CCO_Lung_Fellows_Herbst_Lancet_2015_slides.ppt

KEYNOTE 010

1. Slideset on:
Herbst RS, Baas P, Kim DW, et al.
Pembrolizumab versus docetaxel for previously
treated, PD-L1-positive, advanced non-small-cell
lung cancer (KEYNOTE-010): a randomised
controlled trial. Lancet. 2015;[Epub ahead of
print].
Improved Survival With Pembrolizumab vs
Docetaxel in Treatment-Experienced Pts
With PD-L1–Positive Advanced NSCLC:
KEYNOTE-010
This activity is supported by educational grants from
Genentech, Lilly, and Novartis.

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3. Background: Pembrolizumab in Metastatic
NSCLC
Immunotherapy emerging as treatment option in metastatic NSCLC
[1]
–Suite of monoclonal antibodies that block interaction of PD-1 with its
ligands, PD-L1 and PD-L2, allowing for T-cell activation/proliferation
Pembrolizumab: a fully human IgG4 monoclonal antibody against PD-1
–KEYNOTE-001: ≥ 50% PD-L1 expression associated with improved
outcomes following treatment with 2 mg/kg pembrolizumab every 3 wks
[2]
–Approved for pts advanced or metastatic NSCLC whose tumors express
PD-L1 as determined by and FDA-approved test following disease
progression on platinum-containing chemotherapy (and TKI for pts with
EGFR/ALK aberrations)
Current phase II/III study, KEYNOTE-010, evaluated pembrolizumab vs
docetaxel in treatment-experienced, advanced NSCLC pts with PD-L1
expression ≥ 1% and ≥ 50%
[3]
1.Garon EB. Semin Oncol. 2015;42(suppl 2):S11-S18.
2.Garon EB, et al. N Engl J Med. 2015;372:2018-2028.
3. Herbst RS, et al. Lancet. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com

4. KEYNOTE-010: Phase II/III Trial Schema
Pembrolizumab 2 mg/kg IV Q3W
(n = 345)
Docetaxel* 75 mg/m
2
IV Q3W
(n = 343)
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].
Treatment
continued for 24
mos or until PD
†

or unacceptable
toxicity
*Corticosteroid premedication allowed.
†
Disease progression determined by radiological imaging.
In the case of investigator-assessed clinical disease progression, treatment permitted until
confirmatory scan completed 4-6 wks later.
Stratified by ECOG PS (0 vs 1), region (east
Asia vs not east Asia), and PD-L1 expression
(≥ 50% vs 1% to 49%)
Pts with advanced
NSCLC who progressed
after platinum-based
chemotherapy
(and TKI if EGFR+ or
ALK+);
≥ 1% PD-L1+ tumor cells;
ECOG PS 0-1
(N = 1034)
Pembrolizumab 10 mg/kg IV Q3W
(n = 346)
Slide credit: clinicaloptions.com

5. All pts experienced OS benefit from pembrolizumab
KEYNOTE-010: OS
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].
PD-L1 TPS ≥ 50%PD-L1 TPS ≥ 1%
2 mg/kg vs docetaxel: 10.4 vs 8.5 mos;
HR: 0.71 (95% CI: 0.58-0.88; P = .0008)
10 mg/kg vs docetaxel: 12.7 vs 8.5 mos;
HR: 0.61 (95% CI: 0.49-0.75; P < .0001)
2 mg/kg vs docetaxel: 14.9 vs 8.2 mos;
HR: 0.54 (95% CI: 0.38-0.77; P = .0002)
10 mg/kg vs docetaxel: 17.3 vs 8.2 mos;
HR: 0.50 (95% CI: 0.36-0.70; P < .0001)
Slide credit: clinicaloptions.com
100
80
60
40
20
0
50 10 15 20 25
O
S

(
%
)
Mos
100
80
60
40
20
0
50 10 15 20 25
O
S

(
%
)
Mos
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel

6. KEYNOTE-010: OS Subgroup Analysis
Herbst RS, et al. Lancet. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com
PD-L1 tumor proportion score
≥ 50%
1% to 49%
Tumor sample
Archival
New
Histology
Squamous
Adenocarcinoma
EGFR status
Mutant
Wild-type
Overall
204/442
317/591
266/455
255/578
128/222
333/708
46/86
447/875
521/1033
0.53 (0.40-0.70)
0.76 (0.60-0.96)
0.70 (0.54-0.89)
0.64 (0.50-0.83)
0.74 (0.50-1.09)
0.63 (0.50-0.79)
0.88 (0.45-1.70)
0.66 (0.55-0.80)
0.67 (0.56-0.80)
0.1 1 10
Favors pembrolizumab Favors docetaxel
Events/Pts (n) HR (95% CI)

7. Pembrolizumab achieved significantly longer PFS for pts with PD-L1
TPS ≥ 50%, but did not reach significance for overall population
KEYNOTE-010: PFS
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].
PD-L1 TPS ≥ 50%PD-L1 TPS ≥ 1%
2 mg/kg vs docetaxel: 3.9 vs 4.0 mos;
HR: 0.88 (95% CI: 0.74-1.05; P = .07)
10 mg/kg vs docetaxel: 4.0 vs 4.0 mos;
HR: 0.79 (95% CI: 0.66-0.94; P < .004 [NS])
2 mg/kg vs docetaxel: 5.0 vs 4.1 mos;
HR: 0.59 (95% CI: 0.44-0.78; P = .0001)
10 mg/kg vs docetaxel: 5.2 vs 4.1 mos;
HR: 0.59 (95% CI: 0.45-0.78; P < .0001)
Slide credit: clinicaloptions.com
100
80
60
40
20
0
50 10 15 20 25
P
F
S

(
%
)
Mos
100
80
60
40
20
0
50 10 15 20 25
Mos
P
F
S

(
%
)
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel

8. ORR significantly higher with both 2 mg/kg and 10 mg/kg pembrolizumab vs
docetaxel regardless of PD-L1 TPS
KEYNOTE-010: Duration of Response
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].
PD-L1 TPS ≥ 50%PD-L1 TPS ≥ 1%
Slide credit: clinicaloptions.com
100
80
60
40
20
0
100
80
60
40
20
0
5 10 15 200 5 10 15 200
R
e
s
p
o
n
s
e

(
%
)
R
e
s
p
o
n
s
e

(
%
)
Mos Mo
Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
NR (4.2-10.5)
NR (4.2-12.5)
6 (2.7-6.1)
Median DoR, Mos (95% CI)
NR (4.2-10.4)
NR (4.4-12.6)
8 (2.6-8.3)
Median DoR, Mos (95% CI)
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel

9. KEYNOTE-010: Treatment-Related AEs
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].
AEs in ≥ 10%
Pts, n (%)
2-mg/kg Pembrolizumab
(n = 339)
10-mg/kg Pembrolizumab
(n = 343)
Docetaxel
(n = 309)
Any Grade Grade 3-5Any Grade Grade 3-5 Any GradeGrade 3-5
Any 215 (63) 43 (13) 226 (66) 55 (16) 251 (81) 109 (35)
Decreased
appetite
46 (14) 3 (1) 33 (10) 1 (< 1) 49 (16) 3 (1)
Fatigue 46 (14) 4 (1) 49 (14) 6 (2) 76 (25) 11 (4)
Nausea 37 (11) 1 (< 1) 31 (9) 2 (1) 45 (15) 1 (< 1)
Rash 29 (9) 1 (< 1) 44 (13) 1 (< 1) 14 (5) 0
Diarrhea 24 (7) 2 (1) 22 (6) 0 56 (18) 7 (2)
Asthenia 20 (6) 1 (< 1) 19 (6) 2 (1) 35 (11) 6 (2)
Stomatitis 13 (4) 0 7 (2) 1 (< 1) 43 (14) 3 (1)
Anemia 10 (3) 3 (1) 14 (4) 1 (< 1) 40 (13) 5 (2)
Alopecia 3 (1) 0 2 (1) 0 101 (33) 2 (1)
Neutropenia 1 (< 1) 0 1 (< 1) 0 44 (14) 38 (12)
Slide credit: clinicaloptions.com

10. KEYNOTE-010: Immune-Mediated AEs in
≥ 2% Pembrolizumab-Treated Pts
Herbst RS, et al. Lancet. 2015;[Epub ahead of print].
AEs in ≥ 10%
Pts, n (%)
2-mg/kg Pembrolizumab
(n = 339)
10-mg/kg Pembrolizumab
(n = 343)
Docetaxel
(n = 309)
Any Grade Grade 3-5Any Grade Grade 3-5Any GradeGrade 3-5
Hypothyroidism 28 (8) 0 28 (8) 0 1 (< 1) 0
Pneumonitis 16 (5) 7 (2) 15 (4) 7 (2) 6 (2) 2 (1)
Hyperthyroidism 12 (4) 0 20 (6) 1 (< 1) 3 (1) 0
Colitis 4 (1) 3 (1) 2 (1) 1 (< 1) 0 0
Severe skin
reactions
4 (1) 3 (1) 7 (2) 6 (2) 2 (1) 2 (1)
Pancreatitis 3 (1) 2 (1) 0 0 0 0
Adrenal
insufficiency
2 (1) 0 3 (1) 1 (< 1) 0 0
Myositis 2 (1) 0 1 (< 1) 0 1 (< 1) 0
Thyroiditis 2 (1) 0 0 0 0 0
Type 1 diabetes 1 (< 1) 1 (< 1) 2 (1) 1 (< 1) 0 0
Autoimmune
hepatitis
1 (< 1) 1 (< 1) 2 (1) 0 0 0
Hypophysitis 1 (< 1) 1 (< 1) 1 (< 1) 1 (< 1) 0 0
Slide credit: clinicaloptions.com

11. Conclusions and Faculty Assessment
Pembrolizumab confers a significant survival benefit for treatment-
experienced pts with advanced PD-L1–positive NSCLC
–For pts with PD-L1 TPS ≥ 1%, pembrolizumab associated with significant
improvement in OS, but not PFS, vs docetaxel
–For pts with PD-L1 TPS ≥ 50%, pembrolizumab associated with significant
improvement in OS and PFS vs docetaxel
–Durable responses to pembrolizumab independent of PD-L1 expression
Despite a longer exposure, pembrolizumab associated with fewer AEs
than docetaxel (approximately 15% vs 35%, respectively)
Pembrolizumab represents new standard of care for pts with
NSCLC after treatment with platinum-based chemotherapy
–FDA approval only for pts with ≥ 50% PD-L1 tumor positivity, under
review to amend approval to include pts with PD-L1 TPS ≥ 1%
Herbst RS, et al. Lancet. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com

12. Conclusions and Faculty Assessment
KEYNOTE-010 validated PD-L1 as a biomarker to identify pts who
may derive OS benefit from pembrolizumab
–Expands pt population that experiences a benefit from pembrolizumab to
include PD-L1 TPS ≥ 1%
Supports continued pursuit of immunotherapy for the treatment of
advanced NSCLC
Weaknesses of current study
–Incidence of consent withdrawal in the docetaxel arm was higher than
usual for a phase III study, possibly impacting the data
–Impact of PFS for the total population (PD-L1 TPS ≥ 1%) not reaching
significance despite there being an obvious OS benefit is unclear; PFS
may be suboptimal endpoint to assess efficacy of checkpoint inhibitors
Herbst RS, et al. Lancet. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com

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