1. KEYNOTE-006: Final OS Analysis of Pembrolizumab vs Ipilimumab for Advanced Melanoma
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. KEYNOTE-006: Background
Pembrolizumab: humanized anti–PD-1 monoclonal antibody approved for advanced or metastatic melanoma in > 50 countries
KEYNOTE-006: pembrolizumab 10 mg/kg Q2W and Q3W found superior to ipilimumab[1]
PFS: HR 0.58 for Q2W and 0.58 for Q3W (P < .001)[1]
OS: HR 0.63 for Q2W (P < .0005) and 0.69 for Q3W (P = .0036)[1]
Rate of grade 3-5 treatment-related AEs lower despite longer exposure (13.3% and 10.1% with pembrolizumab vs 19.9% with ipilimumab)[1]
Current report includes the final OS analysis[2]
AE, adverse event.
1. Robert C, et al. N Engl J Med. 2015;372: Schachter J, et al. Society for Melanoma Research 2015 Congress. 3. Schachter J, et al. ASCO Abstract 9504.
Slide credit: clinicaloptions.com

3. KEYNOTE-006: Study Design
Stratified by ECOG PS (0 vs 1), line of therapy (1st vs 2nd), and PD-L1 status (positive* vs negative)
Pembrolizumab 10 mg/kg IV
Q2W for 2 yrs
(n = 278)
Unresectable stage III/IV melanoma,
≤ 1 prior therapy,† known BRAF status,‡ ECOG PS 0-1,
no active brain metastases
(N = 834)
Assessments:
Response at Wk 12, every 6 wks until Wk 48, then every 12 wks
Survival every 12 wks
Pembrolizumab 10 mg/kg IV
Q3W for 2 yrs
(n = 277)
Ipilimumab 3 mg/kg IV
Q3W x 4 doses
(n = 256)
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status.
Primary endpoints: PFS, OS
Secondary endpoints: ORR, response duration, safety
*≥ 1% staining in tumor, adjacent immune cells by IHC (22C3 antibody).
†Excluding anti–CTLA-4, anti–PD-1, or anti–PD-L1 agents.
‡Prior anti-BRAF therapy not required if normal LDH levels, no clinically significant tumor-related symptoms or evidence of rapidly progressing disease.
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

4. KEYNOTE-006: Baseline Characteristics
Pembrolizumab
Q2W (n = 279)
Q3W (n = 277)
Ipilimumab (n = 277)
Median age, yrs (range)
61 (18-89)
63 (22-89)
62 (18-88)
Male, % 58 63
ECOG PS 0, % 70 68
LDH level elevated, % 29 35 33
BRAFV600 mutant, % 38
PD-L1 positive, % 81 80
M1c disease, % 64
1 previous therapy 34
33*
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status.
*1 pt had 2 prior lines of therapy.
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

5. KEYNOTE-006: OS and PFS OS
12-Mo OS, %
24-Mo OS, %
Median OS,
Mos (Range)
Events, n HR
(95% CI)†
P Value
Pembrolizumab Q2W 74 55 NR
(22.1-NR)
122
0.68
( )
.00085
Pembrolizumab Q3W 68
(23.5-NR)
119
( )
.00083
Ipilimumab 59 43
16.0
( )
142 -
PFS*
12-Mo PFS, %
24-Mo PFS, %
Median PFS, Mos (Range)
Events, n HR
(95% CI)†
P Value†
Pembrolizumab Q2W 39 31
5.6
( )
181
0.61
( )
<
Pembrolizumab Q3W 38 28
4.1
( )
183
Ipilimumab 19 14
2.8
( )
202 -
ICR, Independent Review Committee; NR, not reached; RECIST, Response Evaluation Criteria in Solid Tumors.
*RECIST v1.1 by ICR. †P values nominal because no statistical alpha applied to comparison at final analysis. Final data cutoff December 3, 2015.
Ipilimumab outperformed expectations based on historical data for OS, making survival advantage with pembrolizumab less dramatic
OS advantage with pembrolizumab was consistent across subgroups
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

6. KEYNOTE-006: Tumor Response*
Characteristic
Pembrolizumab
Q2W (n = 279)
Q3W (n = 277)
Ipilimumab (n = 278)
ORR, % (95% CI)
37 (30-42)
36 (30-42)
13 (10-18)
Best overall response, % CR 12 13 5 PR 25 23 8 SD 11 15
Non-CR/Non-PD† 4 3 PD 38 42 49
Not evaluable‡ 7 18
No assessment§ 1
< 1
ICR, Independent Review Committee; PD, progressive disease; RECIST; Response Evaluation Criteria in Solid Tumors; SD, stable disease;
*Per RECIST v1.1 by ICR. †Pts without measurable disease per ICR at baseline and neither CR nor progression. ‡Postbaseline scan failed to capture target lesion or target lesion surgically removed. §No postbaseline scan or scan could not be evaluated.
Clinical benefit rate (CR + PR + SD) > 50% for pembrolizumab Q3W arm
CR increased, PR decreased with each subsequent analysis in each arm
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

7. KEYNOTE-006: Duration of Response
Duration of response similar in all treatment arms
Nearly 70% of pts demonstrated no sign of treatment failure at final analysis
Arm
12-Mo
Response, %
18-Mo
Response, %
Responders, n
Median DoR,
Mos (Range)
Ongoing
Pembrolizumab Q2W
74.5
70.6
103 NR
( ) 67
Pembrolizumab Q3W
79.0
67.6
100
( ) 60
Ipilimumab
79.3
70.0 37
(1.1+ to 23.8+) 62
DoR, duration of response; NR, not reached.
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

8. KEYNOTE-006: Safety
Characteristic
Pembrolizumab
Q2W (n = 278)
Q3W (n = 277)
Ipilimumab (n = 256)
Time on therapy, wks
Median (range)
28.1 ( )
24.0 ( )
9.0 ( )
Mean (SD)
44.6 (37.2)
41.7 (37.7)
7.2 (3.1)
Treatment-related AEs,* %
Any grade 82 77 74
Grade 3/4 17 20
Leading to death (grade 5)
< 1†
Leading to discontinuation 7 11 9
AE, adverse event; SD, stable disease.
*Not adjusted for treatment exposure. †Sepsis.
Greater exposure to pembrolizumab not associated with increased toxicity
Grade 3/4 AEs increased ~ 5% since first interim analysis (3x longer follow-up)
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

9. KEYNOTE-006: Immune-Mediated AEs*
Pembrolizumab
Thyroid abnormalities (hyperthyroidism, hypothyroidism, thyroiditis), pneumonitis, nephritis more common
Type 1 diabetes and uveitis only observed in pembrolizumab-treated pts
Hepatitis, myositis similar to rates with ipilimumab
Ipilimumab
Colitis, hypophysitis more common
Discontinuations ~ 5% in all arms
~ 10% of pts experienced grade 3/4 immune-mediated AEs
No significant increase in incidence of immune-related AEs over time
AE, adverse event.
*Not adjusted for exposure.
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

10. KEYNOTE-006: Conclusions
Pembrolizumab associated with superior OS vs ipilimumab in pts with unresectable, stage III/IV melanoma with ≤ 1 previous line of therapy
Median OS for pembrolizumab not reached at median follow-up of 23 mos
At 24 mos, ~ 30% of pembrolizumab-treated pts still alive and free of disease progression
Pembrolizumab responses as durable as those with ipilimumab and continue to accrue, including CRs
Long term safety profile for pembrolizumab remains favorable
Investigators suggest that results confirm pembrolizumab as a standard of care for advanced melanoma
Slide credit: clinicaloptions.com
Schachter J, et al. ASCO Abstract 9504.

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