Ruolo dei checkpoint inhibitors nelle neoplasie del colon-retto:
evidenze scientifiche ed inserimento nell’algoritmo decisionale
Sara Lonardi Marco Tagliamento
Regione del Veneto
CORSO AIOM-SIAPEC DI IMMUNOTERAPIA IN ONCOLOGIA
Torino, 5-6 settembre 2018
MSI
Q1: What is the peculiarity of mCRC when talking about CI?
A new piece on the puzzle of mCRC!
50%
RAS mutations
BRAF mutation
RAS/BRAF wild-type
40% 10%
HER-2 3%
Rearrangem
MSI 5%
Courtesy C. Cremolini
And from the clinical point of view..
Microsatellite instability is associated with..
• Right primary tumor
• Mucinous histology
• Peritoneal and distant nodes metastasis
• BRAF mutations
• Microsatellite instable cancers (MSI-H) have a defect in repairing DNA resulting in a very high mutation rate
• Higher number of neoantigens in MSI-H tumors attracts tumor-
infiltrating lymphocytes (TILs) and overexpression of programmed death- 1 (PD-1) and PD-1 ligand 1 (PD-L1) which inhibits tumor cell killing
MSI
T Cell T Cell
T Cell
T Cell
T Cell
NON-MSI Tumor Cell
Dienstmann R, et al. J Clin Oncol. 2014;32:Abstract 3511.
Strickland KC, et al. Oncotarget. 2016;7:13587–13598.
Microsatellite instability in mCRC
The 4 ’’W’’ of MSI
• Who:
every colon cancer
• When:
At the first diagnosys, on primary tumor
• What test:
IHC or pCR are both ok
… and WHY?
… and WHY?
Le et al, N Eng J Med 2015
Type of response MSI
(n=10)
MSS (n=18)
Complete Response 0% 0%
Partial Response 40% 0%
Objective Response Rate 40% 0%
Disease Control Rate 90% 11%
Q2: Which scenario are we facing?
A doublet plus…
✓ Bevacizumab → majority of pts
✓ Aflibercept → only with FOLFIRI;
✓ Ramucirumab → only with FOLFIRI;
✓ anti-EGFRs → only RAS and BRAF wt;
mainly if shrinkage is needed
Second line options summary
✓ Anti-EGFR (pani, cet +/- irinotecan)
In RAS wt pts not previously treated with anti-EGFR
✓ Chemo Rechallenge
No prospective evidences
Carefully consider previous benefit and toxicity
Treatment options in later lines
✓ Small molecules: Regorafenib
✓ Chemotherapy: Trifluridine/tipiracil (TAS-102)
Q3: Which results from monotherapy
14
Primary analysis (N = 74): efficacy per BICR and safety;
median follow-up, 21 months (range, 17–40)c
Nivolumab 3 mg/kg Q2W
• Histologically
confirmed metastatic or recurrent CRC
• dMMR/MSI-H per local laboratory
• ≥ 1 prior line of therapy
Monotherapy Cohorta
Primary endpoint:
• ORR per investigator assessment
Other key endpoints:
• ORR per BICR, DCRb, DOR, PFS, OS, and safety
CheckMate-142 Monotherapy Cohort Study Design
Prior Therapies
15 Presented by: Dr. Michael J. Overman
All patients N = 74 Prior lines of therapy, n (%)
0 1 2
≥ 3
1 (1) 11 (15) 22 (30) 40 (54) Prior therapies received, n (%)
Fluoropyrimidines (5-FU/capecitabine) Oxaliplatin
Irinotecan
VEGF inhibitorsd EGFR inhibitorse Regorafenib
Other
73 (99) 71 (96) 55 (74) 57 (77) 31 (42) 12 (16) 11 (15)
More than 80% pts received nivo as 3’ line or more!
16 Presented by: Dr. Michael J. Overman
Response and Disease Control
All patientsa N = 74 ORR, n (%)
[95% CI]
25 (34) [23.2, 45.7]
Best overall response, n (%) CR
PR SD PD
Unable to determine
7 (9) 18 (24) 23 (31) 22 (30)
4 (5) Disease control, n (%)d
[95% CI]
46 (62) [50.1, 73.2]
Median DOR (range), mo NR (1.4+ to 31.6+) Median duration of SD (range), mo 8.3 (4.2, NE)
Best Reduction in Target Lesion: All Patients
60% of patients had a reduction in tumor burden from baseline
Group A:patients received ≥3 prior chemotherapies including a fluoropyrimidine, oxaliplatin, and irinotecan
Group B: patients did not receive prior treatment with all 3 of these chemotherapies (fluoropyrimidine, oxaliplatin and irinotecan)Presented by: Dr. Michael J. Overman 17
-100 -80 -60 -40 -20 0 20 40 60 80 100
Best reduction from baseline in target lesion size (%)a
†
Progression-Free Survival: All Patients
18 No. at Risk
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
74 44 35 31 29 27 15 14 14 12 6 1 0
Progression-free survival (%)a
100 90 80 70 60 50 40 30 20 10 0
All patients n = 74 Median PFS (95% CI), months 6.6 (3.0, NE) PFS rate (95% CI), %
12 months 18 months
44 (32.6, 55.3) 44 (32.6, 55.3)
Overall Survival: All Patients
No. at Risk
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Months
74 44 35 31 29 27 15 14 14 12 6 1 0 0
Overall survival (%)
100 90 80 70 60 50 40 30 20 10 0
All patients n = 74
Median OS (95% CI), months NR (19.6, NE) OS rate (95% CI), %
12 months 18 months
72 (60.0, 80.9) 67 (54.9, 76.9)
19
Q4: what about combinations?
Mechanism of action of
Ipilimumab and Nivolumab
T cell Tumor cell
TCR MHC
PD-L1 PD-1
- - -
T cell Dendritic
cell
MHC TCR
CD28
B7 CTLA-4
- - -
Activation
(cytokines, lysis, proliferation, migration to tumor)
B7 +++
+++
CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)
anti-CTLA-4 anti-PD-1
+++
PD-L2 PD-1
anti-PD-1
- - -
Mechanism of action of Nivolumab and Ipilimumab
Tumor Microenvironment
Presented by: Prof Thierry André
Primary endpoint:
• ORR per investigator
assessment (RECIST v1.1)
Other key endpoints:
• ORR per BICR, DCRb, DOR, PFS, OS, and safety
• Histologically
confirmed metastatic or recurrent CRC
• dMMR/MSI-H per local laboratory
• ≥ 1 prior line of therapy
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W
(4 doses and then nivolumab 3 mg/kg Q2W)
Combination Cohorta
CheckMate-142 Combination Cohort Study Design
Prior Therapies
23
Nivolumab + ipilimumab N = 119
Prior lines of therapy, n (%)a 1
2
≥ 3
27 (23) 43 (36) 48 (40) Prior therapies received, n (%)
Fluoropyrimidineb Oxaliplatin
Irinotecan
VEGF inhibitorsc EGFR inhibitorsd Regorafenib
Trifluridine/tipiracil Other chemotherapy
Other experimental drugs
118 (99) 111 (93) 87 (73) 68 (57) 35 (29) 11 (9)
2 (2) 8 (7) 3 (3)
aOne patient had received no prior lines of therapy.
More than 75% pts received nivo-ipi as 3’ line or more!
3 5 12
26 31
38 51,3
31 3,4
CR PR SD PD Unknown
Patients (%)
ORR [95% CI]: 31% [20.8, 42.9]
Nivolumab1 N = 74c Nivolumab + ipilimumab
N = 119a
ORR [95% CI]: 55% [45.2, 63.8]
20 40 60 80 100
0
DCRbwas 80% [95% CI: 71.5, 86.6] with combination therapy and 69% [57.1, 79.2] with monotherapy1,d Combination therapy provided a numerically higher ORR, including CRs, and DCR relative
to monotherapy during a similar follow-up periodd
aMedian follow-up was 13.4 (range, 9–25) months.
b Disease control was defined as patients with a CR, PR, or SD for ≥12 weeks.
c Median follow-up was 13.4 (range, 10–32) months.
d CheckMate-142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison.
1. Overman MJ et al. Lancet Oncol 2017;18:1182–1191.
Investigator-Assessed Response and Disease Control
24 Presented by: Prof Thierry André
Best Reduction in Target Lesions
Presented by: Prof Thierry André 25
78% of patients had a reduction in tumor burden from baseline with combination therapy Nivolumab + ipilimumab
Bestreductionfrom baseline in targetlesion size (%)
100
50 75
0
-50
-75 -25 25
-30 20
-100
********** ********
**** *******
*** ********* ****
*** ********* ****
**
**
Nivolumab +
ipilimumaba,d Nivolumab1,e,f 9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7]
12-mo rate (95% CI), % 85 (77.0, 90.2) 73 [61.5, 82.1]
Nivolumab +
ipilimumaba,b Nivolumab1,e,f 9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5]
12-mo rate (95% CI], % 71 (61.4, 78.7) 50 [38.1, 61.4]
Combination therapy provided improved long-term clinical benefit relative to monotherapy during a similar follow-up period
Nivolumab 74 48 41 32 17 12 12 11 6 3 0
Nivolumab
Months No. at Risk
119
Nivolumab + ipilimumab 95 86 78 39 12 11 10 3 0 0
100 90 80 70 60 50 40 30 20 10 0
0 3 6 9 12 15 18 21 24
Progression-free survival(%)c
27 30
Nivolumab + ipilimumab
100 90 80 70 60 50 40 30 20 10 0
0 3 6 9 12 15 18 21 24
Overall Survival (%)
27 30 33
Months
119 113 107 104 78 33 19 17 11 0 0 0
Nivolumab + ipilimumab
74 64 59 55 37 21 19 17 11 6 1 0
Nivolumab
Presented by: Prof Thierry André 26
Progression-Free and Overall Survival
Q5: there are other biomarkers in MSI-H patients?
Nivolumab + ipilimumab (N = 119)
n ORRa DCRa,b
Tumor PD-L1 expression, n (%)
≥ 1% 26 14 (54) 20 (77)
< 1% 65 34 (52) 51 (78)
BRAF/KRAS mutation status, n (%)
Wild type 31 17 (55) 24 (77)
BRAF mutant 29 16 (55) 23 (79)
KRAS mutant 44 25 (57) 37 (84)
Clinical history of Lynch syndromec, n (%)
Yes 35 25 (71) 30 (86)
No 31 15 (48) 25 (81)
Response and Disease Control in Patient Subsets
Presented by: Prof Thierry André 28
• Responses were observed irrespective of tumor PD-L1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome
Q6: what about safety?
Safety Summary
• ORR (63%) in patients (n=16) who discontinued treatment due to a study drug-related AE was consistent with the
overall population
• No new safety signals or treatment- related deaths were reported
• For combination therapy relative to monotherapy:1,b,c,d
– Any-grade TRAEs (73%; 70%) were comparable
– Grade 3–4 TRAEs (32%; 20%) were acceptable
– TRAEs leading to discontinuation (13%;
7%) were modest
30 Presented by: Prof Thierry André
Patients, n (%)
Nivolumab + ipilimumab N = 119
Any grade Grade 3–4
Any TRAE 87 (73) 38 (32)
Any serious TRAE 27 (23) 24 (20)
Any TRAE leading to
discontinuation 15 (13)a 12 (10)
TRAEs reported in > 10% of patients
Diarrhea 26 (22) 2 (2)
Fatigue 21 (18) 2 (2)
Pruritus 20 (17) 2 (2)
Pyrexia 18 (15) 0
Increased AST 17 (14) 9 (8)
Hypothyroidism 16 (13) 1 (1)
Nausea 15 (13) 1 (1)
Increased ALT 14 (12) 8 (7)
Rash 13 (11) 2 (2)
Hyperthyroidism 13 (11) 0
Patient-Reported Outcomes
Presented by: Prof Thierry André 31
Nivolumab + ipilimumab
Statistically significant and clinically meaningful improvements were achieved in key patient- reported outcomes, with improvements maintained for extended periods while on treatment
-30 -20 -10 0 10 20
30 EQ-5D VASa
Weeks
Better **
** ** ** ** ** ** **
** **
7 13 19 25 31 37 43 49 55 61 67
0
104 91 78 69 69 62 62 65 52 40 25 14
* P < 0.05; ** P < 0.01.
Worse
EORTC QLQ-C30 global health status/QoLa
-30 -20 -10 0 10 20 30 40
Weeks Least squares mean change from baseline (95% CI)
** ** **
** **
**
**
** ** **
** ** *
**
**
BetterWorse
7 13 19 25 31 37 43 49 55 61 67 73 79 85 91
0
107 98 84 78 75 67 68 71 57 45 31 16 10 11 10 10 Patient no.
* P < 0.05; ** P < 0.01.
