The combination of chemotherapy (and

immunotherapy) and immunotherapy

in the front-line treatment of NSCLC

Marina C. Garassino
Struttura Semplice Oncologia Toraco polmonare
Fondazione IRCCS Istituto Nazionale de Tumori

ISTITUTO NAZIONALE
PER LO STUDIO
E LA CURA DEI TUMORI
 Complex scenario
CT-IO
• KEYNOTE 189 (PFS, OS)
• IMPOWER 150 (PFS, OS pending Press realease)
• IMPOWER 131
IO-IO
• CHECKMATE 223 (PFS)
• MYSTIC (Press Release PFS monotherapy)
• POSEIDON
CT-IO

ISTITUTO NAZIONALE
PER LO STUDIO
E LA CURA DEI TUMORI
 ISTITUTO NAZIONALE
PER LO STUDIO
E LA CURA DEI TUMORI
 Chemotherapy Enhances Anti-Cancer Immune Response: Rational
Partner for Immunotherapy
• Increasing T-cell penetrance in the tumor

• Enhancing effector T-cell function

• Eliminating
immunosuppressive cells:
T-regulatory cells

• Improving recognition of
• Enhancing maturation and tumor antigens by T-cell
activation of dendritic cells
toward antigen presentation

• Inducing immunogenic cell death

• Eliminating immunosuppressive cells: T-regs,
myeloid-derived suppressor cells, M2 macrophages ISTITUTO NAZIONALE
PER LO STUDIO
E LA CURA DEI TUMORI
 KEYNOTE-189 Study Design (NCT02578680)
Key Eligibility Criteria Pembrolizumab 200 mg + Pembrolizumab
• Untreated stage IV Pemetrexed 500 mg/m2 + 200 mg Q3W for
N = 410 up to 31 cycles
nonsquamous NSCLC Carboplatin AUC 5 OR
Cisplatin 75 mg/m2 +
• No sensitizing EGFR or Pemetrexed
ALK alteration Q3W for 4 cycles 500 mg/m2 Q3W
• ECOG PS 0 or 1 R
(2:1)
• Provision of a sample for
PD-L1 assessment Placebo (normal saline) + Placebo (normal saline)
• No symptomatic brain Pemetrexed 500 mg/m2 + for up to 31 cycles
metastases Carboplatin AUC 5 OR +
N = 206 Cisplatin 75 mg/m2 Pemetrexed
• No pneumonitis requiring
Q3W for 4 cycles 500 mg/m2 Q3W
systemic steroids

Stratification Factors
• PD-L1 expression
(TPSa <1% vs ≥1%)
• Platinum
(cisplatin vs carboplatin) Pembrolizumab PDb
• Smoking history 200 mg Q3W
(never vs former/current) for up to 35 cycles
aPercentage of tumor cells with membranous PD-L1 staining assessed using the PD-L1 IHC 22C3 pharmDx assay. bPatients could crossover during the induction or maintenance phases.
To be eligible for crossover, PD must have been verified by blinded, independent central radiologic review and all safety cri teria had to be met.
Analysis Populations and End Points
Analysis Populations End Points for Discussion
• Efficacy • Primary
– Intention-to-treat (ITT) – Overall survival
• Safety – Progression-free survival
– All patients who received ≥1 dose of
• Secondary
study medication
– Response rate
– Duration of response
– Safety
• Exploratory
– Effect of PD-L1 expression
on efficacy
– Patient-reported outcomes
 Statistical Considerations
• Planned enrollment: 570 patients
– Actual enrollment: 616 patients
• Overall alpha for study: strictly controlled at one-sided α = 2.5%
– Study had 90% power to show HR for PFS of 0.70 at one-sided α = 0.0095 and
HR for OS of 0.70 at a one-sided α = 0.0155
– Protocol specified 2 interim analyses before the final analysis
• First interim analysis (reviewed by external, independent data monitoring committee)
– Planned to occur after enrollment complete and ~370 PFS events observed a
– Data cutoff date: Nov 8, 2017
– Median follow-up: 10.5 months (range, 0.2-20.4)
– Observed number of events: 410 for PFS, 235 for OS
– One-sided alpha levels b: 0.00559 for PFS, 0.00128 for OS

ISTITUTO NAZIONALE
aItwas anticipated that there would be ~242 OS events at that time. PER LO STUDIO
b Multiplicity adjusted based on the observed number of events using the O’Brien -Fleming spending function. E LA CURA DEI TUMORI
 Disposition of Study Treatment
616 patients
randomly allocated

Pembro/Pem/Platinum Placebo/Pem/Platinum
• 410 allocated • 206 allocated
• 405 treateda • 202 treatedb

• 137 (33.8%) ongoing • 36 (17.8%) ongoing

• 268 (66.2%) discontinued • 166 (82.2%) discontinued
– 150 (37.0%) radiographic PD – 119 (58.9%) radiographic PD
– 78 (19.3%) AEs – 21 (10.4%) AEs
– 16 (4.0%) consent withdrawal – 8 (4.0%) consent withdrawal
– 11 (2.7%) clinical PD – 13 (6.4%) clinical PD
– 9 (2.2%) physician decision – 3 (1.5%) physician decision
– 4 (1.0%) new anticancer tx – 2 (1.0%) new anticancer tx

a2AEs, 1 clinical PD, 1 death, and 1 protocol violation. b2 consent withdrawal, 1 protocol violation, and 1 physician decision.
Data cutoff date: Nov 8, 2017.
 Disposition of Study Treatment
616 patients
randomly allocated

Pembro/Pem/Platinum Placebo/Pem/Platinum
• 410 allocated • 206 allocated
• 405 treateda • 202 treatedb

41.3%
• 137 (33.8%) ongoing Crossoverc • 36 (17.8%) ongoing
• 268 (66.2%) discontinued 67 in-study pembro • 166 (82.2%) discontinued
– 150 (37.0%) radiographic PD + – 119 (58.9%) radiographic PD
– 78 (19.3%) AEs 18 off-study anti–PD-(L)1 – 21 (10.4%) AEs
– 16 (4.0%) consent withdrawal = – 8 (4.0%) consent withdrawal
– 11 (2.7%) clinical PD 41.3% of ITT – 13 (6.4%) clinical PD
– 9 (2.2%) physician decision 50.0% excluding those – 3 (1.5%) physician decision
– 4 (1.0%) new anticancer tx still on therapy – 2 (1.0%) new anticancer tx

a2 AEs, 1 clinical PD, 1 death, and 1 protocol violation. b2 consent withdrawal, 1 protocol violation, and 1 physician decision. cAn additional 13 patients received other subsequent therapy
(6.3% of ITT, 7.6% excluding those still on therapy). Data cutoff date: Nov 8, 2017.
 Frequency of PD-L1 TPS Categories
50
Pembro/Pem/Platinum
45
40 Placebo/Pem/Platinum
Frequency, %

34.0%
35 31.0% 30.6% 31.2% 32.2%
30 28.2%
25
20
15
10 5.6%
7.3%
5
0
<1% 1-49% ≥50% Not evaluable
Not evaluable refers to specimens with an inadequate number of tumor cells or no tumor cells seen; these patients were includ ed in the PD-L1 TPS <1% group for randomization
stratification but excluded from analyses of efficacy by TPS. Data cutoff date: Nov 8, 2017.
 Overall Survival, ITT Events HR (95% CI) P
Pembro/Pem/Plat 31.0% 0.49 <0.00001
100
(0.38-0.64)
Placebo/Pem/Plat 52.4%
90
69.2%
80 49.4%
70

60
OS, %

50 Median (95% CI)

NR (NE-NE)
40
11.3 mo (8.7-15.1)
30

20

10

0
0 3 6 9 12 15 18 21
M o n th s
N o . a t R is k

410 377 347 278 163 71 18 0

206 183 149 104 59 25 8 0 ISTITUTO NAZIONALE
PER LO STUDIO
Data cutoff date: Nov 8, 2017. E LA CURA DEI TUMORI
 Overall Survival by PD-L1 TPS
TPS <1% TPS 1-49% TPS ≥50%
HR HR HR
Events (95% CI) Pa Events (95% CI) Pa Events (95% CI) Pa
Pembro/Pem/Plat 38.6% 0.59 0.0095 28.9% 0.55 0.0081 25.8% 0.42 0.0001
Placebo/Pem/Plat 55.6% (0.38-0.92) 48.3% (0.34-0.90) 51.4% (0.26-0.68)

100 61.7% 100 71.5% 100 73.0%

90 52.2% 90 50.9% 90 48.1%
80 80 80

70 70 70

60 60 60

OS, %

OS, %
OS, %

50 50 50

40 40 40

30 30 30

20 Median (95% CI) 20 Median (95% CI) 20 Median (95% CI)

15.2 mo (12.3-NE) NR (NE-NE) NR (NE-NE)
10 10 10
12.0 mo (7.0-NE) 12.9 mo (8.7-NE) 10.0 mo (7.5-NE)
0 0 0
0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21

M o n th s M o n th s M o n th s
N o . a t R is k N o . a t R is k N o . a t R is k
127 113 104 79 42 20 6 0 128 119 108 84 52 21 5 0 132 122 114 96 56 25 6 0
63 54 45 32 21 6 1 0 58 54 47 32 17 5 2 0 70 64 50 35 19 13 4 0

aNominal and one-sided. Data cutoff date: Nov 8, 2017.

 OS by PD-L1>50 TPS 024 vs 189
TPS ≥50%
HR
Events (95% CI) Pa
25.8% 0.42 0.0001
51.4% (0.26-0.68)

100 73.0%
90 48.1%
80

70

60

OS, %
50

40

30

20 Median (95% CI)

NR (NE-NE)
10
10.0 mo (7.5-NE)
0
0 3 6 9 12 15 18 21

M o n th s
N o . a t R is k
132 122 114 96 56 25 6 0
70 64 50 35 19 13 4 0

aNominal and one-sided. Data cutoff date: Nov 8, 2017.

 OS by PD-L1>50 TPS 024 vs 189
TPS ≥50%
HR
Events (95% CI) Pa
25.8% 0.42 0.0001
51.4% (0.26-0.68)

100 73.0%
HR 0.42 KN189 90 48.1%

HR 0.60 KN024 =0.70 80

70

60

OS, %
50

40

30

20 Median (95% CI)

NR (NE-NE)
10
10.0 mo (7.5-NE)
0
0 3 6 9 12 15 18 21

M o n th s
N o . a t R is k
132 122 114 96 56 25 6 0
70 64 50 35 19 13 4 0

aNominal and one-sided. Data cutoff date: Nov 8, 2017.

 Progression-Free Survival, ITT
(RECIST v1.1, BICR) Events HR (95% CI) P
Pembro/Pem/Plat 59.5% 0.52 <0.00001
100
(0.43-0.64)
Placebo/Pem/Plat 80.6%
90
34.1%
80 17.3%
70

60
PFS, %

50 Median (95% CI)

8.8 mo (7.6-9.2)
40 4.9 mo (4.7-5.5)
30

20

10

0
0 3 6 9 12 15 18 21
M o n th s
N o . a t R is k

410 322 256 149 60 17 5 0

206 141 80 40 16 3 1 0
BICR, blinded, independent central review. Data cutoff date: Nov 8, 2017.
 PFS by PD-L1 TPS
TPS <1% TPS 1-49% TPS ≥50%
HR HR HR
Events (95% CI) Pa Events (95% CI) Pa Events (95% CI) Pa
Pembro/Pem/Plat 72.4% 0.75 0.0476 54.7% 0.55 0.0010 51.5% 0.36 <0.00001
Placebo/Pem/Plat 85.7% (0.53-1.05) 75.9% (0.37-0.81) 80.0% (0.25-0.52)

100 19.1% 100 37.5% 100 44.9%

90 15.7% 90 19.6% 90 15.4%
80 80 80

70 70 70

60 60 60
PFS, %

PFS, %
P F S ,%
50 50 50

40 40 40

30 30 30

20 Median (95% CI) 20 Median (95% CI) 20 Median (95% CI)

10 6.1 mo (4.9-7.6) 10 9.0 mo (7.1-11.3) 10 9.4 mo (9.0-13.8)
5.1 mo (4.5-6.9) 4.9 mo (4.7-6.9) 4.7 mo (3.1-6.0)
0 0 0
0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21

M o n th s M o n th s M o n th s
N o . a t R is k N o . a t R is k N o . a t R is k
127 88 60 31 12 3 2 0 128 101 84 47 21 6 2 0 132 112 95 60 23 7 1 0
63 44 27 16 4 0 0 0 58 44 23 11 6 1 0 0 70 43 26 11 5 2 1 0

aNominal and one-sided. BICR, blinded, independent central review. Data cutoff date: Nov 8, 2017.
 PFS by PD-L1 TPS
(024-189)
TPS ≥50%
HR
Events (95% CI) Pa
51.5% 0.36 <0.00001
80.0% (0.25-0.52)

100 44.9%
90 15.4%
80

70

60

PFS, %
50

40

30

20 Median (95% CI)

10 9.4 mo (9.0-13.8)
4.7 mo (3.1-6.0)
0
0 3 6 9 12 15 18 21

M o n th s
N o . a t R is k
132 112 95 60 23 7 1 0
70 43 26 11 5 2 1 0

aNominal and one-sided. BICR, blinded, independent central review. Data cutoff date: Nov 8, 2017.
 PFS by PD-L1 TPS
(024-189)
TPS ≥50%
HR
Events (95% CI) Pa
51.5% 0.36 <0.00001
80.0% (0.25-0.52)

100 44.9%
90 15.4%
80

70
HR 0.36 KN189 =0.72 60

PFS, %
HR 0.50 KN024 50

40

30

20 Median (95% CI)

10 9.4 mo (9.0-13.8)
4.7 mo (3.1-6.0)
0
0 3 6 9 12 15 18 21

M o n th s
N o . a t R is k
132 112 95 60 23 7 1 0
70 43 26 11 5 2 1 0

aNominal and one-sided. BICR, blinded, independent central review. Data cutoff date: Nov 8, 2017.
 Response Rate and Duration, ITT
(RECIST v1.1, BICR) Pembro/ Placebo/
Best Response,a Pem/Plat Pem/Plat
n (%) (N = 410) (N = 206)
100
90 CR 2 (0.5%) 1 (0.5%)
Δ28.5
80 PR 193 (47.1%) 38 (18.4%)
P < 0.0001
ORR, % (95% CI)

70
SD 152 (37.1%) 106 (51.5%)
60
47.6%
PD 36 (8.8%) 36 (17.5%)
50
40
Pembro/ Placebo/
30 18.9% Duration of Pem/Plat Pem/Plat
20 response, mo (N = 195) (N = 39)
10 Median 11.2 7.8
0
Pembro/Pem/Plat Placebo/Pem/Plat Range 1.1+ to 18.0+ 2.1+ to 16.4+
aAnadditional 27 (6.6%) patients in the pembro/pem/plat arm and 25 (12.1%) in the placebo/pem/plat arm did not have ≥2 evaluable sets of radiographic images.
BICR, blinded, independent central review. Data cutoff date: Nov 8, 2017.
 Response Rate by PD-L1 TPS
(RECIST v1.1, BICR) Pembro/Pem/Platinum
Placebo/Pem/Platinum

100
90
Pa < 0.0001
80
Pa = 0.0001
ORR, % (95% CI)

70
60 Pa = 0.0055
50
40
30
20
10
32.3% 14.3% 48.4% 20.7% 61.4% 22.9%
0
TPS <1% TPS <1%
TPS <1% TPS 1- 1-49%
TPS TPS 1- TPS ≥50% TPS ≥50%
TPS ≥50%
P C 49% P
(Includes all49%
CRs) P C
aNominal and one-sided.
BICR, blinded, independent central review. Data cutoff date: Nov 8, 2017.
 Summary of Adverse Events
Pembro/Pem/Platinum Placebo/Pem/Platinum
N = 405 N = 202
All cause 404 (99.8%) 200 (99.0%)
Grade 3-5 272 (67.2%) 133 (65.8%)
Led to death 27 (6.7%) 12 (5.9%)
Led to discontinuation
All treatmenta 56 (13.8%) 16 (7.9%)
Any treatment 112 (27.7%) 30 (14.9%)
Immune mediated 92 (22.7%) 24 (11.9%)
Grade 3-5 36 (8.9%) 9 (4.5%)
Led to death 3 (0.7%) 0
aIncludespatients who discontinued pembrolizumab or placebo, pemetrexed, and carboplatin for an adverse event at any time and patients who discontinued pembrolizumab or placebo
and pemetrexed for an adverse event after completing 4 cycles of platinum.
Data cutoff date: Nov 8, 2017.
 Adverse Events (All Cause): Frequency ≥20%
Grade
60 1-2 3-5
55 Pembro/Pem/Platinum
50
Placebo/Pem/Platinum
45
Frequency, %

40
35
30
25
20
15
10
5
0

Data cutoff date: Nov 8, 2017.

 Immune-Mediated Adverse Events
Grade
10
1-2 3-5
9 Pembro/Pem/Platinum
8
Placebo/Pem/Platinum
7
Frequency, %

6
5
4
3
2
1
0

aIncludes 3 grade 5 events. Data cutoff date: Nov 8, 2017.

 Renal Events
• Acute kidney injury
– Frequency: 5.2% in pembrolizumab/pemetrexed/platinum arm vs
0.5% in placebo/pemetrexed/platinum arm
– Grade 3-5 frequency: 2.0% vs 0%
– Grade 5 frequency: 0.5% (n = 2)
– Most events occurred in the setting of acute illness and were likely multifactorial

• Nephritisa
– Frequency: 1.7% in pembrolizumab/pemetrexed/platinum vs
0% in placebo/pemetrexed/platinum arm
– Grade 3-5 frequency: 1.5% vs 0%
– Grade 5 frequency: 0%

aIncludespreferred terms of autoimmune nephritis, nephritis, and tubulointerstitial nephritis.

Data cutoff date: Nov 8, 2017.
Summary
• Pembrolizumab plus pemetrexed and platinum provided superior OS
compared with placebo plus pemetrexed and platinum (HR 0.49)
– Benefit observed irrespective of PD-L1 TPS: HR 0.59 for TPS <1%,
0.55 for TPS 1-49%, and 0.42 for TPS ≥50%
• PFS was superior (HR 0.52)
• ORR was higher (47.6% vs 18.9%) with durable response
• AE frequency and severity similar between arms
– Pembrolizumab did not appear to exacerbate pemetrexed and
platinum-associated AEs
– Pemetrexed and platinum did not appear to exacerbate
pembrolizumab-associated AEs
– Exception may be renal toxicity
Conclusions
• Adding pembrolizumab to pemetrexed and platinum induction
therapy and pemetrexed maintenance therapy significantly
improves OS, PFS, and ORR in patients with untreated metastatic
nonsquamous NSCLC without sensitizing EGFR or ALK alterations

• Pembrolizumab plus pemetrexed and platinum has a

manageable safety profile

• Pembrolizumab plus pemetrexed and platinum may be a new

standard of care for first-line treatment of metastatic nonsquamous
NSCLC, irrespective of PD-L1 expression
 5

IMpower150 Study Design

Maintenance therapy
(no crossover permitted)
Arm A
Stage IV or Atezolizumabb + Treated with
Atezolizumabb
recurrent metastatic Carboplatinc + Paclitaxeld atezolizumab
nonsquamous NSCLC 4 or 6 cycles until PD by

Survival follow-up
Chemotherapy-naivea RECIST v1.1
Tumor tissue available for Arm B or loss of clinical
biomarker testing Atezolizumabb + Atezolizumabb benefit
R
Any PD-L1 IHC status Carboplatinc + Paclitaxeld +
1:1:1
Stratification factors: + Bevacizumabe Bevacizumabe AND/OR
• Sex 4 or 6 cycles
• PD-L1 IHC expression (SP142) Treated with
• Liver metastases Arm C (control) bevacizumab
Carboplatinc + Paclitaxeld until PD by
N = 1202 Bevacizumabe RECIST v1.1
+ Bevacizumabe
4 or 6 cycles

The primary PFS analysis of IMpower150 assessed whether the addition of atezolizumab to Arm C provided clinical benefit
- This analysis will focus on whether this combination provides clinical benefit in key biomarker and special interest subgroups
a Patients with a sensitizing EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with one or more
approved targeted therapies. Kowanetz M, Socinski M, et al. AACR 2018
b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m 2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w. IMpower150: Efficacy Across Subgroups
 11

IMpower150 Demonstrated PFS Benefit in Arm B vs C in the ITT-WT

Arm B: Arm C:
Landmark PFS, % atezo + bev + CP bev + CP

Progression-Free Survival (%)

12-month 37% 18%

HRa, 0.62
(95% CI: 0.52, 0.74)
P < 0.0001

Median, 6.8 mo Median, 8.3 mo

(95% CI: 6.0, 7.1) (95% CI: 7.7, 9.8)

Time (months)

OS positivity has since been reached (March 2018) and will be presented at an upcoming meeting
Atezo, atezolizumab; bev, bevacizumab; CP, carboplatin + paclitaxel.
a Stratified HR.

Data cutoff: September 15, 2017 Kowanetz M, Socinski M, et al. AACR 2018
Reck M, et al. ESMO IO 2017 [LBA_PR1]. IMpower150: Efficacy Across Subgroups
 14
PFS Benefit in Arm B was Observed Across All Biomarker Subgroups,
Including PD-L1–Negative Patients (by SP142 IHC)
Median PFS, mo
Subgroup n (%)a Arm B Arm C
0.51
Teff-high 284 (43%) 11.3 6.8
0.76
Teff-low 374 (57%) 7.3 7.0

0.39
PD-L1–High (TC3 or IC3) 135 (20%) 12.6 6.8
0.56
PD-L1–Low (TC1/2 or IC1/2)b 224 (32%) 8.3 6.6
0.77
PD-L1–Negative (TC0 and IC0) 338 (49%) 7.1 6.9

0.62
ITT-WT 692 (100%) 8.3 6.8

0.25 1.0 1.25

Hazard Ratioc
In favor of Arm B: In favor of Arm C:
atezo + bev + CP bev + CP

Teff gene signature enriches for PFS similarly to PD-L1 IHC, including biomarker–negative patients
Atezo, atezolizumab; bev, bevacizumab; CP, carboplatin + paclitaxel; IC, tumor-infiltrating immune cells; TC, tumor cells.
a Teff % prevalence out of those tested in ITT-WT (n = 658); PD-L1 IHC % prevalence out of ITT-WT (n = 692), using the SP142 assay.
b Mutually exclusive subgroup that excluded TC3 or IC3 patients.
c Stratified HRs for ITT-WT and Teff-high WT populations; unstratified HRs for all other subgroups.

TC3 or IC3 = PD-L1 +≥ 50% ofTC or≥ 1 0 % ofI

C;TC1 /2/
3 orIC1 /2/3 =PD-L1 +≥ 1 % ofTC orI C;TC0a ndIC0=PD-L1+ < 1% of TC and IC.
Data cutoff: September 15, 2017. Kowanetz M, Socinski M, et al. AACR 2018
Reck M, et al. ESMO IO 2017 [LBA_PR1]. IMpower150: Efficacy Across Subgroups
 5

IMpower150 Study Design

Maintenance therapy
(no crossover permitted)
Arm A
Stage IV or Atezolizumabb + Treated with
Atezolizumabb
recurrent metastatic Carboplatinc + Paclitaxeld atezolizumab
nonsquamous NSCLC 4 or 6 cycles until PD by

Survival follow-up
Chemotherapy-naivea RECIST v1.1
Tumor tissue available for Arm B or loss of clinical
biomarker testing Atezolizumabb + Atezolizumabb benefit
R
Any PD-L1 IHC status Carboplatinc + Paclitaxeld +
1:1:1
Stratification factors: + Bevacizumabe Bevacizumabe AND/OR
• Sex 4 or 6 cycles
• PD-L1 IHC expression (SP142) Treated with
• Liver metastases Arm C (control) bevacizumab
Carboplatinc + Paclitaxeld until PD by
N = 1202 Bevacizumabe RECIST v1.1
+ Bevacizumabe
4 or 6 cycles
26
 CheckMate-227 (Part 1): 1L Any Histology Nivolumab + Ipilimumab vs.
Platinum Doublet Chemotherapy

Nivolumab 3 mg/kg Q2W + Ipilimumab 1

Original Design N=~650 mg/kg Q6W
N = 1100 patients
1a
PD-L1+ R Nivolumab monotherapy
(≥1%) 1:1:1 240 mg Q2W
Key eligibility criteria:
• Stage IV NSCLC
• No prior systemic therapy Platinum Doublet Disease
• WT EGFR/ALK progression
• CNS adequately treated at or
least 2 weeks prior to start
Nivolumab 3 mg/kg Q2W + Ipilimumab 1 unacceptable
Stratification N=~450
mg/kg Q6W toxicity
• (squamous vs non- 1b
PD-L1‒ R
squamous) (<1%) 1:1:1
Nivolumab 360 mg Q3W + Chemotherapy

Co-primary endpoints: Platinum Doublet

• OS, PFS
Secondary endpoints:
• ORR & Safety
ISTITUTO NAZIONALE
PER LO STUDIO
Chemo = Gem/Cis or Carbo (SQ) Pem/Cis or Carbo (non-SQ) E LA CURA DEI TUMORI
 CheckMate-227 (Part 1): 1L Any Histology Nivolumab + Ipilimumab vs.
Platinum Doublet Chemotherapy

Nivolumab 3 mg/kg Q2W + Ipilimumab 1

mg/kg Q6W
N=~1300
N = 1100
1750 patients
1a
PD-L1+ R Nivolumab monotherapy
(≥1%) 1:1:1 240 mg Q2W
Key eligibility criteria:
• Stage IV NSCLC
• No prior systemic therapy Platinum Doublet Disease
• WT EGFR/ALK progression
• CNS adequately treated at or
least 2 weeks prior to start
Nivolumab 3 mg/kg Q2W + Ipilimumab 1 unacceptable
Stratification N=~450
mg/kg Q6W toxicity
• (squamous vs non- 1b
PD-L1‒ R
squamous) (<1%) 1:1:1
Nivolumab 360 mg Q3W + Chemotherapy

Co-primary endpoints: Platinum Doublet

• OS, PFS
Secondary endpoints: Amendment 1:
• ORR & Safety Increased the size of Part 1A to lower potential for imbalances in the PD-L1 (+)
ISTITUTO NAZIONALE
PER LO STUDIO
Chemo = Gem/Cis or Carbo (SQ) Pem/Cis or Carbo (non-SQ) E LA CURA DEI TUMORI
 CheckMate-227 (Part 1): 1L Any Histology Nivolumab + Ipilimumab vs.
Platinum Doublet Chemotherapy

Nivolumab 3 mg/kg Q2W + Ipilimumab 1

mg/kg Q6W
N=~1300
N = 1750
1166 patients
1a
PD-L1+ R Nivolumab monotherapy
(≥1%) 1:1:1 240 mg Q2W
Key eligibility criteria:
• Stage IV NSCLC
• No prior systemic therapy Platinum Doublet Disease
• WT EGFR/ALK progression
• CNS adequately treated at or
least 2 weeks prior to start
Nivolumab 3 mg/kg Q2W + Ipilimumab 1 unacceptable
mg/kg Q6W toxicity

X
Stratification N=~450
• (squamous vs non- 1b
PD-L1‒ R
squamous) (<1%) 1:1:1
Nivolumab 360 mg Q3W + Chemotherapy

Co-primary endpoints: Platinum Doublet

• OS, PFS
Secondary endpoints:
• ORR & Safety Amendment 3: Lest optimized the endpoints in part 1
ISTITUTO NAZIONALE
PER LO STUDIO
Chemo = Gem/Cis or Carbo (SQ) Pem/Cis or Carbo (non-SQ) E LA CURA DEI TUMORI
 CheckMate-227 (Part 1): 1L Any Histology Nivolumab + Ipilimumab vs.
Platinum Doublet Chemotherapy

Nivolumab 3 mg/kg Q2W + Ipilimumab 1

mg/kg Q6W
N = 1166 patients
R
1:1:1 Nivolumab 3 mg/kg Q2W + Ipilimumab 1
Key eligibility criteria: mg/kg Q6W
• Stage IV NSCLC
• No prior systemic therapy Platinum Doublet Disease
• WT EGFR/ALK progression
R
• CNS adequately treated at 1:1
or
least 2 weeks prior to start
Nivolumab 3 mg/kg Q2W + Ipilimumab 1 unacceptable
Stratification
mg/kg Q6W toxicity
• (squamous vs non-
R Platinum Doublet
squamous) 1:1:1

Platinum Doublet

ISTITUTO NAZIONALE
PER LO STUDIO
Chemo = Gem/Cis or Carbo (SQ) Pem/Cis or Carbo (non-SQ) E LA CURA DEI TUMORI
 CheckMate-227 (Part 1): 1L Any Histology Nivolumab + Ipilimumab vs.
Platinum Doublet Chemotherapy

(45% TMB High)

1166patients
N = 524 patients N = 583

Nivolumab 3 mg/kg Q2W + Ipilimumab 1

Key eligibility criteria: mg/kg Q6W
• Stage IV NSCLC
• No prior systemic therapy
• WT EGFR/ALK R
• CNS adequately treated at 1:1
least 2 weeks prior to start
N= 583
Stratification
• (squamous vs non- Platinum Doublet
squamous)

ISTITUTO NAZIONALE
PER LO STUDIO
Chemo = Gem/Cis or Carbo (SQ) Pem/Cis or Carbo (non-SQ) E LA CURA DEI TUMORI
 CheckMate-227 (Part 1): 1L Any Histology Nivolumab + Ipilimumab vs.
Platinum Doublet Chemotherapy

(45% TMB High)

524 patients
N = 303 N = 152
262

Nivolumab 3 mg/kg Q2W + Ipilimumab 1

Key eligibility criteria: mg/kg Q6W
• Stage IV NSCLC
• No prior systemic therapy Disease
• WT EGFR/ALK progression
R
• CNS adequately treated at 1:1
or
least 2 weeks prior to start unacceptable
Stratification
N= 152
262 toxicity
• (squamous vs non- Platinum Doublet
squamous)

Co-primary endpoints:
• PFS TMB High IMPROVED PFS in TMB (High) patients
• OS PD-L1 (+)
Secondary endpoints:
ISTITUTO NAZIONALE
• ??? PER LO STUDIO
Chemo = Gem/Cis or Carbo (SQ) Pem/Cis or Carbo (non-SQ) E LA CURA DEI TUMORI
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)

PFS in Patients With High TMB (≥10 mut/Mb)

by Tumor Histology
Non-squamous Squamous
Nivo + ipi Chemo Nivo + ipi Chemo
100 (n = 95) (n = 104) 100 (n = 44) (n = 56)
Median PFS, moa 9.5 5.6 Median PFS, mob 4.9 4.3
80 HR 0.55 80 HR 0.63
95% CI 0.38, 0.80 95% CI 0.39, 1.04
PFS (%)

60 60
1-y PFS = 46% Nivolumab +
ipilimumab
40 40 1-y PFS = 36% Nivolumab +
ipilimumab

20 1-y PFS = 17% 20

1-y PFS = 7%
Chemotherapy Chemotherapy
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Months Months
No. at risk
Nivo + ipi 95 59 49 41 27 18 8 1 0 44 26 17 14 9 6 3 2 0
Chemo 104 70 38 15 6 6 4 0 0 56 33 13 2 1 0 0 0 0

a95% CI: nivo + ipi (5.6 mo, NR), chemo (4.5, 7.0 mo); b95% CI: nivo + ipi (2.7, 13.7 mo), chemo (3.2, 5.6 mo) 39
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)

PFS in Patients With High TMB (≥10 mut/Mb)

by Tumor PD-L1 Expression
≥1% PD-L1 expression <1% PD-L1 expression
Nivo + ipi Chemo Nivo + ipi Chemo
100 100
(n = 101) (n = 112) (n = 38) (n = 48)
Median PFS, moa 7.1 5.5 Median PFS, mob 7.7 5.3
80 HR 0.62 80 HR 0.48
95% CI 0.44, 0.88 95% CI 0.27, 0.85
PFS (%)

60 60
1-y PFS = 45% Nivolumab +
1-y PFS = 42% Nivolumab +
ipilimumab
ipilimumab
40 40

20 1-y PFS = 16% 20

1-y PFS = 8% Chemotherapy
Chemotherapy
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Months Months
No. at risk
Nivo + ipi 101 65 50 40 26 16 7 2 0 38 20 16 15 10 8 4 1 0
Chemo 112 73 35 13 6 5 3 0 0 48 30 16 4 1 1 1 0 0

a95% CI: nivo + ipi (5.5, 13.5 mo), chemo (4.3, 6.6 mo); b95% CI: nivo + ipi (2.7 mo, NR), chemo (4.0, 6.8 mo) 40
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)

PFS: Nivolumab + Ipilimumab vs Nivolumab in Patients

With High TMB (≥10 mut/Mb) and ≥1% PD-L1 Expression
100
Nivo + ipi Nivo
(n = 101) (n = 102)
80 HR (95% CI) 0.75 (0.53, 1.07)

60
PFS (%)

1-y PFS = 42%

40 Nivolumab + ipilimumab

Nivolumab
1-y PFS = 29%
20
Chemotherapy
1-y PFS = 16%
0
0 3 6 9 12 15 18 21 24
No. at risk
Months
Nivo + ipi 101 65 50 40 26 16 7 2 0
Nivo 102 51 41 34 20 11 4 0 0
Chemo 112 73 35 13 6 5 3 0 0
41
 Three main phenotypes and multiple
uncertainties
Immune-excluded
CT+IO
CTIO

Immune-
desert
CT+IO
Inflamed
CTIO
IOCT
CT+IO

Can we increase the patient population that responds to Immunotherapy?

Genotype and immunephenotype

Wellenstein, MD, Cell 2018

TMB independent of immunephenotype
(BIRCH, FIR, POPLAR)
Targeted panel TMB validation and IO threshold definition
1. WES
• Coding regions of 21,522 genes
• TMB defined as the number of missense mutations in the tumor exome
2. FoundationOne®
• A targeted gene panel of 324 cancer-related genes
• TMB defined as the number of somatic mutations (missense, synonymous, short indels) per megabase
of tumor genome examined

WES Foundation
200 missense 10 mut/mb
mutations

1. Szustakowski J et al. SITC 2017. 3. Szustakowski J et al. AACR 2018. 5528 Ramalingam S et al, AACR 2018
My personal conclusions
• Only available data on OS (interim analysis!) for IO
chemotherapy in all comers
• For patients with PD-L1>50% pembro alone and CT-IO
represent a standard of care (comorbidities, burden of
disease could make the difference)
• TMB is still far to come in Europe (need of a »Blueprint»)
• OS data for IO-IO are still awaited! IO-IO PD-L1 NEG TMB
high?
• URGENT NEED of personalized medicine