Transcript Update on Cervical Cancer - Dana

Update on Cervical Cancer
Alexi A. Wright, MD MPH
Assistant Professor, Harvard Medical School
Dana-Farber Cancer Institute
Boston MA
Cervix cancer
1) Risk Factors
2) Staging
3) Treatment for early stage cancer
4) Recurrent cancer
5) New Directions
Burden of Disease in US and Abroad
Cancer
New
cases,
U.S.
New
cases,
globally
Deaths,
U.S.
Deaths,
globally
Uterine
corpus
54,870
287,000
10,170
74,000
Ovary
21,980
204,499
14,270
140,000
Cervix
12,360
529,000
4020
273,505
Int J of Cancer 2010
and cdc.gov
GLOBOCAN,
2008
Risk Factors
• Early age of first intercourse
• Multiple sexual partners
• Infection with high risk HPV
HPV 16 &18 account for 70% of all cervix
cancers. 2-14 other HPV types account for 30%
• Immunosuppression
• Cigarette smoking
HPV vaccine
• HPV vaccination is recommended for
women who are HPV-negative. Should
be given prior to start of sexual activity
• Reduces the incidence of pre-malignant
vulvar, cervical, and vaginal lesions
• HPV vaccine is approved for use in
women aged 9 to 26; data also exists in
women up to age 45 who are HPV
negative
Lancet 2007
Munoz 2010
Cervix cancer staging
Mutch, Gyn Onc 2009
Cervical cancer staging (cont)
Mutch et al, Gyn Onc 2009
Staging of Cervical Cancer
Husband & Reznek, Imaging in Oncology,
1998
Five-Year Survival
Stage I
Stage
IIA
Stage
IIB
Stage
IIIA
Stage
IIIB
Stage
IV
Treatment of cervix cancer
• For patients with lower stage cancer Surgery
Stage IA1: hysterectomy, negative cone
margins, trachelectomy depending on fertility.
Stage IA2: surgery or brachytherapy +/-RT or
tracelectomy.
IB1: surgery, XRT, or trachelectomy
IB2 and stage IIA: pelvic RT or surgery
Stage IA1: Stromal invasion ≤3 mm and ≤7mm in horizontal
Stage IA2: Stromal invasion >3mm and ≤5 mm, ≤7mm in
horizontal spread
Stage IB: visible lesions
NCCN.org
Treatment of cervix cancer
Stage IB2 and higher: Pelvic RT and
concurrent cisplatin
NCCN.org
Six RCTs Show Chemotherapy
Improves Survival
1.2
1
0.8
0.6
0.4
0.2
0
GOG 85
GOG 120
(CDDP)
GOG 120
(C/5FU/HU)
GOG 123
SWOG 8997 RTOG 9001
NCCN.org
NCI Alert, 1999: Addition of platinumbased therapy improves outcomes
NEJM, Thomas 1999
Consider carboplatin or 5-FU in
pts with renal dysfunction
Treatment of metastatic
cervix cancer
Systemic Therapy
NCCN.org
GOG 240
Stage IVB or
recurrent/
persistent
carcinoma of
the cervix
 Measurable
disease
 GOG PS 0-1
R
A
N
D
O
M
I
Z
E
Paclitaxel + cisplatin
Paclitaxel +cisplatin
+bevacizumab
Paclitaxel + topotecan
Paclitaxel + topotecan
+ bevacizumab
ASCO 2013, NEJM 2014
Bevacizumab Improves Survival
Overall survival:
16.8 vs. 12.9 months for women chemotherapy +
bevacizumab vs. women receiving chemotherapy
alone
HR 0.74 (95% CI 0.58-.94), P=0.01
Progression Free Survival:
8.2 vs. 5.9 months for those who received
chemotherapy + bevacizumab vs. those who
received chemotherapy alone.
HR 0.67 (95% CI 0.54-0.82), p = 0.0002
NEJM 2014
August 2014: FDA approves avastin for advanced cervical
cancer combined with chemotherapy
• 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
A Single Arm, Single Stage Phase II
trial of GSK1120212 and
GSK2141795 in Persistent or
Recurrent Cervical Cancer
NCT01958112
PI: Ursula Matulonis, MD
Dana-Farber Cancer Institute
Boston, MA
Rationale: Oncogenic mutations
• Cervical cancer harbors somatic mutations; mutations in
RAS are found in adenocarcinomas and PI3kinase
pathway mutations found in both squamous cell and
adenocarcinomas1,2.
• Activity of single agent PI3kinase inhibitors observed in
cervical cancer @DFCI.
• Pre-clinical and translational studies support the use of
PI3K/AKT and MEK inhibitors together given the
redundancy of the pathways and negative feedback
loops.
1Wright
2Ojesina
et al, Cancer 2013
et al Nature 2014
High Rates of PIK3CA and RAS mutations
• Based on pre-clinical work @ DFCI/HCC;
80 cases of either squamous cell or
adenocarcinoma of the cervix from Brigham
and Women’s Hospital Pathology
• DNA extracted and Oncomap performed
(mass spectrometry-based genotyping
platform) and were validated using
orthogonal chemistry
Wright et al, Cancer 2013
Patient Characteristics (n=80)
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
Drug Administration
GSK1120212 (trametinib): 1.5 mg PO once per
day continuously
GSK2141795: 50 mg PO once daily continuously
Each cycle = 28 days; restaging every 2 cycles
25
Primary Objective
• To assess the activity of the combination of
GSK1120212 (trametinib) and GSK2141795
in patients with recurrent or persistent
cervical cancer per overall response rate
using RECIST 1.1.
26
Secondary Objectives
• Duration PFS
• Duration of OS
• Toxicity
Exploratory:
• Describe the mutation and co-mutation rates of
genes in the PI3K and RAS-ERK signaling pathways
in recurrent cervical cancer.
• To explore the association of mutational status with
clinical benefit from GSK1120212 (trametinib) and
GSK2141795.
27
Statistical Analysis
Sample size:
 Sample size is 35 participants.
 There is a 91% power to detect an improvement in
response rate from 0.07 to 0.22 using a one-sided 0.09level exact binomial test.
Therefore, the null hypothesis will be rejected if 5 or
more participants respond to the trial therapy.
 The null hypothesis of 0.07 is based on a weighted
average of the observed response rates from the 11
cohorts enrolled to GOG 127 and 227 series.
One patient still on
with SD for
> one year
Novartis has opted to stop development of one of the drugs, so
the study closed as of earlier in 2015
Immuno-oncology agents for
recurrent cervical cancer
Human cancer immunotherapy with antibodies
to the PD-1 and PD-L1 pathway
Antigen-presenting cells take up antigen (Ag) released from cancer cells and present it to T
cells. Cancer cells can also present Ag to activated T cells in the context of the MHC.
On T cell activation, PD-1 receptors are expressed on T cells and inhibit immune responses
by engagement of PD-L1 and PD-L2 on APCs and PD-L1 on cancer cells.
Therefore, monoclonal antibody (mAb)-mediated specific blockade of the PD-1/PD-L1/PD31
L2 pathway can enhance antitumor immunity.
Ohaegbulam KC, et al. Trends in Molecular Medicine, 2015
Immunotherapy in Cervical Cancer
• PD-1 and PD-L1 expression on cervical T cells and
dendritic cells, respectively, has been reported to be
associated with high risk-HPV positivity and to be increased
in parallel with increasing cervical intraepithelial neoplasia
(CIN) grade.(Yang et al, 2013)
• Furthermore, increased expression of PD-1 and its ligand
PD-L1 correlates with impaired cell-mediated immunity in
high-risk HPV-related CIN.(Yang et al, 2013)
• In cervical cancer, PD-1 is expressed by a vast number of
infiltrating CD8 T cells, suggesting that blocking of PD-1
could have therapeutic potential in cervical cancer (Karim et
al, 2009)
• Cervical cancer is associated with a high neoantigen load
(Nature 2013)
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Neoantigen Load and Tumor Types:
Possible use as a biomarker of activity for IO agents
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Alexandrov et al., Nature 2013
Schumacher et al, Science 2015
New directions in recurrent
cervix cancer
• Immunotherapy studies:
NRG-GY002 Phase II nivolumab for recurrent cervix cancer
(NCT02257528)
GOG Phase II of ipilimumab for recurrent HPV+ cervical
cancer that is metastatic or recurrent (NCT01693783)
Phase I study of chemoradiation followed by ipilimumab for
patients with locally advanced cervical cancer
(NCT01711515).
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