Download Eric Van Cutsem, UZ Leuven

Immunooncology in GI cancer:
Anti-PD and anti-PDL antibodies
Prof Eric Van Cutsem, MD, PhD
Digestive Oncology
Leuven, Belgium
[email protected]
History of Checkpoint Inhibitors:
Key Milestones
• Checkpoint inhibitors, discovered in the 1990s, have had a major impact on
the treatment of multiple cancer types, particularly over the past 5 years
APPROVALS BY CANCER TYPE
Bladder cancer
R/M SCCHN
Classical Hodgkin’s
lymphoma
Melanoma
NSCLC
RCC
Nivolumab4
Ipilimumab2
Pembrolizumab2
Nivolumab (SQ)2
Nivolumab6
Nivolumab3
2011
2012
2013
2014
Nivolumab2
Nivolumab (NSQ)2
Nivolumab7
Nivolumab + ipilimumab2
Pembrolizumab
(PD-L1+)2,5
2015
Pembrolizumab1
Nivolumab + ipilimumab1
1
Nivolumab
Pembrolizumab (PD-L1+)1
First checkpoint
Nivolumab (NSQ)1
inhibitor
1
(ipilimumab)
Nivolumab (SQ)1
2016
Nivolumab1
Atezolizumab1
Nivolumab1
Atezolizumab1
Nivolumab1
Pembrolizumab (1L)1
Pembrolizumab1
1. U.S. Food and Drug Administration. http://www.fda.gov. Accessed November 11, 2016. 2. European Medicines Agency. http://www.ema.europa.eu. Accessed
November 11, 2016. 3. Human anti-human pd-1 monoclonal antibody "OPDIVO® intravenous infusion 20 mg/100/mg" receives manufacturing and marketing approval in
Japan for the treatment of unresectable melanoma. [press release] public [email protected]; July 4, 2014. 4. ONO Pharmaceutical Co, Ltd. [press release]. March 23,
2015. 5. Merck [press release]. June 27, 2016. http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda-pembrolizumab-approved-europeancommission-patients-a. Accessed August 8, 2016. 6. ONO Pharmaceutical Co, Ltd. [press release]. December 17, 2015. 7. Bristol-Myers Squibb Company [press
release]. November 22, 2016.
Tumors Use Complex, Overlapping Mechanisms to
Evade and Suppress the Immune System1
A. Ineffective presentation
of tumor antigens
(eg, downregulation of MHC I)
B. Recruitment of immunosuppressive
cells with inactive T cells
(eg, Tregs, MDSCs)
DC
Inactive T cell
Tumor-associated
antigens
D. Tumor release of
immunosuppressive factors
(eg, TGF-β, IDO, IL-10, IL-4
from CSCs2)
Active T cell
Tumor
cells
Immunosuppressive
factors
Treg
C. T-cell checkpoint
dysregulation
(eg, CD27, CD137, CTLA-4,
LAG-3, OX-40, PD-1, TIM-3)2
CD, cluster of differentiation; CSC, cancer stem cells; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IDO, indoleamine 2,3-dioxygenase; LAG-3;
lymphocyte activation gene-3; IL, interleukin; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; PD-1, programmed
death-1; TGF-β, transforming growth factor beta; TIM-3, T cell immunoglobulin and mucin domain-3; Treg, regulatory T cell.
1. Vesely MD et al. Ann Rev Immunol. 2011;29:235-271. 2. Todaro M et al. Cell Stem Cell. 2007;1(4):389-402. 3. Clinicaltrials.gov.
General Approaches for Cancer
Immunotherapy
Immune agonists
Peptide vaccine
DC vaccine
Genetic vaccine
IL-2
IFN
IL-15
IL-21
Active immunotherapy
Adoptive cell transfer
immunotherapy
T-cell cloning
CD40
CD137
OX40
Immune checkpoint
inhibitors
CTLA-4
PD-1
TCR or CAR
genetic engineering
Slide credit: clinicaloptions.com
Potential Immuno-oncology Targets
Dendritic cell
TumorRegulatoryassociated
T cell
T cell macrophage
(APC)
NK cell
Tumor cells
Immune Cell Targets1-5
Activating
CD137
OX40
CD27
Inhibitory
CTLA-4
PD-1
LAG-3
CSF1R
TGFR
IDO
Tumor Cell Target2,6-10
PD-L1
BCR-ABL
CXCR4
HER2
Glypican-3
CD30
Immune
Stimulation/Modulation11
GM-CSF
IL
Oncogenic virus targets
Checkpoint inhibitor strategies in gi cancers
Activating receptors*
Inhibitory receptors*
CTLA-4
CD27
PD-1
OX40
T cell
TIM-3
CD137
LAG-3
Adapted from Pardoll DM 2012.
Tumors may exploit immune checkpoint pathways
to evade immune detection
* The image shows only a selection of the receptors/pathways involved.
Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
Rationale for Combination Immunotherapy
Sharma P, et al. Science. 2015;348:56-61.
Nivolumab[1]
100
80
First occurrence of new lesion
Pt off study
60
40
20
0
-20
-40
-60
-80
-100
0 10 20 30 40 50 60 70 80 90 100110 120 130 140
Wks Since Treatment Initiation
 ORR
– Melanoma: 28%
– NSCLC: 18%
– Renal cell cancer: 27%
Change in Target Lesions From Baseline (%)
Change in Target Lesions From Baseline (%)
Response Rates With Anti–PD-1 Antibodies
Pembrolizumab[2]
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Prior ipilimumab treatment
No prior ipilimumab treatment
Individual Pts Treated With Pembrolizumab
 Confirmed ORR
– Melanoma: 38% (comparable ±
previous ipilimumab)
1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.
2. Hamid O, et al. N Engl J Med. 2013;369:134-144.
OS plateau demonstrates
long-term benefit
100
80
3-year OS
rate=22%
20
0
0
OS (%)
OS (%)
100
80
60
60
40
100
Checkmate 025: Nivo Monotherapy in 2L+ RCC2
Ipilimumab
Censored
12 24 36
60
72
84
96
60
40
2-yr OS =23%
20
Nivolumab
Docetaxel
2-yr OS=8%
0
6
9
12
15
18
21
0
100
80
3
24
27
30
40
Nivo-1/Ipi-3
Nivo 3
20
0
0
3
6
9
12
15
18
21
24
Time (months)
27
30
33
12 15 18 21 24 27 30 33
Time (months)
Checkmate 057: Non-squamous NSCLC3
40
2-yr OS=29%
Nivolumab
2-yr OS=16%
Docetaxel
0
0
100
80
60
60
9
20
OS (%)
OS (%)
Checkmate 032: SCLC4
6
60
33
80
3
80
Time (months)
100
Nivolumab
Everolimus
40
20
108 120
Time (months)
Checkmate 017: Squamous NSCLC3
0
HR 0.73, 95% CI 0.57–0.93,
P=0.002
0
48
OS(%)
OS (%)
10-Year Follow-up With Ipilimumab in Melanoma1
40
20
0
3
6
9
12
15
18
21
24
27
30
Time (months)
Checkmate 141: Nivolumab in R/M SCCHN After Platinum Therapy5
1-year OS=36.0%
Nivolumab
Investigators Choice
0
3
6
1-year OS=16.6%
9
12
15
18
Time (months)
Nivolumab is currently not approved for SCLC.
1. Schadendorf D et al. J Clin Oncol. 2015;33(17):1889-1894. 2. Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813. 3. Borghaei H et al. Poster presentation at
ASCO 2016. 9025. 4. Hellmann MD et al. Oral presentation at WCLC 2016. 4397. 5. Ferris RL et al. Oral presentation at ASCO 2016. 6009.
Rationale for Immuno-oncology
in GI Cancers
 New treatments are needed in gastrointestinal (GI) cancers to
improve survival over standard of care1-3
 Subsets of GI cancers are highly immune-infiltrated3-6
 In CRC, MSI-H tumors have an exceptionally high mutational load and
increased levels of tumor-infiltrating lymphocytes (TILs)3-4
 EBV positive gastric cancers have a higher percentage of tumor
infiltrating lymphocytes compared to EBV negative cancers5
 Checkpoint proteins are highly expressed in some GI cancers, and
immune-related biomarkers have prognostic significance3,6-9
1. Mohamed A et al. Crit Rev Oncol Hematol. 2014;91(2):186-196. 2. Ohashi S et al. Gastroenterology. 2015;149(7):1700-1715. 3. Jacobs J et al. J Immunol Res.
2015;2015:158038. 4. Le DT et al. N Engl J Med. 2015;372(26):2509-2520. 5. Grogg KL et al. Mod Pathol. 2003; 16(7): 641-651. 6.Tsuchikawa T et al. Clin Exp
Immunol. 2011;164(1):50-56. 7. Ohigashi Y et al. Clin Cancer Res. 2005;11(8):2947-2953. 8. Raufi AG, Klempner SJ. J Gastrointest Oncol. 2015;6(5):561-569. 9.
Zhang L et al. Int J Clin Exp Pathol. 2015;8(9):11084-11091.
New Molecular Subtypes in Gastric Cancer May
Help to Predict Response to Therapies
•
•
•
•
•
•
•
•
Microsatellite Instability (MSI)
Gastric cancer subtypes
Hypermutation
Gastric-CIMP
MLH1 silencing
Mitotic pathways
Genomically Stable (GS)
Diffuse histology
CDH1, RHOA mutations
CLDN18-ARHGAP fusion
Cells adhesion
Chromosomal Instability (CIN)
• Intestinal histology
• TP53 mutation
• RTK-RAS activation
•
•
•
•
•
Epstein-Barr Virus (EBV)
PIK3CA mutation
PD-L1/2 overexpression
EBV-CIMP
CDKN2A silencing
Immune cell signaling
TCGARN. Nature. 2014;513(7515):202-209.
PD-L1 Status and Outcome:
Gastric Cancer
PD-L1 expression
Negative
Positive
Negative-censored
Positive-censored
Cumulative Survival
1.0
0.8
PD-L1 Negative
(n=65)
0.6
0.4
PD-L1 Positive
(n=67)
0.2
0.0
0
24
48
72
96
120
144
168
Time after surgery (months)
PD-L1 is associated with poor prognosis in gastric cancer patients
Zhang L et al. Int J Clin Exp Pathol. 2015;8(9):11084-11091.
New Molecular Subtypes in Colorectal Cancer May
Help to Predict Response to Therapies
Colorectal cancer subtypes
•
•
•
•
MSI Immune (14%)
MSI, CIMP high, hypermethylation
BRAF mutations
Immune infiltration/activation
Worse survival after relapse
Canonical (37%)
• SCNA high
• WNT and MYC activation
Transverse
colon
Ascending
colon
Sigmoid
colon
Descending
colon
Mesenchymal (23%)
• SCNA high
• Stromal infiltration, TGF-β activation,
angiogenesis
• Worse relapse-free and overall survival
Metabolic (13%)
• Mixed MSI status, SCNA low, CIMP low
• KRAS mutations
• Metabolic deregulation
Rectum
Guinney J et al. Nat Med. 2015;21(11):1350-1356.
Immuno-oncology Therapies for Tumor
Immune Subgroups in CRC
Immune
Subgroup
Escape
Mechanisms
Immuno-therapeutic
Goals
Immune
checkpoints:
PD-1 axis, LAG3, CTLA-4
Boost intratumor CTLs
Inflammatory
CRC
mesenchymal
• Hypoxia
• TGFβ
• PD-1 axis
• Dampen inflammation
• Anti-angiogenic
and suppression
• Anti-TGFβ
• Establish normoxia
• Checkpoint
• Boost intratumor
blockade
suppressed CTLs
Immune
neglected
CRC canonical
and metabolic
Low class I MHC
expression
• Attract CTLs in tumors • CAR T cells
• Bypass class I MHC
• Bi-specific
presentation
antibodies
Immunogenic
Molecular
Subgroups
CRC
hypermutated
Potential
Approach
Checkpoint
blockade
Becht E et al. Curr Opin Immunol. 2016;39:7-13.
Gastric cancer
Pembrolizumab: KEYNOTE-0121,2
Gastric cancer cohort of a phase Ib multicohort study of pembrolizumab in subjects with
advanced solid tumors1
N=39
Key Eligibility Criteria
• Recurrent, metastatic or persistent,
PD-L1–positive (≥1%) GC or GEJ
• ECOG PS ≤1
• Any number of prior treatment
regimens
•
•
•
•
Pembrolizumab
10 mg/kg Q2W
For 24 months or until confirmed
disease progression, death,
unacceptable toxicity, withdrawal
of consent, or investigator decision
Primary Outcome Measures: AEs, AEs leading to discontinuation, ORR by RECIST v1.1
Secondary Outcome Measures: ORR by Central Radiology Assessment (Asia Pacific participants)
67% of patients had received ≥2 prior therapy lines
40% of the screened patients were PD-L1–positive
AE, adverse event; ECOG, Eastern Cooperative Oncology Group; GC, gastric cancer; GEJ, gastro-esophageal junction; ORR, objective response
rate; PD-L1, programmed death ligand-1; PS, performance status; Q2W, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors.
1. Clinicaltrials.gov. NCT01848834. 2. Muro K et al. Lancet Oncol. 2016;17(6):717–726.
KEYNOTE-012: Objective Response
Central Review*
Confirmed Response by
RECIST v1.1
Investigator Review
Asia
(n=17)
Rest of the World
(n=19)
Asia
(n=19)
Rest of the World
(n=20)
24 (7–50)
21 (6–46)
37 (16–62)
30 (12–54)
Complete response, %
0
0
0
0
Partial response, %
24
21
37
30
Stable disease, %
Progressive disease,
18
11
11
5
41
63
53
65
No assessment†, %
0
5
0
0
Not determined, %
18
0
0
0
Time to response, wks
8
8
8
8
Duration of response, wks
40
NR
40
42
ORR, % (95% CI)
Best overall response
%
*Three patients were not included in the central review because the central reviewer deemed their tumors not to be measurable. †Patient
discontinued therapy because of clinical progression before the first scan.
Muro K et al. Lancet Oncol. 2016;17(6):717–726.
Nivolumab ± Ipilimumab:
CheckMate 0321,2
Phase I/II, open-label, multi-tumor cohort study in patients who received nivolumab
monotherapy or in combination with ipilimumab.
N=160
Key Eligibility Criteria
• Locally advanced or metastatic
gastric, esophageal, or GEJ cancer
• Progression on ≥1 prior
chemotherapy
• ECOG PS 0 or 1
•
•
n=59
n=49
n=52
Nivolumab 3 mg/kg Q2W
Nivolumab 1 mg/kg +
Ipilimumab 3 mg/kg Q3W for
4 cycles
Nivolumab 3 mg/kg +
Ipilimumab 1 mg/kg Q3W for
4 cycles
Nivolumab
3 mg/kg Q2W
Primary Endpoint: ORR by RECIST v1.1
Secondary and Exploratory Endpoints: TRAEs, OS, PFS, DOR, PK/PD/Immunogenicity, PD-L1, MSI
79% of patients had received ≥2 prior therapy lines
DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; GEJ, gastro-esophageal junction; MSI, microsatellite instability; ORR, objective response
rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival; PK/PD, pharmacokinetic/pharmacodynamics; PS= performance
score; Q2W, every 2 weeks; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; TRAE, treatment-related adverse event.
1. Janjigian YY et al. Oral presentation at ASCO 2016. 4010. 2. ClinicalTrials.gov. NCT01928394.
CheckMate 032: PD-L1 & Objective Response
Nivo 3 mg/kg
(n=59)
Nivo 1 mg/kg +
Ipi 3 mg/kg
(n=49)
Nivo 3 mg/kg +
Ipi 1 mg/kg
(n=52)
≥1%
27
(8, 55)
44
(14, 79)
27
(6, 61)
<1%
12
(3, 31)
21
(8, 40)
0
(0, 13)
PD-L1 baseline
expression
•
•
•
Up to 44% of patients with PD-L1+ tumors responded to nivolumab 1 mg/kg +
ipilimumab 3 mg/kg
While efficacy was observed in patients with both PD-L1+ and PD-L1- tumors,
further study is required to explore any potential trends in response
PD-L1 expression assessed by DAKO, MSI
Ipi, ipilimumab; MSI, microsatellite instability; Nivo, nivolumab; PD-L1, programmed death ligand-1.
Janjigian YY et al. Oral presentation at ASCO 2016. 4010.
Nivolumab
ONO-4538-12* (Ph III) Nivo vs PBO
 Opdivo (nivolumab) Demonstrates Overall Survival
Benefit in Patients With Unresectable Advanced or
Recurrent Gastric Cancer in Phase 3 Study
 Opdivo is the first and only Immuno-Oncology agent to
demonstrate overall survival advantage in patients with
unresectable advanced or recurrent gastric cancer
refractory to, or intolerant of, standard therapy
Press Release – BMS
Thursday, November 10, 2016 6:55 am EST
Summary of Selected Phase II/III
Immuno-oncology Trials for Gastric/GEJ Cancer
1st Line
Maintenance
Nivolumab
Ipilimumab
ONO-4538-37* (Ph II)
Nivo + CT vs CT
NCT01585987†‡ (Ph II)
Ipi vs SOC
Durvalumab
Pembrolizumab
KEYNOTE-062* (Ph III)
Pembro ± CT vs PBO + CT (PD-L1+/HER2-)
PLATFORM§ (Ph II)
HER2-: MTN Durva vs CT or observation;
HER2+: MTN Trast ±Durva
Pembrolizumab
Avelumab
KEYNOTE-059 (Ph II)
Pembro ± Cis + 5-FU (3L+ for mono; 1L for mono
and combo)
JAVELIN Gastric 100† (Ph III)
MTN Avel vs CT or BSC
Avelumab
Efficacy data recently presented
JAVELIN Solid Tumor† (Ph Ib)
Subgroups: 2L and maintenance Avelumab in 1L;
3L
efficacy expansion
*Unresectable advanced or recurrent cancer. †Locally advanced or metastatic cancer. ‡MTN following 1L CT. §Gastric, GEJ, or esophageal cancer. Clinicaltrials.gov.
Accessed June 2016. 1L, first-line; 2L, second-line; 3L, third-line; 5-FU, 5-fluorouracil; Avel, avelumab; BSC, best-supportive care; Cis, cisplatin; CT,
chemotherapy; Durva, durvalumab; GEJ, gastro-esophageal junction; HER, human epidermal growth factor receptor; Ipi, ipilimumab; MTN, maintenance; Nivo,
nivolumab; PBO, placebo; PD-L1, programmed death ligand-1; Pembro, pembrolizumab; SOC, standard of care; trast, trastuzumab.
Summary of Selected Phase II/III
Immuno-oncology Trials for Gastric/GEJ Cancer
3rd Line+
Refractory to Standard Regimens
2nd Line
Nivolumab ± Ipilimumab
Nivolumab
CheckMate 358 (Ph I/II, EBV+ gastric cohort)
ONO-4538-12* (Ph III) Nivo vs PBO
Nivolumab ± Ipilimumab
CheckMate 032† (Ph I/II)
Durvalumab
NCT02340975 (Ph I/II) Durva vs treme vs durva + treme
Avelumab
JAVELIN Gastric 300 (Ph III) Avel + BSC vs BSC ± CT
Avelumab
JAVELIN Solid
Tumor†
(Ph Ib) Subgroups: 2L and maintenance Avelumab in 1L; 3L efficacy expansion
Efficacy data recently presented
*Unresectable advanced or recurrent cancer. †Locally advanced or metastatic cancer. Clinicaltrials.gov. Accessed June 2016.
1L, first-line, 2L, second-line; 3L, third-line; Avel, avelumab; BSC, best-supportive care; CT, chemotherapy; Durva, durvalumab; GEJ, gastro-esophageal junction;
Ipi, ipilimumab; MTN, maintenance; Nivo, nivolumab; PBO, placebo; SOC, standard of care; treme, tremelimumab.
Summary of Selected Phase II/III
Immuno-oncology Trials for Gastric/GEJ Cancer
2nd Line+
Pembrolizumab
KEYNOTE-061*† (Ph III)
Pembro vs paclitaxel
Pembrolizumab‡
3rd Line+
Pembrolizumab
KEYNOTE-059 (Ph II)
Pembro ± (Cis + Capecitabine + 5-FU)
(3L+ for mono; 1L for mono and combo)
NCT02268825* (Ph I/II)
Pembro + mFOLFOX6
Pembrolizumab
NCT02689284* (Ph I/II)
Pembro ± marg (HER2+)
Pembrolizumab
KEYNOTE-012 (Ph I)
Efficacy data recently
presented
*Unresectable advanced or recurrent cancer. †Locally advanced or metastatic cancer. ‡1L patients may also be enrolled
GEJ, or esophageal cancer. Clinicaltrials.gov. Accessed June 2016.
1L, first-line; 3L, third-line; 5-FU, 5-fluorouracil; Cis, cisplatin; combo, combination therapy; GEJ, gastro-esophageal junction; HER, human epidermal growth factor
receptor; marg, margetuximab; mono, monotherapy; pembro, pembrolizumab.
OESOPHAGEAL CANCER
SCC
ADC
Summary of Nivolumab and
Pembrolizumab Trials
Nivolumab was well-tolerated and demonstrated antitumor activity in pretreated
esophageal cancer patients1
o
o
mOS: 10.8 months
ORR by Central Review: 17%
(11/64)
o
o
Responses were durable
Tolerable safety profile
Pembrolizumab was well-tolerated and demonstrated antitumor activity in
pretreated PD-L1+ esophageal cancer patients2
o
o
o
ORR for squamous cell carcinoma:
29% (5/17)*
ORR for adenocarcinoma: 40%
(2/5)*
o
o
Responses were durable
Tolerable safety profile
* Both confirmed and unconfirmed responses are included.
1. Kojima T et al. Poster presentation at ASCO GI 2016. TPS175. 2. Doi T et al. Poster presentation at ASCO 2016.4046
COLORECTAL CANCER
Transverse
colon
Ascending
colon
Sigmoid
colon
Rectum
Descending
colon
dMMR/MSI-H Prevalence in Cancers
100
80
60
40
20
0
MSI-H frequency (%)
MSI-H frequency (%)
Individual Studies Reporting MSI-H
Frequency in Various Cancer Types
50
Individual Studies Reporting MSI-H
Frequency in Colon Cancer by
Stage
40
30
20
10
0
I
II
III
Colon cancer stage
IV
DMMR, deficient mismatch repair; MSI-H, high-frequency microsatellite instability.
Lee V et al. Oncologist. 2016;21:1-12.
Selected mCRC Trials of Immuno-Oncology
Therapies With Data Available
Anti–PD-1,
Anti–PD-L1, or
Anti–CTLA-4
Adjuvant
Nivolumab +
Ipilimumab
(Anti–PD-1 + Anti–CTLA-4)
1st Line
2nd Line
3rd Line+
Refractory to Standard
Regimens
Nivolumab ± Ipilimumab
CheckMate 142 (Ph I/II)
Nivo ± Ipi
Pembrolizumab
Pembrolizumab
NCT01876511 (Ph II)
Pembro
(Anti–PD-1)
Atezolizumab
Atezolizumab
NCT01988896† (Ph Ib)
Atezo + cobimetinib
(Anti–PD-L1)
MSI-H cohort or selection
Clinicaltrials.gov. Accessed June 2016.
Pembrolizumab: NCT01876511
Mixed-dMMR/MSI-Status mCRC1,2
Phase II multicenter, open-label trial of pembrolizumab as monotherapy in three
different treatment-refractory patient populations
Key Inclusion Criteria
N=83
dMMR CRC
pMMR CRC
dMMR non-CRC
n=28
n=25
Pembrolizumab
10 mg/kg Q2W
n=30
• Primary Outcome Measures: irPFS*†, irORR† (using irRC)
• Secondary Outcome Measures: OS, irPFS/PFS (using irRC and RECIST 1.1), ORR, IRAEs,
MSI and treatment response, markers of MSI status
• dMMR and pMMR CRC groups had received a median of 3 and 4 prior
treatment regimens, respectively
1. Clinicaltrials.gov. NCT01876511. 2. Le DT et al. Oral presentation at ASCO 2016. TPS3631.
Pembrolizumab: NCT01876511
Summary of Clinical Activity1
ORR, %
(95% CI)
57
(39–73)
0
(0–13)
DCR, %
(95% CI)
89
(73–96)
16
(6–35)
CR, %
11
0
PR, %
46
0
SD*, %
32
16
PD, %
4
44
NE, %
7
40
PFS, mo
NR
2.3
OS, mo
NR
5.98
100
% Change From Baseline SLD
Response
dMMR CRC pMMR CRC
n=28
n=25
Best Radiographic Response1,2
pMMR CRC
dMMR CRC
50
20% increase (PD)
0
30% decrease (PR)
-50
-100
*At Week 12.
1. Le DT et al. Oral presentation at ASCO 2016. TPS3631. 2. Le DT et al. N Engl J Med. 2015;372(26):2509-2520.
Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with
metastatic colorectal cancer (mCRC) with and without high
microsatellite instability (MSI-H): CheckMate-142 interim results
Study objective
• To assess the efficacy and safety of nivolumab + ipilimumab vs nivolumab alone in
patients with mCRC with or without MSI
≥2L
Key patient inclusion criteria
• Histologically confirmed CRC
MSI-H
• ECOG PS ≤1
• PD on ≥1 therapy (MSI-H) or the
latest treatment (all), or
intolerance or refusal to take CT
≥3L
• (n=120)
MSS
*3 mg/kg q2w; †NIVO 3 mg/kg.+ IPI 1 mg/kg q3w, then
NIVO 3 mg/kg q2w; ‡NIVO 1 mg/kg.+ IPI 3 mg/kg q3w,
then NIVO 3 mg/kg q2w. NIVO, nivolumab; IPI,
ipilimumab.
NIVO*
NIVO† + IPI†
(n=30)
• Recurrent/metastatic disease
PRIMARY ENDPOINT(S)
• ORR (MSI-H; RECIST v1.1)
NIVO* (n=70)
NIVO† + IPI† (n=10)
NIVO‡ + IPI ‡ (n=10)
SECONDARY/EXPLORATORY ENDPOINTS
• Radiology review committee-assessed ORR (MSS)
• OS, PFS
• Safety
Overman et al. J Clin Oncol 2016; 34 (suppl): abstr 3501
Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic
colorectal cancer (mCRC) with and without high microsatellite instability
(MSI-H): CheckMate-142 interim results
PFS in patients with MSI-H
Key results
100
Median, m
(95% CI)
NIVO 3
mg/kg (n=70)
NIVO 3 mg/kg +
IPI 1 mg/kg (n=30)
17.1 (8.6, NE)
NE (3.4, NE)
Median, m
(95% CI)
100
45.9
66.6
NIVO 3
mg/kg (n=70)
NIVO 3 mg/kg +
IPI 1 mg/kg (n=30)
17.1 (8.6, NE)
NE (NE, NE)
75.0
85.1
6-m, %
80
OS, (% of patients)
PFS, (% of patients)
6-m, %
OS in patients with MSI-H
60
40
Nivolumab
20
Nivolumab + Ipilimumab
80
60
40
Nivolumab
20
Nivolumab + Ipilimumab
0
0
0
3
6
MSI-H
ORR, % (95% CI)
MSS
9
12
Time (months)
15
18
21
0
3
6
9
12
Time (months)
15
18
NIVO 3 mg/kg (n=47)
NIVO 3 mg/kg + IPI 1 mg/kg (n=27)
25.5 (15.4, 38.1)
33.3 (18.6, 50.9)
NIVO 1 mg/kg + IPI 3 mg/kg (n=10)
NIVO 3 mg/kg + IPI 1 mg/kg (n=10)
10 (n=1)
0
mPFS, m (95% CI)
2.28 (0.62, 4.40)
1.31 (0.89, 1.71)
mOS, m (95% CI)
11.53 (0.62, NE)
3.73 (1.22, 5.62)
ORR, %
21
Overman et al. J Clin Oncol 2016; 34 (suppl): abstr 3501
Durable Responses in Phase II studies
Pembrolizumab[2]
First new lesion
PR
SD
100
75
50
25
0
-25
-50
-75
-100
0
•
6
12 18 24 30 36 42 48 54 60 66
Wks Since Start of Treatment
Advanced, refractory squamous
NSCLC (N = 117)
–
–
–
Mismatch repair–proficient
colorectal cancer
PD or could not be determined
Pts still on treatment
ORR: 14.5%
Median time to response: 3.3 mos
Median DoR: NR
Change in Tumor Marker
Level (%)
Change in Target Lesions
From Baseline (%)
Nivolumab[1]
Mismatch repair–deficient
colorectal cancer
200
Mismatch repair–deficient
noncolorectal cancer
100
0% (no change)
0
-100
0
•
100
200
Days
300
400
Progressive metastatic carcinoma ±
mismatch repair deficiency (N = 41)
–
–
ORR: 40% for MSI high CRC, 0% for
MSS CRC
Median PFS and OS: NR for MSI high
CRC
1. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.
2. Le DT, et al. N Engl J Med. 2015;372:2509-2520.
Clinical activity and safety of cobimetinib (cobi) and
atezolizumab in colorectal cancer (CRC)
Study objective
• To investigate the efficacy and safety of cobimetinib (MEK inhibitor) + atezolizumab (antiPDL-1 mAb) in patients with CRC
Key patient inclusion criteria
• CRC with measurable
disease (RECIST v1.1)
• ECOG PS ≤1
Cobimetinib 20–60 mg/d
(21d on/7d off)* +
Atezolizumab 800 mg IV q2w
PD
(n=23)
PRIMARY ENDPOINT
• Safety
*Dose escalation.
SECONDARY ENDPOINTS
• ORR
• PFS, OS
Bendell et al. J Clin Oncol 2016; 34 (suppl): abstr 3502
Clinical activity and safety of cobimetinib (cobi) and
atezolizumab in colorectal cancer (CRC)
Key results
6-month PFS, % (95% CI)
6-month OS, % (95% CI)
ORR, % (95% C)
KRAS mutant (n=20)
39 (0.16, 0.61)
77 (0.57, 0.97)
20 (5.7, 43.7)
All patients (n=23)
35 (0.14, 0.56)
72 (0.52, 0.93)
17 (5.0, 38.8)
Change in sum of longest
diameters from baseline, %
Change in tumour burden
PD
SD
CR/PR
Discontinued atezolizumab
New lesion
100
80
60
40
20
0
–20
–40
–60
–80
–100
0
3
6
9
12
15
18
21
24
Time on study (months)
Bendell et al. J Clin Oncol 2016; 34 (suppl): abstr 3502
Selected Ongoing Immuno-Oncology
Trials for mCRC
Adjuvant
1st Line
Anti–PD-1,
Anti–PD-L1, or
Anti–CTLA-4
2nd Line
Nivo ± Ipi (Ph I/II)
Nivo + Ipi + cobimetinib (Ph I/II)
Pembro+mFOLFOX6
(Ph II)
Pembro vs SOC (Ph III)
MSI:
mFOLFOX6
± Pembro
FP + bev vs FP + bev +
atezo (Ph II)
Pembro (Ph II)
Pembro+RT/ablation* (Ph II)
Pembro + azaC (Ph II)
Pembro (Ph II)
Pembro+RT/ablation*
(Ph II)
Durva (Ph II)
Atezo ± cobimetinib vs
regorafenib (Ph III)
Atezo + cobimetinib
(Ph Ib)
Efficacy data recently presented
Trials with MSI-H cohort or
selection
Clinicaltrials.gov. Accessed November 2016.
Rationale for Nivolumab in Metastatic
SCC Anal Cancer
 Approximately 80-95% of cases
are linked to human papillomavirus
(HPV).
 The role of HPV in the
tumorigenesis of SCCA provides
rationale for the use of immune
checkpoint blockade agents as a
novel therapy for treatment of
patients with a virally driven
disease.
Morris VK et al. The Oncologist, 2015, Sarup-Hansen E et al. J Clin Oncol ,2014
NCI9673:
N (%)
CR
2 (5.4%)
PR
7 (18.9%)
SD
17 (45.9%)
PD
8 (21.6%)
Unevaluable
3 (8.1%)
ORR (ITT,
N=37)
9 (24.3%)
% ta r g e t le s io n r e d u c tio n
Response Rate
f r o m b a s e lin e b y R E C IS T 1 . 1
Nivolumumab (3 mg/kg q2w) in pretreated (at least one line)
squamous cell carcinoma of the anal canal
100
90
80
70
60
50
40
30
20
10
0
-1 0
-2 0
-3 0
-4 0
-5 0
-6 0
-7 0
-8 0
-9 0
-1 0 0
P r o g r e s s iv e D is e a s e
S ta b le D is e a s e
P a r t ia l R e s p o n s e
PD
PR
P a t ie n t
ORR (Evaluable,
N=34)
9 (26.5%)
C. Eng et al, ESMO GI, Barcelona 2016
Hepatocellular carcinoma
Phase I/II safety and antitumor activity of nivolumab in
patients with advanced HCC: Interim analysis of the
CheckMate-040 dose expansion cohort
Inclusion Criteria:
• Advanced HCC
• Child-Pugh score
≤ 6 (ie, CP A)
• ≥ 1 prior line of
systemic therapy
Primary Objective
• ORR (RECIST v1.1)
Secondary Objectives
• CR
• DCR
• Duration of response
• Time to response
• Time to progression
• PFS
• OS and OS rate
Sangro B et al, ASCO 2016; Poster 4078
Phase I/II safety and antitumor activity of nivolumab in
patients with advanced HCC: Interim analysis of the
CheckMate-040 dose expansion cohort
Objective Responses (investigator-assessed best
overall response)
Sangro B et al, ASCO 2016; Poster 4078
Phase 3 studies of checkpoint inhibitors
in HCC
A Randomized, Open-label Phase 3 Study of
Nivolumab Versus Sorafenib as First-Line
Treatment in Patients With Advanced
Hepatocellular Carcinoma
HCC
Child Pugh A
ECOG 0/1
Nivolumab
R
n=726
A Phase III Study of Pembrolizumab (MK3475) vs. Best Supportive Care as SecondLine Therapy in Subjects With Previously
Systemically Treated Advanced
Hepatocellular Carcinoma (KEYNOTE-240)
HCC
Child Pugh A
ECOG 0/1
Sorafenib
Primary Endpoints:
• Time to Progression (TTP)
• Overall Survival
Secondary Endpoints
• Overall Response Rate
• Progression Free Survival (FPS)
• Programmed Death (PD)-L1 expression
Progression during
or after treatment
with sorafenib or
intolerance to
sorafenib
N=408
Pembrolizumab
R
Placebo
Primary endpoint:
• Overall survival and PFS
Main secondary endpoints:
• Overall response rate, DCR,
duration or response, TTP
• Safety
https://clinicaltrials.gov/Source: NCT02576509
https://clinicaltrials.gov/ct2/show/NCT02702401