1. Combined Inhibition of PD-L1, MEK, and BRAF Active in Advanced Melanoma CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting*
May 29 - June 2, 2015
*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 program is supported by educational grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

2. Targeted Inhibition in Current Melanoma Treatment
BRAF inhibitor (eg, dabrafenib) ± MEK inhibitor (eg, trametinib) results in clinically significant responses in BRAFV600-mutant melanoma, but durability transient
Immunotherapy responses in melanoma more durable
BRAF/MEK inhibition modifies tumor-immune response interaction
Hypothesis: combining anti–PD-L1 immunotherapy with BRAF and MEK inhibitors may increase frequency of durable responses in advanced BRAF-mutant melanoma
Current multicenter, open-label, phase I study evaluated combining MEDI4736 (anti–PD-L1 antibody) with trametinib ± dabrafenib in advanced melanoma
Ribas A, et al. ASCO Abstract 3003.

3. Combined PD-L1, MEK, BRAF Inhibition in Advanced Melanoma: Study Design
Phase I study: 3 pt cohorts and regimens evaluated
All pts had stage IIIC/IV melanoma and ECOG PS 0-1
Prior immunotherapy permitted, but not BRAF or MEK inhibitors
BRAF V600E/K mutation–positive pts
M + T + D MEDI or 10 mg/kg q2w for 12 mos +
Trametinib 2 mg QD + Dabrafenib 150 mg BID, both until PD
(n = 26)
M + T
MEDI mg/kg q2w for 12 mos +
Trametinib 2 mg QD until PD
(n = 20)
BRAF wild-type pts
BID, twice daily; D, dabrafenib; ECOG PS, Eastern Cooperative Oncology Group performance status; M, MEDI4736; PD, progressive disease; q2w, every 2 weeks; QD, once daily; T, trametinib.
T  M Trametinib 2 mg QD for 6 wks, with
MEDI mg/kg q2w started at Wk 4 for 12 mos
(n = 19)
BRAF wild-type pts
Ribas A, et al. ASCO Abstract 3003.

4. Combined PD-L1, MEK, BRAF Inhibition in Adv Melanoma: Baseline Characteristics
M + T + D
(n = 26)
M + T
(n = 20)
T → M (n = 19)
Mean age, yrs (range)
47.2 (23-71)
62.2 (31-85)
58.7 (34-84)
Male, % 54 65 53
ECOG PS 0, % 73 NA
Mutation status, %
BRAF WT
BRAF V600E
BRAF V600E/K
NRAS 27
100 15 32
Stage IV disease, % 81 90 79
Prior systemic treatment, %
Median regimens (range) 38
0 (0-2) 60
2 (0-4) 74
1 (0-4)
Any prior immunotherapy, %
Anti–CTLA-4
Anti–PD-1
Cytokine-based therapy 23 55 30 35 42 26
D, dabrafenib; ECOG PS, Eastern Cooperative Oncology Group performance status; M, MEDI4736; NA, not assessed; T, trametinib.
Ribas A, et al. ASCO Abstract Reprinted with permission.

5. Combined PD-L1, MEK, BRAF Inhibition in Adv Melanoma: Overall Safety
Treatment-Related Safety Outcome, %
M + T + D
(n = 26)
M + T
(n = 20)
T → M (n = 19)
Any AE
100 95
Grade ≥ 3 AE 46 45 47
Serious AE 31 20 21
AE leading to discontinuation of any drug 12 15
AE leading to death
AE related to MEDI4736 54 35 42
AE related to trametinib and/or dabrafenib 85 79
AE, adverse event; D, dabrafenib; DLTs, dose-limiting toxicities; M, MEDI4736; T, trametinib.
DLTs observed in 2 pts
Reversible grade 3 thrombocytopenia in M + T + D cohort
Reversible grade 3 choroidal effusion in M + T cohort
Ribas A, et al. ASCO Abstract Reprinted with permission.

6. Combined PD-L1, MEK, BRAF Inhibition in Adv Melanoma: Treatment-Related AEs
M + T + D (n = 26)
M + T (n = 20)
T → M (n = 19)
All Gr
Gr ≥ 3
Diarrhea 39 4 50 32 5
Fatigue 58 30 26
Pyrexia 77 10 11
Rash 31 35 47
Chills 54
Vomiting 42
Arthralgia
Nausea 21
Peripheral edema 19 15
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; D, dabrafenib; DLTs, dose-limiting toxicities; Gr, grade; M, MEDI4736; T, trametinib.
ALT/AST increases (19%, mostly < grade 3) also observed with M + T + D
No severe hypertension observed in M + T + D cohort
Ribas A, et al. ASCO Abstract Reprinted with permission.

7. Combined PD-L1, MEK, BRAF Inhibition in Advanced Melanoma: Response
Efficacy Outcome
M + T + D
(n = 26)
M + T
(n = 19)
T → M (n = 15)
ORR, % 69 21
13*
DCR, %
100 79 80
SD ≥ 12 wks, % 15 53 40
Ongoing responders, % 89 50
Range of ongoing response duration, wks
7.7+ to 50.6+
7.9+ to 24.7+
7.0+
*Median follow-up of 2.7 mos. 5 additional pts with ongoing unconfirmed PR.
D, dabrafenib; DCR, disease control rate; M, MEDI4736; ORR, overall response rate; PR, partial response; SD, stable disease; T, trametinib.
Evidence of immune activation posttreatment observed in all cohorts
Included increases in tumor-infiltrating CD8+ cells and increased plasma levels of interferon gamma and other Th1-associated factors
Strongest and most consistent immune activation response observed with M + T + D vs M + T or T → M cohorts
Ribas A, et al. ASCO Abstract Reprinted with permission.

8. Combined PD-L1, MEK, BRAF Inhibition in Advanced Melanoma: Conclusions
Combination treatment with PD-L1 inhibitor, MEK inhibitor, and BRAF inhibitor feasible and tolerable
No MTD identified; full doses of all agents selected for dose expansion
Toxicity profiles of combinations consistent with single-agent toxicity profiles
No apparent exacerbation of immune-related AEs
Patients with BRAF-mutant melanoma treated with MEDI trametinib + dabrafenib showed greatest immune activation and achieved highest response rates
Majority of pts have ongoing responses
Markers of immune activation observed in all cohorts following treatment initiation
AEs, adverse events; MTD, maximum tolerated dose.
Ribas A, et al. ASCO Abstract 3003.

9. Go Online for More CCO Coverage of ASCO 2015!
Short slidesets of all the key data
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Gastrointestinal cancers
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Hematologic malignancies
Immunotherapy
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