1. KEYNOTE-029 Expansion Cohort: Pembrolizumab + Ipilimumab Safe, Active in 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-029: Pembrolizumab + Ipilimumab in Advanced Melanoma: Background
Rationale for CTLA-4 and PD-1/PD-L1 blockade in melanoma well established[1]
CTLA-4 inhibition (eg, by ipilimumab) effective during priming phase
PD-1/PD-L1 inhibition (eg, by pembrolizumab, nivolumab) effective at tumor bed during effector phase
Pembrolizumab and nivolumab demonstrate improved survival outcomes vs ipilimumab[2,3]
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg in combination improved PFS, ORR vs either as monotherapy, but with increased toxicity[3,4]
KEYNOTE-029 expansion cohort study evaluated safety, efficacy of pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg in pts with advanced melanoma[5]
1. Ribas A. N Engl J Med. 2012;366: Robert C, et al. N Engl J Med. 2015;372: Larkin J, et al. N Engl J Med. 2015;373: Postow MA, et al. N Engl J Med. 2015;372: Long GV, et al. ASCO Abstract 9506.
Slide credit: clinicaloptions.com

3. KEYNOTE-029: Study Design
Phase I trial
Dose Run-In (Phase Ia)[1]
Dose Expansion (Phase Ib)[2]
Pts with advanced melanoma, ≥ 0 prior therapies OR
pts with advanced RCC, ≥ 1 prior therapy
Pts with advanced melanoma;
ECOG PS 0-1;
≥ 0 prior therapies, no prior PD-1, PD-L1, or anti–CTLA-4
(N = 153)
Pembrolizumab 2 mg/kg
Q3W, ≤ 24 mos +
Ipilimumab 1 mg/kg
Q3W x 4 doses
Dose run-in (phase Ia): dose determined to be tolerable, active based on DLT rate[1]
Dose expansion (phase Ib)[2]
Primary endpoint: safety
Secondary endpoints: DoR, ORR, OS, PFS
DLT, dose-limiting toxicity; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; PS, performance score; RCC, renal cell carcinoma;
1. Atkins MB, et al. ASCO Abstract 3013.
2. Long GV, et al. ASCO Abstract 9506.
Slide credit: clinicaloptions.com

4. KEYNOTE-029: Baseline Characteristics
Pembrolizumab + Ipilimumab
(N = 153)
Median age, yrs (range)
60 (22-82)
Male, % 66
ECOG PS 0, % 74
LDH level elevated, % 24
BRAFV600 mutant, %
36*
PD-L1 positive, %
83†
M1c disease, % 56
No previous therapy, % 87
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status.
*13 pts with prior BRAF ± MEK inhibitor therapy. †2 pts with tumors not evaluable for PD-L1 expression. PD-L1 positivity defined as ≥ 1% staining in tumor, adjacent immune cells by IHC (22C3 antibody).
Slide credit: clinicaloptions.com
Long GV, et al. ASCO Abstract 9506.

5. KEYNOTE-029: Adverse Events
Category, %
Treatment Related
(N = 153)
Immune Mediated*
Any grade 95 58
Grade 3/4 42 25
Led to death
Led to ipilimumab discontinuation only 10 8
Led to pembrolizumab discontinuation† 7 4
Led to ipilimumab and pembrolizumab discontinuation‡
*Regardless of investigator attribution. †After discontinuation or completion of ipilimumab. ‡Includes 1 pt who discontinued ipilimumab (due to colitis) and then pembrolizumab (due to increased lipase).
72% of pts received all 4 doses of ipilimumab
Slide credit: clinicaloptions.com
Long GV, et al. ASCO Abstract 9506.

6. KEYNOTE-029: Adverse Events
Treatment-Related AEs (> 15% Pts), %
Any Grade
(N = 153)
Grade
3/4
Fatigue 46
Pruritus 39
Rash 3
Diarrhea 24
< 1
Lipase increased 18 14
Vitiligo
Dry mouth 16
Nausea
Hypothyroidism
Immune-Mediated AEs per Pt, %
Any Grade
(N = 153)
Grade 3/4 42 75 1 31 22 2 19 3 7 4
< 1
Most common immune-mediated AEs: hypothyroidism, hyperthyroidism, hypophysitis, pneumonitis, hepatitis, colitis, and skin reactions
145 total events were managed with systemic treatment* with corticosteroids (57%), infliximab (7%), or other (4%)
76% of any grade AEs and 81% of grade 3/4 AEs had resolved† at data cutoff
AE, adverse event.
* ≥ 1 systemic treatments allowed.
†Excluding endocrinopathies.
Slide credit: clinicaloptions.com
Long GV, et al. ASCO Abstract 9506.

7. Pembrolizumab + Ipilimumab (N = 153)
KEYNOTE-029: Response
Characteristic
Pembrolizumab + Ipilimumab (N = 153)
ORR, % (95% CI)
57 (49-65)
DCR, % (95% CI)
78 (71-85)
Best overall response, % CR 10 PR 47 SD 22 PD 20
No assessment 2
DCR, disease control rate; PD, progressive disease; SD, stable disease.
81% of pts experienced some tumor reduction; median change: -54.5%
Tumor response in both PD-L1–positive or PD-L1–negative status
98% of responders maintained response at time of data cutoff
Robust responses experienced in all subgroups
Slide credit: clinicaloptions.com
Long GV, et al. ASCO Abstract 9506.

8. KEYNOTE-029: PFS and OS 70% of pts progression free at 6 mos
Events: 49 (32%)
Median PFS: NR
93% of pts alive at 6 mos
Median OS: NR
Median follow-up: 10.0 mos (range: mos)
NR, not reached.
Slide credit: clinicaloptions.com
Long GV, et al. ASCO Abstract 9506.

9. KEYNOTE-029: Conclusions
Combination of pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg appears to have manageable toxicity profile
72% of pts received all 4 doses of ipilimumab
Grade 3/4 immune-mediated AEs: 25%
No treatment-related deaths
Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg produces robust, durable responses in pts with advanced melanoma
ORR: 57%
ORR similar across key subgroups
Durable response in 98% of pts
DoR: 6+ to 43+ wks; 6-mo PFS: 70%
AE, adverse event; DoR, duration of response.
Slide credit: clinicaloptions.com
Long GV, et al. ASCO Abstract 9506.

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