ASCO 2015 Melanoma Immunotherapy Thomas Olencki, DO Division of Medical Oncology Department of Internal Medicine The Ohio State University Wexner Medical Center Columbus, Ohio

1. ASCO 2015
Melanoma Immunotherapy
Thomas Olencki, DO
Division of Medical Oncology
Department of Internal Medicine
The Ohio State University Wexner Medical Center
Columbus, Ohio
June 13, 2015

2. Melanoma Is What Gives
Cancer A Bad Name
George Canellos
Adapted from Michael Atkins

3. 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

4. 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

5. High Dose IL-2 In Metastatic Melanoma
Response durations for pts who achieved a CR/ PR
Atkins, JCO 17:2105, 1999
3.7%

6. High Dose IL-2 In Metastatic Melanoma
Survival for the whole study population (270 patients)
OS – 11.4 months at median follow up of 62 mos
Atkins, JCO 17:2105, 1999
Stage IV

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

8. Immune Therapy
Also Now Known As Checkpoint Inhibitors

9. Monoclonal Antibody Therapy
• Nomenclature for monoclonal Ab:
– CTLA-4
• Ipilimumab (Yervoy®) - BMS
– PD -1
• Nivolumab (Opdivo®) – Bristol-Myers Squibb
• Pembrolizumab (Keytruda®) - Merck

10. Ipilimumab

11. Ipilimumab
Ag presenting
Dendritic cell
Or
Tumor cell MHC II Ag TCR
CD 28 – T cell stimulation (with IL-2 production)CD 80 B 7.1
CD 86 B 7.2
Activated T Cell
CTLA-4 – T cell inhibition (induction of tolerance)
− CD152

12. Ipilimumab (2)
Ag presenting
Dendritic cell
Or
Tumor cell MHC II Ag TCR
CD 28 – Unopposed T cell stimulationCD 80 B 7.1
CD 86 B 7.2
Activated T Cell
Unopposed autoimmune effects:
- rash and vitiligo
- hypopituitarism
- diarrhea and colitis
- hepatitis

13. Ipilimumab (3)
• Humanized IgG1k
– T1/2 20 - 30 days
– administered IV q 3 wks x 4 doses
• Breaks immune system tolerance for the tumor
• Ipilimumab an early check point regulator of T cell Fx
– thought to be active in the lymph node

14. 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  q 3 wks x 4 doses

15. Phase III Ipilimumab – 2nd Line Tx
Ipilimumab alone
OS 24% at 2+ yrs
Overall survival
Hodi, NEJM 363:711 2010

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

17. Phase III Ipilimumab – 2nd Line Tx
• Results
ipi ipi and gp100 gp100 Korn
PFS 2.8 mos 2.8 mos 2.8 mos 1.7
med OS 10.1 mos 10 mos 6.4 mos 6.2
12 mos 46% 44% 25% 26%
24 mos 24% 22% 14%
RR 11% 6% 2%
Clin Benefit * 29% 22% 11%
* CR, + PR, + SD
Hodi, NEJM 363:711, 2010

18. Phase III Dacarbazine +/- Ipilimumab
1st Line Tx
R
A
N
D
O
M
I
Z
E
Ipilimumab 10 mg/kg + DTIC
DTIC
502 pts
1:1 ratio
Robert, NEJM 364:2517, 2011
Open 8/2006 - 1/2008

19. Phase III Dacarbazine +/- Ipilimumab
1st Line Tx
Robert, NEJM 364:2517, 2011
Overall Survival

20. Phase III Dacarbazine +/-Ipi 1st Line
• Results
Ipi and DTIC DTIC Korn
PFS NA NA 1.7
med OS 11.2 mos 9.1 mos 6.2
12 mos 47% 36% 26%
24 mos 28% 18%
36 mos 21% 12%
RR 15% 10%
Robert, NEJM 364:2517, 2011

21. 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.
3 yr surv of 21%

22. 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
Ribas, JCO 33: 1865, 2015; Schadendorf, JCO 33:1889, 2015

23. Nivolumab or Pembrolizumab

24. PD-1 / PD-L1 Interaction
Tumor
MHC II Ag TCR
Activated T Cell
(B7-H1) PD-L1
PD-1 - T cell inhibition
PD-1/PD -L1 is a regulator of T cell function in the tumor
and peripheral blood

25. PD-1 / PD-L1 Interaction
Tumor
MHC II Ag TCR
Activated T Cell
B7-H1 – PD-L1
PD-1 - T cell inhibition
Nivolumab / Pembrolizomab
Brahmer, JCO 28:3167, 2010
Induction of tolerance
Results:
PR and SD with
few side effects

26. Brief Review Of 3 Trials
• Nivolumab 1st line
• Pembrolizumab vs ipilimumab
• Nivolumab and Ipilimumab

27. Phase III Nivolumab vs DTIC
As 1st Line Therapy
R
A
N
D
O
M
I
Z
E
Ipilimumab 3 mg/kg
DTIC 1000 mg/m2
418 pts
1:1 ratio
Robert, NEJM 372:320, 2015
Open 1/2013 - 2/2014
All patients
BRAF
wild type

28. Phase III Nivolumab vs DTIC
As 1st Line Therapy
• Results
Nivolumab DTIC
PFS 5.1 mos 2.2 mos
med OS not reached 10.8 mos
12 mos 73% 40%
RR 40% 14%
• Conclusions: Trial significant for ↑ PFS, OS & RR
Robert, NEJM 372:320, 2015

29. Phase III Nivolumab vs DTIC
As 1st Line Therapy - OS
Robert, NEJM 372:320, 2015

30. Phase III Nivolumab vs DTIC
As 1st Line Therapy - PFS
Robert, NEJM 372:320, 2015

31. Pembrolizumab vs Ipilimumab
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
Robert, NEJM 372:320, 2015
Open 9/2013 - 3/2014
Pembrolizumab 10 mg/kg q 2 wks

32. Pembrolizumab vs Ipilimumab
Robert, NEJM 2015
Ipilimumab
Pembrolizumab
Progression free survival

33. Pembrolizumab vs Ipilimumab
Robert, NEJM 2015
Ipilimumab
Overall survival

34. Pembrolizumab vs Ipilimumab
• Results
pembrolizumab (q3wk) ipilimumab
PFS 4.1 mos 2.8 mos
med OS not reached not reached
12 mos 68% 58%
RR 33% 12%
• Conclusions: Trial stopped early by the DSMB because of
superiority of pembrolizumab
Robert, NEJM 372:320, 2015

35. Combination
PD-1 Inhibition And Anti-CTLA-4
Or
Nivolumab And Ipilimumab

36. Phase III Nivolumab And Ipilimumab
Or Monotherapy
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 May 31, 2015 Epub
945 pts with
No prior Tx
58% had
M1c poor risk
visceral disease
Nivolumab 3 mg/kg
1:1:1 randomization

37. Median PFS In Intention To Treat Pts
Nivo and Ipi
11.5 mos
Ipilimumab
2.9 mos
Larkin, NEJM May 31, 2015 Epub
Nivolumab 6.9 mos

38. Phase III Nivo And Ipi Or Monotherapy
• Response results
Ipi and Nivo Nivo Ipilimumab
ORR 58% 44% 19%
CR 12% 9% 2%
PR 46% 35% 17%
SD 13% 11% 22%
PD 23% 38% 49%
Unknown 7% 8% 10%
Larkin, NEJM May 31, 2015 Epub

39. Tumor-burden
change
from baseline
Nivo
Nivo & Ipi
Ipi
35%↓
52%↓
6%↑
Larkin, NEJM
May 31, 2015 Epub

40. Median PFS In PD-L1 + Tumors
Ipi and Nivo 14 mos
Ipilimumab
3.9 mos
Nivolumab
14 mos
Larkin, NEJM May 31, 2015 Epub

41. Median PFS In PD-L1 Negative Tumors
Ipi and Nivo
11.2 mos
Ipilimumab
2.8 mos
Nivolumab
5.3 mos
Larkin, NEJM May 31, 2015 Epub

42. Phase III Nivo And Ipi Or Monotherapy
• Response by PD-L1 status
Nivo & Ipi Nivo Ipi
PD-L1 ≥ 5% 72% 57% 21%
PD-L1 < 5% 54% 41% 18%
67% of pts who DC’ed combination Tx due to AE developed a
response. One half of those responses were after Tx ended.
Only about 25% pts are PD-L1+ (BMS testing)
Larkin, NEJM May 31, 2015 Epub

43. Phase III Nivo And Ipi Or Monotherapy
• Adverse events:
– combination arm
• diarrhea- 44%
• fatigue – 35%
• puritus – 33%
• incidence of Gr 3 and 4 – 55%
• 36% of pts had AE that led to DC of TX – diarrhea & colitis
• NO patient deaths
– use of steroids did NOT prevent responses
– absolutely need to wean steroids over a minimum of 4 wks
Larkin, NEJM May 31, 2015 Epub
Atkins, Plenary Session, ASCO 2015

44. 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
• Response and PFS presented today
• Overall survival pending longer follow up
• Toxicity moderate to severe but manageable

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

46. Predictors Of Response
• Primed tumor – CD8 infiltrate within tumor
– Can be primed by prior or concurrent therapy with
ipilimumab
– Increased number of T reg cells and expression of
suppressive IDO (surrogate for immune infiltrate)
• Absolute lymphocyte count at beginning of 2nd
course of > 1,000 (for ipilimumab)
Allison, Plenary Session of ASCO 2015
Postow, JCO 33:1974, 2015

47. 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 different on primary versus metastatic sites
• Should not be used at this time for clinical decisions
Adapted from Atkins, Plenary Session, ASCO 2015

48. Other T Cell/Tumor Interactions
Allison, Plenary Session of ASCO 2015

49. Conclusions (1)
• Combination Tx with nivolumab and ipilimumab indicated for
those pts who need a resp. and can the tolerate toxicity
• Single agent PD-L1 therapy indicated when toxicity a
concern
• Nivolumab & ipilimumab are more effective than nivo alone
• Nivo/ Pembro or nivolumab 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

50. Conclusions (2)
• Use of steroids to treat toxicity does not negate therapeutic
effect
• B raf mutation status does not predict for response to
checkpoint blockade therapy
• High LDH may not be an absolute negative indicator of
response to 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 2015)
Adapted from Atkins, Plenary Session, ASCO 2015

51. Melanoma Is What Gives
Cancer A Bad Name
But now we can do
something about it!