Download 1 - Mito Group

Terapia Medica del
Carcinoma Della Cervice
Uterina
Enrica Mazzoni
Oncologia Medica & Breast Unit
Ospedale –“ Sen. A. Perrino” –
Brindisi
Cervical Cancer:The Burden
Unmet Needs in Advanced Cervical Cancer
 1/3 invasive cervical cancer patients die of their disease
 Recurrence rate
- Stage IB: 20%
- Stage II: 40%
- Stage III: 60%
 Majority of recurrence occur within 2 years of diagnosis, prognosis is poor.
 Cervical Cancer is a relatively chemo-resistant disease, due in part to barriers for
drug delivery as for instance:
–Prior radiotherapy
–Renal dysfunction
–Previous cddp-radiotherapy
 Cisplatin 50 mg/mq every 3 weeks was for 2 decades the standard of care:
- Response rate 20%
- PFS 2.8 to 3.2 months
- Median survival 6.2-8.0 months
- More active than carboplatin

Two ways to increase response without prolongation in Survival
Increase platinum dose
Add Ifosfomide to cisplatin
Thipgen et al. 1981; Omura et al. 1997; Long et al. 2005; Moore et al. 2004
Chemotherapy: few advances in treating
persistent, recurrent cervical cancer
Trial
(year)
GOG-0169
(2004)
GOG-0179
(2005)
GOG-0204
(2009)
JGOG-0505
(2012)
n
264
364
513
253
Regimen
OS,
months
PFS,
months
RR,
%
Remarks
Cisplatin
8.8
2.8
19
Improvement in ORR and PFS
Cisplatin + paclitaxel
9.7
4.8
36
No significant OS improvement
Cisplatin
6.5
2.9
13
Supports cisplatin-topotecan label
Some argue that OS in the cisplatincontrol arm was low due to high
radiotherapy-cisplatin use
Cisplatin + topotecan
9.4
4.6
27
Cisplatin + paclitaxel
12.9
5.8
29
Cisplatin + topotecan
10.3
4.6
23
Cisplatin + gemcitabine
10.3
4.7
22
Cisplatin + vinorelbine
10.0
4.0
26
Cisplatin + paclitaxel
18.3
6.90
n/a
No difference between cisplatin- and
carboplatin-paclitaxel
Carboplatin + paclitaxel
17.5
6.21
n/a
However, OS benefits suggests that
population is different
Consolidated cisplatin-paclitaxel as
standard of care
No other combination was better
High unmet need in treating metastatic or recurrent cervical cancer
GOG 204: Overall Survival
By Treatment Group
Treatment
CIS+PAC
CIS+VIN
CIS+GEM
CIS+TOP
Proportion Surviving
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
Alive Dead Total
29
74 103
23
85 108
20
92 112
22
89 111
24
36
Months on Study
BJ Monk et al J Clin Oncol. 2009 Oct 1;27(28):4649-55.
Carboplatin or Cisplatin
• CIS-PTX: GRADE3-4 neutropenia 78.2%; febrile neutropenia 12.9%;
neuropathy 3%, vomiting 19.8%)
• Renal function, may be impaired in CC patients
• Phase II trials about CBDCA-PTX in CC: RRs 40-78%,mPFS 3-6 mts, 9.613 mts.
• NEED COMPARISON CIS-PTX vs. CBDCA-PTX
PALLIATIVE INTENT OF SYSTEMIC CHEMOTHERAPY!!
Lorusso et al, Gyn Onc, 2014
R
Accrual: 253 pts
TP
TC
Tax135 mg/m2
p1q21+Cis 50 mg/m2
p2q21
Tax175 mg/m2+AUC5
p1q21
Kitagawa R et al. J Clin Onc 2015
TOXICITY
TP(%)
TC(%)
Neutropenia
85.5
76.2
Febril neutropenia
16
7.1
Anemia
31.2
44.4
Other GI
6.4
3.2
Fatigue
4
7.9
Neuropathy
0
4.8
OS Platinum naive pts:
20 mts PC vs 27 mts TP
TP remains the standard
regimen for patients without
prior cisplatin-based therapy,
such as those with primary
stage IVB cervical cancer with
adequate renal function.
Kitagawa R et al. J Clin Onc 2015
CECILIA (MO29594): trial design
A MULTICENTRE OPEN-LABEL SINGLE-ARM PHASE II STUDY
EVALUATING THE SAFETY AND EFFICACY OF Bevacizumab IN
COMBINATION WITH CARBOPLATIN AND PACLITAXEL IN PATIENTS
WITH METASTATIC, RECURRENT OR PERSISTENT CERVICAL CANCER
Metastatic, recurrent
or persistent cervical
cancer patients
Carboplatin AUC5 q3w*
not amenable to curative
treatment with surgery
and/or radiation therapy
n=150
•
Paclitaxel 175mg/m2 q3w*
Bevacizumab 15mg/kg q3w
AUC, area under the concentration curve; q3w, every 3 weeks
*Minimum of 6 cycles, unless toxicity necessitates discontinuation of one or both chemotherapy
agents, in which case non-implicated drug(s) and Bevacizumab can be continued alone
MO29594– Adapted from
https://clinicaltrials.gov/ct2/show/NCT02467907?term=bevacizumab+cervical&rank=5
Until disease
progression,
unacceptable
toxicity or
withdrawal
of consent
MITO (Multicentre Italian Trials in Ovarian cancer) - CERV2 trial: a
randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in
advanced and/or recurrent cervical cancer
PFS
OS
Anti-VEGF hypothesis: tumor hypoxia and
1-2
viral oncogenes drive angiogenesis
1.Tewari KS et al. ASCO 2013 J Clinic Oncol 2013: 31; 2. Jackson MW et al. Onco Targets Ther 2014; 7: 751-759.
Rationale for using Anti-VEGF in cervical cancer:
angiogenesis plays a central role in cervical
carcinogenesis and disease progression1-6
A
Figure 11
B
1. Tewari KS et al. ASCO 2013 J Clinic Oncol 2013: 31; abstr3 - Last access Feb 2015; 2. Jackson MW, et al. Onco Targets Ther 2014; 7: 751-759; 3. Tewari KS et al. *N Engl JMed
2014; 370: 734-743; 4. Monk BJ, et al. J Clin Oncol 2009; 27: 1069-1074; 3. Schefter TE et al. Int J Radiat Oncol Biol Phys 2010; 78: S395; 5. Schefter TE et al. Int J Radiat Oncol
Biol Phys 2012; 84: S17; 6. Zighelboim I, et al. J Clin Oncol 2012.
GOG 227: bevacizumab in persistent or
recurrent squamous cervical cancer
Recurrent
cervical cancer
n=46
Bevacizumab
15 mg/kg iv
every 3w
• Progression disease
• Unacceptable toxicity
• Receipt of other
anticancer therapy
• Voluntary withdrawal
• Phase II, single agent trial
• Primary endpoints: 6 months-PFS and safety (frequency and severity of adverse events)
• Secondary endpoints: clinical response, PFS and OS distribution, impact of potential
prognostic factors on PFS and OS
Monk BJ et al. J Clin Oncol 2009; 27:1069-1074
GOG 227 : results
Bevacizumab seems to be well tolerated and
active in the second- and third-line treatment
of patients with recurrent cervical cancer and
merits phase III investigation1
Efficacy
11 pts* survived progression free for at least
6 months, and 5‡ patients experienced RP .
Response duration = 6.21 months.
PFS = 3.40 months (95%CI, 2.53 to 4.53
months)
OS = 7.29 months (95%CI, 6.11 to 10.41
months)
1. Monk BJ et al. J Clin Oncol 2009; 27:1069-1074
Safety
RTOG 417: bevacizumab in combination with
radiotherapy and cisplatin chemotherapy in locally
advanced cervical carcinoma1
Advanced cervical
carcinoma (FIGO stage
IIB-IIIB or IB-IIA with
pelvic node metastasis
and/or tumour size ≥ 5
cm
n=57
RT
45 Gy (over
5 ws in 25
once daily
fractions)
Bevacizumab 10 mg/kg
Iv q2 weeks (days 1, 15
and 29, total 3 doses)
during chemoradiation,
before cisplatin and on
the same day as cisplatin
Phase II, single arm trial
Primary endpoints: treatment-related serious adverse events rates and adverse events
rates within the first 90 days
Secondary endpoints: treatment-related serious adverse events rates and adverse
events rates at any time, DFS, OS, angiogenic markers
1. Schefter TE et al. Int J Radiat Oncol Biol Phys. 2012;83:1179-84
RTOG 417: results
•
Bevacizumab + RT is feasible and safe with respect to the protocol-specified treatmentrelated SAEs and AEs 1
1. Schefter TE et al. Int J Radiat Oncol Biol Phys. 2012;83:1179-84
AVF3864: activity and safety of the combination of
topotecan, cisplatin and bevacizumab in recurrent or
persistent carcinoma of the cervix1
Persistent or
recurrent
cervical cancer
n=27
Cisplatin (50 mg/m2) + topotecan
(0.75 mg/m2) + bevacizumab (15
mg/kg)
Phase II, single arm trial
Primary endpoint: 6 months PFS
1. Zighelboim I et al. Gynecol Oncol 2013; 130(1)
Until PD
or toxicity
AVF386: results
•
The addition of bevacizumab to topotecan
and cisplatin results in an active but highly
toxic regimen1
Efficacy
6-month PFS = 59% (80% CI: 46-70%).
In 26 evaluable patients:
1 CR (4%; 80% CI: 0.4–14%)
8 PR (31%; 80% CI: 19–45%)
lasting a median of 4.4 months.
10 patients had SD (39%; 80% CI: 25–53%)
with median duration of 2.2 months.
PFS = 7.1 months (80%; CI: 4.7–10.1)
OS = 13.2 months (80% CI: 8.0–15.4).
Zighelboim I et al. Gynecol Oncol 2013; 130(1)
Safety
GOG-0240: study design
Stratification factors
- Stage IVB vs recurrent/persistent disease
- Performance status
- Prior cisplatin Rx as radiation sensitizer.
N Engl J Med 2014; 370(8): 734-743
GOG-0240: Objectives
– Primary endpoints to determine
• If adding bevacizumab to chemotherapy improves OS
• If a non-platinum doublet (topotecan/paclitaxel) improves OS
• The tolerability of the four regimens (adverse events by CTCAE v3 and v4).
– Secondary endpoints
• Impact of bevacizumab and non-platinum doublet on progression-free survival (PFS) and overall
response rate (ORR) by RECIST v1.0.
– Exploratory endpoints
• Impact on Health-Related Quality of Life (HRQoL)
– Functional assessment of cancer therapy – Cervix Ca Trial Outcome Index (FACT-Cx TOI).
1. Tewari KS, et al. ASCO 2013 J Clinic Oncol 2013; 31. abstr 3 2. 3. Tewari KS, et al. *N Engl J Med 2014; 370(8): 734-743.
GOG-240: Cis+Pac vs Topo+Pac
• study results comparing non-platinum doublet vs platinum doublet
Topotecan + paclitaxel shown to not be superior or inferior to cispaltin + paclitaxel.
1.0
Cis + Pac
(n= 229)
Topo + Pac
(n= 223)
81 (35)
93 (42)
15
12.5
0.9
Events, n (%)
Proportion Surviving
0.8
Median OS, mos
0.7
HR=1.20 (98.74% CI; 0.82–1.76)
P (one-sided)=0.880
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
Months on Study
Tewari KS, et al. *N Engl J Med 2014; 370(8): 734-743.
24
GOG 240:
Cis+Pac vs Topo+Pac Toxicity
TP worse
TP better
GOG 240 suppl appendix Tewari KS, et al. *N Engl J Med 2014; 370(8): 734-743
GOG 240: OS for Chemo vs Chemo + Bev
Events, n (%)
Median OS, mos
Chemotherapy
(n=225)
Chemotherapy +
Bev (n=227)
178 (79)
170 (75)
13.3
16.8
HR=0.65 (97% CI, 0.62-0.95)
P=0.0068
Tewari KS, et al. *N Engl J Med 2014; 370(8): 734-743.
GOG 240: ESMO 2014 updates
Events, n (%)
Median OS, mos
No Bev
(n=225)
Bevacizumab
(n=227)
178 (79)
170 (75)
13.3
16.8
HR=0.765 (95% CI, 0.62-0.95)
P=0.0068
Final OS: chemo vs chemo plus bev
No Bev
(n=225)
Bevacizumab
(n=227)
Events, n (%)
206 (92)
199 (88)
Median PFS,
mos
6.0
8.2
HR=0.684 (95% CI, 0.56-0.84)
p=0.0002
RR, %
36
49
p=0.0032
Updated PFS: chemo vs chemo plus bev
1. Adapted from Tewari KS, et al. ESMO 2014
GOG 240: tossicità di particolare interesse
1. Adapted from Tewari KS, et al. ESMO 2014
Milestones
EMA Decision 30 March 2015
CHMP Positive Opinion 26 February 2015
Bevacizumab, in associazione con paclitaxel e cisplatino o, in alternativa, a
paclitaxel e topotecan in donne che non possono essere sottoposti a
terapia a base di platino, è indicato per il trattamento di pazienti adulte
affette da carcinoma della cervice persistente, ricorrente o metastatico.
Progress in Survival in Advanced and
Recurrent Cervical Cancer
GOG 240 Cisplatin + Paclitaxel + Bevacizumab
GOG 169 Cisplatin + Paclitaxel
GOG 110 Cisplatin + Ifosfamide
GOG 204 Cisplatin + Paclitaxel
GOG 149 Cisplatin + Ifosfamide + Bleomycin
GOG 64 Cisplatin
GOG 179 Cisplatin + Topotecan
Unmet Needs in Advanced Cervical Cancer
 Bevacizumab combined with CP is standard of care for metastatic disease[1]
 Limited treatment options after progression on first-line therapy
–Many pts platinum resistant
–Many pts are quite fragile to receive second-line therapy after progressing on Cis-tax-bev
–Median OS of ~ 7 mos[2]
–Enrollment in clinical trials encouraged[3]
1. Tewari KS, et al. *N Engl J Med 2014; 370(8): 734-743 2. Tewari KS, et al. Clin Cancer Res. 2014;20:5349-5358
2. NCCN Guidelines: Cervical Cancer. V1 2016.
THE OUTBACK TRIAL/GOG 0274
A Phase III trial of adjuvant chemotherapy
following chemoradiation as primary
treatment for locally advanced cervical
cancer compared to chemoradiation alone
Linda Mileshkin on behalf of ANZGOG
Kathleen Moore on behalf of the GOG
ClinicalTrials.gov Identifier: NCT01414608
•
•
•
•
Failed first-line cytotoxic drug treatment
125 mg/m(2) IV over 30 minutes on days 1, 8, and 15 of each 28 day cycle
Median PFS = 5.0 months
Median OS = 9.4 months
• 10 (28.6%; CI 14.6%-46.3%) of 35 patients = PR
• 15 patients (42.9%) had SD
Alberts DS, et al. Gynecol Oncol. 2012;127(3):451-455.
KEYNOTE-028: Pembrolizumab
in PD-L1+ Advanced Cervical
Cancer
CCO Independent Conference Coverage*
of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical
information to healthcare professionals through conference coverage and other educational
programs.
This activity is supported by educational grants from Amgen, Ariad,
Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech,
Incyte, Merck, and Taiho Pharmaceuticals.
KEYNOTE-028: Study Design
PD-L1+* metastatic or
unresectable cervical
cancer; ECOG PS 0/1;
failure of or ineligibility
for standard therapy;
measurable disease
(RECIST v1.1)
(N = 24)
Pembrolizumab
10 mg/kg IV Q2W
CR, PR, or SD: treat for 24 mos or
until PD‡ or intolerable toxicity
Confirmed PD‡ or unacceptable
toxicity: discontinue pembrolizumab
Response
assessment†
• Primary endpoints: ORR (RECIST v1.1), safety
• Secondary endpoints: PFS, OS, response duration
Frenel JS, et al. ASCO 2016. Abstract 5515.
KEYNOTE-028 : Baseline Characteristics
Characteristic
Median age, yrs (range)
Race, white/Asian/not specified, %
Pts (N = 24)
41 (26-62)
63/4/33
ECOG PS of 1, %
75
Histology, %
Squamous cell carcinoma
Adenocarcinoma
96
4
Metastatic stage, %
MX
M0
M1
Unknown
4
25
63
8
Prior radiotherapy, %
96
Prior lines of therapy for advanced disease,%
1
2
≥ 3
38
25
38
Prior platinum, %
96
Prior bevacizumab, %
42
Frenel JS, et al. ASCO 2016. Abstract 5515.
Slide credit: clinicaloptions.com
KEYNOTE-028: Response
Response by RECIST v1.1
Criteria and Investigator
Review*
Pembrolizumab
(N = 24)
n
%
95% CI
ORR†
4
17
5-37
 PR
4
17
5-37
SD
3
13
3-32
PD
16
67
45-84
No assessment‡
1
4
< 1-21
*All pts with evaluable disease who received ≥ 1 dose pembrolizumab. †No CRs. ‡Pt had no postbaseline
response evaluation.
• 38% of pts had decreased tumor size
• Median time to response: 8 wks (range: 8-36 wks)
• Median response duration: 26 wks (range: 18-52 wks)
Frenel JS, et al. ASCO 2016. Abstract 5515
KEYNOTE-028: Secondary Endpoints
• Median PFS: 2 mos (95% CI: 2-4)
• 6-mo PFS: 21%
• 12-mo PFS: 8%
• Median OS: 9 mos (95% CI: 4-12)
• 6-mo OS: 67%
• 12-mo OS: 33%
• Presenter mentioned that at data cutoff (February 17,
2016), all pts had PD and discontinued treatment
Frenel JS, et al. ASCO 2016. Abstract 5515.
Slide credit: clinicaloptions.com
KEYNOTE-028: Conclusions
• Pembrolizumab active in pts with PD-L1+ advanced cervical cancer[1]
• Durable responses lasting median of 26 wks
• Some responses lasted 1 yr
• Median OS was 9 mos with 6-mo survival rate of 67%
• Safety profile of pembrolizumab in pts with advanced cervical cancer
consistent with other tumor types
• No treatment-related grade 4 AEs; no mortality due to treatment
• Multicohort phase II KEYNOTE-158 study under way to further
evaluate safety profile and clinical benefit of pembrolizumab in
advanced cervical cancer[2]
1. Frenel JS, et al. ASCO 2016. Abstract 5515.
2. ClinicalTrials.gov. NCT02628067.
Slide credit: clinicaloptions.com
•
Advaxis Sponsored Ph 3: ADXS11-001 Administered Following Chemoradiation as Adjuvant Treatment for High Risk Locally Advanced Cervical Cancer:
AIM2CERV
•
Cervix Cancer
•
• FIGO IB2, IIA2 and IIB with + pelvic nodes
•
•FIGO IIIA, IIIB and IVA
•
• All FIGO stages with + para-aortic nodes
•
R 2:1
•
*EBRT with Cisplatin
•
*EBRT with Cisplatin
•
ARM A
Placebo
wks 3, 6, 9 and every 8 wks for 1 year ( ie. 8 doses)
•
ARM B ADXS-HPV wks3,6,9andevery8wks for 1 year ( ie. 8 doses)
•
8 weeks
•
N=450
•
1o endpoint: Progression Free Survival 2o endpoint: Overall Survival
•
*Concurrent chemo radiation therapy administered with curative intent according to national/institutional guidelines
63%
For invasive cancer in women aged 20–29, we project a 63% reduction in rates
by 2025 with 80% vaccine coverage and no cross-protection, based on an
estimated 79% reduction in vaccinated women. If only 70% coverage is
achieved, the reduction will be more moderate (55%).
Terapia Medica del
Carcinoma Della Cervice
Uterina
[email protected]