Download Update on cervical cancer studies - Dana

Update on treatment for cervical cancer
Ursula Matulonis, M.D.
Director and Program Leader
Gynecologic Oncology Program
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School
Boston MA
[email protected]
Disclosures
• I, Ursula Matulonis, have been asked to disclose any
significant relationships with commercial entities that
are either providing financial support for this program
or whose products or services are mentioned during
my presentations.
• I have the following relationships to disclose:
Member of the Independent Data monitoring
committee for the NCI-run study AIM2SERV study
(ADXS11-001 vaccine) – uncompensated
• I will discuss the use of vaccines in a manner not
approved by the U.S. Food and Drug Administration.
• But in accordance with ACIP recommendations.
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Cervical cancer
• Risk Factors:
– Early age of first intercourse
– Multiple sexual partners
– Infection with high risk HPV:
HPV 16 and 18 account for 70% of all cervix cancer. Remaining 30%
include approx 12-14 other HPV types
– Immunosuppression
– Cigarette smoking
• Cervix cancer statistics
New cases in US: 12,360
New case worldwide: 529,000
Deaths in US: 4020
Deaths worldwide: 273,505
Int J of Cancer 2010
and cdc.gov
Histologic Subtypes
• Squamous Cell Carcinoma
• Adenocarcinoma
• Other epithelial
Adenosquamous
Glassy cell
Carcinoid
Neuroendocrine
Small cell
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Treatment strategies
• Chemotherapy
• Targeted therapy
• Immunotherapy
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GOG 240
Eligibility
confirmed
Paclitaxel +
cisplatin
Paclitaxel +
cisplatin +
bevacizumab
Primary Endpoints:
• Overall survival (OS)
• Frequency and severity of
toxicity
Secondary Endpoints:
• Progression-free survival
(PFS)
• Tumor response
Paclitaxel +
topotecan
Paclitaxel +
topotecan +
bevacizumab
NEJM 2014
Opened: 4/6/2009
accrual = 450 pts.
GOG 240
Eligibility:
• Primary Stage IVB or recurrent/persistent carcinoma of
the cervix
• Measurable disease
• GOG performance status 0-1
Bevacizumab added to chemotherapy because of single
agent activty in squamous cell cervical cancer (JCO
2009)
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Results 240
Overall survival primary endpoint:
Improved OS for pts receiving bevacizumab:
16.8 months versus 12.9 months
HR 0.74 (95% CI 0.58-.94), P=0.0132
PFS:
Improved PFS for pts receiving bev:
8.2 months vs. 5.9 months
HR 0.67 (95% CI 0.54-0.82), p = 0.0002
•
Recommended dose of avastin is 15 mg/kg every 3 weeks administered in combination with
one of the following chemotherapy regimens:
Paclitaxel and cisplatin (3 choices)
1) Day 1 paclitaxel 135 mg/m2 IV over 24 hours, Day 2 cisplatin 50 mg/m2 IV plus avastin
2) Day 1 paclitaxel 175 mg/m2 IV over 3 hours, day 2 cisplatin 50 mg/m2 IV plus avastin
3) Day 1 paclitaxel 175 mg/m2 IV over 3 hours plus cisplatin 50 mg/m2 IV plus avastin
Paclitaxel and topotecan (only 1 regimen)
Day 1 paclitaxel 175 mg/m2 IV over 3 hours plus avastin,
Days 1-3 topotecan 0.75 mg/m2 IV over 30 mins
Genetics of cervical cancer
• Aberrations in PI3K, RAS pathways
• Less common: p53, HER2
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Patient Characteristics (n=78)
Age, mean (SD)
Race
White
Black
Other
Histology
Adenocarcinoma
Squamous cell carcinoma
Stage
IA2
IB1
IB2
IIA
IIB
IIIB
IV
Grade
Well differentiated
Moderately differentiated
Poorly differentiated
44.5 (11.0)
63 (80.8%)
9 (11.5%)
4 (5.1%)
41 (52.6%)
37 (47.4%)
11 (14.1%)
34 (43.5%)
2 (2.6%)
8 (10.2%)
13 (16.7%)
5 (6.4%)
5 (6.4 %)
23 (29.5%)
32 (41.0%)
21 (21.8%)
Wright et al, Cancer 2013
High Rates of PIK3CA Mutations
in Both AC and SCC
E545K
Mutations
Overall n=78
E542K
AC (n=41; 32%)
SCC (n=37; 35%)
E453k
P=0.47
R88Q
0
2
4
Patients
6
8
Wright et al, Cancer 2013
KRAS Mutations
Detected in AC Only
Mutations
G12A
Overall n=78
G12D
AC (n=41; 17%)
SCC (n=37; 0%)
G12V
P=0.004
G13D
0
1
2
Patients
3
Wright et al, Cancer 2013
Mutations found in several important
oncogenic pathways
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Ojesina et al Nature 2014
Targeted therapy based on genetics
• Phase II trial of GSK1120212 (MEK inhibitor)
and GSK2141795 (AKT inhibitor) in recurrent
cervical cancer NCT01958112
• Closed prior to full accrual in Dec 2015
because company pulled support and
withdrew further development of the AKT
inhibitor
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New directions using immunotherapy
• Immunotherapy agents currently in testing
– Pembrolizumab1: 13% RR; median DOR 19 weeks
(ASCO 2016)
– Nivolumab: GOG study and awaiting results
– Ipilimumab2: CTEP trial, ~10% RR
• HPV E7 vaccines
Examples:
– ADXS11-001 is a live attenuated Listeria monocytogenes
immunotherapy engineered to secrete an HPV16-E7 fusion
protein targeting HPV-transformed cells
– E711-19 vaccine
1ASCO
2ASCO
2016
2015
Is cervical cancer a good target for
immunotherapy?
• E6 and E7 viral proteins
• Mutational burden
• 67% of squamous cell cancers of the cervix
and 43% of vulvar cancers will have
coamplication of CD274 and PDCD1LG2, genes
that encode PD-L1 and PD-L2
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Howitt et al, JAMA Onc 2016
Neoantigen Load and Tumor Types:
Possible use as a biomarker of activity for IO agents
Alexandrov et al., Nature17
2013
Schumacher et al, Science 2015
ADXS11-001 (HPV-directed)
• Vaccine using Listeria monocytogenes which is
a bacterium that can be genetically modified
to express/secrete fusion proteins with
antigens specific to certain cancer models
such as cervical cancer
• E7 protein in HPV
• Several trials underway in cervical cancer
Cory et al, Human Vaccines and
Therapeutics 2014
Use of ADXS11-001 in high risk
newly diagnosed cervical cancer
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NCT02853604
A Phase Ib/II trial to test the safety and efficacy of
vaccination with E711-19 nanomer for the treatment of
incurable HPV16-related anal, head and neck,
and cervical cancer in HLA-A*02 positive patients
E711-19 nanomer is a single peptide antigen from
HPV 16 protein E7
Goal of Clinical Trial
1. To establish safety of E711-19 vaccination
2. Assess immunological and clinical
response
Endpoints
Primary Objectives
•Evaluate changes in epitope-specific CD8+ T cells in peripheral blood and/or
tumor tissue
•Evaluate the safety of E711-19 vaccination in HLA-A2 positive patients with
incurable HPVOC, cervical cancer, and anal cancer
Secondary Objectives
•To estimate progression free survival, time to progression, median duration of
response and overall survival
•Evaluate the best overall response rate (ORR, CR, PR) using modified RECIST
v1.1
•To evaluate the biologic correlates of response to therapy by determining the
antigen-specific CD8 T cells elicited by E711-19 pMHC multimer binding assay,
their activation status, effector/memory phenotype, cytokine profile, quantitation
per ml blood, perforin/granyme content, CD4 activation status, including Treg
profiling.
Statistical Considerations
Based on primary objectives to evaluate changes in antigen-specific CD8+ T
cells in the peripheral blood and/or tumor tissue
Responders defined as patients with at least a five-fold increase in number of
CD8+ T cells in the peripheral blood and/or tissue
Simon two-stage design to minimize the number of patients exposed to this
regimen
Null hypothesis: ‘response rate’ is not clinically meaningful (<10%).
Alternative hypothesis is that the response rate is clinically meaningful (>10%).
Key Patient Eligibility
Inclusion:
Histologically or cytologically proven HPVOC, cervical cancer, or anal
cancer (p16 pos/IHC pos)
Incurable disease
Positive for HLA-A2
Any number of prior therapies allowed
Accessible tumors for sequential biopsies
Exclusion:
•PS 3 or greater
•Autoimmune disorder, HIV pos, transplant recipients
•Lab abnormalities >1.5x upper limit of normal
Trial Design
44 patients for total of 40 evaluable patients enrolled (20 patients with HPVOC, 10
patients with cervical cancer and 10 patients with anal cancer).
Given prevalence of HLA-A*02 in general population ~ 30%, HLA screening of 132
patients will be required
Patients will receive DPX-E7 vaccine subcutaneously (100ug/dose, 0.1cc) on days
1 and 22 (+/- 3 days) and every 8 weeks thereafter, until intolerable SE or
progression occurs
Cyclophosphamide 50 mg po bid one week on/one week off starting 7 days
before the first vaccination and continuing until one week following last projected
injection will be administered..
Screening
for HLA-A2
phenotype
Informed
Consent,
Registration
Enrollment
Injection with E7 11-19
nanomer
Safety evaluation,
radiographic markers of
response
Day 1,22, then q8weeks
Correlative
Immunological Studies
Cyclophosphamide 50mg bid x7d
Conclusions
• Cervical cancer is a worldwide problem
• For women with advanced cancer at diagnosis
or who eventually develop recurrent and
metastatic cancer, systemic chemotherapy is
used
• Newer therapies are needed, and
immunotherapy trials are underway
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