I tumori gastrointestinalimedia.aiom.it/userfiles/files/doc/AIOM-Servizi/... · Immunonoterapia nel...
Transcript of I tumori gastrointestinalimedia.aiom.it/userfiles/files/doc/AIOM-Servizi/... · Immunonoterapia nel...
Carmine Pinto
Clinical Cancer Centre
Oncologia Medica
IRCCS-Arcispedale S.Maria
Nuova Reggio Emilia
I tumori
gastrointestinali
Agenda
“Mutation burden” and Immunogenicità
Immunonoterapia nel carcinoma gastrico
Immunonoterapia nel carcinoma colo-rettale
Slide 18
Mutation burden vs response to PD-1/PD-L1 blockade
Potential Immuno-Oncology Targets
EFFECTOR
CELL
BCR-ABL DR5 TKIs
CXCR4 BET ADCs
PD-1 TIM-3 LAG-3
CTLA-4 TIGIT
CCR2/5 IL-8
GITR OX40 CD137
ICOS CD27 IL-2
KIR SLAMF7
Radiation Chemotherapy Vaccines Viruses CD40
Inhibit/target tumor cell pathways
3
Block tumor inhibition/checkpoints
4
Block inhibitory stromal effects
5
1
Optimize antigen presentation
6
Block or deplete immune regulators
7
Activate T effector cells
Enhance NK-cell activity
2
IDO CD73 CSF1R
Glutaminase CTLA-4-NF CTLA-4-Probody
CCR4 TGFß
ADCs, antibody drug conjugates; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCR4, chemokine CXC motif receptor 4; GITR, glucocorticoid-induced tumor necrosis factor receptor-related protein; IDO, indoleamine 2, 3-dioxygenase; KIR, killer cell immunoglobulin-like receptor; LAG3, lymphocyte-activation gene 3; NK, natural killer; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; SLAMF7, signaling lymphocytic activation molecule family member 7.Chen DS, Mellman I. Immunity.2013; 39:1-10.
We can modulate
immune response to
restore the ability of
effector cells to traffic
to the tumor to detect
and destroy cancer
cells1-6
Potential Immuno-Oncology Targets in
GI Cancers1
*The image shows only a selection of the receptors/pathways involved.2
CD137, cluster of differentiation 137; CD27, cluster of differentiation 27; CTLA-4, cytotoxic T-lymphocyte antigen-4; LAG-3; lymphocyte activation gene-3; PD-1, programmed death receptor-1; TIM-3, T-cell immunoglobulin and mucin domain-3.
1. Clinicaltrials.gov. Accessed July 16, 2017. 2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
PD-1
CTLA-4
Inhibitory receptors* Activating receptors*
TIM-3
LAG-3
CD27
OX40
CD137
Tumors may exploit immune checkpoint signals to evade immune detection2
Predictive/prognostic biomarkers
in GI cancers (Hot vs Cold tumors)
Activity of checkpoint inhibitors in MSI-high metastatic
colorectal cancer
Similar activity in MSI-high non-colorectal GI cancers
(gastric cancer)
NGS provides information about tumor mutational
burden
Activity of checkpoint inhibitors and HBV status (gastric
cancer)
Immune signatures (Asian vs non-Asian populations in
gastric cancer; Immunoscore in colon cancer)
6/9 Gastro-Intestinal
cancers
Signaling mechanisms of PD-1 and PD-L1 inhibition
of PD-1 signaling in H-MSI cancers
Lemery et al, NEJM 2017
Meta-analysis on PD-L1 prognostic and
predictive value in GI cancers
Results for Overall Survival
Dai et al, OncoTargets Ther, 2017
Agenda
“Mutation burden” and Immunogenicità
Immunonoterapia nel carcinoma gastrico
Immunonoterapia nel carcinoma colo-rettale
Classificazione su base molecolare
31%
Sottotipi di carcinoma gastrico
Sottotipo Incidenza
(%)
Caratteristiche patologiche e
cliniche
Casratteristiche molecolari
EBV 9 Maschi 81%
Fondo/corpo
Estensiva DNA metilazione
PIK3CA m 80%
PD- L1-2 iperespressione
EBV-CIMP
CDKN2A silenziamento
Segnali di citochine
alterate
MSI 22 Età mediana 72 aa
Moderata DNA metilazione
Ipermutazioni
CIMP-gastrico
MLH1 silenziamento
Variazione di pathways
mitotiche
Instabilità
cromosomiale
50 Giunzione esofago-gastrica
Sottoistotipo intestinale
TP53
RTK-RAS attivazione
Genoma
stabile
20 Sottoistotipo diffuso
Età più precoce mediana 59 aa
CDH1 e RHOA mutazioni
CLDN18-ARHGAP fusione
Adesione cellulare
Prognosis associated with subtypes
Sohnet al, Clin Cancer Res 2017
Br J Surg, 2017
Forest plot for the effect of microsatellite instability (MSI) status on overall survival
Br J Surg, 2017
PD-L1 Status and Outcome in Gastric Cancer
PD-L1, programmed death ligand 1.
1. Zhang L et al. Int J Clin Exp Pathol. 2015;8(9):11084-11091. 2. Zhang M, et al. Sci Rep. 2016;6:1-92.
0.0
Cu
mu
lati
ve
Su
rviv
al
0.2
0.4
0.6
1.0
0.8
48 72 96 168 0
Time After Surgery (months)
PD-L1 Positive
(n=67)
PD-L1 Negative
(n=65)
24 144 120
PD-L1 Expression
Negative
Positive
Negative-censored
Positive-censored
• PD-L1 is associated with poor prognosis in gastric cancer patients1
• Overexpression of PD-L1 in about 25%–65% of gastric cancer patients suggests that immune checkpoint
inhibition may be an effective therapy2
Elevated PD-L1 and PD-L2 Expression in EBV+ Gastric Cancer
Slide 23
Immuno-Oncology Studies
*Clinical trial includes patients with gastroesophageal junction cancer.
1L, first-line; 2L, second line; 3L, third line; 5FU, 5-florouracil; adj, adjuvant; BSC, best supportive care; cape, capecitabine; CapeOX, capecitabine + oxaliplatin; chemo, chemotherapy; FOLFOX, oxaliplatin + leucovorin + fluorouracil; FP, fluoropyrimidine; GEJ, gastroesophageal junction; I-O, immuno-oncology; PBO, placebo; PD-L1, programmed death ligand 1; S-1, tegafur-gimeracil-oteracil potassium; SOX, tegafur/gimeracil /oteracil potassium + oxaliplatin; XELOX, oxaliplatin + capecitabine.
1. Clinicaltrials.gov. Accessed June 29, 2017. 2. Ohashi S et al. Gastroenterology. 2015;149(7):1700-1715. 3. Lote H et al. Cancer Treat Rev. 2015;41(10):893-903.
Combination Therapy Monotherapy
JAVELIN Solid Tumor*: Ph 1 Avelumab
NCT02340975*: Ph 1/2 Tremelimumab ± durvalumab
Checkmate 032*: Ph 1/2 Nivolumab ± ipilimumab
KEYNOTE-061*: Ph 3 Pembrolizumab vs paclitaxel
2L
+
NCT02864381*: Ph 2 Nivolumab ± andecaliximab
ECHO-203: Ph 1/2 Durvalumab ± epacadostat
KEYNOTE-059*: Ph 2 Pembrolizumab
1L
+ JAVELIN Gastric 100*: Ph 3
1L Mnt: Avelumab vs oxaliplatin + FP
KEYNOTE-062*: Ph 3 (PD-L1+) Pembrolizumab ± (cisplatin + 5-FU/cape)
vs PBO + (cisplatin + 5-FU/cape)
PLATFORM*: Ph2 1L Mnt: Durvalumab/capecitabine NCT02443324*: Ph 1
Pembrolizumab + ramucirumab
ATTRACTION-04* (ONO-4538-37): Ph 2/3 Nivolumab + SOX/CapeOX vs PBO +
SOX/CapeOX
ATTRACTION-05* (ONO-4538-38): Ph 3 Nivolumab + S-1/CapeOx vs PBO +
S-1/CapeOx
Neo
-
/Ad
j
ATTRACTION-02* (ONO-4538-12): Ph 3 Nivolumab vs PBO
JAVELIN Gastric 300*: Ph 3 Avelumab + BSC vs BSC ± chemo 3
L+
KEYNOTE-585*: Ph 3 Pembrolizumab + (cisplatin + 5-FU/cape) vs
PBO + (cisplatin + 5-FU/cape)
KEYNOTE-059*: Ph 2 Pembrolizumab ± (cisplatin + 5-FU/cape)
LEGEND
I-O/non–I-O combination clinical trials
I-O/I-O combination clinical trials
Monotherapy clinical trials
I-O/I-O & I-O/non-I-O combinations trial
Checkmate 649*: Ph 3 Nivolumab + ipilimumab/XELOX/FOLFOX
vs XELOX/FOLFOX
KEYNOTE-059*: Ph 2 Pembrolizumab
KEYNOTE-059: Pembrolizumab
Phase 2 Multicohort Study of Pembrolizumab for G/GEJ Adenocarcinoma
Primary Endpoints: ORR by RECIST v1.1, safety and tolerability
Secondary Endpoint: DOR by central review, PFS, OS
Exploratory Biomarker Endpoints: Efficacy by microsatellite instability and gene expression profile
*Capecitabine was used in place of 5-FU only in Japan.
5-FU, 5-fluorouracil; CT, chemotherapy; DOR, duration of response; G, gastric; GEJ, gastro-esophageal junction; ORR, objective response; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; q3w, every 2 weeks; RECIST, Response Evaluation Criteria In Solid Tumours.
1. Fuchs C, et al. ASCO 2017. Abstract 4003. 2. Bang et al. ASCO 2017. Abstract 4012. 3. Catenacci DV et al. World GI 2017. Abstract LBA-009.
Pembrolizumab
200 mg q3w
Cohort 1
• ≥2 prior lines of CT
For 24
months or
until
progression,
intolerable
toxicity, or
other reason
Cohort 2
• No prior therapy
Cohort 3
• No prior therapy
• PD-L1 positive Pembrolizumab
200 mg q3w
Pembrolizumab 200 mg q3w +
Cisplatin 80 mg/m2 q3w +
5-FU 800 mg/m2 q3w or
Capecitabine 1000 mg/m2 q3w*
Follow-up for
survival by
telephone
until death,
withdrawal, or
study end
n=252
n=2591
n=313
Objective Response
Median (range) follow-up in cohort 1 (all patients): 5.6 months (0.5–24.7)1
Median (range) follow-up in cohort 1 (3L and 4L+ patients): 5.8 months (0.5–21.6)2
*Only confirmed responses were included.
†CR + PR + SD≥2 months
CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. 1. Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28. 2. Adapted from Fuchs C et al. Oral presentation at ASCO 2017. Abstract 4003.
All Patients1 (N=259)
Third Line2 (n=134)
Fourth Line+ (n=125)
Response*
% 95% Cl % 95% Cl % 95% Cl
ORR (CR + PR)
12 8–17 16.4 10.62–
23.8 6.4 2.8–12.2
CR 3 1-6 3.0 0.8–7.5 1.6 0.2–5.7
PR 9 6–13 13.4 8.2–20.4 4.8 1.8–10.2
SD 16 12–21 NR NR
PD 56 49–62 NR NR
DCR† 27 22–33 31.3 23.6–39.9 22.4 15.4–30.7
KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy
PFS and Overall Survival in All Patients
CI, confidence interval; mos, months; no, number; OS, overall survival; PFS, progression free survival.
Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28.
Data cutoff: April 21, 2017.
KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy
Pro
gre
ss
ion
-Fre
e S
urv
iva
l, (
%)
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Median (95% CI) 6-month
rate
2.0 (2.0-2.1) mos 14.6%
No. at Risk
259 137 55 37 28 25 8 6 4 2 1 0 0 0
Ove
rall
Su
rviv
al,
(%
)
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Median (95% CI) 6-month
rate
5.5 (4.2-6.5) mos 45.7%
259 203 147 115 95 78 54 36 27 14 8 2 1 0
No. at Risk
Objective Response by Biomarker Expression
*Only confirmed responses were included. †CR + PR + SD≥2 months. ‡Positivity based on PD-L1 expression on tumour cells, lymphocytes and macrophages.
CI, confidence interval; CPS, combined positive score;CR, complete response; DCR, disease control rate; GEP, gene expression profile; MSI, microsatellite instable; MSI-H, microsatellite instable high; NR, not reported; ORR, objective response rate; PD-L1, programmed death-ligand 1; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease.
1. Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28. 2. Adapted from Fuchs C et al. Oral presentation at ASCO 2017. Abstract 4003.
• 57% of patients were PD-L1 positive as determined by CPS‡
• Responses observed regardless of PD-L1 status, although numerically higher in PD-L1+ patients
• 57.1% ORR in MSI-H patients (n=7) versus 9.0% in non-MSI-H (n=167)
• T-cell–inflamed GEP score significantly associated (P=0.014) with improved response to pembrolizumab
18-G
en
e T
-cell–in
flam
ed
GE
P S
co
re
0.5
Nonresponder Responder
0.0
-0.5
Response
PD-L1 Expression1 MSI Status2
PD-L1 Positive (n=148)
PD-L1 Negative (n=109)
MSI-High (n=7)
Non–MSI-High (n=167)
% 95% CI % 95% CI % 95% CI % 95% CI
ORR 16 11-23 6 3-13 57.1 18.4-90.1 9.0 5.1-14.4
CR 3 1-8 3 1-8 14.3 0.4-57.9 2.4 0.7-6.0
PR 13 8-19 3.7 1-9 42.9 9.9-81.6 6.6 3.3-11.5
SD 18 12-25 15 9-23 NR NR
PD 53 44-61 60 50-69 NR NR
DCR† 34 26-42 19 12-28 71.4 29.0-96.3 22.2 16.1-29.2
KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy
18-Gene T-cell–inflamed GEP Score2
Treatment-Related Adverse Events
Median (range) duration of exposure was 2.1 (0.0-23.7) months
KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy
aAbnormal hepatic function, bile duct stenosis, encephalitis, increased blood bilirubin level, hyperglycemia, acute kidney injury, and pneumonitis.
AE, adverse event.
Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28. Data cutoff: April 21, 2017.
Event, n (%) N = 259
Any 159 (61)
Grades 3-5
Anemia, grade 3
Fatigue, grade 3
Dehydration, grade 3
46 (18)
7 (3)
6 (2)
3 (1)
Serious 29 (11)
Led to Discontinuationa 7 (3)
Led to Death
Acute kidney injury
Pleural effusion
2 (1)
1 (1)
1 (1)
Efficacy Endpoints Responseb
All Patients N=25
PD-L1 Positivea n=16
PD-L1 Negative n=8
% (95% CIb) % (95% CIb) % (95% CIb)
ORR 60 (39-79) 69 (41-89) 38 (9-76)
DCRc 80 (59-93) 75 (48-93) 75 (35-97)
CR 4 (0-20) 0 (0-22) 13 (0-53)
PR 56 (35-76) 69 (41-89) 25 (3-65)
SD 32 (15-54) 19 (4-46) 50 (16-84)
PD 4 (0-20) 6 (0-30) 0 (0-37)
KEYNOTE-059 Cohort 2: 1L Pembrolizumab + Cisplatin + 5-FU/Capecitabine
aPD-L1 positive was defined as combined positive score (CPS) ≥1 (previously reported as and equivalent to CPS ≥1%), where CPS = number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells x 100.bOnly confirmed responses were included.cCR + PR + SD ≥6 months.
AE, adverse event; CI, confidence interval; CR, complete response; DCR, disease control rate; mo, month; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression-free survival; PR, partial response; SD, stable disease.
Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28.
12% (n=3) of patients discontinued because of chemotherapy-related AEs (stomatitis, hypoacusis, and increased creatinine level)
Pro
gre
ss
ion
-Fre
e S
urv
iva
l,
%
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
No. at Risk
25 24 21 17 8 8 5 4 3 3 3 3 0 0
Ove
rall
Su
rviv
al,
%
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
25 24 22 19 18 17 13 12 12 10 8 7 1 0
Median (95%
CI)
6-mo
rate
6.6 (5.9-10.6)
mo 68.0%
Median (95%
CI) 6-mo rate
13.8 (8.6-NR)
mo 76.0%
Progression-Free Survival
(total population) Overall Survival
(total population)
Data cutoff: April 21, 2017.
• Median (range) follow-up in cohort 2: 13.8 (1.8-24.1) mos
Outcomes in 1L PD-L1+ Patient Population
• Safety was consistent with previous reports, with no new signals identified
Overall Survival
Confirmed Responsea
N=31
% 95% CI
ORR (CR + PR) 26 12-45
CR 7 1-21
PR 19 8-38
SD 29 14-48
PD 39 22-58
DCRb 36 19-55
Median (Range)
DOR, months 9.6 (2.1-17.8+)
Median (95% CI)
PFS, months 3.3 (2.0-6.0)
PFS, 6-month rate 34.9%
• Median follow-up:17.5 months (range: 1.7-20.7)
Median
(95% CI)
6-mo
rate
20.7 mo
(9.2–20.7) 72.9%
KEYNOTE-059 Cohort 3: 1L Pembrolizumab in PD-L1+ Patients
a Only confirmed responses were included. bCR + PR + SD ≥6 months.
1L, first line; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not estimable; NR, not reported; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to tumour response.
Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28.
Data cutoff: April 21, 2017.
100
90
80
70
60
50
40
30
20
10
0
Ove
rall
Su
rviv
al,
%
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (months No. at risk
31 29 23 21 21 19 18 17 14 9 3 0 0 0
Study Design Phase 3 randomized, multicenter, double-blinded trial of nivolumab in patients with unresectable advanced gastric or gastroesophageal junction cancer refractory to or intolerant of standard therapy
Patients were permitted to continue treatment beyond initial RECIST v1.1–defined disease progression, as assessed by the investigator, if receiving clinical benefit and tolerating study drug
Retrospective determination of tumor PD-L1 expression, defined as staining in ≥1% (or ≥5%) of tumor cells, was performed in a central laboratory using immunohistochemistry (28-8 pharmDx assay) for patients with available tumor samples
AEs, adverse events; BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; Q2W, every two weeks; R, randomization; TTR, time to treatment response.
Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.
ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients
2:1
Nivolumab
3 mg/kg IV Q2W
Placebo
Key eligibility criteria:
•Unresectable advanced or
recurrent gastric or
gastroesophageal junction
cancer
•Refractory to/intolerant of
≥2 standard therapy
regimens
•ECOG PS of 0 or 1
Primary endpoint:
• OS
Secondary endpoints:
• Efficacy (PFS, BOR,
ORR, TTR, DOR, DCR)
• Safety
Exploratory endpoint:
• PD-L1 tumor
expressiona
Stratification:
•Country (Japan vs South Korea
vs Taiwan)
•ECOG PS (0 vs 1)
•Number of organs with metastases
(<2 vs ≥2)
Ra
nd
om
iza
tio
n
Baseline Characteristics
79.1%
ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients
Nivolumab 330 275 192 143 123 97 84 54 34 22 12 7 6 1 0
Placebo 163 121 82 54 37 24 18 8 6 5 4 3 3 2 0
Months
Median OS, months
(95% CI)
Nivolumab 5.3 (4.6–6.4)
Placebo 4.1 (3.4–4.9)
Hazard ratio, 0.62 (95% CI: 0.50–0.76)
P < 0.0001
No. at Risk
12-month OS rate
27%
12%
24-month OS rate
*Time from first dose to data cut-off for surviving patients.
CI, confidence interval; OS, overall survival.
Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.
Overall Survival
ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients
Ov
era
ll S
urv
ival (%
)
2 0 4 6 8 10 12 14 16 18 20 22 24 26 28
0
10
20
30
40
50
60
70
80
90
100
• Compared to placebo, treatment with nivolumab resulted in a 38% reduction in risk of death
12%
5%
Placebo
Nivolumab
Median follow-up*: 15.7 months (range, 12.1–27.2)
PD-(L)1 Inhibition Demonstrated Long-Term OS
Benefits Across Tumor Types
2L, second line; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; KN, KEYNOTE; Nivo, nivolumab; NSCLC, non-small cell lung cancer; OS, overall survival; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; R/M, recurrent or metastatic; SCCHN, squamous cell carcinoma of the head and neck.
1. Adapted from Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813. 2. Adapted from Borghaei H et al. Poster presentation at ASCO 2016. 9025. 3. Adapted from Ferris RL et al. Oral presentation at ASCO 2016. 6009. 4. Adapted from Rittmeyer A et al. Lancet. 2017;389:255-26. 5. Adapted from Herbst RS et al. Oral presentation at WCLC 2016. 6769.
Checkmate 057: Non-squamous NSCLC2
Time (months)
OS
(%
)
Docetaxel
Nivolumab
Checkmate 025: Nivo Monotherapy in 2L+ RCC1
27 18 15 9 6 21 12 3 0 24 30 0 3 6 12 9 15 18 21 24 27 33 30
OS
(%
)
Time (months)
Everolimus
Nivolumab
100
80
60
0
40
20
100
80
60
40
0
20
Checkmate 141: Nivolumab in R/M SCCHN After Platinum Therapy3
Time (months)
OS
(%
)
Nivolumab
100
Investigators Choice
Checkmate 017: Squamous NSCLC2
OS
(%
)
0 3 6 9 12 15 18 33 27 24 21 18 15 12 9 6 3 0 30
Docetaxel
Nivolumab
Time (months)
100
80
60
40
0
20
0
20
40
60
80
OAK: 2L+ NSCLC (ITT population)4
100
OS
(%
)
Time (months)
Docetaxel
Atezolizumab
KN-010: ≥1% PD-L1 2L+ NSCLC5
OS
(%
)
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 0 5 10 15 20 25 30 35
Pembro 2
Docetaxel
Pembro 10
Time (months)
0
20
40
60
80
HR=0.73 (98.5% CI: 0.57–0.93)
HR=0.62 (95% CI: 0.47–0.80)
HR=0.75 (95% CI: 0.63–0.91)
HR=0.70 (95% CI: 0.51–0.96)
Pembro 2: HR=0.72 (95% CI: 0.60–0.86) HR=0.73 (95% CI: 0.62–0.87)
Pembro 10: HR=0.60 (95% CI: 0.49–0.72)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
ONO-
4538
Placeb
o
PD-L1 <1% PD-L1 ≥1%
Median OS, months (95% CI)
Nivolumab
(n=114)
6.1 (4.8–8.6)
Placebo
(n=52)
4.2 (3.0–6.9)
Hazard ratio: 0.71
(95% CI: 0.50–1.01)
Median OS, months (95% CI)
Nivolumab
(n=16)
5.2 (2.8–9.4)
Placebo
(n=10)
3.8 (0.8–5.0)
Ov
era
ll S
urv
ival (%
)
Nivolumab 11
4
10
0 75 56 49 42 37 24 15 11 7 3 2 1 0
Placebo 52 40 27 22 16 14 11 6 5 4 3 2 2 2 0
Nivolumab 16 15 10 7 5 4 4 2 2 0 0 0 0 0 0
Placebo 10 8 4 2 1 1 1 0 0 0 0 0 0 0 0
Months Months
No. at Risk
*n=192 PD-L1 evaluable patients.
CI, confidence interval; OS, overall survival; PD-L1, programmed death ligand 1.
Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.
Overall Survival by PD-L1 Expression Level ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients
Survival advantage was observed for nivolumab versus placebo regardless of PD-L1 expression
Hazard ratio: 0.58
(95% CI: 0.24–1.38)
Ov
era
ll S
urv
ival (%
) No. at Risk
• 26/192 patients were determined to be PD-L1 positive as detected by DAKO 28-8 of tumor cells only
Nivolumab 3 mg/kg (n = 268)
Placebo (n = 131)
ORR, n (%) 95% CI
P value
31 (12) 8–16
P<0.0001
0 0–2.8
Best Overall Response, n (%)
CR 0 0
PR 31 (12) 0
SD 77 (29) 33 (25)
PD 124 (46) 79 (60)
NE 36 (13) 19 (15)
DCR, n (%) 95% CI
P value
108 (40) 34.4–46.4 P=0.0036
33 (25) 18.0–33.5
Median TTR*, mos (range) 1.6 (1.4–7.0) —
Median DOR*, mos (95% CI) 9.8 (6.4–20.5) —
Efficacy
*n=31 patients.
2L, second line; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; mos, months; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumours; SD, stable disease; TTR, time to tumour response.
Adapted from Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.
ATTRACTION-02 (ONO-4538-12): 2L+ Nivolumab Monotherapy
Patients, n (%)
Nivolumab 3 mg/kg n = 330
Placebo n = 161
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any treatment-related AE 142 (43) 36 (11) 43 (27) 7 (4)
Serious treatment-related AEs 35 (11) 23 (7) 8 (5) 4 (2)
Treatment-related AEs leading to discontinuation
9 (3) 4 (1) 4 (2) 3 (2)
Treatment-related AEs leading to dose delay
29 (9) 16 (5) 2 (1) 1 (<1)
Treatment-related deaths 5 (2) 2 (1)
Treatment-related AEs (>2%) Pruritus Diarrhea Rash Fatigue Decreased appetite Nausea Malaise AST increased Hypothyroidism Pyrexia ALT increased
30 (9) 23 (7) 21 (6) 18 (5) 16 (5) 15 (5) 13 (4) 11 (3) 11 (3) 9 (3) 8 (2)
0
2 (<1) 0
2 (<1) 4 (1)
0 0
2 (<1) 0
1 (<1) 1 (<1)
9 (6) 3 (2) 5 (3) 9 (6) 7 (4) 4 (2) 6 (4) 3 (2)
1 (<1) 3 (2)
1 (<1)
0 0 0
2 (1) 1 (<1)
0 0 0 0 0 0
AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Adapted from Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.
Safety Summary
ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients
Study Design
*Nivolumab + ipilimumab combination treatment administered for 4 cycles followed by nivolumab 3 mg/kg IV Q2W. † Time from first dose to data cut-off; follow-up was shorter for patients who died prior to data cut-off.
1L, first line; EG, esophagogastric (included gastric/esophageal/gastroesophageal junction cancer), ORR, objective response rate; OS, overall survival; PD L1, programmed death-ligand 1; PFS, progression-free survival; Q2W, once every two weeks; Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumours.
Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.
Nivolumab 3 mg/kg +
Ipilimumab 1 mg/kg IV Q3W*
(NIVO 3 + IPI 1)
n=52
Nivolumab 1 mg/kg +
Ipilimumab 3 mg/kg IV Q3W*
(NIVO 1 + IPI 3)
n=49
Nivolumab 3 mg/kg IV Q2W
(NIVO 3)
n=59
Western patients with advanced/metastatic EG cancer
with progression on ≥1 prior chemotherapy
N = 160
Median (range)
follow-up, mo†: 28 (17 to 35) 24 (21 to 33) 22 (19 to 25)
Primary endpoint: Secondary endpoints: Exploratory endpoint:
• ORR per RECIST v1.1 • OS
• PFS
• Time to response
• Duration of response
• Safety
• PD-L1 tumor expression
(Dako 28-8 pharmDx assay)
• ORR and OS by MSI status
Checkmate 032: 2L+ Nivolumab ± Ipilimumab in Western Patients
Objective Response
NIVO 3 n = 59
NIVO 1 + IPI 3 n = 49
NIVO 3 + IPI 1 n = 52
ORR, n (%)* 7 (12) 12 (24) 4 (8)
[95% CI] [5, 23] [13, 39] [2, 19]
BOR, n (%)*
Complete response 1 (2) 1 (2) 0
Partial response 6 (10) 11 (22) 4 (8)
Stable disease 12 (20) 8 (16) 15 (29)
Progressive disease 34 (58) 23 (47) 24 (46)
Not evaluable 6 (10) 6 (12) 9 (17)
DCR, n (%)† 19 (32) 20 (41) 19 (37)
Median TTR (range), months
1.6 (1.2 to 4.0) 2.7 (1.2 to 14.5) 2.6 (1.3 to 2.8)
Median DOR (95% CI), months
7.1 (3.0, 13.2) 7.9 (2.8, NE) NR (2.5, NE)
* Investigator review. † Patients with a BOR of complete response, partial response, or stable disease.
2L, second line; BOR, best objective response; CI, confidence interval; DCR, disease control rate; DOR, duration of response; IV, intravenous; NE, not estimable; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO3 + IPI, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; NR, not reached; Q2W, once every two weeks; Q3W, once every 3 weeks; TTR, time to treatment response.
Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.
Checkmate 032: 2L+ Nivolumab ± Ipilimumab
mPFS (95% CI),
months
6-month PFS rate,
%
12-month PFS rate,
%
NIVO 3 1.4 (1.2–1.5) 17 8
NIVO 1 + IPI 3 1.4 (1.2–3.8) 24 17
NIVO 3 + IPI 1 1.6 (1.4–2.6) 12 10
Progression-Free Survival and Overall Survival
*Investigator review.
1L, first line; CI, confidence interval; mOS, median OS; mPFS, median PFS; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO 3 + IPI 1, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; OS, overall survival; PFS, progression-free survival; Q2W, once every two weeks; Q3W, once every 3 weeks.
Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.
Progression-Free Survival Overall Survival
mOS (95%
CI),
months
12-
month
OS
rate, %
18-
month
OS
rate, %
NIVO 3 6.2 (3.4–12.4) 39 25
NIVO 1 +
IPI 3
6.9 (3.7–11.5) 35 28
NIVO 3 +
IPI 1
4.8 (3.0–8.4) 24 13
Checkmate 032: 2L+ Nivolumab ± Ipilimumab
No. at Risk:
59 13 10 6 5 3 1 1 1 1 0
Pro
ba
bil
ity o
f P
FS
*
Time (months)
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
3 6 9 12 15 18 21 24 27 30
49 16 10 7 6 5 5 4 1 0 0
52 13 5 4 4 3 2 2 0 0 0
NIVO 3
NIVO 3 + IPI 1
NIVO 1 + IPI 3
59 40 26 21 20 15 11 5 5 4 1 0
Time (months)
Pro
ba
bil
ity o
f S
urv
ival
0 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
3 6 9 12 15 18 21 24 27 30 33
49 35 24 19 14 14 11 8 3 0 0 0
52 33 20 18 11 8 4 3 0 0 0 0
No. at Risk:
NIVO 3
NIVO 3 + IPI 1
NIVO 1 + IPI 3
Efficacy by PD-L1 Status1 and MSI-H Status2
NIVO 3 n=59
NIVO 1 + IPI 3 n=49
NIVO 3 + IPI 1 n=52
PD-L1 expression ≥1% n=16
<1% n=26
≥1% n=10
<1% n=32
≥1% n=13
<1% n=30
OS rate (95% CI), %
12 mos 34 (12–57) 45 (25–62) 50 (18–75) 32 (16–48) 23 (6–47) 25 (11–42)
ORR, % 19 12 40 22 23 0
MSI-H expression MSI-H n = 7
Non-MSI-H n = 18
MSI-H n = 2
Non-MSI-H n = 21
MSI-H n = 2
Non-MSI-H n = 22
OS rate (95% CI), %
12 mos 57 (17–84) 33 (14–54) 50 (1–91) 36 (16–56) 50 (1–91) 23 (8–43)
18 mos 29 (4–61) 17 (4–36) 50 (1–91) 30 (12–50) 50 (1–91) 6 (0–23)
ORR, n (%)* 2 (29) 2 (11) 1 (50) 4 (19) 1 (50) 1 (5)
DCR, n (%)† 5 (71) 5 (28) 1 (50) 9 (43) 1 (50) 8 (36)
mDOR (95% CI), mos
10 (7–13) NR (3–NE) NR (NE–NE) 5 (3–NE) NR (NE–NE) 3 (NE–NE)
*Investigator Review. † Patients with a BOR of complete response, partial response, or stable disease.
2L, second line; CI, confidence interval; DCR, disease control rate; DOR, duration of response; mos, months; mDOR, median duration of response; MSI-H, microsatellite instability high; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 3 + IPI 1, 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO3 + IPI Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1.
1. Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014. 2. Ott P et al. Poster presentation at ESMO 2017. Abstract 674P.
• Responses were observed irrespective of PD-L1 • Clinical activity and durable responses were observed in both MSI-H and non-MSI-H patients
Checkmate 032: 2L+ Nivolumab ± Ipilimumab
Patients, n (%)
NIVO 3 n=59
NIVO 1 + IPI 3 n=49
NIVO 3 + IPI 1 n=52
Any Grade Grade 3–4
Any Grade Grade 3–4
Any Grade Grade 3–4
Any TRAE 41 (69) 10 (17) 41 (84) 23 (47) 39 (75) 14 (27)
Serious TRAEs 6 (10) 3 (5) 21 (43) 17 (35) 13 (25) 9 (17)
TRAEs leading to treatment discontinuation
2 (3) 2 (3) 10 (20) 10 (20) 7 (13) 5 (10)
TRAEs in ≥15% of patients in any treatment arm
ALT increased 5 (8) 2 (3) 8 (16) 7 (14) 5 (10) 2 (4)
AST increased 7 (12) 3 (5) 8 (16) 5 (10) 2 (4) 1 (2)
Decreased appetite 9 (15) 0 5 (10) 0 3 (6) 0
Diarrhea 9 (15) 1 (2) 15 (31) 7 (14) 5 (10) 1 (2)
Fatigue 20 (34) 1 (2) 14 (29) 3 (6) 10 (19) 0
Pruritus 10 (17) 0 9 (18) 1 (2) 12 (23) 0
Rash 5 (8) 0 10 (20) 0 8 (15) 0
Treatment-Related Adverse Events
One Grade 5 TRAE was reported (tumor lysis syndrome in a patient treated with NIVO 3 + IPI 1)
2L, second line; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO 3 + IPI 1, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; Q2W, once every two weeks; Q3W, once every 3 weeks. TRAE, treatment-related adverse event.
Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.
Checkmate 032: 2L+ Nivolumab ± Ipilimumab
Study Design1,2
Randomized, multicenter, phase 2/3 trial of nivolumab + chemotherapy as first-
line treatment in patients with unresectable advanced or recurrent GC or GEJC
Key Inclusion Criteria
• Treatment-naïve patients
• Unresectable advanced or recurrent HER2-negative GC/GEJC
• ECOG PS 0–1
• Neoadjuvant or adjuvant chemotherapy completed ≥180 days prior to recurrence
• Primary Outcome Measures: – PFS (Part 2) – OS (Part 2)
• Secondary Outcome Measures: – ORR, PFS, DOR, DCR, TTR, BOR, lesion size (Part 2) – Safety (Parts 1 and 2)
• Start Date: March 2016 • Estimated Study Completion Date: NA • Estimated Primary Completion Date: August 2020 • Status: Recruiting • Study Sites: Japan, Korea, Taiwan • Study Director: Ono Pharmaceutical/Bristol-Myers Squibb
Nivolumab 360 mg IV Q3W + SOX*
*IV oxaliplatin 130 mg/m2 on day 1 followed by 20 days off and oral SOX or oral capecitabine twice daily for 14 days followed by 7 days. SOX dose was mg/m2/dose (body surface area <1.25 m2, 40 mg/dose; ≥1.25 and <1.5 m2, 50 mg/dose; ≥1.5 m2, 60 mg/dose. Capecitabine dose was 1,000 mg/m2/dose (body surface area <1.36 m2, 1,200 mg/dose; 1.36 and <1.66 m2, 1,500 mg/dose; 1.66 and <1.96 m2, 1,800 mg/dose; 1.96 m2, 2,100 mg/dose). Treatment continued until progressive disease per RECIST v1.1, unacceptable toxicity, or withdrawal of consent. †Investigator will choose SOX or CapeOX therapy, taking into account the condition of each patient.
1L, first line; BOR, best overall response; CapeOX, capecitabine, oxaliplatin; chemo, chemotherapy; CR, complete response; DCR, disease control rate; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HER2, human epidermal growth factor receptor 2; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PS, performance status; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumours; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TTR, time to response.
1. Clinicaltrials.gov. NCT02746796. Accessed June 27, 2017. 2. Adapted from Kang YK. Poster presentation at ESMO 2017. Abstract 671P.
Part 1 (n=40) Part 2 (n=~650)
R
Placebo + SOX/CapeOX†
Nivolumab + SOX/CapeOX†
Nivolumab 360 mg IV Q3W + CapeOX*
ATTRACTION-04 (ONO-4538-37): 1L Nivolumab + SOX/CapeOX
R 1:1
• Continuation to Part 2 criteria:
– Confirmed tolerability and safety
– At least 2/15 subjects had
CR or PR by RECIST v1.1
Efficacy
ATTRACTION-04 (ONO-4538-37) Part 1: 1L Nivolumab + SOX/CapeOX
aDefined as disappearance of all non-lymph node target lesions. Any pathological target lymph nodes must have had a reduction in the short axis to <10 mm. bDefined as the percentage of patients in whom the BOR is CR, PR, or SD. COne patient had a protocol deviation of nivolumab treatment for another study and was excluded from efficacy analyses.
1L, first line; BOR, best overall response; CapeOX, capecitabine, oxaliplatin; CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not evaluable; Nivo, nivolumab; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TTR, time to treatment response.
Adapted from Kang YK. Poster presentation at ESMO 2017. Abstract 671P.
Time Since Treatment Initiation (months)
Ch
an
ge
Fro
m B
as
eli
ne
in
th
e S
um
of
the
Lo
ng
es
t T
arg
et
Le
sio
n D
iam
ete
rs,
(%)
Tumor Reduction
Nivo + CapeOx
Time Since Treatment Initiation (months)
-30% Tumor Reduction
20% Tumor Increase 20% Tumor Increase
-30% Tumor Increase
0 1 2 3 4 5 6 7 8 9 10
-100
-75
-25
0
25
50
-50
0 1 2 3 4 5 6 7 8 9 10
-100
-75
-25
0
25
50
-50
Discontinued
On-treatment
Nivo + SOX
Ch
an
ge
Fro
m B
as
eli
ne
in
th
e S
um
of
the
Lo
ng
es
t T
arg
et
Le
sio
n D
iam
ete
rs,
(%)
Discontinued
On-treatment
Nivolumab + SOX n=21
Nivolumab + CapeOX n=17c
ORR, % (95% CI) 67 (43–85) 71 (44–90)
BOR, n (%)
CRa 1 (5) 0
PR 13 (62) 12 (71)
SD 4 (19) 2 (12)
PD 2 (10) 2 (12)
Not evaluable 1 (5) 1 (6)
DCR,b n (%) 18 (86) 14 (82)
Median TTR, months (range) 2.1 (1.2–4.3) 1.4 (1.2–4.3)
Median DOR, months (95% CI) NR (4.3–NE) 5.8 (2.8–NE)
Safety
ATTRACTION-04 (ONO-4538-37) Part 1: 1L Nivolumab + SOX/CapeOX
*One patient had grade 2 increased aspartate aminotransferase attributed to nivolumab and grade 2 intracranial hemorrhage attributed to SOX and one patient had grade 3 increased alanine aminotransferase attributed to nivolumab.
1L, first line; CapeOX, capecitabine, oxaliplatin; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TRAE, treatment-related adverse event.
Adapted from Kang YK. Poster presentation at ESMO 2017. Abstract 671P.
Patients, n (%)
Nivolumab + SOX n=21
Nivolumab + CapeOX n=18
Any grade Grade 3–4 Any grade Grade 3–4 Any treatment-related AE 21 (100) 11 (52) 18 (100) 12 (67)
Treatment-related AEs leading to discontinuation
2 (10)a 1 (5) 0 0
Treatment-related AEs leading to dose delay
10 (48) 5 (24) 8 (44) 4 (22)
Treatment-related deaths 0 0
Treatment-related AEs (≥25%)
Diarrhea 13 (62) 1 (5) 8 (44) 1 (6)
Peripheral sensory neuropathy 12 (57) 1 (5) 12 (67) 2 (11)
Decreased appetite 11 (52) 0 10 (56) 2 (11)
Nausea 10 (48) 0 9 (50) 2 (11)
Decreased neutrophil count 10 (48) 3 (14) 10 (56) 1 (6)
Decreased platelet count 9 (43) 0 4 (22) 1 (6)
Fatigue 7 (3) 0 6 (33) 1 (6)
Peripheral neuropathy 6 (29) 1 (5) 2 (11) 0
Constipation 5 (24) 0 5 (28) 0
Vomiting 5 (24) 0 6 (33) 0
Peripheral edema 5 (24) 0 1 (6) 0
Palmar-plantar erythrodysesthesia syndrome
0 0 8 (44) 0
Slide 30
JAVELIN Basket Trial: Avelumab
Chung et al, Abstract 4009, ASCO 2016
Slide 32
JAVELIN Basket Trial: Avelumab
Chung et al, Abstract 4009, ASCO 2016
NCT02443324: Phase 1 Multi-Cohort Study of
Ramucirumab Plus Pembrolizumab
Phase 1a: DLT Assessment (n=6 to 12)
Primary: Safety and tolerability Secondary: PK
Schedule 1: Ram 8mg/kg, Day 1 and 8 Pembro 200 mg fixed, Day 1 Both IV every 3 weeks
Schedule 2: Ram 10 mg/kg, Day 1 Pembro 200 mg fixed, Day 1 Both IV every 3 weeks
Phase 1b: Cohort Expansion (n=155)a
Primary: Safety and tolerability Secondary: PK and efficacy Exploratory: Biomarkers and IG
Cohort A: Gastric/GEJ (2L+)
Cohort A2: Gastric/GEJ (1L)
Cohort B: Gastric/GEJ (2L+)
Inte
rim
An
aly
sis
All treated patients
≥2nd-Line Cohorts A/B,
n=41
1st-Line Cohort A2,
n=28 Median follow-up duration, mo (95% CI)
10.3 (9.7–15.5)
4.6 (2.3–5.8)
BOR, n (%)
CR – –
PR 3 (7) 4 (14)
SD 18 (44) 14 (50)
PD 13 (32) 5 (18)
Not Evaluable 7 (17) 5 (18)
ORR 7%b 14%c
DCRd 51% 64%
Median DOR, mo (95% CI)
6.7 (4.4–6.7) NR
Median TTR, mo (95% CI)
1.4 (1.4–4.1) 2.0 (1.3–3.6)
Duration of SD, mo (95% CI)
5.0 (4.0–8.5) 5.6 (3.2–5.8)
Efficacy Outcomes in Evaluable Patients
aPatients may continue treatment for up to 35 cycles, until confirmed progressive disease or discontinuation for any other reason. bObjective response rate in the response evaluable population (n=34) was 9%. cObjective response rate in the response evaluable population (n=23) was 17%. dPatients with best response of CR, PR, or SD.
1L, first line; 2L, second line; BOR, best overall response; CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; GC, gastric cancer; GEJ, gastroesophageal junction; GEJC, GEJ cancer; IG, immunogenicity; NR, not reached; ORR, objective response rate; PD, progressive disease; PK, pharmacokinetics; PR, partial response; Pembro, pembrolizumab; Ram, ramucirumab; SD, stable disease; TTR, time to response.
Adapted from Chau I et al. Poster presentation at ASCO 2017. Abstract 4046, showing only the GC/GEJC cohorts.
• The safety profile of ramucirumab combined with pembrolizumab is consistent with
monotherapy treatment for each drug, with no additive toxicities
NCT02572687: A Multi-Cohort Phase 1 Study
of Ramucirumab Plus Durvalumab
G/GEJ N=26
BOR, n (%)
CR -
PR 4 (15%)
SD 8 (31%)
PD 11 (42%)
NEb 3 (12%)
ORR, n (%) 4 (15%)c
DCR (CR+PR+SD), n (%)
12 (46%)d
Median DOR, mos (95% CI)
5.6 (-,-)
Median TTR, mos (95% CI) 1.5 (1.3, 5.6)
aPatients are treated until confirmed progressive disease, or any other decision to discontinue. bPatients have not had their first scan on treatment. cObjective response rate in the response evaluable population (n=23) was 17%. dDisease control rate in the response evaluable population (n=23) was 52%.
BOR, best overall response; CI, confidence interval; CR, complete response; DCR, disease control rate; DLT, dose limiting toxicities; DOR, duration of response; G, gastric; GEJ, gastroesophageal junction; IG, immunogenicity; mos, months; NE, not evaluable; ORR, objective response rate; PK, pharmacokinetics; PR, partial response; Q2W, every 2 weeks; SD, stable disease; TTR, time to response.
Adapted from Golan T et al. Poster presentation at 19th World Congress on Gastrointestinal Cancer. Abstract PD-010 to show only GC/GEJC cohorts.
Phase 1a Phase 1b
Cohort Expansiona
(n=~60 patients)
Primary: Safety
Secondary: PK, IG, preliminary efficacy
Exploratory: Biomarker DL
T R
ev
iew
G/GEJ
(28-day treatment cycle)
Ramucirumab 8 mg/kg
Q2W
Durvalumab 750 mg Q2W
Summary of Responses
• Combination of durvalumab and ramucirumab in patients with advanced G/GEJ
adenocarcinoma did not reveal any unexpected safety signals
• No SOC5 FP/Pt ± RT
• Ramucirumab ± paclitaxel3,4
• Irinotecan, docetaxel or paclitaxel1
2L
• Pt + FP doublet- or triplet- based regimen
• Trastuzumab + cisplatin + capecitabine/5-FU
(Neo)Adjuvant1
HER2 positive
HER2 negative 1L1
• 6–8 cycles or until disease progression
Maintenance
Potential for checkpoint inhibitor Ab therapy
± other I-O agents
± antiangiogenics
± cytotoxics
± other targeted therapy
If prolonged progression-free interval after 1L, can rechallenge with Pt/FP2
May discontinue due to toxicity or
infection
1L, first line; 2L, second line; 3L, third line; 5-FU, 5-fluorouracil; Ab, antibody; FP, fluoropyrimidine; HER2, human epidermal growth factor 2; I-O, immuno-oncology; Pt, platinum; RT; radiation therapy; SOC, standard of care.
1. Waddell T et al. Ann Oncol. 2013;24(suppl 6):vi57-vi63. 2. Hershman DL et al. J Clin Oncol. 2014;32(18):1941-1967. 3. Fuchs CS et al. Lancet. 2014;383(9911):31-39. 4. Wilke H et al. Lancet Oncol. 2014;15(11):1224-1235. 5. Smyth EC et al. Ann Oncol. 2016;27(suppl 5):v38-v49.7.
Future Directions in Gastric Cancer
3L+
Agenda
“Mutation burden” and Immunogenicità
Immunonoterapia nel carcinoma gastrico
Immunonoterapia nel carcinoma colo-rettale
Slide 3
Molecular classification of colon cancer
Guinney et al, Nature Medicine 2015
Slide 4
Mutational load differences
Histology of MSI Cancers
Histology of MSI cancers
Slide 6
dMMR in colorectal cancer
15% of colorectal
carcinomas across
all stages
Slide 9
Galon et al, ASCO 2016
Immunoscore as prognostic marker in stage
I/II/III colon cancer
Slide 7
Immunoscore as prognostic marker in stage
I/II/III colon cancer
Galon et al, ASCO 2016
Slide 8
Immunoscore as prognostic marker in stage
I/II/III colon cancer
Galon et al, ASCO 2016
Slide 18
Immunoscore as prognostic marker in stage
I/II/III colon cancer
Galon et al, ASCO 2016
The immunoscore study
Immunoscore as prognostic marker in stage
I/II/III colon cancer
Study implications
Immunoscore as prognostic marker in stage
I/II/III colon cancer
Single agent anti-PD1 in mCRC
MSI-H in mCRC ≈ 4%
dMMR Status: Prevalence1
dMMR/MSI-H Status and Outcomes in mCRC
dMMR, n
(%)
pMMR, n
(%) Total, N
CAIRO* 18 (5.6%) 304 (94.4%) 322
CAIRO2* 29 (5.6%) 487 (94.4%) 516
COIN† 65 (4.4%) 1396
(95.6%) 1461
FOCUS‡ 41 (5.4%) 723 (94.6%) 764
Pooled data
set 153 (5.0%)
2910
(95.0%) 3063
*dMMR testing assessed by IHC, with PCR in the absence of MMR protein expression. †dMMR testing assessed by PCR. ‡dMMR testing assessed by IHC.
CRC, colorectal cancer; dMMR, mismatch repair deficient; HR, hazard ratio; MSI-H, microsatellite instability high; OS, overall survival; pMMR, mismatch repair proficient.
1. Venderbosch S et al. Clin Canc Res. 2014;20:5322-5530. 2. Tabernero J (Venook AP). Presented at ASCO 2017.
CALGB/SWOG 804052
Median OS (95% CI)
MSI-H
MSS
1.00
0.75
0.50
0.25
0 12 24 36 48 60 72
Time From Randomization (months)
Pro
po
rtio
n
Wit
ho
ut
Eve
nt
0.00
n=31
n=444
21.0 months (11.8–41.8)
33.3 months (30.1–35.7)
Unadjusted model HR: 1.39, P=0.13
Overall Survival: Pooled Data Set1 Median OS
dMMR BRAF mutation (n=53): 11.7 months
dMMR BRAF wild-type (n=100): 15.0 months
pMMR BRAF mutation (n=197): 11.3 months
pMMR BRAF wild-type (n=2713): 17.3 months
BRAFwt and pMMR
BRAFmt
pMMR
1.0
0.8
0.6
0.4
0.2
0 10 20 30 40 50 60
OS (months)
Su
rviv
al
Pro
ba
bil
ity
P<0.001
0.0
BRAFwt and dMMR
BRAFmt
dMMR
Checkpoint Inhibition Represents a Logical
Therapeutic Target in dMMR/MSI-H mCRC
dMMR/MSI-H tumors are highly
immunogenic, which may make
these tumors susceptible to
immune checkpoint inhibitors1
dMMR/MSI-H mCRC tumors exhibit
high mutational load, increased
presence of tumor-specific
neoantigens, and increased
immune infiltration1,2
Several immune checkpoint
proteins,including PD-1, PD-L1 and
CTLA-4, may be highly expressed2
CTLA-4, cytotoxic T-lymphocyte antigen 4; dMMR, mismatch repair deficient; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; TIL, tumor-infiltrating lymphocyte.
1. Llosa NJ et al. Cancer Discov. 2015;5(1):43-51. 2. Le DT et al. N Engl J Med. 2015;372(26).2509-2520.
Selected Planned/Ongoing Immuno-Oncology
Trials for dMMR/MSI-H mCRC1
Combination Therapy Monotherapy
Checkmate 142: Ph 2
1L, nivolumab + ipilimumab
KEYNOTE-177: Ph 3
1L, pembrolizumab vs chemo ±
bevacizumab/cetuximab
COMMIT (NCT02997228): Ph 3
1L, FOLFOX + bevacizumab ±
atezolizumab
* Chemotherapy (standard treatment; FOLFOX or FOLFIRI) ± targeted therapy(panitumumab, cetuximab, bevacizumab, or afibercept)
1L, first line; 2L, second line; chemo, chemotherapy; dMMR, mismatch repair deficient; FOLFOX, fluorouracil + leucovorin + oxaliplatin; mFOLFOX, leucovorin calcium + fluorouracil + oxaliplatin; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high.
1. Clinicaltrials.gov. Accessed June 27, 2017. 2. Paul B et al. Immunotherapy. 2016;8(6):693-704.
• Treatment of dMMR/MSI-H mCRC with immuno-oncology compounds has shown promising results2
Checkmate 142: Ph 2
2L+, nivolumab + BMS-986016
(anti-LAG3)
Corvus (NCT02655822): Ph 1
2L-6L, atezolizumab ± CPI-444
ECHO-202/KEYNOTE-037: Ph 1/2
2L+, pembrolizumab + epacadostat LEGEND
Clinical trial is not yet opened
Clinical trial is ongoing
Checkmate 142: Ph 2
2L+, nivolumab + ipilimumab
1L 2L+
SAMCO (NCT03186326): Ph 2
2L+, avelumab vs chemo ± targeted
therapy*
Checkmate 142: Ph 2
2L+, nivolumab monotherapy
KEYNOTE-164: Ph 2
2L, pembrolizumab
NCT02227667: Ph 2
3L+, durvalumab
Response
dMMR
CRC
n=28
pMMR CRC
n=25
ORR, n (%)
[95% CI]
16 (57%)
[39–73]
0 (0%)
[0–13]
DCR, n (%)
[95% CI]
25 (89%)
[73–96]
4 (16%)
[6–35]
CR, n (%) 3 (11%) 0 (0%)
PR, n (%) 13 (46%) 0 (0%)
SD,* n (%) 9 (32%) 4 (16%)
PD, n (%) 1 (4%) 11 (44%)
NE†, n (%) 2 (7%) 10 (40%)
PFS, mo NR 2.3
OS, mo NR 5.98
*At Week 12. †Patients were considered not evaluable if they did not undergo a 12 week scan.
CRC, colorectal cancer; CI, confidence interval; CR, complete response; DCR, disease control rate; dMMR, mismatch repair deficient; IRAE, immune-related adverse event; irORR, immune-related objective response rate; irPFS, immune-related progression-free survival; irRC, immune-related response criteria; mCRC, metastatic colorectal cancer; MSI, microsatellite instability; NE, not evaluable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; pMMR, mismatch repair proficient; PR, partial response; Q2W, every two weeks; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.
1. Le DT et al. Oral presentation at ASCO 2016. 103. 2. Le DT et al. N Engl J Med. 2015;372(26):2509-2520.
Summary of Clinical Activity1,2
Phase 2, open-label trial of pembrolizumab as
monotherapy in 3 different treatment-refractory patient
populations
n=28
dMMR CRC
pMMR CRC
n=25
n=30 dMMR non-CRC
Key Inclusion Criteria
Pembrolizumab 10 mg/kg Q2W
N=83
• 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
• No new safety signal reported
KEYNOTE-016: Pembrolizumab
Study Design1,2
Phase 2 multicenter, multicohort trial of pembrolizumab as monotherapy in
patients with previously treated, locally advanced unresectable or metastatic
colorectal cancer
1EP, primary endpoint; 2EP, secondary endpoint; DCR, disease control rate; DOR, duration of response; EGFR, epidermal growth factor receptor; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; Q3W, every 3 weeks; Q9W, every 9 weeks; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors; PFS, progression-free survival; OS, overall survival; VEGF, anti-vascular endothelial growth factor.
1. Diaz LA et al. Poster presentation at ASCO 2017. Abstract 3071. 2. Clinicaltrials.gov. NCT02460198. Accessed August 28, 2017.
KEYNOTE-164: Pembrolizumab
NCT02460198, N=120
PD or
intolerable
toxicities
Safety follow-up (≤90 days)
Survival follow-up (Q9W)
200 mg pembrolizumab IV on Day 1 Q3W for up to
35 cycles (approx 2 years)
Patients
• Locally advanced unresectable or
metastatic dMMR/MSI-H mCRC
• ≥2 prior therapies (must include
prior fluoropyrimidine, oxaliplatin,
and irinotecan)
• ECOG PS 0 or 1
• Measurable disease
• Adequate organ function
• Primary Outcome Measures: ORR per RECIST v1.1
• Secondary Outcome Measures: DOR, DCR, PFS, OS
Ch
an
ge
Fro
m B
as
eli
ne
(%
)
100
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
Results
*2 patients were nonevaluable.
CI, confidence interval; CRC, colorectal cancer; CR, complete response; DCR, disease control rate; mos, months; IRC, independent central radiology review; mDOR, median duration of response; mos, months; mPFS, median progression-free survival; MSI-H, microsatellite instability high; mTTR, median time to response; NR, not reached; OS, overall survival; PR, partial response; SD, stable disease.
Adapted from Diaz LA et al. Poster presentation at ASCO 2017. Abstract 3071.
MSI-H CRC
N=61*
n % (95% CI)
ORR 17 28% (17–41)
Complete
response 0 0
Partial
response 17 28% (17–41)
Stable disease 14 23% (13–36)
Progressive
disease 28 46% (33–59)
DCR
(CR+PR+SD) 31 51% (38–64)
mTTR, mos
(range) 4 (2–10)
mDOR, mos
(range) NR (2.9+–12.5+)
mPFS, mos
(95% CI) 2.3 (2.1–8.1)
12 mos OS 72%
KEYNOTE-164: Pembrolizumab
Best Percentage Change From Baseline in Target Lesion Size
(RECIST v1.1 by IRC)
Prior lines of
therapy, n (%)
1 6 (10%)
2 28 (46%)
3 13 (21%)
4 5 (8%)
≥5 6 (10%)
Safety1
CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability-high.
1. Diaz LA et al. Poster presentation at ASCO 2017. Abstract 3071. 2. Keytruda Prescribing information. Keytruda U.S. Product Information. Available at: https://www.accessdata.fda.gov/drugsatfda_ docs/label/2017/125514s014lbl.pdf. Accessed August 28, 2017.
• Pembrolizumab is approved in the US for the treatment of adult and pediatric patients with unresectable
or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have
no satisfactory alternative treatment options, or CRC that has progressed following treatment with
a fluoropyrimidine, oxaliplatin, and irinotecan2
Events MSI-H CRC
N=61, n (%)
Any grade 35 (57%)
Grade 3–4 9 (15%)
Led to death
(Grade 5) 0
Led to
discontinuation 1 (2%)
Events ≥10% Any grade Grade 3–4 Grade 5
Arthralgia 10 (16%) 0 0
Nausea 9 (15%) 0 0
Diarrhea 8 (13%) 0 0
Asthenia 7 (12%) 1 (2%) 0
Pruritus 7 (12%) 0 0
Fatigue 6 (10%) 2 (3%) 0
KEYNOTE-164: Pembrolizumab
Study Design
Tumor imaging assessments were performed every 6 weeks for 24 weeks and thereafter every 12 weeks until disease progression or
discontinuation
Treatment beyond progression was permitted if the patient was determined by the investigator to be benefiting from and tolerating study
therapy, and consent was provided by the patient
Primary Outcome Measures: ORR per investigator assessment (RECIST v1.1)
Secondary Outcome Measures: ORR per blinded independent central review (BICR), PFS, OS, and safety
*Number of patients from interim analysis.
BICR, blinded independent committee review; CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors.
1. Andre T et al. Poster presentation at ASCO 2017. Abstract 3531. 2. Overman MJ et al. Oral presentation at ASCO GI 2017. Abstract GI17.
Checkmate 142: Nivolumab ± Ipilimumab Cohorts
Monotherapy
Arm (n=74)
Patients
Combination
Arm (n=84*)
If ≥ 7/19 confirmed
responders,
continue enrollment
If ≥ 7/19 confirmed
responders, continue
enrollment
Stage 1 Stage 2
Nivolumab 3 mg/kg Q2W
Nivolumab 3 mg/kg Q2W
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg
Q3W (4 doses, then
nivolumab 3 mg/kg Q2W)
• Histologically confirmed
metastatic/
recurrent CRC
• dMMR/MSI-H per local
laboratory
• ≥1 prior line of therapy
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg
Q3W (4 doses, then
nivolumab 3 mg/kg Q2W)
Disease Characteristics and Prior Therapy<br />Nivolumab ± Ipilimumab in Metastatic CRC
Checkmate 142: Nivolumab ± Ipilimumab Cohorts
Response Rates*
†Symbol “+” indicates a censored value. January 2017 data cutoff.
CI, confidence interval; CR, complete response; IQR, interquartile range; NE, not evaluable; NR, not reached; PR, partial response; SD, stable disease; TTR, time to respond.
Adapted from Overman MJ et al. Lancet Oncol. 2017. doi:10.1016/S1470-2045(17)30422-30429.
Patients
dMMR/MSI per
Local
Laboratory
(n=74)
Objective Response, n (%)
[95% CI]
23 (31.1%)
[20.8–42.9]
CR, n (%) 0
PR, n (%) 23 (31%)
SD, n (%) 28 (38%)
PD, n (%) 19 (26%)
Not determined, n (%) 4 (5%)
Disease Control for ≥12 weeks, n (%) [95% CI]
51 (69%)
(57–79)
Median Duration of Response, Months (range)
NR
(NE)
Median TTR, Months (IQR)
2.8
(1.4–3.2)
Checkmate 142: Nivolumab Monotherapy
100
75
50
25
0
-25
-50
-75
-100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 122 138
Ch
an
ge in
Su
m o
f T
arg
et
Lesio
ns
Fro
m B
aselin
e (
%)
Tumor Reduction
Confirmed partial response or complete response
First documented occurrence of new lesion
Patient off treatment
% change truncated to 100%
Weeks
CI, confidence interval; CRC, colorectal cancer; dMMR, mismatch repair deficient; mOS, median overall survival; mPFS, median progression-free survival; MSI-H, microsatellite instability high; NE, not estimable;
PFS, progression-free survival.
Overman MJ et al. Lancet Oncol. 2017. doi:10.1016/S1470-2045(17)30422-30429.
Investigator-Assessed PFS and OS
Checkmate 142: Nivolumab Monotherapy
Progression-free Survival Nivolumab (n=74)
mPFS, months (95% CI) 14.3 (4.3–NE)
12-month rate, % (95% CI) 50% (38–61)
Pro
gre
ss
ion
-Fre
e S
urv
iva
l (%
)
0 3 6 9 12 15 18 21 24
74 (0) 48 (2) 41 (3) 32 (9) 17 (22) 12 (26) 12 (26) 11 (27) 0 (38)
100
90
80
70
60
50
40
30
20
10
0
Number at risk (numbered censored)
27 30
6 (32) 3 (35)
MSI-H/dMMR mCRC per Local Lab
Overall Survival Nivolumab
(n=74)
mOS, months (95% CI) NR (18.0–NE)
12-month rate, % (95% CI) 73% (62–82)
74 (0) 64 (3) 59 (3) 55 (3) 37(18) 21 (34) 19 (34) 17 (34) 0 (51) 1 (50) 11 (40) 6 (45)
Ove
rall
Su
rviv
al
(%)
0 3 6 9 12 15 18 21 33
Time Since Start of Treatment (months)
24
100
90
80
70
60
50
40
30
20
10
0
MSI-H/dMMR mCRC per Local Lab
Number at risk (number censored)
27 30
Time Since Start of Treatment (months)
Censored observations Censored observations
Safety
The most common grade 3/4 TRAEs were increased concentrations of lipase (6 [8%]) and amylase (2 [3%])
Five (7%) patients discontinued treatment due to drug-related adverse events, including increased ALT, colitis,
duodenal ulcer, acute kidney injury, and stomatitis (one each)
No deaths were reported due to study drug toxicity
*One Grade 5 event of sudden death was reported; this death was not attributed to study drug toxicity on autopsy.
AE, adverse event; ALT, alanine aminotransferase; TRAE, treatment-related adverse event.
Overman M et al. Lancet Oncol. 2017 Jul 19. pii: S1470-2045(17)30422-30429.
Patients, n (%)
All Patients
(N=74)
Grade 1-2 Grade 3 Grade 4
Any TRAE* 36 (49%) 13 (18%) 2 (3%)
TRAEs reported in ≥10%
of patients
Fatigue
Diarrhea
Pruritus
Rash
Nausea
Hypothyroidism
16 (22%)
15 (20%)
10 (14%)
8 (11%)
7 (10%)
7 (10%)
1 (1%)
1 (1%)
0
0
0
0
0
0
0
0
0
0
0
Checkmate 142: Nivolumab Monotherapy
Patients with CR, PR, or SD for ≥12 weeks. CI, confidence interval; CR, complete response; dMMR, mismatch repair deficient; DOR, duration of response; MSI-H, microsatellite instability high; NE, not estimable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TTR, time to response.
Andre T et al. Poster presentation at ASCO 2017. Abstract 3531.
dMMR/MSI-H (n=84)
Investigator assessed ORR, n
(%)
[95% CI]
46 (55%)
[43.5–65.7]
Best overall response, n (%)
CR
PR
SD
PD
Not determined/reported
2 (2%)
44 (52%)
26 (31%)
9 (11%)
3 (4%)
Disease control for ≥12
weeks,* n (%)
[95% CI]
66 (79%)
[68.3–86.8]
Median TTR, months (range) 2.8 (1.1–14.0)
Median DOR, months,
[95% CI]
NR
[NE–NE]
Efficacy
Ch
an
ge in
Targ
et
Lesio
n F
rom
Baselin
e (
%)
Time Since Start of Treatment (weeks)
0 78 72 66 60 54 48 42 36 30 24 18 12 6 84 90
100
75
50
25
-25
-50
-75
-100
0
1st occurrence of new lesion
CR or PR
On treatment
Checkmate 142: Nivolumab + Ipilimumab Combination
Off treatment
Confirmed CR or PR per investigator.
CR, complete response; PR, partial response.
Andre T et al. Poster presentation at ASCO 2017. Abstract 3531.
100
75
50
25
0
-25
-50
-75
-100
Bes
t R
ed
uc
tio
n f
rom
Bas
eli
ne in
Targ
et
Les
ion
(%
)
Best Reduction in Target Lesion Size
Checkmate 142: Nivolumab + Ipilimumab Combination
• 80% of patients had a reduction in tumor burden from baseline
CI, confidence interval; NE, no estimatable; OS, overall survival; PFS, progression-free survival.
Andre T et al. Poster presentation at ASCO 2017. Abstract 3531.
Investigator-Assessed PFS and OS
Checkmate 142: Nivolumab + Ipilimumab Combination
Pro
ba
bilit
y o
f S
urv
iva
l
Time (months)
0 3 6 9 12 15 18 21
84 77 73 40 22 19 13 0
1.0
0.9
0.8
0.5
0.4
0.3
0.2
0.0
0.6
0.1
0.7
No. at
Risk
OS rate (95% CI), %
6-month 89 (80.2–94.2)
9-month 88 (78.1–93.1)
Median OS (95% CI), months
NR (NE–NE)
Overall Survival
No. at
Risk
Pro
ba
bilit
y o
f P
FS
1.0
0.9
0.8
0.5
0.4
0.3
0.2
0.0
0.6
0.1
0 3 6 9
Time (months)
12 15 18 21
65 35 17 13 8 1 0 84
0.7
Progression-free Survival
PFS rate (95% CI), %
6-month 77 (66.5–85.1)
9-month 77 (66.5–85.1)
Median PFS (95% CI), months
NR (11.5–NE)
Safety
AEs were manageable, with Grade 3/4 TRAEs reported in 29% of patients
No treatment-related deaths were reported in this study
*All events (ALT level increase, autoimmune hepatitis, colitis, dyspnea, necrotizing myositis, pneumonitis, immune sarcoidosis, transaminase increase, thrombocytopenia) occurred in one patient each with the exception of acute kidney injury, which was reported in 2 patients.
AE, adverse event; ALT, alanine aminotransferase; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; TRAE, treatment-related adverse events.
Andre T et al. Poster presentation at ASCO 2017. Abstract 3531.
dMMR/MSI-H
(n=84)
Patients, n (%) Any Grade Grade 3 or 4
Any TRAE 57 (68%) 24 (29%)
Serious TRAEs 15 (18%) 14 (17%)
Discontinuation due to TRAEs* 11 (13%) 8 (9%)
TRAEs reported in ≥10% of
patients
Diarrhea
Fatigue
Aspartate aminotransferase
increase
Pyrexia
Pruritus
Alanine aminotransferase
increase
Nausea
Hyperthyroidism
Hypothyroidism
20 (24%)
14 (17%)
14 (17%)
13 (16%)
13 (16%)
12 (14%)
12 (14%)
11 (13%)
11 (13%)
1 (1%)
1 (1%)
8 (9%)
0
2 (2%)
7 (8%)
0
0
0
Checkmate 142: Nivolumab + Ipilimumab Combination
Cohort Disease State Regimens Endpoint(s)
Monotherapy 2L+ mCRC Nivolumab
Primary Endpoint:
ORR (investigator assessment)
Secondary Endpoint:
ORR (BICR)
Other Endpoints:
PFS, OS, biomarkers, safety,
and tolerability
Nivolumab + Ipilimumab 2L+ mCRC
Nivolumab + ipilimumab
3 1L mCRC Nivolumab + ipilimumab
5 2L+ mCRC Nivolumab + anti-LAG3
Overview of Ongoing dMMR/MSI-H Cohorts in
Checkmate 142
1L, first line; 2L, second line; BICR, blinded independent central review; dMMR, mismatch repair deficient; LAG, lymphocyte activation gene; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
Clinicaltrials.gov. NCT02060188. Accessed June 21, 2017.
Checkmate 142: MSI-H Cohorts
Several Exploratory Immuno-Oncology Trials
for non-MSI-H mCRC Are Ongoing1
1L, first line; 2L, second line; CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; Ph, phase.
1. Clinicaltrials.gov. Accessed June 27, 2017. 2. Le DT, et al. N Engl J Med. 2015;372:2509-2520.
Checkmate 142: Ph 2 2L+, nivolumab + ipilimumab + cobimetinib
Checkmate 142: Ph 2 2L+, nivolumab + daratumumab
NCT02335918: Ph 1/2 2L+, nivolumab + varlilumab
NCT02512172: Pilot/Ph1 1L+, pembrolizumab + CC-486, or
romidepsin
• Patients with MSS CRC have not been shown to benefit from
single agent PD-1/PD-L1 inhibition2
Phase Ib Dose Escalation and Cohort Expansion Study (NCT01988896)
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
NCT01988896: Atezolizumab
PD-L1 and MEK Inhibition: A Rational Combination
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
NCT01988896: Atezolizumab
Baseline Characteristics
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Baseline Characteristics (cont.)
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Efficacy: Confirmed Objective Response
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Efficacy: Change in Tumor Burden
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Efficacy: Duration of Treatment and Response
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Efficacy: Progression-Free Survival And Overall Survival
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Safety: Treatment-related AEs
NCT01988896: Atezolizumab
Phase 1b Dose Escalation and Cohort Expansion in
MSI-Unselected CRC1,2
Baseline Patient Characteristics
Presented By Rachel Sanborn at 2017 ASCO Annual Meeting
Phase 1 Combination of anti-CD27 agonist antibody
varilumab with nivolumab in advanced solid tumors
CRC 42
Varlilumab & Nivolumab Combination Therapy is Well Tolerated
Presented By Rachel Sanborn at 2017 ASCO Annual Meeting
Phase 1 Combination of anti-CD27 agonist antibody
varilumab with nivolumab in advanced solid tumors
Tumor Response
Presented By Rachel Sanborn at 2017 ASCO Annual Meeting
Phase 1 Combination of anti-CD27 agonist antibody
varilumab with nivolumab in advanced solid tumors
Durable Response in MMR-proficient CRC Patient
Presented By Rachel Sanborn at 2017 ASCO Annual Meeting
Phase 1 Combination of anti-CD27 agonist antibody
varilumab with nivolumab in advanced solid tumors
Further Investigation in Late-Phase
CRC Clinical Trials
COTEZO (NCT02788279): Ph3 3L+, atezolizumab ± cobimetinib
(up to 5% dMMR/MSI-H)
1L, first line; 3L, third line; CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; Ph, phase.
Clinicaltrials.gov. Accessed June 27, 2017.
MODUL (NCT02291289): Ph 2 1L Maintenance, atezolizumab +
bevacizumab
Conclusions - Results
Advanced esophagogastric cancer
PD-1/PD-L1 blockade is active
Anti-CTL4 + anti-PD-1 may be more active than anti-PD-1
but with more toxicity
Advanced colorectal cancer
PD-1/PD-L1 blockade is active in MSI-H patients
PD-1 inhibition is progressing as the standard of care for the
treatment of MSI-H mCRC
Emerging data with immuno-oncology combinations have
demonstrated potential for even greater clinical benefit
ORR of 55% for patients receiving nivolumab + ipilimumab
combination therapy
PD-1/PD-L1 + MEK-inhibition may be active in MSS patients
Conclusions – Future directions
Biomarker development
Peri-operative and adjuvant setting
Maintenance therapy in metastatic disease
Combinatorial approaches
Chemotherapy
Target therapies
Checkpoint antagonists/agonists
Immune modulators
Loco-regional treatment (ablation, chemoradiation) for
abscopal effect