keynote 177 phase III trial of first line pembrolizumab vs CT in MSI H mCRC

KEYNOTE-177: Phase III Trial of First-line
Pembrolizumab vs Chemotherapy in
MSI-H/dMMR Metastatic CRC
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Highlights of the 2020 ASCO Virtual Scientific Meeting, May 29-31, 2020
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KEYNOTE-177: Background
 Deficiencies in dMMR can lead to MSI-H, which is found in ~ 5% of patients with mCRC[1,2]
‒ This disease type typically responds poorly to chemotherapy
‒ Unique biology of MSI-H/dMMR mCRC well suited to immune checkpoint inhibition: features
high tumor mutation burden, high levels of tumor neoantigens, and increased immune cell
infiltration
 Prior phase II studies demonstrated durable antitumor activity and acceptable safety with
use of pembrolizumab in previously treated MSI-H mCRC[3,4]
‒ Pembrolizumab approved for previously treated MSI-H metastatic tumors regardless of tumor
type or site[5]
 Current phase III study compared efficacy and safety of first-line pembrolizumab vs
standard therapy in patients with MSI-H mCRC[6]
1. Innocenti. JCO. 2019;37:1217. 2. Venderbosch. Clin Cancer Res. 2014;20:5322. 3. Le. NEJM. 2015;372:2509.
4. Le. J Clin Oncol. 2020;38:11. 5. Pembrolizumab PI. 6. Andre. ASCO 2020. Abstr LBA4.

KEYNOTE-177: Study Design
Andre. ASCO 2020. Abstr LBA4. Slide credit: clinicaloptions.com
 Randomized, open-label phase III trial
Patients with
treatment-naive MSI-H
(PCR)/dMMR (IHC)
stage IV CRC;
ECOG PS 0/1;
measurable disease
(N = 307)
Investigator-choice of chemotherapy*
(n = 154)
Pembrolizumab 200 mg Q3W for up to 35 cycles
(n = 153)
 Dual primary endpoints: PFS,†
OS
‒ Trial positive if pembrolizumab superior to
chemotherapy for either primary endpoint
 Secondary endpoints: ORR,†
safety
 Data cutoff: February 29, 2020
 Median follow-up: 28.4 mos in
pembrolizumab arm, 27.2 mos in
comparator arm
*Chemotherapy options included mFOLFOX6 or FOLFIRI ± bevacizumab or cetuximab.
†
Blinded independent central review per RECIST v1.1.
Crossover permitted at
disease progression

KEYNOTE-177: Baseline Characteristics
Andre. ASCO 2020. Abstr LBA4.
Characteristic Pembrolizumab (n = 153) Chemotherapy (n = 154)
Median age, yrs (range) 63.0 (24-93) 62.5 (26-90)
Male, n (%) 71 (46) 82 (53)
ECOG PS 0, n (%) 75 (49) 84 (55)
Region, n (%)
 W. Europe/N. America
 Asia
 Rest of world
109 (71)
22 (14)
22 (14)
113 (73)
26 (17)
15 (10)
Metachronous disease, n (%) 80 (52) 74 (48)
Hepatic metastases, n (%) 71 (46) 54 (35)
Right-sided / left-sided tumor, n (%) 102 (67) / 46 (30) 107 (70) / 42 (27)
Prior neoadjuvant/adjuvant therapy, n (%) 38 (25) 45 (29)
Mutation status, n (%)
 Wild-type BRAF, KRAS, and NRAS
 BRAF V600E mutant
 KRAS or NRAS mutant
 Not evaluable
34 (22)
34 (22)
33 (22)
52 (34)
35 (23)
43 (28)
41 (27)
38 (25)

KEYNOTE-177: PFS (Primary Endpoint; ITT)
Andre. ASCO 2020. Abstr LBA4. Reproduced with permission. Slide credit: clinicaloptions.com
PFS
(%)
Mos
Patients at Risk, n
153 96 77 72 64 60 55 37 20 7 5 0 0
154 100 68 43 33 22 18 11 4 3 0 0 0
12-mo rate
55%
37%
24-mo rate
48%
19% Median, Mos (95% CI)
16.5 (5.4-32.4)
8.2 (6.1-10.2)
Pembrolizumab
Chemotherapy
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44 48
Events, % HR (95% CI) P Value
54 0.60 .0002
73 (0.45-0.80)

KEYNOTE-177: PFS Subgroup Analysis
0.1 1 10
Site of Primary Tumor
Right
Left
KRAS/NRAS
KRAS/NRAS all WT
KRAS or NRAS mutant
BRAF
BRAF WT
BRAF V600E
Stage
Recurrent metachronous
Newly diagnosed
Rest of World
Geographic Region
Asia
W Europe/N America
Sex
Male
Female
Age
> 70 yrs
≤ 70 yrs
Overall
Events/Patients, N
195/307
132/217
63/90
91/153
104/154
90/159
105/148
28/48
146/222
21/37
87/154
108/153
78/131
51/77
95/151
51/74
137/209
50/88
HR (95% CI)
0.60 (0.45-0.80)
0.52 (0.37-0.75)
0.77 (0.46-1.27)
0.59 (0.38-0.90)
0.58 (0.39-0.87)
0.37 (0.24-0.59)
0.84 (0.57-1.24)
0.65 (0.30-1.41)
0.62 (0.44-0.87)
0.40 (0.16-0.98)
0.53 (0.34-0.82)
0.70 (0.47-1.04)
0.50 (0.31-0.80)
0.48 (0.27-0.86)
0.44 (0.29-0.67)
1.19 (0.68-2.07)
0.54 (0.38-0.77)
0.81 (0.46-1.43)
Favors chemotherapy
Favors pembrolizumab
ECOG PS
0
1

Efficacy Outcomes (ITT) Pembrolizumab (n = 153) Chemotherapy (n = 154) P Value
ORR, % 43.8 33.1 .0275
DCR (CR + PR + SD), % 64.7 75.3
Best overall response, %
 CR
 PR
 SD
 PD
 Not evaluable
 No assessment
11.1
32.7
20.9
29.4
2.0
3.9
3.9
29.2
42.2
12.3
1.3
11.0
Median time to response, mos (range) 2.2 (1.8-18.8) 2.1 (1.7-24.9)
KEYNOTE-177: Other Efficacy Endpoints
 36% of patients in chemotherapy arm crossed over to receive pembrolizumab; 23% received anti–PD-1/PD-L1
therapy outside of study
 OS analysis ongoing

KEYNOTE-177: Duration of Response
Patients
in
Response
(%)
Median DoR, Mos (95% CI)
NR (2.3+ to 41.4+)
10.6 (2.8 to 37.5+)
≥ 24-mo response duration
83%
35%
Mos
Patients at Risk, n
67 64 57 50 48 41 29 13 6 4 2 0 0
51 48 35 19 13 11 9 5 2 1 0 0 0
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44 48
Pembrolizumab
Chemotherapy

KEYNOTE-177: Overall Safety
Adverse Events, % Pembrolizumab
(n = 153)
Chemotherapy
(n = 143)
Any AEs 97 99
Treatment-related AEs
 Grade ≥ 3
 Discontinuation
 Death
80
22
10
0
99
66
6
1
Immune-mediated AEs
 Grade ≥ 3
 Discontinuation
 Death
31
9
7
0
13
2
0
0

KEYNOTE-177: Adverse Events
AEs (Incidence ≥ 20% in Either Arm, or ≥ 5% if
Immune Mediated), %
Pembrolizumab (n = 153) Chemotherapy (n = 143)
All Grades Grade ≥ 3 All Grades Grade ≥ 3
Diarrhea 25 2 52 10
Fatigue 21 2 44 9
Nausea 12 0 55 2
Decreased appetite 8 0 34 2
Stomatitis 5 0 30 4
Alopecia 3 0 20 0
Vomiting 3 0 28 4
Decreased neutrophil count 1 0 23 17
Neutropenia 0 0 21 15
Peripheral sensory neuropathy 0 0 20 2
Hypothyroidism 12 0 2 0
Colitis 7 3 0 0
Infusion reactions 2 0 8 1

Conclusions
 Pembrolizumab produced significant and clinically meaningful improvements in
outcomes vs standard therapy in treatment-naive patients with MSI-H mCRC
‒ Median PFS: 16.5 vs 8.2 mos (HR: 0.60, 95% CI 0.45-0.80; P = .0002)
‒ ORR: 43.8% vs 33.1% (P = .0275)
‒ Median DoR: not reached vs 10.6 mos
 Pembrolizumab associated with favorable safety profile vs chemotherapy
‒ Grade ≥ 3 treatment-related AEs: 22% vs 66%
 KEYNOTE-177 deemed a positive study based on PFS outcomes; OS outcomes still
awaited
 Investigators concluded that single-agent pembrolizumab should be the new first-
line standard of care for patients with MSI-H mCRC

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