By Thomas Olencki, DO

1. ASCO 2016
Melanoma Update
Thomas Olencki, DO
Division of Medical Oncology
Department of Internal Medicine
The Ohio State University Wexner Medical Center
Columbus, Ohio
June 18, 2016

2. p <0.0001
151413121110
Balch, JCO 19:3635, 2001.
987
Survival (years)
ProportionSurviving
6543210
1.0
0.8
0.6
0.4
0.2
0.0
Survival Curve Of Patients With
Metastatic Melanoma

3. What Are Benchmarks For Treatment Of
Metastatic Melanoma ?
• Evaluated
– 2100 patients
– 70 arms of 42 trials in cooperative groups
• Results
– OS
• median - 6.2 mos
• 12 mos rate – 26%
– PFS
• median – 1.7 mos
• 6 mos rate – 15%
Korn, JCO 26:527, 2008
“Clinical benefit”
CR+PR+SD
New “Benchmark”
for phase 2 trails

4. Advantages Of Immunotherapy
• Searching for tumor activating mutation less critical
• Immune system may “adapt” to specific tumor
characteristics
• Potential for long-term durable response

5. Immune Therapy
Also Now Known As Checkpoint Inhibitors

6. Monoclonal Antibody Therapy
• Nomenclature for monoclonal Ab checkpoint
inhibitors:
– CTLA-4 – early inhibitor and most active in lymph node
• Ipilimumab (Yervoy®) – BMS
– PD -1 – later inhibitor in peripheral blood or tumor
• Nivolumab (Opdivo®) – Bristol-Myers Squibb
• Pembrolizumab (Keytruda®) - Merck

7. Ipilimumab

8. Phase III Ipilimumab – 2nd Line Tx
R
A
N
D
O
M
I
Z
E
Ipilimumab 3 mg/kg IV
Ipilimumab 3 mg/kg IV & gp 100
Open 9/2004 – 8/2008
Double blind
(3:1:1; for ipi, ipi & gp100 and gp100 alone)
Hodi, NEJM 363:711, 2010
676 pts with
prior Tx
melanoma
70% had
M1c poor risk
visceral disease
gp 100 vaccine
All drugs à q 3 wks x 4 doses

9. Phase III Ipilimumab – 2nd Line Tx
Ipilimumab alone
OS 24% at 2+ yrs
Overall Survival
Hodi, NEJM 363:711 2010
OS at 1 yr 46%

10. Phase III Ipilimumab – 2nd Line Tx
Overall Survival
Hodi, NEJM 363:711 2010
Flat survival curve
24 to 36 mos

11. Long Term Survival With Ipilimumab
Schadendorf, JCO 33:1889, 2015
OS of 4,846 pts Tx on trial
and from Expanded Access
Program.
Survival plateau starts at 3
yrs and extends to 10 yrs
in some pts.
Median OS was 9.5 mos
3 yr OS of 21%

12. LDH May Be Most Accurate Predictor Of
Response To Ipilimumab
Kelderman, Cancer Immuno Immunother 63:449. 2014

13. Conclusions Regarding Ipilimumab
• Tolerable to wide range of pt’s
– borderline PS − elderly
– treated brain mets − uveal and mucosal primaries
• Combination with chemo Tx may not improve efficacy
• Associated with
– RR 10-15%
– PFS of about 3 mos
– Stable OS of 21% at 3 yrs extending to 10 years in some pts
• Benefit of ipilimumab – increase in overall survival
• LDH may predict who will respond
Ribas, JCO 33: 1865, 2015; Schadendorf, JCO 33:1889, 2015

14. Nivolumab or Pembrolizumab

15. Brief Review Of 3 Trials
• Nivolumab - Phase 1
• Pembrolizumab vs ipilimumab
• Nivolumab and Ipilimumab

16. Phase I Nivolumab Dose Finding Study
• All 107 pts had to have had prior therapy
• 62% had 2 or more different therapies
• These were real world patients with bulky disease
• Stable brain metastasis were acceptable
• This is the 1st long-term follow-up study of the
nivolumab therapy
Hodi, AACR April, 2016

17. Hodi, AACR April, 2016
34% 5 yr OS
Phase I Nivolumab 5 Year OS Results

18. Pembrolizumab vs Ipilimumab
Keynote-006
R
A
N
D
O
M
I
Z
E
Pembrolizumab 10 mg/kg q 3 wks
Ipilimumab 3 mg/kg q 3 wks
834 pts
1:1:1 ratio
≤ 1 therapy
Robert, NEJM 372:320, 2015; Schachter, ASCO 2016 # 9504
Open 9/2013 - 3/2014
Pembrolizumab 10 mg/kg q 2 wks
Median FU – 23 mos

19. Pembrolizumab vs Ipilimumab
Keynote-006
• Response (23 mos median follow up)
pembrolizumab (q3wk) ipilimumab
ORR 36% 13%
CR 13% 5%
PR 23% 8%
SD 16% 18%
PD 42% 49%
Not eval 6% 18%
Schachter, ASCO 2016 #9504

20. Schachter, ASCO 2016 #9504
Pembrolizumab vs Ipilimumab
Keynote-006

21. Pembrolizumab vs Ipilimumab
Keynote-006
Schachter, ASCO 2016 #9504
Median
PFS

22. Pembrolizumab vs Ipilimumab
Keynote-006
Schachter, ASCO 2016 #9504
Median
OS

23. Pembrolizumab vs Ipilimumab
Keynote-006
• In this study, ipilimumab pts faired better than in prior studies
• No difference in PFS or OS was seen with the different
pembrolizumab schedules
• Pembrolizumab (40% OS) found to be more effective than ipi
(22% OS) at 3 yr. OS in all subgrps. analyzed
• Pembrolizumab PFS curve flattens at 20 months
• Pembrolizumab ( anti-PD-1 Tx) represents a new “standard
of care” over ipilimumab for metastatic melanoma patient’s
Schachter, ASCO 2016 #9504

24. Combination
PD-1 Inhibition And Anti-CTLA-4
Or
Nivolumab And Ipilimumab
(CheckMate 067)

25. Phase III Nivolumab And Ipilimumab
Or Monotherapy (CheckMate 067)
R
A
N
D
O
M
I
Z
E
Ipi 3 mg/kg & Nivo 1 mg/kg IV
Ipilimumab 3 mg/kg I
Open 7/2013 – 3/2014
Double blind
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505
945 pts with
No prior Tx
58% had
M1c poor risk
visceral disease
Nivolumab 3 mg/kg
1:1:1 randomization

26. Median PFS In Intention To Treat Pts
Nivo and Ipi
11.5 mos
Ipilimumab
2.9 mos
Larkin, NEJM 373:23, 2015; Wolchok, ASCO 2016 #9505
Nivolumab 6.9 mos

27. Median PFS – CheckMate 067
Median 20.7 mos Follow-up
Nivo and Ipi
11.5 mos
Ipilimumab
2.9 mos
Nivo 6.9 mos
Wolchok, ASCO 2016 #9505

28. Phase III Nivo And Ipi Or Monotherapy
• Response results – at 20.7 mos FU
Ipi and Nivo Nivo Ipilimumab
ORR 58% 44% 19%
CR 12% 10% 2%
PR 46% 34% 17%
SD 13% 11% 22%
PD 23% 38% 49%
Unknown 7% 8% 10%
Med resp dur NR 22 mos 14 mos
Ongoing resp 73% 72% 52%
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505

29. Tumor-burden
change
from baseline
Nivo
Nivo & Ipi
Ipi
35%↓
52%↓
6%↑ Larkin, NEJM
373:23, 2015

30. Wolchok, ASCO 2016 #9505

31. Median PFS In PD-L1 + Tumors
Ipi and Nivo 14 mos
Ipilimumab
3.9 mos
Nivolumab
14 mos
Now NR
Now 20 mos
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505

32. Median PFS In PD-L1 Negative Tumors
Ipi and Nivo
11.2 mos
Ipilimumab
2.8 mos
Nivolumab
5.3 mos
Larkin, NEJM 373:23, 2015; Wolchok, ASCO 2016 #9505

33. Phase III Nivo And Ipi Or Monotherapy
• Response by PD-L1 status
Nivo & Ipi Nivo Ipi
PD-L1 ≥ 5% 72% 58% 21%
PD-L1 < 5% 55% 41% 18%
• 69% of pts who DC’ed combination Tx due to AE developed
a response.
• 50% of those responses were after Tx ended.
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505

34. Early Phase 2 Randomized Study Of
Nivolumab And Ipilimumab vs Ipilimumab
• Pt numbers small - 95 in combination and 47 in Ipi
• Follow-up is short at 2 years
• All patients previously not treated
Postow, AACR April 2016

35. Postow, AACR, 2016
Phase II Study Of Nivolumab And Ipilimumab vs. Ipilimumab

36. Postow, AACR 2016
months
Phase II Study Of Nivolumab And Ipilimumab vs. Ipilimumab

37. Phase III Nivo And Ipi Or Monotherapy
• Adverse events:
– combination arm
• rash/ pruritis – 60%
• diarrhea - 45%
• hepatic – 32%
• pulmonary – 7%
• renal – 6%
• incidence of Gr 3 and 4 – 56%
• 39% of pts had AE that led to DC of TX
• NO patient deaths
Larkin, NEJM 373:23, 2015; Wolchok, ASCO 2016 #9505

38. Phase III Nivo And Ipi Or Monotherapy
• Combination Tx with Nivo and Ipi represents a
dramatic therapeutic breakthrough for pts
• In PDL-1 status
– for PDL1+ Nivo = Nivo & Ipi PFS
– for PDL1− Need Nivo and Ipi for PFS benefit
• Nivo/ipi active in any sub grp. including ≥ 2 x LDH
• Responses and Overall Survival durable
• Toxicity moderate to severe but manageable
– should not use in pts with “minimal reserve”

39. Predictors Of Response
And
Resistance

40. Mutational Density
As A Predictor Of Response
Alexandrov, Nature 500:415, 2013

41. Factors Affecting
Response And Resistance
Charen, ASCO 2016 Special Session - Rathmell

42. Predictors Of Response – PD-1
• PD-L1 level evaluation
– Technically difficult
– Tumor heterogeneity limits reliability
– Expression inducible by PD-1 therapy
– No standard assay comparable between companies
– Significant variability
• Tumor versus CD8 PD-1 levels
• Levels different on fresh versus frozen versus archival tissue
• Levels maybe different on primary versus metastatic sites
• Should not be used at this time for clinical decisions
Adapted from Atkins, Plenary Session, ASCO 2015

43. What About The Pt With
Borderline PS?

44. What About Grandma?
• Pts who may not tolerate combination therapy include:
– poor social support
– living a long distance from medical care
– poorly controlled diabetes
– deconditioned elderly
• Sequential use of checkpoint inhibitors is often better
tolerated and safer than combination Tx
• Is there a preferred sequence?
– PD-1 inhibitor followed by ipilimumab
– Ipilimumab followed by a PD-1 inhibitor
• CheckMate 064 addressed this issue
Weber, Lancet Oncol pub online June 4, 2016

45. CheckMate 064 – Phase 2
R
A
N
D
O
M
I
Z
E
Nivolumab
Open 4/2013 – 7/2014
Weber, Lancet Oncol pub online June 4, 2016
140 pts
≤ 1 prior Tx
Nivolumab
Ipilimumab
Ipilimumab
RR – 41%
OS – NR
RR – 20%
OS – 16.9 mos
Median follow-up of 19.8 months
12 wks

46. CheckMate 064 - OS
Weber, Lancet Oncol pub online June 4, 2016
Nivo-Ipi
Ipi-Nivo

47. CheckMate 064
• Results
– Overall survival follow-up is ongoing
• Given the opportunity, nivolumab followed by ipilimumab
sequence may provide > clinical benefit to pts
• Toxicity comparable between both arms at 12 weeks, but
greater in the Nivo à Ipi arm the latter 12 weeks
• Hazard ratio 0.57 in favor of Nivo à Ipi arm
• All prior assigned grps did better on Nivo à Ipi arm
Weber, Lancet Oncol pub online June 4,2016

48. The B raf Mutation Pt

49. What Is The Best Way To Tx Pts With
B raf Mutation + Melanoma?
• No one really knows
• Emotional topic with no firm data
• Phase 3 study recently opened EA6134
• Optimal therapy may include up front: B raf, MEK
and PD-1 inhibitor simultaneously

50. EA 6134 - Intergroup
R
A
N
D
O
M
I
Z
E
B raf
V600
mutation
positive
Nivo and Ipi
Dabrafenib and
tremetinib
PD
PD
C
R
O
S
S
O
V
E
R
Nivo and Ipi
Dabrafenib and
tremetinib
OSU Contact: Joanne Jeter MD
614-293-4320

51. Conclusions (1)
• Combination Tx with nivolumab and ipilimumab indicated for
those pts who need a resp. and can tolerate the toxicity
• Single agent PD-L1 therapy indicated when toxicity a
concern
• Nivolumab & ipilimumab are more effective than nivo alone
• Nivo/ Pembro alone or with ipilimumab are both more active
than ipilimumab alone
• Nivo/ Pembro and nivolumab with ipilimumab represent a
“new standard of care”
Adapted from Atkins, Plenary Session, ASCO 2015

52. Conclusions (2)
• Steroids to Tx toxicity does not negate therapeutic effect
• B raf mutation status does not predict for response to
checkpoint blockade therapy
• The most effective Tx (targeted vs immune vs combination)
for B raf mutation pt’s remains to be determined
• High LDH (≥ 2 x nl) is not a negative indicator of response
to combination checkpoint therapy
• HD IL-2 may be safely and effectively administered to those
pts that progress on any checkpoint inhibitor therapy
(Buchbinder and McDermott, ASCO 2016 #e21006)
Adapted from Atkins, Plenary Session, ASCO 2015

53. Summary
Therapy Resp. Rate OS (5 yr)
High dose IL-2 15% 6%
Ipilimumab 10 - 20% 20%
Nivo/pembro 30 – 40% 34%
Nivo/Ipi 55 - 60% 64% (at 2 yrs)

54. Research Lake at OSU (3.5 acres)