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?