Download Identifying Predictor(s) of Response

Integration of Immunotherapy Across
the Spectrum of Lung Cancer
Karen Kelly, MD
Professor of Medicine
Associate Director for Clinical Research
Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon
Endowed Chair in Cancer Clinical Research
UC Davis Comprehensive Cancer Center
Objectives
1. Review the current status of immunotherapy
2. Identify determinants of response
3. Discuss strategies to enhance efficacy
Case Presentation
DW is a 54-year-old white male with a T2aN3M0, Stage III-B
squamous carcinoma of the left lung diagnosed in December
2013. The patient received concurrent chemoradiation therapy
with weekly pacltaxel and carboplatin followed by two cycles of
full dose paclitaxel + carboplatin.
Patient achieved a PR but 4
months later a surveillance scan
revealed liver metastases. His
sister is a nurse and they want
to know about immunotherapy.
PMH: Type II DM, HTN, COPD,
sleep apnea
SH: Former smoker quit in 2008; 30 pack years
PE: Mildly obese WM; PS 0
Case Presentation
I informed the patient that an immune checkpoint
inhibitor (ICI) was not FDA approved. I evaluated
him for an ICI clinical trial but he was ineligible due
to lack of tissue and he was too anxious to wait for
a biopsy to be performed and analyzed.
What would you recommend?
1. Gemcitabine and carboplatin
2. Docetaxel
3. Docetaxel and ramicirumab
4. Gemcitabine
5. RFA to the two liver lesions
Case Presentation
The patient was treated with docetaxel for 4 cycles
and progressed in the liver with multiple new
lesions. He underwent a liver biopsy and was
placed on a phase I trial of an PDL-1 inhibitor. He
is s/p 2 cycles with a MR
Basic Immunology
The innate response is the rapid
recognition and eradication of invading
pathogens (macrophages, monocytes,
eosinophils, NK cells) and soluble
mediators (activation of the complement
cascade and acute phase reactants)
Activation of the innate response
triggers the expression of costimulatory
molecules and cytokines that allows for
the specific adaptive response by
cellular (T and B cells) and
humoral elements.
Activation requires antigenic fragments
be presented by MHC to antigen
specific receptors on cytotoxic (CD8) T
cells
Ploegh HL Cancer Immunol Res 1:5-10; 2013; Ploegh HL Science 280 248-253, 1998
History of Immunotherapy in Lung Cancer
Randomized Phase III Trials
MAGRIT
Stage 1B-III
Adj MAGE-A3
vs. Placebo
SWOG
LS-SCLC
Maintenance
α Interferon
vs. OBS
LCSG 771
Stage I NSCLC
Adj BCG
vs. Placebo
1970
1970
START2
Stage III NSCLC
Adj Tecemotide
vs. Placebo
SILVA
LS-SCLC
Maint Bec2/BGG
vs. Observation
CALGB
LS-SCLC
Chemo XRT ±
BCG
1980
1980
1990
1990
2000
2000
START
Stage III NSCLC
Adj Tecemotide
vs. Placebo
2010
2010
Cancer Immunity Cycle
Chen DS, et al. Immunity. 39:1-10, 2013.
T Cell Targets For Immunoregulatory
Antibody Therapy
Mellman I et al. Nature: 480: 480-9, 2011
Immune Checkpoint Inhibitors
T cell death
Sznol M et al Clin Can Res 19:1021-1034, 2013
Comparison of Therapeutic Antibodies
Blocking PD-1/PDL-1 Interaction
IgG1 wt
Examples: Curetech Anti-PD-1
†at
IgG4 hinge mutant
IgG1 Engineered
BMS Anti-PD-1
Merck Anti-PD-1
Genentech Anti-PD-L1
MedI-4736
ADCC intact 
Potential to deplete activated T
cells and TILs and diminish
activity
40% reduced ADCC† 
Potential to deplete activated T
cells and TILs and diminish
activity
Blocks PD-1/PD-L2 interaction
in lungs 
Potential for autoimmune
pneumonitis
Blocks PD-1/PD-L2 interaction
in lungs 
Potential for autoimmune
pneumonitis
No ADCC† 
Decreased potential to deplete
activated T cells and TILs
Leaves PD-1/PD-L2 interaction
intact in lungs 
Decreased potential for
autoimmune pneumonitis
Blocks PD-L1/B7.1 interaction 
Potential for enhanced priming
clinically relevant doses
Courtesy of Dr. Herbst
Safety, Activity, and Immune Correlates of
Anti–PD-1 Antibody in Cancer
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD,
Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L,
Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S,
McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M.
No. Pts
OR (CR/PR)
No. Pts (%)
SD 24 wk
No. Pts (%)
PFS
(mos,median)
NSCLC
(1-10)
129
22 (17)
13 (10)
2.3
MEL
(0.1-10)
107
33 (31)
7 (7)
3.7
RCC
(1 or 10)
34
10 (29)
9 (27)
7.3
Tumor Type
(dose, mg/kg)
Immune Checkpoint Inhibitors
Anti-tumor activity consistent across the drug class
N
RR
N (%)
Nivolumab1
129
22 (17)
MK-34752,3
33
129
7 (21)
25 (19)
MPDL3280A4
53
12 (23)
BMS 9365595
49
5 (10)
MEDI-47366
6
3/6 (50)
Agent
NSCLC
1Brahmer
et. al. WCLC, 2013, 2Garon et. al. WCLC 2013, 3Ghandi et. al. AACR 2014, 4Horn et. al. WCLC 2013,
5Brahmer et. al. NEJM 2012, 6 Khleif et. al. WCLC 2013
Characteristics of Responses
in NSCLC Patients Treated With Nivolumab
Time to and duration of
response while on
treatment
Ongoing response
Squamous
Time to response
Response duration following
latest reported dose of therapy
Non-squamous
0
16
32
48
64
80
96
112
128
144
160
Time (week)
• Response occur within 8-12 weeks (black dot)
• Responses occur in nonsquamous and squamous histology
• Responses can last after agent has been discontinued (red bar)
Brahmer J et al. J Thorac Oncol 2013; 8(2s), abstr MO18.03, S365
OS by Nivolumab Dose in NSCLC Patients
Group
100
Censored
90
80
Median OS, mo (95% CI)
1 mg/kg
9.2 (5.3, 11.1)
3 mg/kg
14.9 (7.3, –)
10 mg/kg
9.2 (5.2, 12.4)
OS (%)
70
1-year OS Rate 56% (17 patients at risk)
60
50
2-year OS Rate 45% (9 patients at risk)
40
30
20
10
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
Months Since Treatment Initiation
 ORR was 3%, 24.3% and 20.3%, respectively for nivolumab 1, 3, and 10
mg/kg doses, respectively
Rizvi et al. LALC Meeting 2014
Mechanism of Action
CD8+ T cells
Activation of cytotoxic T cells
Increased γ interferon
Herbst RS et al. Nature 515: 563-7, 2014
Phase II Trial: Immune Checkpoint Inhibitor
Ramalingam S et al. CMSTO, 2014
Phase II Trial: Immune Checkpoint Inhibitor
Ramalingam S et al. CMSTO, 2014
Phase II Trial: Immune Checkpoint Inhibitor
Ramalingam S et al. CMSTO, 2014
Phase II Trial: Immune Checkpoint Inhibitor
Ramalingam S et al. CMSTO, 2014
Phase II Trial: Immune Checkpoint Inhibitor
*Based on July 2014 DBL; Symbols represent censored observations
Ramalingam S et al. CMSTO, 2014
CheckMate -017, A Phase 3 Study of Opdivo (Nivolumab) Compared to
Docetaxel in Patients with Second-Line Squamous Cell Non-small Cell
Lung Cancer (BMS press release, January 2015)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Previously Tx
Squamous Cell
Histology
N=272
Nivolumab
Nivolumab
Nivolumab
3 mg/kg q 3 wks
Docetaxel
75 mg/m2 q 3 wks
Docetaxel
Standard of Care Treatment Algorithm for Patients
with Advanced NSCLC with PS 0-2
Non-Squamous Cell
ALK Gene Fusion
ROSI Gene Fusion
EGFR
Mutation +
Squamous Cell
Wild type
First line
treatment
Crizotinib
Erlotinib
Afatinib
Platinum with Pemetrexed
Or
Platinum with Taxane
Platinum Doublet***
+ Bevacizumab*
Maintenance
(responders only)
+ Bevacizumab
Pemetrexed
Erlotinib
Second/Third
Line treatment
ALK+
Treatment as
per wild type
algorithm
Pemetrexed**
Docetaxel**
Erlotinib**
Nivolumab
Docetaxel +
Ramucirumab
*Bevacizumab is not recommended in patients with untreated brain metastases, clinically significant hemoptysis or tumor cavitation
**Treatment agent based on prior treatments, side effects profile, patient preference
***Common platinum partners include Paclitaxel, Docetaxel, Abraxane, Gemcitabine, Vinorelbine
Erlotinib
Second line Phase III Trials
Trial
Agent
PD-L1 Status
Checkmate
057
Nivolumab vs. docetaxel
(non-squamous)
Not required
Keynote 010
Pembrolizumab vs. docetaxel
PD-L1 positive
OAK
MPDL3280A vs. docetaxel
PD L1 positive
LUNG-MAP
MEDI4736 vs docetaxel
Not required
First Line Immunotherapy in Advanced NSCLC
KEYNOTE-001: Randomized Dose Comparison
•
•
•
•
•
•
•
•
Treatment-naïve, stage IV NSCLC
ECOG PS 0-1
EGFR negative
No ALK rearrangement
PD-L1 positive (≥1% staining)
No systemic steroid
No autoimmune disease
No or stable brain mets
Pembro
10 mg/kg Q3W
Progressive
Disease
Pembro
10 mg/kg Q2W
Progressive
Disease
R*
1:1
Mandatory Biopsy
Within 60 Days of First Dose
*First 11 patients were randomized to 2 mg/kg or 10 mg/kg Q3W
Objectives
•
Evaluate safety, tolerability, and clinical activity of pembrolizumab
•
Evaluate correlation between clinical activity of pembrolizumab and PD-L1 expression
Balmanoukian SA, et al. Abstract #2
Antitumor Activity by Pembrolizumab Dose
RECIST v1.1, Central Review
Pembro
Dose
n
irRC, Investigator Review
ORR
DCR
ORR
DCR
n (%)
[95% CI]
n (%)
[95% CI]
n (%)
[95% CI]
n (%)
[95% CI]
n
2 mg/kg
Q3W
6
2 (33%)
[4%-78%]
3 (50%)
[12%-88%]
6
4 (67%)
[22%-96%]
5 (83%)
[36%-100%]
10 mg/kg
Q3W
20
4 (20%)
[6%-44%]
14 (70%)
[46%-88%]
22
10 (46%)
[24%-68%]
18 (82%)
[60%-95%]
10 mg/kg
Q2W
16
5 (31%)
[11%-59%]
10 (63%)
[35%-85%]
17
7 (41%)
[18%-67%]
12 (71%)
[44%-90%]
Total
42
11 (26%)
[14%-42%]
27 (64%)
[48%–78%]
45
21 (47%)
[32%-62%]
35 (78%)
[63%-89%]
Interim Median PFS:
• 27.0 weeks (95% CI, 13.6-45.0) by RECIST v1.1 per central review
• 37.0 weeks (95% CI, 27.0-NR) by irRC per investigator review
Maximum Percent Change from Baseline in
Tumor Size in Evaluable Patients (N=35)
(Central Review, RECIST v1.1)
10 mg/kg Q3W
10 mg/kg Q2W
2 mg/kg Q3W
*
Still on treatment
*
* * * *
* *
*
*
* *
* * *
* *
* * *
* *
Rizvi NA et al. J Clin Oncol. 32(5s) Abstract 8007, 2014
Time to and Durability of Response
Pembro 2 mg/kg Q3W
Pembro 10 mg/kg Q3W
Pembro 10 mg/kg Q2W
Partial Response
Progression
On Treatment
RECIST v1.1 Central Review
Individual Patients Treated With Pembro
Individual Patients Treated With Pembro
irRC Investigator Review
0
•
•
10
20
30
Time, weeks
40
11 of 11 (100%) responses are ongoing
– Median duration of response not reached
(median follow-up, 36 weeks)
7 of 11 (64%) responders remain on treatment
– Median duration of treatment: 27.1 weeks
(range, 15.0+ – 48.3+)
0
50
•
10
20
30
40
Time, weeks
50
60
19 of 21 (90%) responses are ongoing
– Median duration of response not reached
(median follow-up, 36 weeks)
• 18 of 21 (86%) responders remain on treatment
– Median duration of treatment: 27.1
weeks (range, 6.1 – 57.1+)
Rizvi NA et al. J Clin Oncol. 32(5s) Abstract 8007, 2014
First Line Immunotherapy in
Advanced NSCLC
Pembrolizumab
Number of Patients
45
ORR
26%
SD
38%
PFS (median)
27 weeks
Nivolumab
20
30%
35%
36 weeks
Gettinger SN et al. ASCO 2014 #8024
First Line Immunotherapy + Chemotherapy in
Advanced NSCLC
CA209-012 (CheckMate 012) Study Design:
Chemotherapy-naïve patients with stage IIIB or IV NSCLC
Squamous
Non-squamous
Nivolumab 10 mg/kg IV Q3W +
Gem 1250 mg/m2
+ Cis 75 mg/m2
(four 21-day cycles)
Nivolumab 10 mg/kg IV Q3W +
Pem 500 mg/m2
+ Cis 75 mg/m2
(four 21-day cycles)
Any histology
Nivolumab 10 mg/kg IV Q3W +
Pac 200 mg/m2
+ Carb AUC 6
(four 21-day cycles)
Nivolumab 5 mg/kg IV Q3W +
Pac 200 mg/m2
+ Carb AUC 6
(four 21-day cycles)
Nivolumab 5 mg/kg IV Q3W
until disease progression or
unacceptable toxicity
Nivolumab 10 mg/kg IV Q3W
until disease progression or unacceptable toxicity
Primary objective: safety and tolerability
Secondary objectives: ORR and PFS rate at 24 weeks
Exploratory objective: OS
Antonia SJ et al. CMSTO Abstract #3, 2014
Efficacy Endpoints
Nivolumab 10 mg/kg
Nivolumab 5 mg/kg
Gem/Cis
(n = 12)
Pem/Cis
(n = 15)
Pac/Carb
(n = 15)
Pac/Carb
(n = 14)
ORR, %
33
47
47
43
SD, %
58
47
27
43
18-month OS rate, %
33
60
40
86
Median OS, weeks
51
83
65
NR
NR = not reached
Overall Survival by Treatment Arm
Regimen
100
mOS (wks)
Nivolumab 10 mg/kg + Gem/Cis
51
Nivolumab 10 mg/kg + Pem/Cis
83
x Nivolumab 10 mg/kg + Pac/Carb
65
Nivolumab 5 mg/kg + Pac/Carb
NR
OS (%)
80
60
40
20
0
B/L
12
24
36
48
60
72
84
Time Since First Dose (Weeks)
96
108
120
132
Ongoing Phase III Trials
Trial
Line of
Therapy
Agent
PD-L1 Status
CheckMate 026
First
Nivolumab vs.
investigator choice
chemotherapy
PD-L1 positive
Keynote 042/42
First
Pembrolizumab vs.
investigator choice
chemotherapy
PD-L1 positive
ARCTIC
Third Line
MEDI4736 vs.
Chemotherapy
Not required
PACIFIC
Locally
Advanced
Following concurrent
chemo-RT vs. placebo
Not required
Phase III Trials in Development:
1) Maintenance therapy in advanced NSCLC
2) Adjuvant therapy
Pseudo-Progression
iRECIST
May occur in 7-10% of patients
Comparison: RECIST-irRC Criteria*
RECIST
irRC
New, measurable
lesions (i.e. ≥5 x 5 mm)
Always represent PD
Incorporated into tumor burden
New, nonmeasurable
lesions (i.e. <5 x 5 mm)
Always represent PD
Do not define progression (but preclude
irCR)
Non-index lesions
Changes contribute to defining BOR of CR,
PR, SD, and PD
Contribute to defining irCR (complete
disappearance required)
Complete Response
(CR)
Disappearance of all extranodal target
lesions. All pathological lymph nodes must
have decreased to <10 mm in short axis
Disappearance of all lesions in two
consecutive observations not less than 4
weeks apart
Partial Response (PR)
At least a 30% decrease in the SLD of target
lesions, taking as reference the baseline sum
diameters
≥50% decrease in tumor burden
compared with baseline in two
observations at least 4 weeks apart
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR
nor sufficient increase to qualify for PD
50% decrease in tumor burden compared
with baseline cannot be established nor
25% increase compared with nadir
Progressive Disease
(PD)
SLD increased by at least 20% from the
smallest value on study (including baseline, if
that is the smallest)
The SLD must also demonstrate an absolute
increase of at least 5 mm (two lesions
increasing from 2 mm to 3mm, for example,
does not qualify)
At least 25% increase in tumor burden
compared with nadir (at any single time
point) in two consecutive observations at
least 4 weeks apart
*Total Burden=SPD index lesions + SPD new, measurable lesions
Wolchok J et al Clin Can Res 19:7412-7420, 2009
Treatment Related Adverse Events
• Fatigue is the most common AE (24%)
• Grade 3-4 AEs are uncommon (6-12.6%)
System
Immune Related Adverse Events
Gastrointestinal
Colitis (Diarrhea, perforation)
Renal
Acute Interstitial Nephritis (Increased serum
Creatinine)
Pulmonary
Pneumonitis (dyspnea, cough)
Dermatologic
Dermatitis (Lichenoid/ spongiotic dermatitis,
rash), Vitaligo
Hepatic
Hepatitis (elevated LFTs)
Neurologic
Central and Peripheral (Aseptic Meningitis,
Guillan-Barre Syndrome, Myasthenia Gravis
Endocrine
Hypophysitis, thyroiditis, adrenal insufficiency
Ocular
Uveitis, Iritis
Identifying Predictor(s) of Response
Nivolumab
(anti-PD-1)
Pembrolizumab MEDI4736
MPDL3280A
(anti-PD-1) (anti-PD-L1) (anti-PD-L1)
80
70
60
50
40
all patients
PD-L1+
30
PD-L1-
20
10
0
Responses are higher in PD-L1+ tumors but seen in PD-L1- tumors
Lipson, Taube, et al. Semin Oncol. In press.
Identifying Predictor(s) of Response
Challenges
PD-L1 negative
PD-L1 positive (TC)
PD-L1 positive (IC)
PD-L1 IHC Expression By Various Assays
Tumor
GNE
DAKO 28-8
Merck CC23
5H1
Melanoma
40%
45%
71%
42%
45-50%
49%
45%
(25% if ≥50% Staining)
NSCLC
Renal
20%
24%
Bladder
21%
28%
Head And Neck
31%
46%
Glioblastoma
25%
100%
• No validated assay
• Variable cut off levels for positivity
Identifying Predictor(s) of Response
Immune Cell PD-L1 Expression
Patients treated with MDPL3280A
NSCLC
Herbst RS et al. Nature 515: 563-7, 2014
Identifying Predictor(s) of Response
Prevalence of PD-L1 IHC Expression?
Prognostic significance of PD-L1 Expression?
Author
N
Stage
(TC)PD-L1 (IC)PD-L1
Prognosis
D’Incecco
2015
122
IV
55.3%
Herbst
2015
184
IV
24%
Velcheti
2014
204
340
I-IV
I-IV
25%
36%
PD-L1 associated
with better survival
Mu
2011
109
I-IV
53%
PD-L1 associated
with poor survival
254 (adeno)
37 (adeno)
139 (squamous)
16 (squamous)
I-IIIa
IIIb-IV
I-IIIa
IIIb-IV
31%
19%
31%
31%
Kowanetz
2010
D’Incecco A et al. Br J Can 112: 95-102, 2015; Herbst RS et al. Nature 515: 563-7, 2014
Velcheti V et al. Lab Invest 94: 107-16, 2014; Mu CY et al. Med Oncol 28: 682-8, 2011
Kowanetz M et al. WCLC 2013 Abstract
26%
49%
27%
54%
38%
Identifying Predictor(s) of Response
Tumor-Infiltrating Lymphocytes Ovarian
(TIL cells)
The presence of TIL
cells at diagnosis
correlates with
improved clinical
outcomes
CD3/AE1AE3
Colon
Melanoma
Breast
Zhang L et al. NEJM 348:203-13, 2003
Galon J et al. Science 313: 1960-4, 2006
Azimi F et al. J Clin Oncol 30: 2678-83, 2012
Adams S et al. J Clin Oncol 2014 [Epub ahead of print]
Identifying Predictor(s) of Response
Tumor-Infiltrating Lymphocytes (TIL cells)
• 552 patients from two cohorts
• TIL cells did not correlate with OS
• CD8 expression is an independent
favorable prognostic marker
Schalper, KA et al. JNCI 107:epublished Feb 3, 2015
Identifying Predictor(s) of Resistance
CD8 negative
Minimal CD8 expression
Tumor rim CD8 expression
No evidence of CD8 T cell activity
Herbst RS et al. Nature 515: 563-7, 2014
Identifying Predictor(s) of Response
Mutational Burden
n=17
n=17
n=16
n=18
11/43
1/10
Median PFS
NR vs 3.4 mo
HR 0.19 (0.08-0.47)
P = 0.0004
RR 59% vs 12%
•
•
•
•
Median PFS
NR vs 3.5 mo
HR 0.15 (0.06-0.39)
P = 0.0001
ORR 56% vs 17%
Median PFS
14.5 mo vs 3.5 mo
HR 0.23 (0.09-0.58)
P = 0.0002
Median values used to determine high vs low
No mutations or copy number alterations in CD274 (PDL-1 gene)
Smoking history did not discriminate for responders
Molecular smoking signature correlated with mutational burden
Rizvi NA et al. Science 348:124-8, 2015
Combined Immunomodulation
Chen DS, et al. Immunity. 2013;39:1-10.
Combined Immunomodulation
Phase I Trial of Ipilumumab and Nivolumab in First Line NSCLC N=49
ORRs: 8/49 (16%); PFS: 14 -16 wks
Treatment related Grade 3 or 4 AE (49%); Discontinuation (35%)
Antonia SJ, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8023)
Top Questions about
Immune Checkpoint Inhibitors
•
•
•
•
•
•
Anti- PD1 vs. Anti-PDL1?
Ideal schedule/duration of therapy?
Will/should PDL1 status guide treatment?
Sequencing/Maintenance Therapy?
Optimal Combinations?
Mechanisms of Resistance?
Summary
• Immune checkpoint inhibitors represent a new class of
agents that are showing great promise for the treatment
of advanced NSCLC.
• Immune checkpoint inhibitors have a distinct toxicity
profile and response assessment that must be taken into
account in treating patients with these agents.
• Immune checkpoint inhibitors represent the first of
several strategies targeting the immune system for
therapeutic benefit.
I have your molecular profile,
tumor PDL-1, Immune PDL-1
and CD8 expression levels and
a variety of other tumor assay
results for us to discuss
and use to select your
treatment
Question
• Mrs. LW is a 45 year old Asian never smoker with stage
IV adenocarcinoma of the lung with multiple bilateral
pulmonary nodules and bone metastases. Her tumor
was EGFR/ALK/ROS-1 wild type and PDL-1 negative.
What is her chance of responding to an immune
checkpoint inhibitor?
1. 70%
2. 50%
3. 10%
4. 5%
Question
• What immune related adverse event occurs in >5% of
patients receiving nivolumab?
1.
2.
3.
4.
5.
Colitis
Pneumonitis
Hepatitis
Hypthyroidism
Uveitis