1. Improved Survival With Nivolumab vs DTIC in Treatment-Naive Pts With Advanced Melanoma Without a BRAF Mutation: CheckMate 066
Slideset on: Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2014;372:
This activity is supported by educational grants from Bristol-Myers Squibb and Genentech.

2. About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. Case
A 58-yr-old gentleman with history of CAD s/p CABG X4 and ICD placement in 2007, history of biventricular block and tachycardia with pacemaker, hypertension, diabetes, and hyperlipidemia
Newly diagnosed metastatic melanoma, initially presenting with persistent productive cough with CT scan showing lymphadenopathy in the chest and liver lesions
LN biopsy and core biopsy of liver lesion both revealed metastatic melanoma
No primary lesion identified
BRAF negative
CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CT, computed tomography; ICD, implantable cardioverter defibrillators; LN, lymph node; s/p, status post.

4. What treatment options can we offer this patient with newly diagnosed metastatic melanoma?

5. Nivolumab in Previously Untreated Melanoma Without BRAF Mutation

6. Background: Nivolumab in Metastatic Melanoma
Global incidence of unresectable, advanced, or metastatic melanoma increasing and mortality remains high
Nivolumab: fully human IgG4 monoclonal antibody against PD-1
Blocks interaction with PD-1 ligands, PD-L1 and PD-L2, allowing T-cell activation and proliferation
Has shown clinical activity in treatment-experienced pts with advanced solid tumors, including melanoma
Phase I: 28.0% to 30.8% ORR and 6.0% SD at 24 wks with favorable safety profile
Phase III in pts with advanced melanoma not responding to ipilimumab: higher ORR compared with chemotherapy (32% vs 11%)
ORR, objective response rate; SD, stable disease.
Robert C, et al. N Engl J Med. 2014;372:

7. CheckMate 066: Study Schema
Stratified by PD-L1 status (positive vs negative/ indeterminate) and metastasis stage (M0/M1a/M1b vs M1c)
Nivolumab 3 mg/kg IV q2w + Placebo IV q3w (n = 210)
Dacarbazine 1000 mg/m2 q3w + Placebo IV q2w (n = 208)
Unresectable, treatment-naive stage III or IV melanoma, wild-type BRAF, ECOG PS 0-1, 18 yrs of age or older
(N = 418)
Treatment continued until disease progression* or unacceptable toxicity
ECOG, Eastern Cooperative Oncology Group; IV, intravenous; OS, overall survival; PS, performance status; q2w, every 2 weeks; q3w, every 3 weeks.
*Treatment permitted after disease progression at investigator’s discretion in pts experiencing clinical benefit.
Primary objective: OS
Robert C, et al. N Engl J Med. 2014;372:

8. CheckMate 066: OS and PFS All pt subsets had OS benefit from nivolumab
HR for death: 0.42 (99.79% CI: ; P < .001)
HR for death or disease progression: 0.43 (95% CI: ; P < .001)
100
100 90 90 80
Nivolumab 80
mPFS (95% CI) 70 70
Nivolumab Dacarbazine
5.1 mos ( ) 2.2 mos ( ) 60
Dacarbazine 60
Overall Survival (%) 50
Progression-free Survival (%) 50 40
OS, overall survival; PFS, progression-free survival 40 30 30
Nivolumab
mOS (95% CI) 20 20
Nivolumab Dacarbazine
Not reached 10.8 mos ( )
Dacarbazine 10 10 3 6 9 12 15 18 3 6 9 12 15 18
Mos
Mos
Robert C, et al. N Engl J Med. 2014;372:

9. CheckMate 066: Duration of Response
ORR significantly higher with nivolumab vs dacarbazine (40.0% vs %, respectively; P < .001)
100 90
Nivolumab 80 70 60
Dacarbazine
Pts With ORR (%) 50 40
DoR, duration of response; ORR, objective response rate. 30
Median DoR (95% CI) 20
Nivolumab Dacarbazine
Not reached 6.0 mos (3.0-not reached) 10 3 6 9 12 15
Mos
Robert C, et al. N Engl J Med. 2014;372:

10. CheckMate 066: Most Common AEs
AEs, n (%)
Nivolumab (n = 206)
Dacarbazine
(n = 205)
Any Grade
Grade 3/4
Any
192 (93.2)
70 (34.0)
194 (94.6)
78 (38.0)
Treatment-related AE
153 (74.3)
24 (11.7)
155 (75.6)
36 (17.6)
Fatigue
41 (19.9)
30 (14.6)
2 (1.0)
Pruritus
35 (17.0)
1 (0.5)
11 (5.4)
Nausea
34 (16.5)
85 (41.5)
Diarrhea
33 (16.0)
Vomiting
13 (6.3)
43 (21.0)
Serious treatment- related AE
19 (9.2)
12 (5.8)
18 (8.8)
12 (5.9)
AE, adverse event.
Robert C, et al. N Engl J Med. 2014;372:

11. Strengths and Weaknesses of the Study
First study to assess anti–PD-1 antibody in pts who were previously untreated, likely bringing checkpoint blockade to frontline for melanoma
Demonstrates superior efficacy of nivolumab to standard chemotherapy
Provide evidence of pseudoprogression by allowing pts who experienced PD by RECIST to remain on study
Weaknesses
Up to 38% of patients in dacarbazine arm received ipilimumab at PD, which may skew OS data (impact of this is unclear)
Unclear how nivolumab compares with other checkpoint inhibitors and BRAF/MEK inhibitors in the first-line setting
OS, overall survival data; PD, progressive disease.
Robert C, et al. N Engl J Med. 2014;372:

12. Future Directions
Optimal sequence of immunotherapy approach and BRAF/MEK inhibition yet to be determined[1]
Several trials exploring various combinations and sequences of treatment ongoing or in development[2,3]
Further exploration of “pseudoprogression” phenomenon
Need to differentiate between true and false negatives with PD-L1 expression to identify which pts will truly benefit from PD-1 inhibitor therapy
Head-to-head comparison to determine if nivolumab is superior to ipilimumab in frontline setting is ongoing
Phase III CheckMate 067[3]
1. Robert C, et al. N Engl J Med. 2014;372: ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

13. Conclusions
Nivolumab confers significant survival benefit for pts with previously untreated advanced melanoma compared with dacarbazine
Median OS not yet reached in pts taking nivolumab (vs 10.8 mos w/DTIC)
1-yr survival rate of 73% with nivolumab
PFS significantly longer with nivolumab vs DTIC (5.1 vs 2.2 mos; P < .001)
Survival advantage with nivolumab regardless of PD-L1 expression across all pt subgroups
ORR, CR, and PR all higher in nivolumab arm
Median DOR not yet reached with nivolumab (vs 6.0 mos with DTIC)
Among pts treated beyond PD, 8.1% achieved ≥ 30% reduction in tumor burden of target lesion with nivolumab vs 3.8% with DTIC
CR, complete response; DOR, duration of response; DTIC, dacarbazine; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response.
Robert C, et al. N Engl J Med. 2014;372:

14. Go Online for More CCO Coverage of Immunotherapy!
Downloadable slidesets of key data A CME-certified text module on immunotherapy with expert faculty commentary on key studies
clinicaloptions.com/oncology