immunotherapy vs. chemoimmunotherapy in first line · javelin avelumab merckkga keynote...
Post on 21-Jul-2020
4 Views
Preview:
TRANSCRIPT
Immunotherapy vs. Chemoimmunotherapy
In First Line
Martin J. Edelman, MD, FACPG. Morris Dorrance Professor of Medicine
Fox Chase Cancer Center
Disclosures• Scientific Advisory Board: Biomarker strategies • Advisor: Windmil Therapeutics , Syndax• Advisory boards: Armo, Bergen • Data Safety Monitoring Boards: Astra-Zeneca,
Takeda, Boehringer Ingelheim • Research funding: Apexigen, BMS, Nektar,
Precision Oncology
You can’t know the players without a scorecard: Trial Nomenclature
Trial Terms Agent Company
Trees (Birch, Poplar,Oak)/IMpower
Atezolizumab Genentech/Roche
Checkmate Nivolumab BMS
Nautical (Atlantic, Pacific, Mystic, Neptune)
Durvalamab Astra Zeneca
Javelin Avelumab Merck KGA
Keynote Pembroluzimab Merck
NSCLC: First Line Randomized TrialsChemotherapy vs. Immunotherapy
Study Author Year Selection N Control Experimental Arm OS :Control(PFS)
OS: Exp(PFS)
HR
KN024 Reck(NEJM)
2016, 2019
PD-L1 >50% 305 Platinum doublet Pembro 14.2(6.0)
30(10.3)
0.63 (p=.002)
CM 026 Carbone (NEJM)
2017 PD-L1>1% 541 Platinum doublet (by histology)
Nivo 13.2 14.4 NS
CM227 Borghaei(ASCO 2018)
2018 PDL-1<1% 363 Platinum doublet (by histology)
Nivo (4.6) (5.7) .74(.68 nonsqu)(.92 sq)
CM227 Hellman(NEJM)
2019 PD-L1 any 1166 Platinum doublet (by histology)
Nivo+Ipi 13.9 17.1 0.73
KN042 Mok(Lancet 2019)
2018 PD-L1>1%Squam and nonsquam
809 CBDCA/PacCBDCA/Pem (maint)
Pembro 12.1 16.7 .81 (p=.0018)
MYSTIC Rizvi(ESMO Immuno2018, Ann Oncol 2019)
2018 PD-L1> 25% 325 Platinum based chemotherapy
Durva or Druva + Tremi (12.9) (11.9) 0.85(p = .202)
KN = Keynote CM = CheckMate IM = IMpower
NSCLC: First Line Chemotherapy vs. ChemoimmunotherapyRandomized Trials
Study Author Year Selection N Control Experimental Arm OS :Control(PFS)
OS: Exp(PFS)
HR
KN021 (cohort G)
Langer(Lancet Oncol)
2017 Nonsquam 123 Carbo/Pem (maint) Carbo/Pem/Pembro 20.9 NR 0.54(p=0.0067
KN189 Gandhi(NEJM)
2018 NonsquamAny PD-L1
616 (2:1) Carbo/Pem (maint) Carbo/Pem/Pembro 11.3(4.9)
NR(8.8)
0.49(p<.00001)
IM150 Socinski 2018 Nonsquam 1202 CPac+bev CP+bev+atezoCP+atezo (NR)
14.4 19.2 HR =0.775 (p=.026)
IM131 Jotte(NEJM)
2018 Squamous 1021 CPac or CnabPac Cpac/nabPac + Atezo 13.9(5.6)PFS12mo =12%
14(6.3)PFS12mo= 24.7%
.96(.72)(p<.0001)
KN407 Paz-Ares(NEJM)
2018 SquamousAny PD-L1
559 CPac or CnabPac CP/nabP + Pemb 11.3 15.9 .64, p<.001
IM 132 Papadimitrakopoulou 2018 Nonsquam 578 CisPem or Carbo/Pem(maint)
CisPem or Carbo/Pem + Atezo
(5.2) (7.6) OS HR = 0.81 (p=.08)(PFS HR = 0.60)
KN = Keynote CM = CheckMate IM = IMpower
What do we know about immunotherapy vs.
chemoimmunotherapy?
• Nothing• No prospective trials have been completed.
Pembrolizumab
Induction Maintenance
2nd Line Treatment
Carbo/Pemetrexed/
Pembrolizumab
Pembrolizumab
Pemetrexed/Pembrolizumab
Carbo/Pemetrexed/Pembrolizumab
Not Specified
Carbo/Pemetrexed
≥1%
TPS
posit
ive
Rand
omiza
tion*
Arm
AArm B
Arm C
1st Line Treatment
A Randomized, Phase III Study of Firstline Immunotherapy alone or in Combination with Chemotherapy in Induction/Maintenance or Post-progression in Advanced Nonsquamous Non-Small Cell Lung Cancer (NSCLC) with Immunobiomarker SIGNature-driven Analysis
Sequential vs Combination Therapy: INSIGNA
SWOG-ECOG collaboration NCTN NCI network (A. Chiang, H. Borghaei)
What are the considerations?• Biomarker status
– PD-L1 < 1%– PD-L1 1-49%– PD-L1 > 50%
• Mutational status– EGFR, ALK– Other
• Performance status
Keynote Studies (Pembroluzimab)Study PI Histology PD-L1 Chemotherapy
regimenExperimental arm
KN 024 Reck Any >50% Pt based doublet Pembro
KN 042 Mok Any >1% “ Pembro
KN 189 Gandhi Nonsquamous Any Pt-Pemetrexed Chemo+ pembro
KN 407 Paz-Ares
Squamous Any Pt-paclitaxel/nabpaclitaxel
Chemo+ pembro
PD-L1< 1%(Dual immunotherapy or Chemoimmunotherapy vs. Chemotherapy)
Study N RR% PFS OS 12mo% 24mo%
CM 227 <1%(nivo/ipi)
187 ns ns 17.2 60 40
KN407<1% 95 63.2 6.3 15.9 64.2 ns
KN189<1% 127 32.3 6.1 (HR = .59) 61.7 ns
Control
CM227 <1% 186 ns ns 12.2 51 23
KN407<1% 99 40.4 5.3 10.2 43.3 ns
KN189 <1% 63 14.3 5.1 - 52.2 ns
Hellmann, 2019; Paz-Arres, NEJM; Gandhi NEJM
Overall Survival: TPS <1%
KN 189 <1% CM 227KN 407<1%
PFS: <1 %
KN 189(Gandhi)
KN 409 Paz-Arres
PFS differences less impressive than OS, but still favorChemotherapy + immunotherapy or dual immunotherapy
CM 227Hellman
PD-L1 1-49%(Chemoimmunotherapy vs. Chemotherapy)
Study N RR% PFS OS 12mo%
KN407 1-49% 103 49.5 7.2 14 65.9
KN189 1-49% 128 48.4 (HR =.55) (HR =.59) 71.5
Control
KN4071-49% 104 41.3 5.2 11.6 50
KN189 1-49% 58 20.7 - - 50.9
PD-L1 1-49%
KN 189Gandhi
KN 407Paz-Arres
PFS
OS
Keynote studies (PD-L1 >50%)Study N RR% PFS (HR) OS 12mo% 24mo%
KN024 (P) 305 (1:1) 44.8 10.3 (0.5) 30 70 51.5
KN 042>50% (P)
299 39 7.1 20 (65) 45
KN189>50%(P + Chemo)
202 (2:1) 61.9 11.1 (0.36) NR 73 51.9
KN 407(P+ chemo)
73 57.9 8 NR (60) -
Controls
KN 189>50% 22.9 4.8 10 48.6 39.4
KN 024 27.8 6 14.2 54.8 34.5
KN 042>50% 286 32 6.4 12.2 (50) 30
KN 407 73 38.4 4.2 NR (50) -Reck, JCO 2019; Gandhi, NEJM, 2018;Gadgeel, ASCO 2019
Early deterioration with immunotherapy alone
• Many trials have demonstrated an early deterioration with immunotherapy alone treatment.
• First 3-6 months
Does the addition of chemotherapy prevent initial early deterioration?
189, Gandhi042, Mok024, Reck 407, Paz-ArresImmunotherapy Chemoimmunotherapy
Other studies, other drugs• MYSTIC• IMpower
Background
Primary endpoints (PD-L1 TC ≥25%*)• OS (D vs CT)• OS (D+T vs CT)• PFS (D+T vs CT)Key exploratory endpoints• OS by bTMB and tTMB
Durvalumab + tremelimumab (n=372)D 20 mg/kg q4w until disease progression +
T 1 mg/kg q4w for up to 4 doses
Platinum-based CT (n=372) • Paclitaxel + carboplatin OR
• Gemcitabine + cisplatin/carboplatin (squamous) OR• Pemetrexed + cisplatin/carboplatin (non-
squamous)† for up to 6 cycles
Durvalumab (n=374)20 mg/kg q4w until disease progression
R
Stratified by PD-L1 TC
(<25% vs ≥25%*) and histology
1:1:1
• Stage IV NSCLC• All-comers population
(i.e. irrespective of PD-L1 status)
• EGFR–/ALK–• ECOG PS 0/1• Immunotherapy- and CT-naïve
N=1118 randomized
MYSTIC
Rizvi, ESMO IO 2018
TC ≥25% (Primary Endpoint)Durvalumab + tremelimumab vs chemotherapy Durvalumab vs chemotherapy
Prob
abilit
y of O
S
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 39
22.7%
38.3%
36302421 3327Time from randomization (months)
0 3 6 9 12 15 18 39
35.4%
36302421 3327Time from randomization (months)
Prob
abilit
y of O
S
0.0
0.2
0.4
0.6
0.8
1.0
22.7%
No. at riskD 163 134 116 104 93 85 76 66 60 53 25 6 0 0
CT 162 147 123 101 83 67 53 43 35 32 20 2 0 0
No. at riskD+T 163 130 111 92 80 75 68 63 54 50 30 6 1 0
CT 162 147 123 101 83 67 53 43 35 32 20 2 0 0
D(n=163)
CT (n=162)
Events, n (%) 108 (66.3) 128 (79.0)mOS, months(95% CI)
16.3(12.2–20.8)
12.9(10.5–15.0)
HR (97.54% CI)p-value
0.76 (0.56–1.02)0.036
D+T(n=163)
CT(n=162)
Events, n (%) 113 (69.3) 128 (79.0)mOS, months (95% CI)
11.9(9.0–17.7)
12.9(10.5–15.0)
HR (98.77% CI)p-value
0.85 (0.61–1.17)0.202
Rizvi, ESMO IO 2018
IMpower Studies (atezolizumab)
Study PI Histology PD-L1 Chemotherapy regimen
IM 132 Papa nonsquam Platinum/pemetrexed
IM 150 Socinski nonsquam any Carbo/Paclitaxel (arm B)
Carbo/Paclitaxel/Bev (arm C)
IM 150 PD-L1• Similar to the results
with the KN studies, there is benefit to the use of the CPI for all groups, increasing with increasing PD-L1
Socinski, NEJM
IM 132
Papadimitrakopulu, ESMO 2019
EGFR/ALK• Excluded from all studies except IM 150.
– Small #s from a complex trial
• Frequent high level expression of PD-L1• Role of immunotherapy as a single agent
unclear
IMpower150 Study Design
Arm AAtezolizumabb + Carboplatinc +
Paclitaxeld
4 or 6 cycles
Atezolizumabb
Arm C (control)Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Bevacizumabe
Surv
ival
follo
w-u
p
Stage IV or recurrent metastatic nonsquamous NSCLCChemotherapy-naivea
Tumor tissue available for biomarker testing
Any PD-L1 IHC status
Stratification factors:• Sex• PD-L1 IHC expression• Liver metastases
N = 1202
R1:1:1
Arm BAtezolizumabb + Carboplatinc +
Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Atezolizumabb
+ Bevacizumabe
Maintenance therapy(no crossover permitted)
Treated with atezolizumab until PD per RECIST v1.1
or loss of clinical benefit
AND/OR
Treated with bevacizumab until PD per RECIST v1.1
Socinski M, et al. Presented at ASCO Annual Meeting Chicago, Illinois, June 1-5, 2018; Abstract 9002
• Patients baseline characteristics were balanced across all arms
Baseline CharacteristicsBaseline characteristics
Arm A:atezo + CP(N = 402)
Arm B:atezo + bev + CP
(N = 400)
Arm C (control):bev + CP(N = 400)
Median age (range), years 63 (32-85) 63 (31-89) 63 (31-90)Sex, male, n (%) 241 (60%) 240 (60%) 239 (60%)ECOG PS, 0, n (%) 180 (45%) 159 (40%) 179 (45%)Tobacco use history, n (%)
Current smoker | Previous smokerNever smoker
98 (24%) | 227 (57%)77 (19%)
90 (23%) | 228 (57%)82 (21%)
92 (23%) | 231 (58%)77 (19%)
Liver metastases, yes, n (%) 53 (13%) 52 (13%) 57 (14%)EGFR mutation, positive, n (%) 45 (11%) 34a (9%) 45 (11%)EML4-ALK rearrangement, positive, n (%) 9 (2%) 11 (3%) 20 (5%)Teff gene signature expression, high, n (%)b 177 (44%) 166 (42%) 148 (37%)PD-L1 expression, n (%)c
TC3 or IC3TC2/3 or IC2/3TC1/2/3 or IC1/2/3TC0 and IC0
68 (17%)137 (34%)213 (53%)188 (47%)
75 (19%)140 (35%)209 (52%)191 (48%)
73 (18%)133 (33%)195 (49%)205 (51%)
Socinski M, et al. Presented at ASCO Annual Meeting Chicago, Illinois, June 1-5, 2018; Abstract 9002
Reck et al. IMpower150 in EGFR-mt pts
Median, 18.7 mo(95% CI: 13.4, NE)
Median, NE(95% CI: 17.0, NE)
OS in EGFR-mt patients (Arm B vs Arm C)
Data cutoff 22 Jan 2018.
Outcomes of EGFR mut Patients on IM 150
Reck,
Performance Status• Another data free zone.• All studies to date have only included
PS 0-1.• No prospective data re: compromised
PS and outcomes for CKIs.• “real world experience”• Dudnik: Israel Lung Cancer Group,
prospective analysis of second line nivo.
• Ksienski: retrospective, BC Canada. Mostly first line (74%) pembro
Dudnik, Lung Cancer, 2018Ksienski, Lung Cancer 2019
What are the questions we need to ask (but probably won’t)
• Chemotherapy dose/schedule– Why do we continue to dose at MTD?– Which chemotherapy drugs should we be
combining with immunotherapy?
• Duration of therapy?
top related