combination therapies based on pd-1 or pd-l1...
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Combination Therapies Based on PD-1 or PD-L1 Blockade
Melanoma BridgeNaples, Italy
December 4, 2014
Mario Sznol- Yale University (in Absentia)
Summary of Anti-PD-1/PD-L1 Activity in Metastatic Melanoma
Objective Response Rates
Median Duration of Response
Median PFS Median Survival 1/2/3 year survival
Nivolumab Treatment-Naive
40% (CR = 7.6%) NR 5.1 months NR 73%/x/x
Nivolumab (postipilimumab)
26-32% NR NA NA 70%/x/x
Nivolumab(prior Rx, not ipi)
32% 23 months 4 months 17 months 63%/48%/42%
PembrolizumabIpi-Naive
40% NR 5.6 months NR 74%/x/x
Pembrolizumab(post ipilimumab)
21-28% NR 2.9-5.4 months6mth – 34-38%
NR 65%/x/x
Possible Mechanisms for Innate Resistance to PD-1/PD-L1 Blockade
• No tumor antigen specific T-cells in tumor microenvironment• Don’t exist or;• Blocked from entry into tumor
• Insufficient tumor antigen specific T-cells in tumor microenvironment• Dysfunctional tumor antigen specific T-cells in tumor
microenvironment• Other checkpoints present in addition to PD1-PD-L1 pathway• Dysfunction driven by checkpoints other than PD1-PD-L1 pathway• Other mechanisms of T cell suppression
• IDO, TGF-beta, Treg, etc.
• Loss of tumor antigen presentation• Innate tumor cell resistance to immune mediated killing
Combinations Based on PD-1/PD-L1 Blockade • Multiple combinations supported by animal models
• Vaccines• Cytokines (IL-15, IL-21, IFN-alfa,…)• Immune checkpoints
• CTLA-4• LAG-3, TIM-3, B7-H3?
• Co-stimulatory agents – 4-1BB, OX40, CD27, ….• Adoptive Cell Transfer• Inhibitors of infiltrating suppressive MDSC and type 2 macrophages• Enzyme based suppression- IDO• Treg inhibition• Targeted agents• Chemotherapy• Radiation therapy • Anti-angiogenesis agents• HDAC Inhibitors
• No human data yet to reliably predict best combination for individual patient
Synergistic Activity with Anti-PD-1 and Anti-CTLA-4 Antibodies
0 5 10 15 20 250
250
500
750
1000
1250
1500
1750
days
med
ian
tum
or v
olum
em
m3
Control
aCTLA-4 MAb
aPD-1 MAb
Combination aPD-1 + aCTLA-4
Dosing
Combination of Non-Efficacious Doses of anti-PD1 and anti-CTLA-4 Antibodies is Efficacious in Mouse Model
Provided by Alan Korman, BMS
Rationale:Different roles in T cell Differentiation-Compensatory upregulationAnti-CTLA4 elimination of tumor TregAnti-CTLA4 induced tumor T cell infiltration
Phase 1 CA209-004 Cohorts
All dose units are mg/kg. Results from Cohorts 6 and 7 (sequenced treatment cohorts – ipilimumab followed by nivolumab) were reported previously (Kluger et al. ESMO 2014)Ipi = ipilimumab; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks; Q12W = every 12 weeks
Con
curr
ent
The
rapy
Q12W x 8Nivo 0.3 + Ipi 3Cohort 1
(N = 14)Nivo 0.3 Nivo 0.3 + Ipi 3
Nivo 1 + Ipi 3Cohort 2(N = 17)
Nivo 1 Nivo 1 + Ipi 3
Q3W x 4
Q3W x 4
Q3W x 4
Q3W x 4
Q12W x 8
Nivo 3 + Ipi 1Cohort 2a(N = 16)
Nivo 3 Nivo 3 + Ipi 1Q3W
x 4Q3W
x 4Q12W
x 8
Q2W x ≤48
Q2W x ≤48Prior
standard ipilimumab
therapy
Cohort 6(N = 17)
Nivo 1
Cohort 7(N = 16) Nivo 3
Seq
uenc
ed
The
rapy 4–12
weeksfrom last
dose
Nivo 3 + Ipi 3Cohort 3(N = 6)
Nivo 3 Nivo 3 + Ipi 3Q3W
x 4Q3W
x 4Q12W
x 8
Q2W x ≤48Nivo 3Cohort 8
(N = 41)Nivo 1 + Ipi 3 Q3W
x 4
6
Baseline Characteristics
*All treated patientsJUNE 2014 data analysis.ECOG = Eastern Cooperative Oncology Group.
Cohorts 1–3(N = 53)*
Cohort 8(N = 41)*
Median age, years (range) 57 (22–79) 55 (22–80)
Male, n (%) 60 44ECOG performance status, n (%)
01Not reported
83152
66295
Lactate dehydrogenase level, n (%)≤Upper limit of the normal range>Upper limit of the normal range
6238
6139
Systemic cancer therapy, n (%)ImmunotherapyBRAF inhibitor
194
297
Number of prior systemic cancer therapies, n (%)01≥2
602811
492724
7
Activity Summary
Cohort(s) Nivo (mg/kg) + Ipi (mg/kg) Nb ORR,a
% CR, % Aggregate Clinical Activity Rate, %
≥80% Tumor Burden Reduction at 36 Weeks,c %
1–3 53 42 17 72 42
1 0.3 + 3 14 21 14 57 36
2 1 + 3 17 47 18 65 53
2a 3 + 1 16 50 25 88 31
3 3 + 3 6 50 0 83 50
8d 1 + 3 41 44 7 56 29
All Concurrent Cohorts 94 43 13 65 36aPer modified World Health Organization (mWHO) criteria, [CR+PR]/Nx100. bNumber of response-evaluable patients. cBest overall response. dCohort 8 using the phase 2/3 trial dose schedule, started November 2013.
JUNE 2014 data analysis
8
Maximum Response in Target Lesions
Patient
0
50
100
150
200
250
-50
-100
Max
imum
Res
pons
e Fr
om B
asel
ine
in T
arge
t Les
ion
(%)
April 2014 data analysis
Cohorts 1–3
Cohort 8
42% patients had ≥80% reduction in target lesion
29% patients had ≥80% reduction in target lesion
JUNE 2014 data analysis.
Patients
050
100
200
850900
-50
150
-100
9
Metastatic melanoma from anal mucosal primary, Cohort 2: response to ipilimumab 3 mg/kg + nivolumab 1 mg/kg; Received a single dose of combination due to early onset uveitis-responded to high dose steroids
Metastatic melanoma from anal mucosal primary, Cohort 2: response to ipilimumab 3 mg/kg + nivolumab 1 mg/kg; Received a single dose of combination due to early onset uveitis-responded to high dose steroids
Sienkiewicz, Dina, LSienkiewicz, Dina, LUnit#: MR2263994Unit#: MR2263994Acc#: E101524698Acc#: E101524698DOB: 10/7/1967DOB: 10/7/1967F/46 YEARF/46 YEAR
Yale New Haven Hospital Yale New Haven HospitalCT NP 2506 LightSpeed VCTCT NP 2506 LightSpeed VCT
CT CHEST ABDOMEN PELVIS W IV CONTRASTCT CHEST ABDOMEN PELVIS W IV CONTRAST6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH
6/5/2014 1:42:41 PMTech: DMTech: DM
ORAL OMNI & 85CC OMNI 350ORAL OMNI & 85CC OMNI 350HELICAL MODE /1:42:41 PMHELICAL MODE /1:42:41 PMW: 400 C: 40 Z: 1.53W: 400 C: 40 Z: 1.53600 ---600 ---KVp: 120KVp: 120Tilt: 0Tilt: 0FFSFFS
Page: 22 of 51Page: 22 of 51 IM: 22 SE: 601 IM: 22 SE: 601Compressed 8:1Compressed 8:1
--- ------ ---XY: 8.60XY: 8.60
THK: 5THK: 5ASIR: SS20ASIR: SS20
NI: 135NI: 135
RR LL
HH
FF cm cm
Sienkiewicz, Dina, LSienkiewicz, Dina, LUnit#: MR2263994Unit#: MR2263994Acc#: E101726672Acc#: E101726672DOB: 10/7/1967DOB: 10/7/1967F/46 YEARF/46 YEAR
Yale New Haven Hospital Yale New Haven HospitalCT NP 2506 LightSpeed VCTCT NP 2506 LightSpeed VCT
CT CHEST ABDOMEN PELVIS W IV CONTRASTCT CHEST ABDOMEN PELVIS W IV CONTRAST6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH6.1 CHEST - ABDOMEN - PELVIS WITHOUT AND/OR WITH
8/16/2014 10:53:26 AM 8/16/2014 10:53:26 AMTech: mtTech: mt
ORAL OMNI & 85CC OMNI 350ORAL OMNI & 85CC OMNI 350HELICAL MODE /10:53:26 AMHELICAL MODE /10:53:26 AMW: 409 C: 39 Z: 1.22W: 409 C: 39 Z: 1.22600 ---600 ---KVp: 120KVp: 120Tilt: 0Tilt: 0FFSFFS
Page: 25 of 54Page: 25 of 54 IM: 25 SE: 601 IM: 25 SE: 601Compressed 8:1Compressed 8:1
--- ------ ---XY: 6.61XY: 6.61
THK: 5THK: 5ASIR: SS20ASIR: SS20
NI: 135NI: 135
RR LL
HH
FF cm cm
Metastatic melanoma from anal primary –Relapse after approx. 2 years, re-induction with 4 combination doses to near CR;No recurrence of uveitis
Cohort 8, Ipilimumab + nivolumab, response at 12 weeks
Prior therapy with HD-IL2, multiple resections, Vemurafenib, and RT; LDH > 2000 at baseline; LDH nearly normal within 3 weeks
Yale Ipi/Nivo Cohorts 1-3• N=25
– Confirmed PR/CR – 10 (40%)• 7 ongoing near CR• 1 CR ->PD at approx. 2.5 years -> reinduced -> near CR • 1 PD in node and then in brain, DOD at approx. 2 years• 1 PD DOD at > 4 years after multiple therapies
– Of 15 PD/unconfirmed OR:• Mixed response (early brain met), then later bowel mets – now NED
with gamma knife RT + surgery • Mixed Resp at 12 weeks -> off due to tox (lipase) CR with further ipi
alone, single local recurrence resected• uPR -> off due to LFTsPD on steroids stable PR with further ipi alone• 1 prolonged irPR—PD reinduction-> alive with PD• 1 inevaluable – response in brain mets and small systemic DZ (lung/liver)
-2 brain mets RX with GK-RT now NED > 1 year• 1 irSD PD reinduced at approx 3.5 years• 1 SD PD PR to TIL
– 10 total deaths (6 non-responders)• 4 at dose level 1• 1 ocular primary
• Follow-up ≥ 2 years• 8/10 PR/CR remain in CR/near
CR (one required re-induction at 2.5 years)
• 4 with mixed response or transient response remain with NED with additional ipi alone, ipi + surgery, or GKRT + surgery
• 1 with SD x 1 year remains progression-free after TIL
• 2 with waxing and waning disease and slow progression on continued therapy and re-induction
Tail of curve at 50% survival?
Overall Survival
JUNE 2014 data analysis.
Died/Treated Median OS (95% CI)
Cohort 2 4/17 NR (26.8–NR)
Cohorts 1–3 14/53 NR (39.7–NR)
Cohort 8 8/41 NR (10.5–NR)
• Cohort 8 uses the same dosing schedule that is being tested in the phase 3 trial (CA209-067)
Month
OS
(%)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
1-yr OS 94% 2-yr OS
88%
1-yr OS 85% 2-yr OS
79%
Patients at Risk175341
175240
174931
164716
16450
14420
14370
14300
13250
7160
4110
370
350
350
010
010
000
Cohort 2 (Nivo 1 + Ipi 3)Cohorts 1–3Cohorts 8 (Nivo 1 + Ipi 3)
Cohort 2 (N=17)
Cohorts 1–3 (N=53)Cohort 8(N=41)
Lowest survival in cohort 1 –Dose response for nivo versus patient selection
15
Cohort(s) [N*] EvaluableSample, N
ORR, n/N (%)BRAF WT BRAF MT
1–3 [53] 51 18/39 (46) 3/12 (25)8 [41] 39 10/27 (37) 6/12 (50)
*Number of patients treated. MT=mutant (BRAFT V600 mutation positive); WT=wild-type (BRAF V600 mutation negative).
JUNE 2014 data analysis.
ORR and Tumor Burden Change by BRAF Mutation Status
Cohorts 1–3 Cohort 8
-100
50
100
150
200
250
-50
0
BRAF MT BRAF WT BRAF Unknown
Max
imum
Res
pons
e Fr
om B
asel
ine
in T
arge
t Les
ion
(%)
900
-100
0
50
100
-50
800
16
ORR and Tumor Burden Change by PD-L1 Status
Cohort(s) [N*] EvaluableSample, N
ORR, n/N (%)PD-L1 Positive† PD-L1 Negative†
1–3 [53] 37 8/14 (57) 8/23 (35)8 [41] 21 0/0‡ 8/21 (38)
*Number of patients treated. †5% cut-off, tumor cell surface staining. ‡None of the 21 evaluable patient samples was test positive for PD-L1 by 5% tumor cell surface staining cutoff
Cohorts 1–3 Cohort 8
JUNE 2014 data analysis.
PD-L1+ PD-L1- PD-L1 Unknown
Max
imum
Res
pons
e Fr
om B
asel
ine
in T
arge
t Les
ion
(%)
-100
50
100
150
200
250
-50
0
900
-100
0
100
800
17
Treatment-Related AEs Reported in ≥ 15% of Patients*Patients with an event, %
Cohorts 1–3 (N=53) Cohort 8 (N=41)Any Grade Grade 3/4 Grade 5 Any Grade Grade 3/4 Grade 5
All drug-related 97 63 0 98 66 2†Rash 62 4 0 66 10 0Pruritus 57 0 0 46 0 0Fatigue 43 2 0 46 0 0Diarrhea 42 4 0 34 12 0Nausea 23 2 0 24 2 0Lipase increased 26 19 0 17 10 0AST increased 25 13 0 12 7 0Pyrexia 23 0 0 22 0 0ALT increased 23 11 0 12 12 0Amylase increased 21 6 0 12 7 0Vitiligo 15 0 0 7 0 0Abdominal pain 9 0 0 20 2 0Arthralgia 9 0 0 20 0 0*Listing adverse events reported in ≥ 15% of patients in cohorts 1–3 or in cohort 8, sorted by any grade frequency in cohort 1–3; †One patient died due to grade 5 multi-organ failure related to study treatment in cohort 8ALT = alanine aminotransferase; AST = aspartate aminotransferase.
JUNE 2014 data analysis. 18
Treatment-Related Immune-Mediated* AEs
Patients with an event, %
Cohorts 1–3 (N=53) Cohort 2 (N=17) Cohort 8 (N=41)Any
GradeGrade
3/4Any
GradeGrade
3/4Any
GradeGrade
3/4
Skin 79 4 88 0 78 17
Gastrointestinal 43 9 35 12 37 20
Hepatic 30 15 35 18 15 12
Endocrine 17 4 24 6 24 4
Pulmonary 8 2 12 6 5 2
Renal 6 6 6 6 0 0
Hypersensitivity /InfusionReaction 2 0 6 0 2 0
*Immune-mediated adverse events are events with potential immunologic causes and those that require more frequent monitoring or intervention with immune suppression or hormone replacementJUNE 2014 data analysis.
• Standard safety guidelines available to manage immune-mediated AEs with immune suppressing medication
19
PD-1/PD-L1 Blockade + anti-CTLA-4Next Steps and Questions• Randomized trials versus ipilimumab (069) and versus ipilimumab or
nivolumab (067) were completed • Concurrent versus sequential
• Gene expression (Dhodapkar et al, SITC 2014) suggest concurrent administration produces unique biological effects
• Management of adverse events • Predictive biomarkers? • Biology of acquired resistance?• Safe triple combinations? (anti-VEGF, others)
20
Antigen Presenting Cell or Tumor T-lymphocyte Function (excluding Treg)
Peptide-MHC T cell receptor Signal 1
CD80/CD86 (B7.1, B7.2) CD28/CTLA-4 Stimulatory/inhibitory
CEACAM-1 and TIM-3 CEACAM-1 inhibitory
CD70 CD27 stimulatory
LIGHT HVEM stimulatory
HVEM BTLA, CD160 inhibitory
PD-L1 (B7-H1) PD-1 and CD80 Inhibitory (Th1)
PD-L2 (B7-DC) PD1 and ? Inhibitory (Th2) or stimulatory
OX40L OX40 stimulatory
4-1BBL CD137 stimulatory
CD40 CD40L Stimulatory to DC/APC
B7-H3 ? Inhibitory or stimulatory
B7-H4 ? inhibitory
PD-1H (Vista) ? inhibitory
GAL9 TIM-3 inhibitory
MHC class II LAG-3 inhibitory
B7RP1 ICOS stimulatory
MHC class I KIR Inhibitory or stimulatory
GITRL GITR stimulatory
CD48 2B4 (CD244) inhibitory
HLA-G, HLA-E ILT2, ILT4; NKG2a inhibitory
MICA/B, ULBP-1, -2, -3, and -4+- NKG2D Inhibitory or stimulatory
CD200 CD200R inhibitory
CD155 TIGIT/CD226 Inhibitory/stimulatory
IDOTregMDSCMacrophagesTGF-beta
VaccinesCytokines
Non-ImmunotherapyVEGF/VEGFRiRTMolecular targetsChemoRx
In our melanoma gene expression database, high levels of:CEACAM-1B7-H3CD200CD155 (PVR)
TIM3
Hirano et al, Cancer Res, Feb, 2005
41BB + anti-PDL1
PD-1 Pathway BlockadeCombinations in Development
• Ipilimumab (anti-CTLA-4)• Tremelimumab (anti-CTLA-4)• Bevacizumab• IFNs – RCC/melanoma• IL-21 – terminated?• IL-2 (proposed)• anti-LAG3• anti-KIR• peptide vaccines• Oncolytic viruses (Tvec)• Anti-OX40 (proposed)• Anti-CD27• Anti-CD137• Treg inhibitors - mogamulizumab• Adoptive Cell Therapy • Dabrafenib +/- Trametinib• Vemurafenib +/-Cobimetinib• RT
Response to Ipi-Nivo
June 2013 July 2013 Feb 2014
Pt recently progressed on ACT*
Conclusions
• If phase 3 trials confirm early data, anti-PD-1 + anti-CTLA4 will become SOC for metastatic melanoma (wtBRAF and mBRAF)
• Following for long term survival • Toxicity high but manageable (similar to ipi 10 mg/kg)
• Approaches to improve ipi/nivo not immediately obvious• Multiple combinations supported by animal model data
• But clinical correlative data not yet available to select ‘best’ regimens for subsets of patients
• Clinical endpoints for studies may need to evolve• 3-year survival rates? • ‘Durable’ CR or near CR?
Credits
• CA209-004• Jedd Wolchok• Margaret Callahan• Harriet Kluger• Michael Atkins• John Kirkwood• Mary Ruisi• Ashok Gupta• Alan Korman• Many others