making progress in the treatment of estrogen receptor positive metastatic breast cancer
TRANSCRIPT
Ian KropDana-Farber Cancer Institute
Harvard Medical SchoolSeptember 2016
Making progress in the treatment of estrogen receptor positive
metastatic breast cancer
The Old Approach
A little treatment A lot of treatment
Invasive Breast Cancer Subsets Defined by IHC
All Breast Cancers
Triple negative
15%
Burstein, Goldhirsch. St Gallen 2007.
ER+65%-75%
HER2+15%-20%
3
HER2+ Estrogen receptor +
Triple Negative
GE
NE
S
TUMORS
Breast cancer is family of different cancers
“Targeted” therapy
• Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent
• Offer the promise of reduced side effects compared to less targeted drugs
Estrogen Receptor Function: The Basics
Estrogen
EstrogenReceptor
Cancer cell
Estrogen Receptor Function: The Basics
Estrogen
EstrogenReceptor
Cancer cell
Estrogen Receptor Function: The Basics
Estrogen
EstrogenReceptor
DNACancer cell
Estrogen Receptor Function: The Basics
Estrogen
EstrogenReceptor
DNACancer cell
Cell Growth
Hormonal therapy
• The original targeted therapy
• Several types:– Tamoxifen
• Blocks estrogen from binding to ER– Aromatase inhibitors (anastrozole, letrozole, exemestane)
• Blocks production of estrogen– Fulvestrant (Faslodex)
• Blocks estrogen from binding to ER and helps degrade ER
Endocrine Therapy Side EffectsGood (tam)• Bone Strengthening
Bad• More common
– Hot Flashes– Vaginal discharge/dryness– Arthralgias (AIs)– Osteopenia/Osteoporosis (AI)
• Rare– Blood Clots (tam)– Endometrial cancer (tam)– Cataracts (tam)– ?stroke (tam)
Blocking cancer cell growth: Cyclin Dependent Kinase (CDK 4/6) inhibition
• A classic feature of breast cancer is uncontrolled growth
• In ER+ breast cancer, out-of-control growth may be due to a failure in the braking system: overactive CDK4/6
CDK 4/6 inhibition blocks cancer cell division
• CDK 4/6 Inhibition: – puts the brakes on cell growth– pushes cancer cells towards cell death
Palbociclib (Ibrance)
• Palbociclib: oral inhibitor of CDK 4/6
• Taken daily, 3 weeks on, 1 week off
• Most common toxicities: low white blood cell count (but no infections), fatigue, mild hair thinning
PALOMA-1 Trial: Schema
• First randomized trial of palbociclib in breast cancer (phase II)
• Women with newly diagnosed metastatic breast cancer were randomized to first-line therapy with letrozole alone, or letrozole + palbociclib
Letrozole
Palbociclib +
Letrozole• Metastatic breast cancer• ER+/HER2-• First line
Time
Perc
enta
ge o
f wom
en W
ITH
OU
T pr
ogre
ssio
n100-
Kaplan Meier plots allow comparison of clinical outcome over time
17
PALOMA-1: Progression-Free Survival (ITT Population)
Finn RS et al. Presented at AACR 2014; San Diego, California, USA
PAL + LET(N=84)
LET(N=81)
Number of Events (%) 41 (49) 59 (73)
Median PFS, months(95% CI)
20.2(13.8, 27.5)
10.2(5.7, 12.6)
Hazard Ratio(95% CI)
0.488(0.319, 0.748)
p-value 0.0004
90
80
70
60
50
40
30
20
10
0
Prog
ress
ion
free
surv
ival
pro
babi
lity
(%)
0 4 8 12 16 20 24 28 32 36 40Time (months)
84 67 60 47 36 28 21 13 8 5 181 48 36 28 19 14 6 3 3 1
PAL + LETLET
Number of patients at risk
100
PALOMA-3 Study Design
• Larger trial in women whose cancer previously showed resistance to endocrine therapy (Phase III)
Placebo +
Fulvestrant
Palbociclib +
Fulvestrant• Metastatic breast cancer• ER+/HER2-• Tumor has shown
resistance to endocrine therapy
0 2 4 6 8 10 12Time (Month)
0
10
20
30
40
50
60
70
80
90
100
Prog
ress
ion
Free
Sur
viva
l Pro
babi
lity
(%)
347 279 132 59 16 6PAL+FUL174 109 42 16 6 1FUL
Number of patients at risk
PALOMA 3: Palbociclib delays cancer progression when added to fulvestrant
CI=confidence interval; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival.
Placebo + Fulvestrant
n=174
Palbociclib +
Fulvestrant
n=347
# Events (%) 93 (53.4) 102 (29.4)
Median PFS
3.8(3.5, 5.5)
9.2(7.5, NE)
Hazard Ratio 0.422 (0.318, 0.560)
<0.000001
Similar benefit seen in all subgroups examined
HOW CAN WE OVERCOME RESISTANCE TO ENDOCRINE THERAPY?
Dual Targeting
An endocrine sensitive cell depends on the estrogen receptor
nucleus
Cancer cell
Estrogen receptor
Dual Targeting
In setting of endocrine resistance, other pathways are activated
nucleus
Cancer cell
Estrogen receptor
Growth factor receptor
PI3K
mTOR
Dual Targeting
In setting of endocrine resistance, other pathways are activated
nucleus
Cancer cell
Estrogen receptor
Growth factor receptor
PI3K
mTOR
Dual Targeting
In setting of endocrine resistance, dual targeting may be important
nucleus
Cancer cell
Estrogen receptor
Growth factor receptor
mTOR
PI3K
BOLERO-2 Study Design
• Trial of mTOR inhibitor added to exemestane (AI) in endocrine resistant ER+ advanced breast cancer
Placebo +
Exemestane
Everolimus+
Exemestane• Metastatic breast cancer• ER+/HER2-• Tumor has shown
resistance to endocrine therapy
Everolimus delays cancer progression
4 month improvement in PFS over AI alone
Baselga et al, NEJM 2012
Hormonal therapy
Hormonal therapy Chemotherapy Chemotherapy
Chemotherapy Chemotherapy Chemotherapy
Herceptin + perjeta +
chemotherapyTDM1 Lapatinib +
CapecitabineHerceptin +
chemotherapyHerceptin +
chemotherapy
Hormone receptorpositive
Triple-negative
HER2-Positive
*Note, these are just examples. Each patient is different and treatment is tailored accordingly.
How Do We Treat Metastatic Breast Cancer?
USING THE IMMUNE SYSTEM TO FIGHT CANCER
Immune system targets
• Bacteria• Viruses
Immune system targets
• Bacteria• Viruses
• Transplanted organs
Immune system targets
• Bacteria• Viruses
• Transplanted organs
• Cancer cells
Our immune system has an on/off switch
T-cells are designed to recognize and kill tumor cells
PD-1 acts as an “off-switch” for T-Cells
PD-1/PD-L1 inactivates T-Cells
Antibodies to PD-1 or PD-L1 prevent tumor cells from inactivating T-cells
Antibodies to PD-1 shrinks cancers in the majority of patients with metastatic melanoma
Why such durable responses in very advanced cancers?
• Immune system targets many parts of the cancer (antigens)– Harder for cancer to escape recognition
• Advanced cancers’ frequent mutations make them more “foreign” to immune system
IMMUNOTHERAPY IN BREAST CANCER
Immune therapy in triple negative cancers
• Highest rate of PD-L1 expression
• Highest rate of mutations
• High level of immune cells in the tumor (TILS)
This presentation is the intellectual property of the presenter, Rita Nanda. Contact [email protected] for permission to reprint and/or distribute.
December 9-13, 2014
Change From Baseline in Target Lesions Over Time(Central Review)
0 8 16 24 32 40 48 56-100
-80-60-40-20
020406080
100
Time, weeks
Chan
ge F
rom
Bas
elin
e, %
Analysis cut-off date: November 10, 2014.
On treatmentDiscontinued treatment
What do these trials tell us?
• Provides proof that immunotherapy can work in breast cancer
• Important to note that:– Only patients with PD-L1 positive TNBC were
included– Only a minority of these patients benefited
Immunotherapy in ER+ breast cancer
– Low PD-L1 expression
– Fewer mutations
– Likely will need something to increase recognition by immune system
Other immunotherapy targets in development
Activating Inhibiting
Mellman et al. Nature, 2011
Ipilimumab
PembrolizumabNivolumab
Conclusion
• Patients with ER+ breast cancer have many treatment options– Hormonal therapies (tamoxifen, AI’s, fulvestrant)– Palbociclib + hormonal therapy– Everolimus + hormonal therapy– Chemotherapy
• A better understanding of mechanisms of resistance to therapy is leading to new treatments
• Clinical trials allow access to new therapies and help us make progress
How Can We Do Better?Participate in Trials!
• Clinical trials exist for patients at any step of their breast cancer journey; trials are a part of the continuum of care
• There are benefits to being on a trial!– a larger treatment team– possible exposure to cutting edge new medications– helping other patients with breast cancer
• None of the advances in breast cancer could have happened without patients volunteering to be in trials!
What are clinical trial phases?Clinical trials are conducted in a series of steps (phases) - each phase is designed to answer a separate research question.
• Phase I: Testing a new treatment in a small group to evaluate safety, dose, and side effects.
• Phase II: Evaluating within a larger group the efficacy and safety of a new treatment • Phase III: A comparison study in a large group to determine if a new treatment
works better than standard therapy. These trials typically involve randomization and may have a placebo; the data from a phase 3 trial can be used for FDA drug approval.
FDA approval
How Do I Enter a Trial?
• Your provider will discuss with you trials of interest, review rationale, as well as risks and benefits
• A research RN will review a consent form with you, which describes the structure and details of the trial
• After a consent is signed, there is a “screening” period to determine if you are eligible
• When eligibility is confirmed, then you register and can begin trial therapy
Clinical Trials: FAQs• If I consent to a trial, do I have to stay on it?
– You can leave a trial at any time if either you or your provider thinks being on the trial is no longer in your best interest
• Will I have to pay more to be on a trial?– All normal procedures are billed to insurance; anything beyond normal care is paid
for by the trial. There should be no “upcharge” for being in a trial
• Is being on a trial busy?– Each trial is different and has a different schedule
• Will I know what medicine I am getting? I don’t want a placebo.– In most trials, both patient and provider know exactly what treatment is being given. – Some larger trials use randomization and placebos, and in some cases neither
patient nor provider know identity of study drug. – But in almost every trial with placebo, at minimum a patient receives best standard
of care.