrent Epithelial Ovarian Carcinoma: A Randomized Phase III study of Peglyated Liposomal Doxorubicin versus Topotecan

Gordon AN, et al. J Clin Oncol. 2001

• 474 patients

• 104 US and internationalsites

Endpoints

• Primary

– Time to progression

• Secondary

– Overall survival

– Response rate

– Toxicity

Topotecan 1.5 mg/m2/day for5 consecutive days, q 21 d

Liposomal doxorubicin

50 mg/m2 q 28 d

NDOMIZATION

ECCO 2003: 5-yr follow up

Liposomal doxorubicin > Topotecan

35%

24%

ALL CASES

Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin inProgressive or Recurrent Ovarian Cancer

Gabriella Ferrandina et al. JCO 2008;26:890-896

©2008 by American Society of Clinical Oncology

Flow-chart treatment in Platinum-Resistant Ovarian Cancer

New Targeted Therapies

• Bevacizumab

• Cediranib

• Nintedanib• Nintedanib

• Pazopanib

• Tivozanib

• Sorafenib

• Sunitinib

Targeting Angiogenesisby targeting VEGFR and PDGFR

↑ VEGF ↑ PDGF

VEGFR PDGFRVEGFVEGF PDGFPDGF

Bevacizumab

Inhibition of progression

Vascularpermeability

Cell survival, proliferation

Vascularformation, maturation

Vascular Endothelial CellPericyte/Fibroblast/

Vascular Smooth Muscle

Pazopanib

Sorafenib

Sunitinib

Axitinib

New Cancer Targets

• Cancer Cell Resistance to treatment – Platinum sensitive versus Platinum Resistance

• Cellular immunity pathways• Checkpoint Inhibitors

• Stromal Interaction with cancer Stromal Interaction with cancer

• Enhance Anti-Cancer Immune Systems

• Vaccines –– FANG individualized vaccine against the original ovarian

cancer cells.

• Monoclonal Antibodies

• Testing drugs that have been approved for other types of cancer (melanoma, breast)

Ovarian Cancer:Why the Anti-Angiogenesis ?

• Tumor angiogenesis is associated with malignantbehavior in ovarian cancer 1,2

• BEV as single-agent showed promising activity inrecurrent ovarian cancer in phase II studies3,4

• BEV combined with chemotherapy showed• BEV combined with chemotherapy showedpositive results in phase III randomized clinicaltrials in both platinum sensitive (OCEANS)5 aswell as platinum resistant ovarian cancer(AURELIA)6

1 Hollingsworth et al. Am J Pathol 1995;147:33–412 Burger et al. J Clin Oncol 2007;25:2902–83 Burger et al. J Clin Oncol 2007;25:5165–714 Cannistra et al. J Clin Oncol 2007;25:5180–65 C Aghajanian, et al. ASCO 20116 Pujade-Lauraine et al. ASCO 2012

Angiogenesis as a Target in Ovarian Cancer: Anti-VEGF-VEGFR Pathway

• Anti-vascular endothelial growth factor (VEGF) therapyimproves progression-free survival (PFS)

• GOG 218* Front-line: BevacizumabHR = 0.72; 95% CI, 0.63–0.821

• ICON 7* Front-line: BevacizumabHR = 0.81; 95% CI, 0.70–0.942

• AGO-OVAR12 Front-line: NintedanibHR = 0.84; 95% CI, 0.72, 0.983HR = 0.84; 95% CI, 0.72, 0.983

• AGO-OVAR16 Maintenance: PazopanibHR = 0.77; 95% CI, 0.64–0.914

• AURELIA** Platinum-resistant, recurrent / 1 or 2 prior regimens: BevacizumabHR = 0.48; 95% CI, 0.38–0.605

• OCEANS* Platinum-sensitive, recurrent / 1 prior regimen: Bevacizumab HR = 0.48; 95% CI, 0.41–0.706

• ICON6 Platinum-sensitive, recurrent / 1 prior regimen: CediranibHR = 0.57; 95% CI, 0.44–0.747

HR = hazard ratio; 95% CI = confidence interval

1. Burger RA et al. N Engl J Med. 2011;365:2473‒2483.2. Perren TJ et al . N Engl J Med. 2011;365:2484‒2496.3. du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503.4. du Bois A et al. LBA ESGO 2013 Liverpool, UK5. Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002.6. Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045.7. Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA

*EMA Approved

*FDA Approved

AURELIA trial design

Platinum-resistant OCa

• ≤2 prior anticancer regimens

• No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of

Treat to PD/toxicity


Investigator’s choice

Optional BEV monotherapyc

BEV 15 mg/kg q3wb

+ chemotherapy

Chemotherapy

R

1:1

Stratification factors:

• Chemotherapy selected

• Prior anti-angiogenic therapy

• Treatment-free interval (<3 vs 3‒6 months from previous platinum to subsequent PD)

radiological evidence of rectosigmoid involvement

PD/toxicitychoice

(without BEV)+ chemotherapy

Chemotherapy options (investigator’s choice):

• Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w

• Topotecan 4 mg/m2 days 1, 8, & 15 q4w (or 1.25 mg/m2, days 1–5 q3w)

• PLD 40 mg/m2 day 1 q4w

Pujade-Lauraine et al ASCO 2012

AURELIA PHASE III STUDY:PFS

Eric Pujade-Lauraine et al. JCO 2014;32:1302-1308


AURELIA PHASE III STUDY:OS

Eric Pujade-Lauraine et al. JCO 2014;32:1302-1308


Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of advanced (FIGO stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer

Bevacizumab is administered in addition to carboplatin Bevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Bevacizumab as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier

The recommended dose of Bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion

Cediranib

• Angiogenesis Inhibitor

– a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases

• Oral• Oral

• Similar Side Effects of Olaparib

– Fatigue, Nausea, diarrhea, hypertension

Cediranib, an Oral Inhibitor of Vascular Endothelial Growth Factor Receptor Kinases,Is an Active Drug in Recurrent Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer

Ursula A. Matulonis et al. JCO 2009;27:5601-5606

Cediranib, an Oral Inhibitor of Vascular Endothelial Growth Factor Receptor Kinases,Is an Active Drug in Recurrent Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer

Ursula A. Matulonis et al. JCO 2009;27:5601-5606


Combination of Olaparib and Cediranib

Based on Phase II Study

• Combined treatment vs monotherapy

– Tumors shrank more dramatically

– Greater delayed progression (compared to standard chemotherapy)chemotherapy)

– More complete remission with combination • (5 women in combination group and 2 women in monotherapy group)

Cediranib: Tirosin Kinase Inhbitor of VEGFR1,2,3

ICON 6Cediranib with Platinum-based Chemotherapy in platinum-

sensitive relapsed ovarian cancer

Arm A

Relapse > 6 months after completion of first line

platinum-based chemotherapy

Randomise2 : 3 : 3

N=456 pts

6 Cycles platinum-basedChemotherapy Carboplatin/paclitaxel Carboplatin/Gemcitabine Single agent platinum

Maintenance phase

Treatment continued to 18 months or until progression (>18 for patients continuing to benefit

Continueplacebo

Switch toplacebo

Maintenance cediranib

Chemotherapy + cediranibChemotherapy + placebo

Arm A(Chemo only)

Arm B (Concurrent) Arm C (Maintenance)

Chemotherapy + cediranib

Ledermann et al ECCO2013

Combination Treatment better than Olaparib Alone by 7 months

Combination Treatment increased progression free survival 3 months in women with BRCA mutation

10 months in women without BRCA mutation

Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian Cancer

Jonathan A. Ledermann et al. JCO 2011;29:3798-3804


Weekly Paclitaxel vs weekly Paclitaxeland Pazopanib in patients with

resistant/refractory ovarian cancer: resistant/refractory ovarian cancer:

Phase II randomized multicenter trial

MITO - 11

Trial design

• Aim of the trial is to compare the PFS of weekly paclitaxel vs weekly paclitaxel and pazopanib

RANDOM

Pazopanib 800 mg/dayPaclitaxel 80 mg/mq

day 1,8 15 - every 28days

Paclitaxel 80 mg/mq

day 1, 8, 15 - every 28 days

Results

Pignata S., Lancet Oncol 2015

Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a

gynecologic oncology group trial

Matei D., JCO 2011

Matei D., JCO 2011

Post-treatment phosphorylated ERK (pERK) levels and survival. Post-treatment pERKlevels and survival. Higher levels of post-treatment pERK were notably associated

with (A) longer progression-free survival (PF) but not (B) overall survival

Matei D., JCO 2011

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and

effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy

K. H. Baumann et al. Ann Oncol 2012;23:2265-2271

© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

AMG386

Recurrent EOC

•≤ 3 prior anticancer regimens


Weekly Paclitaxel+

Stratification factors

•Platinum-free interval (PFI) (≤ 6 vs. > 6 months)•Measurable disease (Yes/No)•Region (North America, Western Europe/Australia, Rest of World)

regimens

•Evaluable or measurable disease

•GOG Performance Status of 0 or 1

•PFI < 12 months


PD/toxicity

Weekly Paclitaxel+

Trebananib

Placebo

R

1:1

46% of patients w ILP>6Months

25% 3 previous lines of therapy.

Lancet Oncol, 2014 Jul;15(8), 799-808

TRINOVA- 1 : Progression-free Survival

Pac + Placebo (n = 458)

Pac + Trebananib (n = 461)

Events, n (%) 361 (79) 310 (67)

Median PFS, months 5.4 7.2

HR = 0.66 (95% CI, 0.57–0.77)P (stratified log rank) < 0.001

Eve

nt-

free

Pro

ba

bili

ty

0.7

0.8

0.9

1.0

Eve

nt-

free

Pro

ba

bili

ty

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Study Month0 3 6 9 12 15 18 21 22

Patients at risk:

461458

356310

176132

10568

5024

2210

142

30

10

Monk BJ et al; Lancet Oncol, 2014 Jul;15(8), 799-808

TRINOVA-1: Overall Survival(Interim Analysis)

Pac + Placebo(n = 458)

Pac + Trebananib (n = 461)

Events, n (%) 163 (36) 150 (33)

Median OS, months 17.3 19.0

HR = 0.86 (95% CI, 0.69–1.08)P (stratified log rank) = 0.19

Eve

nt-

free P

rob

ab

ility

0.7

0.8

0.9

1.0

Eve

nt-

free P

rob

ab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Study Month0 3 6 9 12 15 18 21 24 27

Patients at risk:

461458

430434

342346

242234

163160

10899

6546

2818

63

Monk BJ et al; Lancet Oncol, 2014 Jul;15(8), 799-808

Vanucizumab: RO5520985: A2V CrossMab

(Anti-human VEGF-A &Anti-human/murine Ang-2)

Molecular characteristics

VEGF-A

Anti-VEGF-A

Bevacizumab

Anti-Ang-2

LC06

Ang-2

VL

VH

VL

VH

Knobs- into- Holes

VL

CL

CH1

CH2

CH3

VL

Crossmab technology allows dual binding capabilities

ClinicalTrials.gov Identifier:NCT01688206

VINTAFOLIDE

PRECEDENT:A RANDOMIZED PHASE II STUDY

R. Wendel Naumann et al. JCO 2013;31:4400-4406


Platinum

TRAB

Trabectedin induces DNA damage recognized by NER forming a DNA-trabectedin-protein repair complex

Replication (S-phase)

NER

repair complex(S-phase)

DNA DSB

CELLDEATH

Calgranulin as prognostic marker in advanced OC

Cortesi L. et al., Electrophoresis 2011

Documents

New chemotherapyto overcomeplatinumresistance · 2016-05-30 · Angiogenesis as a Target in Ovarian Cancer: Anti-VEGF-VEGFR Pathway •Anti-vascular endothelial growth factor (VEGF)