Immune Checkpoint Inhibitor Therapy in the

Clinical Management of ES-SCLC

Yasar Ahmed
 Small-Cell Carcinoma

Small-Cell Lung Cancer Trachea

Lung

 High-grade neuroendocrine carcinoma with

Small-cell carcinoma
high metastatic potential (cells under microscope)
 Accounts for ~ 13% of lung cancers in the Bronchi
United States
 Most common genetic alterations: p53 and US Lung Cancer Incidence by Histology
2010-2014[1]
Rb1 inactivation; no clear targetable genetic Large-cell carcinoma
Other
drivers 3% 2%
Adenocarcinoma
 Until recently, first-line treatment for Small-cell carcinoma
metastatic disease has been combination 13%
platinum plus etoposide or irinotecan
Other non-small-cell 47%
 Response rates to first-line chemotherapy are carcinomas
12%
50%-70% but are substantially lower to
subsequent lines of therapy 23%
Squamous and
transitional cell
carcinoma
SCLC Clinical Presentation
 Local symptoms: cough, 50%; dyspnea, 40%; Metastatic Site, % At Presentation At Autopsy
chest pain, 35%; hemoptysis, 20%; Mediastinal LNs 66-80 73-87
hoarseness, 10%
Liver 21-27 69
 Distant symptoms: weight loss, 50%; Bone 27-41 54
weakness, 40%; anorexia, 30%; paraneoplatic Adrenal glands 5-31 35-65
syndrome, 15%; fever, 10% Bone marrow 15-30 NA
 Paraneoplastic syndromes: ectopic hormone- Brain 10-14 28-50
associated syndromes, immune-mediated Retroperitoneal LNs 3-12 29-52
neurologic syndromes Supraclavicular LNs 17 42
Chest CT Brain MRI
Pleural effusion 16-20 30
Contralateral lung 1-12 8-27
Soft tissues 5 19
SCLC Diagnosis and Staging
 Diagnosis by FNA or biopsy  TNM staging system vs
VA staging system
 Staging workup
TNM Staging VA Staging Incidence, %
‒ CT chest/abdomen/pelvis T1-T2, N0, M0 Limited stage ~5
(stage I)
‒ Brain MRI
T any, N any, M0 Limited stage; disease ~ 30
‒ PET scan to rule out distant (stage I-III) burden contained
within radiation field
metastases
T any, N any, M1 Extensive stage; ~ 65
(stage IV) disease burden beyond
radiation field
Historic Management of Small-Cell Lung Cancer
 Historic standard therapy has been platinum + etoposide
‒ Phase II studies of cisplatin/etoposide date back to the 1970s
‒ Initially very effective (high response rates, symptom improvement)
‒ Transient benefit
‒ Progression expected within 6 mos of starting therapy
‒ Median survival limited to 8-10 mos
‒ At relapse, fairly refractory to therapy
‒ > 40 phase III trials challenging first-line treatment of SCLC have failed to
show improved OS
Evolution of Systemic Therapy in Small-Cell Lung Cancer

1970s 1980s 1990s Today

Alkylating-Based Anthracycline-Based Platinum-Based

Checkpoint
Chemotherapy Chemotherapy Chemotherapy
Inhibitors
(CMV) (CAV) (EP)
Rationale
 Cancer cells may possess genetic alterations or perform posttranslational modifications that
can generate neoantigens, which may be recognized by the immune system
MHC
molecules Peptides

Mutant Normal Modified

protein proteins protein
Tumor cell Tumor cell

Mutation Posttranslational
Modification
Pi Somatic Mutation Prevalence
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 Biologic Rationale for Immune Checkpoint Inhibition
as Cancer Therapy
Priming Phase: Lymph Node Effector Phase: Tumor Microenvironment
T-cell
Dendritic
Activation
cell
Tumor
Activated
T-cell
Activating signals Anti–PD-1
TCR Antigen Nivolumab
Anti–CTLA-4 Antigen TCR
MHC Pembrolizumab
Ipilimumab MHC
Avelumab
Tremelimumab B7 CD28
Cemiplimab

Anti–PD-L1
B7 CTLA-4 PD-1 PD-L1 Atezolizumab
Durvalumab

Inhibitory signal blocked Negative regulation blocked

by antibody binding by antibody binding
 Rationale to Combine ICI With Chemotherapy in SCLC
Chemotherapy PD-1/PD-L1 Inhibition

1. Chemotherapy-induced tumor cell 2. PD-L1 overexpression leads to 3. PD-1/PD-L1 inhibition restores 4. Reversal of immune
killing may induce tumor antigen release immune cell evasion and T-cell tumor-specific T-cell immunity suppression leads to deeper,
and exposure to immune system inhibition more durable systemic
antitumor response
Immune Checkpoint Active
Antigens Inhibitor T-Cells Immune Checkpoint
APC
Active Tumor Cells Inhibitor
T-Cells

Antigens CD80

PD-L1 PD-L1 PD-1

Tumor PD-L1
Tumor
Chemotherapy CD80
PD-1
PD-1 Active
T-Cells
Tumor Cells
Inactive Inactive
T-Cells T-Cells
 Overview of Key Studies of Immune Checkpoint Inhibitors
in SCLC
Mar Jun Jun Sep Oct Nov Apr May
2015 2015 2017 2018 2018 2019 2020 2020

NCT01450761 IMpower133 CASPIAN EA5161 KEYNOTE-604

1L

Ipilimumab Atezolizumab Durvalumab Nivolumab Pembrolizumab

+ CT (ES) + CT (ES) + CT (ES) + CT (ES) + CT (ES)
maintenance

NCT02359019 CheckMate 451

Pembrolizumab Nivolumab ±
1L

maintenance ipilimumab (ES)

CheckMate 032 CheckMate 331 KEYNOTE-158/028

≥ 2L

Nivolumab ± Nivolumab Pooled Analysis

ipilimumab (LS/ES) monotherapy Pembrolizumab
(LS/ES) monotherapy

Phase I/II Phase III

IMpower133: Atezolizumab + Chemotherapy for
Advanced SCLC
 Double-blind, randomized, placebo-controlled phase I/III trial
Stratified by sex,
ECOG PS 0 vs 1, brain Induction: 4 x 21-day cycles Maintenance*
metastases: yes vs no
Atezolizumab 1200 mg IV on Day 1 +
Carboplatin AUC 5 mg/mL/min IV on Day 1 +
Etoposide 100 mg/m² on Days 1-3 Atezolizumab
Patients with PD or
measurable ES-SCLC; (n = 201)
ECOG PS 0/1; no prior
loss of
systemic therapy for clinical
Placebo + benefit
ES-SCLC; treated,
Carboplatin AUC 5 mg/mL/min IV on Day 1 + Placebo
asymptomatic brain
Etoposide 100 mg/m² on Days 1-3
mets eligible
(n = 202)
(N = 403)
*PCI per local SoC.
 Coprimary endpoints: OS, PFS by investigator assessment
 Secondary endpoints: ORR, DoR, safety
 IMpower133: PFS (Coprimary Endpoint)
100 Atezolizumab Placebo
+ CP/ET + CP/ET
(n = 201) (n = 202)
80 PFS events, n (%) 171 (85.1) 189 (93.6)
Median PFS, mos 5.2 4.3
(95% CI) (4.4-5.6) (4.2-4.5)
HR (95% CI) 0.77 (0.62-0.96)
60 P Value P = .017
6-mo PFS
PFS (%)

Median follow-up, mos 13.9

40 30.9% 12-mo PFS

Placebo
20 + CP/ET 12.6% Atezolizumab
+ Censored 22.4%
5.4% + CP/ET
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Patients at Risk, n Mos
Atezo + CP/ET 201 190 178 158 147 98 58 48 41 32 29 26 21 15 12 11 3 3 2 2 1 1
Placebo + CP/ET 202 193 184 167 147 80 44 30 25 23 16 15 9 9 6 5 3 3
 IMpower133: OS (Coprimary Endpoint)
100 Atezolizumab Placebo
+ CP/ET + CP/ET
(n = 201) (n = 202)
80 OS events, n (%) 104 (51.7) 134 (66.3)
12-mo OS Median OS, mos 12.3 10.3
(95% CI) (10.8-15.9) (9.3-11.3)
51.7% HR (95% CI) 0.70 (0.54-0.91)
60 P value .0069
OS (%)

40
Atezolizumab
38.2%
20 + CP/ET
Placebo

0
+ Censored + CP/ET

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Patients at Risk, n Mos
Atezo + CP/ET 201 191 187 182 180 174 159 142 130 121 108 92 74 58 46 33 21 11 5 3 2 1
Placebo + CP/ET 202 194 189 186 183 171 160 146 131 114 96 81 59 36 27 21 13 8 3 3 2 2
 IMpower133: OS by Subgroup
Median OS, Mos
Subgroup Atezolizumab + CP/ET Placebo + CP/ET
HR (95% CI)

Male (n = 261) 12.3 10.9 0.74 (0.54-1.02)

Female (n = 142) 12.5 9.5 0.65 (0.42-1.00)

< 65 yrs (n = 217) 12.1 11.5 0.92 (0.64-1.32)

≥ 65 yrs (n = 186) 12.5 9.6 0.53 (0.36-0.77)

ECOG PS 0 (n = 140) 16.6 12.4 0.79 (0.49-1.27)

ECOG PS 1 (n = 263) 11.4 9.3 0.68 (0.50-0.93)

Brain metastases (n = 35) 8.5 9.7 1.07 (0.47-2.43)

No brain metastases (n = 368) 12.6 10.4 0.68 (0.52-0.89)

Liver metastases (n = 149) 9.3 7.8 0.81 (0.55-1.20)

No liver metastases (n = 254) 16.8 11.2 0.64 (0.45-0.90)

bTMB < 10 mut/Mb (n = 139) 11.8 9.2 0.70 (0.45-1.07)

bTMB ≥ 10 mut/Mb (n = 212) 14.6 11.2 0.68 (0.47-0.97)

bTMB < 16 mut/Mb (n = 271) 12.5 9.9 0.71 (0.52-0.98)

bTMB ≥ 16 mut/Mb (n = 80) 17.8 11.9 0.63 (0.35-1.15)

ITT (N = 403) 12.3 10.3 0.70 (0.54-0.91)

0.1 1.0 2.5

Favors Atezolizumab Favors Placebo
IMpower133: Adverse Events
Atezolizumab + CP/ET Placebo + CP/ET
Events, n (%) (n = 198) (n = 196)
≥ 1 AE 198 (100) 189 (96.4)
Grade 3/4 AEs  133 (67.2) 125 (63.8) 
Treatment-related AEs 188 (94.9) 181 (92.3)
Serious AEs 74 (37.4) 68 (34.7)
Immune-related AEs 79 (39.9) 48 (24.5)
AEs leading to withdrawal from any study medication 22 (11.1) 6 (3.1)
 Atezolizumab or placebo 21 (10.6) 5 (2.6)
 Carboplatin 5 (2.5) 1 (0.5)
 Etoposide 8 (4.0) 2 (1.0)
Treatment-related deaths  3 (1.5)  3 (1.5)
 Median duration of treatment with atezolizumab: 4.7 mos (range: 0-21)
 Median no. of doses received: atezolizumab, 7 (range: 1-30); carboplatin, 4; etoposide, 12 (chemotherapy
doses the same for both treatment groups)
CASPIAN: Study Design
 Randomized, open-label, multicenter phase III study
Stratified by planned carboplatin vs cisplatin
Durvalumab + Tremelimumab + EP*
Durvalumab
Q3W x 4 cycles
Treatment-naive, extensive- Q4W
(n = 268)
stage SCLC, WHO PS 0/1,
measurable disease per Durvalumab + EP*
Durvalumab
RECIST v1.1, life expectancy Q3W x 4 cycles Until PD
Q4W
≥ 12 wks, asymptomatic or (n = 268)
treated and stable brain EP*
metastases Q3W x 4-6 cycles† Optional PCI†
(N = 805) (n = 269)
*Etoposide 80-100 mg/m2 with either carboplatin AUC 5-6 or cisplatin 75-80 mg/m2,
durvalumab 1500 mg, tremelimumab 75 mg.
 Primary endpoint: OS †
Per investigator discretion, additional 2 cycles of EP (6 cycles total) and PCI.

 Secondary endpoints: PFS and ORR (investigator-assessed per RECIST v1.1), safety and
tolerability, PROs
CASPIAN: OS for Durvalumab + EP vs EP
Durvalumab + EP EP
1.0 (n = 268) (n = 269)
Events, n (%) 210 (78.4) 231 (85.9)
0.8 Median OS, mos (95% CI) 12.9 (11.3-14.7) 10.5 (9.3-11.2)
HR (95% CI) 0.75 (0.62-0.91; P = .0032)
Probability of OS

0.6 52.8%

0.4
32.0%
39.3% 22.2%
0.2
24.8%
14.4%
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Patients at
Risk, n Mos
D + EP 268 244 214 177 140 109 85 66 41 21 8 2 0
EP 269 243 212 156 104 82 64 48 24 8 0 0 0
CASPIAN: Subgroup OS Analysis for
Durvalumab + EP vs EP
HR (95% CI)
All patients (n = 537) 0.75 (0.62-0.91)
Planned platinum agent Carboplatin (n = 402) 0.79 (0.63-0.98)
Cisplatin (n = 135) 0.67 (0.46-0.97)
Age < 65 yrs (n = 324) 0.72 (0.56-0.91)
≥ 65 yrs (n = 213) 0.84 (0.62-1.12)
Sex Male (n = 374) 0.79 (0.63-0.99)
Female (n = 163) 0.65 (0.45-0.93)
Performance status 0 (n = 189) 0.77 (0.56-1.06)
1 (n = 348) 0.76 (0.60-0.96)
Smoker (n = 500) 0.75 (0.62-0.91)
Smoking status 0.83 (0.41-1.71)
Nonsmoker (n = 37)
Brian/CNS metastases Yes (n = 55) 0.79 (0.44-1.41)
No (n = 482) 0.76 (0.62-0.92)
Liver metastases* Yes (n = 212) 0.87 (0.66-1.16)
No (n = 325) 0.68 (0.53-0.88)
AJCC disease stage at diagnosis Stage III (n = 52) 0.83 (0.44-1.54)
Stage IV (n = 485) 0.75 (0.62-0.92)
Race Asian (n = 78) 0.86 (0.52-1.40)
Non-Asian (n = 458) 0.75 (0.61-0.92)
Region Asia (n = 76) 0.87 (0.53-1.43)
Europe (n = 405) 0.74 (0.60-0.92)
North and South America (n = 56) 0.77 (0.42-1.43)
0.5 1 2
*Post hoc analysis; all other subgroups were prespecified.
Favors D + EP Favors EP
 CASPIAN: PFS for Durvalumab + EP vs EP
D + EP
(n = 268)
EP
(n = 269)
Landmark D + EP EP
PFS, % (n = 268) (n = 269)
Events, n (%) 234 (87.3) 236 (87.7)
1.0 6 mos 45.4 45.8
Median PFS,
5.1 (4.7-6.2) 5.4 (4.8-6.2)
mos (95% CI)
12 mos 17.9 5.3
Probability of PFS

0.8
HR (95% CI) 0.80 (0.66-0.96)
0.6 18 mos 13.9 3.4
24 mos 11.0 2.9
0.4
17.9% 11.0%
0.2 2.9%
5.3%
0  PFS not formally tested for statistical
Patients at
0 3 6 9 12 15 18 21 24 27 30 33 significance
Mos
Risk, n
D + EP 268 220 119 55 45 40 35 24 18 8 5 0
 56.8% in control arm received
EP 269 195 110 33 12 9 7 7 6 1 0 0 6 cycles of EP
CASPIAN: OS for Durvalumab + Tremelimumab + EP
vs EP
1.0 Durvalumab + Tremelimumab + EP EP
(n = 268) (n = 269)
Events, n (%) 207 (77.2) 231 (85.9)
0.8
Median OS, mos (95% CI) 10.4 (9.6-12.0) 10.5 (9.3-11.2)
Probability of OS

HR (95% CI) 0.82 (0.68-1.00); P = .0451*

0.6
43.8% *P ≤ .0418 required for statistical significance.
0.4
30.7%
39.3% 23.4%
0.2
24.8%
14.4%
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Patients at
Risk, n
Mos
D + T + EP 268 238 200 156 114 92 80 67 47 30 11 1 0
EP 269 243 212 156 104 82 64 48 24 8 0 0 0
CASPIAN: OS in All Arms
1.0
D+T+EP
D+EP
0.8 EP
Probability of OS

0.6

32.0%
0.4 30.7% 23.4%
22.2%
0.2
24.8%
14.4%
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Mos
Patient at Risk, n
D+T+EP 268 238 200 156 114 92 80 67 47 30 11 1 0
D+EP 268 244 214 177 140 109 85 66 41 21 8 2 0
EP 269 243 212 156 104 82 64 48 24 8 0 0 0
Median follow-up in censored patients: 25.1 mos (range: 0.1-33.7).
CASPIAN: Safety
Durvalumab + Tremelimumab + EP Durvalumab + EP EP
AEs, n (%)
(n = 266) (n = 265) (n = 266)
Any grade, all-cause AEs 246 (99.2) 260 (98.1) 258 (97.0)
 Grade 3/4 AEs 187 (70.3) 165 (62.3) 167 (62.8)
 Serious AEs 121 (45.5) 85 (32.1) 97 (36.5)
AEs leading to d/c 57 (21.4) 27 (10.2) 25 (9.4)
Immune-mediated AEs 96 (36.1) 53 (20.0) 7 (2.6)
AEs leading to death 27 (10.2) 13 (4.9) 15 (5.6)
 Treatment related 12 (4.5) 6 (2.3) 2 (0.8)
KEYNOTE-604: Study Design
 Multicenter, double-blind, randomized phase III trial
Stratified by platinum (cisplatin vs carboplatin),
ECOG PS (0 vs 1), LDH (≤ ULN vs > ULN)
Pembrolizumab 200 mg Day 1 +
Pembrolizumab 200 mg Day 1
Patients with stage IV SCLC, no Etoposide 100 mg/m2 Days 1-2 +
for ≤ 31 Q3W cycles +
previous systemic therapy, Platinum CT† Day 1 x 4 Q3W cycles
optional PCI‡
ECOG PS 0/1 with adequate (n = 228)
organ function, life expectancy
≥ 3 mos, no unstable brain Placebo (normal saline) Day 1 +
metastases* Placebo (normal saline) Day 1
Etoposide 100 mg/m2 Days 1-2 +
(N = 453) for ≤ 31 Q3W cycles +
Platinum CT† Day 1 x 4 Q3W cycles
optional PCI‡
(n = 225)
*
Patients required to have sample available for biomarker assessment. †Carboplatin AUC 5 or cisplatin 75 mg/m2 on Day 1. ‡Patients with CR or PR
after cycle 4 were eligible for ≤ 25 Gy of PCI in 10 fractions at investigator’s discretion.

 Primary endpoints: PFS per RECIST v1.1 by BICR (IA2 superiority threshold: 1-sided P = .0048),
OS (FA superiority threshold: 1-sided P = .0128)
 Secondary endpoints: ORR and DoR per RECIST v1.1 by BICR, safety
 KEYNOTE-604: PFS in ITT Population
Second Interim Analysis Final Analysis
Median PFS, Median PFS,
Mos(95%
Median PFS, Mos (95%CI)
CI) Mos (95% CI)
Pembro + EP
Pembro-EP 4.5 (4.3-5.4)
4.5 (4.3-5.4) Pembro + EP 4.8 (4.3-5.4)
Placebo + EP
Placebo-EP 4.3 (4.2-4.4)
4.3 (4.2-4.4) Placebo + EP 4.3 (4.2-4.5)
100 HR: 0.75 (95% CI: 0.61-0.91); P = .0023 100
HR: 0.73 (95% CI: 0.60-0.88)
80 6-mo rate 80
34.1%

PFS (%)
60 60
PFS (%)

23.8% 12-mo rate 12-mo rate

13.6% 15.9% 18-mo rate
40 3.1% 40 5.0% 10.8%
20 20 2.1%

0 0
Patients at
0 3 6 9 12 15 18 21 24 27 30 33 Patients at
0 3 6 9 12 15 18 21 24 27 30 33
Risk, n Mos Risk, n Mos
Pembro + EP 228 181 71 31 15 5 1 0 Pembro + EP 228 182 76 42 32 26 15 10 1 1 0 0
Placebo + EP 225 187 50 14 3 1 1 0 Placebo + EP 225 189 56 23 11 4 3 1 1 1 0 0
 KEYNOTE-604: OS in ITT and As-Treated Populations at
Final Analysis
ITT Median OS, As Treated Median OS,
Mos (95% CI) Mos (95% CI)
Pembro + EP 10.8 (9.2-12.9) Pembro + EP 10.8 (9.7-12.9)
Placebo + EP 9.7 (8.6-10.7) Placebo + EP 9.7 (8.6-10.7)
HR 0.80 (95% CI: 0.64-0.98), P = .0164 HR 0.78 (95% CI: 0.63-0.97), P = .0124
100 100
12-mo rate 12-mo rate
80 80 46.0%
45.1%
60 39.9%
60 39.6%

OS (%)
OS (%)

24-mo rate 24-mo rate

22.5% 23.0%
40 40 11.3%
11.2%
20 20
0 0
Patients at
0 3 6 9 12 15 18 21 24 27 30 33 Patients at
0 3 6 9 12 15 18 21 24 27 30 33
Risk, n Mos Risk, n Mos
Pembro + EP 223 198 174 132 102 87 60 31 15 3 1 0 Pembro + EP 223 198 174 132 102 87 60 31 15 3 1 0
Placebo + EP 223 211 169 122 89 63 44 19 8 3 0 0 Placebo + EP 223 211 169 122 89 63 44 19 8 3 0 0
KEYNOTE-604: PFS and OS by Subgroup at Final Analysis
(ITT) PFS OS
Events/Participants HR (95% CI) Events/Participants HR (95% CI)
Overall 416/453 0.73 (0.60-0.88) Overall 357/453 0.80 (0.64-0.98)
Age Age
< 65 yrs 197/216 0.71 (0.54-0.95) < 65 yrs 168/216 0.83 (0.61-1.12)
≥ 65 yrs 219/237 0.72 (0.55-0.94) ≥ 65 yrs 189/237 0.78 (0.59-1.05)
Sex Sex
Male 272/294 0.66 (0.52-0.84) Male 237/294 0.76 (0.59-0.98)
Female 144/159 0.76 (0.54-1.06) Female 120/159 0.88 (0.61-1.26)
ECOG PS ECOG PS
0 102/116 0.63 (0.43-0.94) 0 84/116 0.68 (0.44-1.05)
1 314/337 0.75 (0.60-0.94) 1 273/337 0.86 (0.68-1.09)
Region of enrollment Region of enrollment
East Asia 77/84 0.60 (0.37-0.95) East Asia 64/84 0.72 (0.44-1.19)
Non-East Asia 339/369 0.72 (0.58-0.90) Non-East Asia 293/369 0.84 (0.67-1.06)
Smoking status Smoking status
Current 260/281 0.70 (0.55-0.90) Current 227/281 0.86 (0.66-1.11)
Former 141/156 0.71 (0.50-0.99) Former 118/156 0.71 (0.49-1.02)
LDH concentration LDH concentration
≤ ULN 168/195 0.67 (0.49-0.90) ≤ ULN 137/195 0.72 (0.52-1.01)
> ULN 246/256 0.75 (0.59-0.95) > ULN 219/256 0.84 (0.65-1.10)
No. of metastatic sites No. of metastatic sites
<3 146/161 0.67 (0.48-0.93) <3 115/161 1.04 (0.72-1.50)
≥3 270/292 0.75 (0.59-0.95) ≥3 242/292 0.71 (0.55-0.92)
Baseline brain metastasis Baseline brain metastasis
Yes 50/55 1.06 (0.60-1.86) Yes 44/55 1.32 (0.72-2.42)
No 366/398 0.67 (0.54-0.83) No 313/398 0.75 (0.60-0.94)
Baseline liver metastasis Baseline liver metastasis
Yes 179/187 0.88 (0.65-1.18) Yes 163/187 0.75 (0.55-1.02)
No 237/266 0.62 (0.48-0.81) No 194/266 0.82 (0.62-1.08)
PD-L1 CPS PD-L1 CPS
<1 163/175 0.72 (0.53-0.98) <1 146/175 0.80 (0.58-1.11)
≥1 167/185 0.67 (0.49-0.92) ≥1 134/185 0.84 (0.60-1.18)
Platinum administered Platinum administered
Cisplatin 120/129 0.60 (0.42-0.87) Cisplatin 100/129 0.73 (0.49-1.08)
Carboplatin 290/317 0.75 (0.59-0.95) Carboplatin 251/317 0.83 (0.65-1.07)
0.25 0.5 1 2 4 0.25 0.5 1 2 4
Favors Pembro + EP Favors Placebo + EP Favors Pembro + EP Favors Placebo + EP
 KEYNOTE-604: All-Cause AEs in As-Treated Population at
Final Analysis
All AEs, % Pembrolizumab + EP (n = 223) Placebo + EP (n = 223)
Any grade 100 99.6
Grade 3/4 76.7 74.9 Grade
100 Grade 5* 6.3 5.4 1-2 3-5
Leading to d/c, any tx 14.8 6.3 Pembro + EP
80 Leading to d/c, all tx 4.0 3.6 Placebo + EP
Incidence (%)

60 57.0
53.4
48.4 46.6
43.0
40 38.6 37.7
33.6 30.9 29.6 27.4 27.4
24.7 26.5 26.5
22.0 22.4 20.6 21.1 18.8 19.7 20.2
20

0
nia ia s ea cia ti te o n ue bo- n ia he
a gh
e m u e ati tig m nia ope r u
p e Na lop pe o r Co
u tro An A Ap
n sti p Fa
T
r
h ope uk Dia
Ne
↓
Co cy
t Le
AEs With Incidence ≥ 20%
 KEYNOTE-604: Immune-Mediated AEs in As-Treated
Population at Final Analysis
All AEs, % Pembrolizumab + EP (n = 223) Placebo + EP (n = 223)
Any grade 24.7 10.3
Grade 3/4 7.2 1.3 Grade
100 Leading to death 0 0.4* 1-2 3-5
Leading to d/c, any tx 5.8 0.9 Pembro + EP
80 Leading to d/c, all tx 0.9 0 Placebo + EP
Incidence (%)

60 *Pneumonitis.
10.3

40 6.7

20 4.0
2.2 2.7 2.2 2.2 1.8
0.9 1.3 0.9 0.9 0.4 0.9 0.9
0 0 0
0
s m s m iti s kin ti s iti s n al cy iti s itis
id i idi n S ati l e
r ien s r
ro ro m o ere ons p Co
A d c phy
eph
thy rthy ne u Sev acti He s uffi ypo N
o P
Hy
p y pe Re In H
H AEs With Incidence ≥ 2 Participants
ECOG-ACRIN EA5161: Study Design
 Open-label, randomized phase II trial

Stratified by sex,
LDH ≤ ULN vs > ULN Nivolumab 360 mg IV +
Nivolumab PD or
Cisplatin or Carboplatin + Etoposide*
Q3W for 4 cycles 240 mg IV unacceptable
Patients with Q2W for ≤ 2 years
(n = 80) toxicity
measurable ES-SCLC;
ECOG PS 0/1; no prior
systemic therapy for
ES-SCLC Cisplatin or Carboplatin + Etoposide*
(N = 160) Q3W for 4 cycles Observation
(n = 80)

*Cisplatin or carboplatin by investigator’s choice; cisplatin 75 mg/m2 IV;

carboplatin AUC 5-6 IV; etoposide 100 mg/m2 IV.

 Primary endpoint: PFS

 Secondary endpoints: OS, ORR, safety
ECOG-ACRIN EA5161: PFS (Primary Endpoint)
1.0 Nivo + CE CE
(n = 75*) (n = 70*)
0.9 Events, n 61 65
0.8 Median PFS, mos 5.5 4.7
0.7 HR (95% CI): 0.68 (0.48-1.00); P = .047
Probability of PFS

0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Mos from Randomization
 ECOG-ACRIN EA5161: Survival (ITT)
PFS OS
Nivo + CE CE Nivo + CE CE
(n = 80) (n = 80) (n = 80) (n = 80)
Events, n 66 75 Deaths, n 50 57
Median PFS, mos 5.5 4.6
Median OS, mos 11.3 8.5
1.0 HR: 0.65 (95% CI: 0.46-0.91; P = .012) 1.0 HR: 0.67 (95% CI: 0.46-0.98; P = .038)
0.9 0.9
0.8 0.8
Probability of PFS

Probability of OS
0.7 0.7
0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Mos From Randomization Mos From Randomization
ECOG-ACRIN EA5161: Safety
Grade 3/4 Treatment-Related AEs, % Nivolumab + CE CE
Anemia 20 15
Neutropenia 47 50
Febrile neutropenia 5 4
Thrombocytopenia 18 16
Fatigue 12 7
Lung infection 9 1
Sepsis 1 --
Diarrhea 3 --
Enterocolitis -- 1
Worst degree 77 62

 1 patient in each arm died: NOS with nivolumab + CE, sepsis with CE
 Frontline Chemoimmunotherapy in SCLC:
Summary of Efficacy
Study Name
OS Study Name
PFS
IMpower133 IMpower133
CASPIAN – D CASPIAN – D
CASPIAN – D/T CASPIAN – D/T
KEYNOTE-604 KEYNOTE-604
EA5161 EA5161
OS PFS
0.5 0.75 1.5 0.5 0.75 1.5
0.76 1 0.76 1
Chemotherapy + ICI Chemotherapy Chemotherapy + ICI Chemotherapy
CASPIAN
IMpower133 KEYNOTE-604 EA5161
Durvalumab Durvalumab/Trem
Median PFS, mos 5.2 5.1 4.9 4.5 5.5
 HR (95% CI) 0.77 (0.62-0.96) 0.78 (0.65-0.94) 0.84 (0.70-1.01) 0.75 (0.61-0.91) 0.68 (0.48-1.0)
Median OS, mos 12.3 13 10.4 10.8 11.3
 HR (95% CI) 0.70 (0.54-0.91) 0.73(0.59-0.91) 0.82 (0.68-1.00) 0.80 (0.64-0.98) 0.67 (0.46-0.98)
12-mos OS, % 51.7 52.8 43.8 45.1 ~ 48
24-mos OS, % ~ 22 22.2 23.4 22.5 NR
First-line Combination ICI + Chemotherapy: Summary
 Addition of immune checkpoint inhibition to platinum/etoposide
chemotherapy significantly improves survival in advanced SCLC
‒ Atezolizumab (IMpower133) and durvalumab (CASPIAN) both approved
by the FDA
‒ Positive results with nivolumab and pembrolizumab in a phase II (EA5161)
and phase III (KEYNOTE-604) study, respectively, corroborate original
findings with atezolizumab and durvalumab
 Safety outcomes consistent with known safety profiles of each agent
 Immune checkpoint inhibition plus chemotherapy is new standard of
care for the first-line treatment of ES-SCLC
Select Ongoing Trials of Immunotherapy in SCLC
IO Monotherapy
IO + IO Combinations
IO + Chemotherapy
IO + Targeted Therapy
Regimen Clinical Trial
CRT → durvalumab*  ADRIATIC (1L consolidation, LS)‡
CRT → nivolumab + ipilimumab  STIMULI (1L consolidation, LS)§[
Durvalumab + tremelimumab  BALTIC (2L, ES)§
Pembrolizumab + MK-1308†  NCT03179436 (2L, ES)‡
Pembrolizumab + mRNA-4157  KEYNOTE-603 (2L, ES)‡[
SHR-1316¶ + carboplatin/etoposide  NCT03711305ǁ
Tislelizumab# + carbo/cis + etoposide  NCT04005716‡
Durvalumab + olaparib  MEDIOLA (2L, ES)

*ADRIATIC also investigating consolidation durvalumab + tremelimumab following CRT.

†
Anti–CTLA-4 monoclonal antibody. ¶Anti–PD-L1 monoclonal antibody. #Anti–PD-1 monoclonal antibody.
As of June 2020: ‡Recruiting. §Active but not recruiting. ǁNot yet recruiting.
Limited Efficacy of Pembrolizumab Maintenance
Therapy in ES-SCLC
 Single-arm phase II trial of maintenance pembrolizumab in patients with ES-SCLC
and response to or SD after platinum + etoposide chemotherapy (N = 45)

Patients with ES-SCLC and CR, 1.0

PR, or SD after 4-6 cycles of CT, mPFS: 1.4 mos (95% CI: 1.3-2.8)

Probability of PFS
ECOG PS 0/1; treated brain 0.8 12-mo PFS: 13% (95% CI: 5% to
metastases allowed 25%)
0.6
(N = 45)
0.4
0.2
0
Pembrolizumab 10 mg/kg IV Q2W 0 3 6 9 12 15
up to 24 mos if no PD Mo From First Day of Treatment
Patients at Risk, n
45 16 9 6 4 1
CheckMate 451: Nivolumab + Ipilimumab vs Nivolumab
vs Placebo as Maintenance Therapy for ES-SCLC
 Randomized, double-blind phase III study (minimum follow-up: 9 mos)
Nivolumab 1 mg/kg Q3W +
Ipilimumab 3 mg/kg Q3W Nivolumab
Patients with ES-SCLC and (max 4 doses) 240 mg Q2W
ongoing response of CR, (n = 279)
PR or SD following 4 cycles Until PD or
of first-line platinum-based Nivolumab 240 mg Q2W unacceptable
CT; ECOG PS 0/1; (n = 280) toxicity,
no symptomatic maximum
CNS metastases; 2 yrs
no autoimmune disease
(N = 834) Placebo
(n = 275)

 Primary endpoint: OS, nivolumab + ipilimumab vs placebo

 Secondary endpoints: PFS, nivolumab + ipilimumab vs placebo; PFS and OS, nivolumab vs placebo
 Exploratory endpoints: ORR; DoR; safety and tolerability
CheckMate 451: OS With Nivolumab + Ipilimumab vs
Placebo (Primary Endpoint)
100 Nivo + Ipi Placebo
(n = 279) (n = 275)
Events, n (%) 189 (68) 211 (77)
80 Median OS, mos 9.2 9.6
(95% CI) (8.2-10.2) (8.2-11.0)
HR (95% CI) 0.92 (0.8-1.1)
60 P value .37
OS (%)

40

20 1-yr OS: 41% Nivo + Ipi

1-yr OS: 40% Placebo

0
0 3 6 9 12 15 18 21 24 27 30 33
Patients at Risk, n Mos
Nivo + Ipi 279 230 177 130 100 65 43 30 14 8 3 0
Placebo 275 237 181 139 105 65 41 23 16 7 2 0
CheckMate 451: OS With Nivolumab vs Placebo
100 Nivolumab Placebo
(n = 280) (n = 275)
Events, n (%) 194 (69) 211 (77)
80 Median OS, mos 10.4 9.6
(95% CI) (9.5-12.1) (8.2-11.0)
HR (95% CI) 0.84 (0.7-1.0)
60
OS (%)

40

20 1-yr OS: 44% Nivolumab

1-yr OS: 40% Placebo
40
0
0 3 6 9 12 15 18 21 24 27 30 33

Patients at Risk, n
Mos
Nivolumab 280 242 195 155 114 81 49 37 21 6 2 0
Placebo 275 237 181 139 105 65 41 23 16 7 2 0
Immune Checkpoint Inhibitor Therapy in the
Clinical Management of ES-SCLC
 Overview of Key Studies of Immune Checkpoint Inhibitors
in SCLC
Mar Jun Jun Sep Oct Nov Apr May
2015 2015 2017 2018 2018 2019 2020 2020

NCT01450761 IMpower133 CASPIAN EA5161 KEYNOTE-604

1L

Ipilimumab Atezolizumab Durvalumab Nivolumab Pembrolizumab

+ CT (ES) + CT (ES) + CT (ES) + CT (ES) + CT (ES)
maintenance

NCT02359019 CheckMate 451

Pembrolizumab Nivolumab ±
1L

maintenance ipilimumab (ES)

CheckMate 032 CheckMate 331 KEYNOTE-158/028

≥ 2L

Nivolumab ± Nivolumab Pooled Analysis

ipilimumab (LS/ES) monotherapy Pembrolizumab
(LS/ES) monotherapy

Phase I/II Phase III

CheckMate 032: Nivolumab ± Ipilimumab in Relapsed
SCLC
 Multicohort phase I/II study of nivolumab (n = 245) or nivolumab + ipilimumab (n = 156)

SCLC cohort: PD-L1–unselected patients with PD after ≥ 1 prior platinum-based therapy

Nonrandomized Cohort, Sequential Enrollment Randomized Cohort (N = 242)*
3:2
*1-2 prior
therapies.
Nivo 3 mg/kg Nivo 1 mg/kg + Ipi 3 mg/kg
IV Q2W IV Q3W x 4 cycles Nivo 3 mg/kg Nivo 1 mg/kg + Ipi 3 mg/kg
(n = 98) (n = 61) IV Q2W IV Q3W x 4 cycles
(n = 147) (n = 95)
Until PD or Nivo 3 Q2W
unacceptable toxicity until PD or Until PD or Nivo 3 Q2W
unacceptable toxicity unacceptable toxicity until PD or
unacceptable toxicity
 Primary objective: ORR per RECIST v1.1  Prespecified exploratory objectives:
biomarker analysis, health status by EQ-5D
 Secondary objectives: OS, PFS, DoR, safety
CheckMate 032: ORR by Subgroup in Pooled Cohorts
Nivolumab Nivolumab + Ipilimumab
n ORR, % (95% CI) n ORR, % (95% CI)
Overall population 245 11 (8-16) 156 22 (16-29)
Line of therapy
 2nd line 137 12 (7-18) 98 19 (12-29)
 ≥ 3rd line 108 11 (6-19) 58 26 (15-39)
Platinum sensitivity
 Sensitive 133 13 (8-20) 85 26 (17-36)
 Resistant 110 10 (5-17) 65 15 (8-26)
 CheckMate 032: OS for Nonrandomized Cohort
100 Events, Median OS, Minimum
90 n Mos (95% CI) Follow-up, Mos
80 Nivolumab (n = 98) 82 4.1 (3.0-6.8) 19.6
70 Nivolumab + ipilimumab (n = 61) 47 7.8 (3.6-14.2) 20.2
60
OS (%)

50
1-yr OS: 40%
40
2-yr OS: 26%
30 1-yr OS: 27%
20
10 2-yr OS: 14%
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Mos
Patients at Risk, n
Nivolumab 98 56 39 35 26 21 17 12 7 7 6 4 4 0
Nivolumab + ipilimumab 61 43 33 28 24 21 19 16 14 7 3 1 1 0
 CheckMate 032: Final OS Results of Randomized Cohort
100 Median OS,
90 Mos (95% CI)
80 Nivolumab (n = 147) 5.7 (3.8-7.6)
70 Nivolumab + ipilimumab (n = 96) 4.7 (3.1-8.3)
60
OS (%)

50 30.5%
40 30.2% 21.9%
30 17.9%
23.7%
16.9%
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Patients at Risk, n
Nivolumab 147 91 70 53 39 32 28 25 22 18 13 8 4 0 0
Nivolumab + ipilimumab 96 60 43 33 28 23 21 19 15 14 11 9 3 1 0
 Checkmate 032: Third-line or Later Nivolumab
Monotherapy in Relapsed SCLC
PFS OS
≥ 3L Nivolumab 100 3L+ Nivolumab 100 3L+ Nivolumab
Response (n = 109) (n = 109)
(n = 109)
80 Median PFS, mos 1.4 80 Median OS, mos 5.6
ORR, % (95% CI) 11.9 (6.5-19.5) (95% CI) (1.3-1.6) (95% CI) (3.1-6.8)
 n 13 60 60

PFS (%)

OS (%)
Best overall response, n (%) 40 40 12-mo OS: 28.3%
 CR 1 (0.9) 6-mo PFS: 17.2% 18-mo OS: 20.0%
 PR 12 (11.0) 20 20
 SD 25 (22.9) 0 0
 PD 56 (51.4) 0 3 6 9 12151821242730333639424548 0 3 6 9 12151821242730333639424548
 Unable to determine 14 (12.8) Mos Mos
 Not reported 1 (0.9)
DoR
Median time to response, mos 1.6 100 3L+ Nivolumab
(n = 13)

Patients in Response (%)

Duration of response 80 Median DoR, mos 17.9
 ≥ 6 mos, n (%) 10 (76.9) (95% CI) (7.9-42.0)
 ≥ 12 mos, n (%) 8 (61.5) 60
 Median (95% CI), mos 17.9 (7.9-42.0)
40
 Range, mos 3.0-42.1
20

0
0 3 6 9 12151821242730333639424548
Mos
Accelerated FDA Approval of Nivolumab for Third-line
Treatment of SCLC
 In August 2018, nivolumab received accelerated FDA approval for
third-line treatment of patients with metastatic SCLC who progressed
following platinum-based chemotherapy and ≥ 1 line of therapy
‒ Based on data from CheckMate 032
 Overview of Key Studies of Immune Checkpoint Inhibitors
in SCLC
Mar Jun Jun Sep Oct Nov Apr May
2015 2015 2017 2018 2018 2019 2020 2020

NCT01450761 IMpower133 CASPIAN EA5161 KEYNOTE-604

1L

Ipilimumab Atezolizumab Durvalumab Nivolumab Pembrolizumab

+ CT (ES) + CT (ES) + CT (ES) + CT (ES) + CT (ES)
maintenance

NCT02359019 CheckMate 451

Pembrolizumab Nivolumab ±
1L

maintenance ipilimumab (ES)

CheckMate 032 CheckMate 331 KEYNOTE-158/028

≥ 2L

Nivolumab ± Nivolumab Pooled Analysis

ipilimumab (LS/ES) monotherapy Pembrolizumab
(LS/ES) monotherapy

Phase I/II Phase III

KEYNOTE-028: Pembrolizumab in Advanced SCLC
 Multicohort, open-label phase Ib trial
SCLC Cohort Treat for 2 yrs‡ or
Patients with unresectable, until PD,§
PD-L1–positive* SCLC and failure or intolerable toxicity, or
inability to receive standard therapy; Pembrolizumab study withdrawal
≥ 1 measurable lesion; 10 mg/kg IV Q2W †

ECOG PS 0-1; no prior IO; Survival follow-up

no autoimmune disease or interstitial *PD-L1 ≥ 1% by membrane expression in TC and associated IC or positive staining in stroma
lung disease by prototype IHC assay. †Response assessed every 8 wks for 6 mos, every 12 wks thereafter.
(N = 24; n = 19 for pooled analysis) ‡Patients may be eligible to resume pembrolizumab for up to 1 year if SD or better when
pembrolizumab discontinued. §Patients with PD who are clinically stable can remain on tx until
Confirmation of PD on second scan ≥ 4 wks later.

 Primary endpoint: ORR (per RECIST v1.1), safety

 Secondary endpoints: PFS, OS, duration of response
 Exploratory endpoints: efficacy in biomarker subgroups
KEYNOTE-158: Pembrolizumab for Advanced SCLC
 Multicohort phase II study

SCLC Cohort Treat for 2 yrs† or

Patients with unresectable or
metastatic SCLC with progression on
or intolerance to standard therapy;
ECOG PS 0 or 1;
evaluable tumor for biomarker assay;
no autoimmune disease or
noninfectious pneumonitis
(N = 107; 64 for pooled analysis)
until PD,‡
intolerable toxicity, or
Pembrolizumab study withdrawal
200 mg IV Q3W*
Survival follow-up
*Response assessed every 9 wks in Yr 1, every 12 wks thereafter.
†
Patients may be eligible to resume pembrolizumab for up to 1 year if SD or better when
pembrolizumab discontinued. ‡Patients with PD who are clinically stable can remain on tx until
Confirmation of PD on second scan ≥ 4 wks later.

 Primary endpoint: ORR by central review using RECIST v1.1 criteria

 Secondary endpoints: PFS, OS, DoR, safety
 KEYNOTE-028 and KEYNOTE-158: Pooled Analysis of
Patients Who Received ≥ 2 Prior Lines of Therapy
All Patients (N = 83)
ORR, n (%; 95% CI) 16 (19.3; 11.4-29.4)
Best overall response, n (%) OS
 CR/PR 2 (2)/14 (17)
 SD/PD 15 (18)/45 (54) 100
Median OS,
 Non-CR/non-PD 1 (1)
 No assessment 6 (7) 80 Mos (95% CI)
7.7 (5.2-10.1)
56.3%
60

OS (%)
100 DoR Median DoR,
40 34.3%
Mos (Range)
80 NR (4.1 to 35.8+)
20
60
DoR (%)

40 0
9 patients (61%) had an 0 3 6 9 12 15 18 21 24 27 30 33 36
20 estimated DoR ≥ 18 mos Mos
Patients
0 at Risk, n 83 64 46 38 28 25 23 20 15 4 2 2 2
0 3 6 9 12 15 18 21 24 27 30 33 36
Patients Mos
at Risk, n 16 16 15 13 10 9 9 8 3 2 2 1 0
Accelerated FDA Approval of Pembrolizumab for
Metastatic SCLC
 In June 2019, pembrolizumab received accelerated FDA approval for
patients with metastatic SCLC who progressed following platinum-
based chemotherapy and ≥ 1 line of therapy
‒ Based on data from KEYNOTE-158 and KEYNOTE-028
 Overview of Key Studies of Immune Checkpoint Inhibitors
in SCLC
Mar Jun Jun Sep Oct Nov Apr May
2015 2015 2017 2018 2018 2019 2020 2020

NCT01450761 IMpower133 CASPIAN EA5161 KEYNOTE-604

1L

Ipilimumab Atezolizumab Durvalumab Nivolumab Pembrolizumab

+ CT (ES) + CT (ES) + CT (ES) + CT (ES) + CT (ES)
maintenance

NCT02359019 CheckMate 451

Pembrolizumab Nivolumab ±
1L

maintenance ipilimumab (ES)

CheckMate 032 CheckMate 331 KEYNOTE-158/028

≥ 2L

Nivolumab ± Nivolumab Pooled Analysis

ipilimumab (LS/ES) monotherapy Pembrolizumab
(LS/ES) monotherapy

Phase I/II Phase III

CheckMate 331: Second-line Nivolumab in Patients With
Relapsed SCLC
 Randomized, open-label phase III trial (database lock: September 28, 2018)
‒ Median follow-up: nivolumab, 7.0 mos; CT, 7.6 mos
‒ Minimum follow-up for OS: 15.8 mos

Patients with SCLC and recurrence or PD

Nivolumab
after ≥ 4 cycles of first-line platinum CT
(n = 284)
or CRT; ECOG PS 0 or 1; no symptomatic
CNS metastases; no earlier therapy with
anti–CTLA-4, anti-CD37, or anti–PD-L1 Topotecan or
or anti–PD-L2 agents Amrubicin
(N = 596) (n = 285)

 Primary endpoint: OS
 Secondary endpoints: PFS, ORR
CheckMate 331: OS With Nivolumab vs Chemotherapy
Nivolumab CT
(n = 284) (n = 285)
100 No. of events 225 245
Median OS, 7.5 8.4
mos (95% CI) (5.7-9.2) (7.0-10.0)
80 HR (95% CI) 0.86 (0.72-1.04)
6-mo OS: 60% P value .11
6-mo OS: 55% Piecewise HR (95% CI)
60 0-3 mos 1.46 (1.02-2.11)
OS (%)

12-mo OS: 37% > 3-6 mos 1.03 (0.72-1.49)

12-mo OS: 34% > 6-9 mos 0.83 (0.50-1.38)
40 > 9-12 mos 0.59 (0.35-1.00)
> 12 mos 0.49 (0.33-0.72)

20
Nivolumab
CT
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Patients at Risk, n Mos
Nivolumab 284 209 150 123 99 78 63 49 42 26 9 1 0
CT 285 221 161 128 90 62 41 30 22 11 2 0 0
Minimum follow-up: 15.8 mos; patients censored: 21% of patients in nivolumab arm, 14% of patients in chemotherapy arm.
 CheckMate 331: PFS With Nivolumab vs Chemotherapy
100 Nivolumab CT
(n = 284) (n = 285)
No. of events 258 235
80 Median PFS, 1.5 3.8
mos (95% CI) (1.4-1.5) (3.0-4.2)
HR (95% CI) 1.41 (1.18-1.69)
60
PFS (%)

40 6-mo PFS: 27%

6-mo PFS: 20%
12-mo PFS: 11%
20 12-mo PFS: 10%
Nivolumab
CT
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Patients at Risk, n Mos
Nivolumab 284 74 50 37 27 21 17 15 11 8 2 1 0
CT 285 136 62 34 22 14 13 11 6 2 1 0 0
Is There a Role for IO After First-line Chemo/IO?
Is There a Role for IO After First-line Chemo/IO?
 Both nivolumab and pembrolizumab monotherapies have been
approved by FDA for third-line and beyond treatment of SCLC; however,
these were studied in patients who had not yet received ICI therapy
 ICI monotherapy is not recommended for those patients who
progressed after chemo/IO
 There is no clear long-term benefit to adding ipilimumab to nivolumab
in patients with previously treated SCLC
 Despite some hints at possible biomarkers, none has shown consistent
predictive potential in patients with SCLC and none is routinely used in
clinical practice
Lurbinectedin (PM01183): A Novel Anticancer Drug
 Synthetic, marine-derived tetrahydroisoquinoline alkaloid
‒ Analogue of DNA-damaging agent trabectedin
 Mechanism of action
‒ Blocks activated transcription
‒ Produces DNA double-strand breaks, generating apoptosis
‒ Modulates tumor microenvironment via inhibition of tumor-associated
macrophages
 3 Clinical Trials of Lurbinectedin in SCLC
Trial Phase Patient Population Study Arm(s)
Lurbinectedin + Ib: dose Selected diseases, Cohort A: lurbinectedin 3-5 mg FD D1 + doxorubicin 50 mg/m2 D1
doxorubicin[1,2] escalation, including SCLC; Q3W → lurbinectedin 7 mg FD after doxorubicin cumulative dose of
expansion at ≤ 3 prior lines of CT 450 mg/m2 reached
RD for advanced disease Expansion: RD lurbinectedin 2 mg/m2 + doxorubicin 50 mg/m2 Q3W
Cohort B: lurbinectedin 2 mg/m2 D1 + doxorubicin 40 mg/m2 D1
Q3W → lurbinectedin 4 mg/m2 after doxorubicin cumulative dose of
450 mg/m2 reached
Lurbinectedin + I: dose Selected diseases, Escalation: lurbinectedin D1 Q3W + paclitaxel weekly for 18 wks →
paclitaxel[3,4] escalation, including SCLC; lurbinectedin alone
expansion at ≤ 3 prior lines of CT Expansion: RD lurbinectedin 2.2 mg/m2 D1 + paclitaxel 80 mg/m2 D1,
RD for advanced disease 8 Q3W
Lurbinectedin II: exploratory Selected diseases, Lurbinectedin 3.2 mg/m2, 1-hr IV infusion, Q3W
monotherapy[5,6] basket trial w/ including SCLC;
ORR as primary ≤ 2† prior lines of CT
objective* for advanced disease

*If 1 response in first 15 patients, accrual to continue to 100 evaluable patients. †For SCLC, ≤ 1 previous line of CT.
 Efficacy of Lurbinectedin Monotherapy in SCLC
Plt
sensitive
or CTFI,
resistant? mos
R 2.9 SD Ongoing
S 5.1 PR PD
S 3.5 PR PD
R 1.6 SD PD
S 5.1 PR PD
S 6.2 PR Investigator decision
S 3.7 PR PD Best Response
S 4.6 SD PD
R
S
2.4
4.0 PR
PR
PD
PD CR
S 7.6
R 0.0 SD
PR PD
Ongoing PR
S 6.2 PR Ongoing
R
R
2.3
0.0
PR PD SD
PR Ongoing
R
S
0.9
3.8 SD
SD
PD
TRAE PD
S 3.7 SD PD
S 4.3 PR Ongoing
S
S
7.9
6.4
SD
SD
PD
PD
S Sensitive
R
S
1.2
3.3
SD
SD
PD
PD R Resistant
R 0.6 PR Ongoing
S 7.1
2.3
SD PD UK Unknown
R PD Death
R 0.1 SD Investigator decision
R 2.1 PD PD
S 4.0 PD PD
UK SD Investigator decision Change in tumor burden from BL:
R 2.5 PD PD
R 1.2 PD PD 26% of patients with increase,
S 4.4 PD PD
R 1.7 PD PD 74% with decrease
R 0.4 PD Death
R 0.7 PD

0 1 2 3 4 5 6 7 8 9 10 11 12
PFS (Mos)
Phase II Update: Second-line Lurbinectedin
Monotherapy in Patients With Relapsed Advanced SCLC
 Confirmed ORR of 35.2% with second-line All Platinum Platinum
lurbinectedin surpassed ≥ 30% statistical Outcome [1]
Patients Sensitive† Resistant‡
(N = 105) (n = 60) (n = 45)
cut off for a positive trial[1]
ORR, % 35.2* 45.0* 22.2*
‒ Follow-up: 17.1 mos (IQR: 6.5-25.3) DCR, % 68.6 81.7 51.1
Median DoR, mos 5.3 6.2 4.7
 Outcomes with second-line lurbinectedin
Median PFS, mos 3.5 4.6 2.6
numerically higher than historical  6-mo PFS, % 32.9 43.5 18.8
outcomes with second-line topotecan[1,2] Median OS, mos 9.3 11.9 5.0
 12-mo OS, % 34.2 48.3 15.9
‒ Topotecan ORR: 5%-24%, mOS: 6-8 mos[3]

 Results from phase III ATLANTIS trial of

*All confirmed PRs. †CTFI ≥ 90 days. ‡CTFI < 90 days.
second-line lurbinectedin + doxorubicin vs
investigator’s choice of topotecan or CAV
awaited[4]
 Safety of Lurbinectedin Monotherapy in SCLC
Patients (N = 105) Patients (N = 105)
Laboratory TRAE,
Abnormality,* Grade 1/2 Grade 3 Grade 4 n (%) Grade 1/2 Grade 3 Grade 4
Hematological, n (%) Fatigue 54 (51) 7 (7) 0
 Anemia 91 (87) 9 (9) 0 Nausea 34 (32) 0 0
 Leukopenia 53 (50) 20 (19) 10 (10) Decreased
 Neutropenia 27 (26) 22 (21) 26 (25) 22 (21) 0 0
appetite
 Thrombocytopenia 39 (37) 3 (3) 4 (4) Vomiting 19 (18) 0 0
Biochemical, n/N (%) Diarrhea 13 (14) 1 (1) 0
 Creatanine 86/104 (83) 0 0 Febrile
 ALT 69/103 (67) 5/103 (5) 0 0 2 (2) 3 (3)
neutropenia
 γ-Gutamyl transferase 52/103 (50) 13/103 (13) 2/103 (2)
Pneumonia 0 2 (2) 0
 AST 44/103 (43) 2/103 (2) 0
Skin ulcer 0 1 (1) 0
 Alkaline phosphatase 31/103 (30) 3/103 (3) 0

*Regardless of relation to study drug.

Lurbinectedin Approval
 On June 15, 2020, the FDA approved lurbinectedin for treatment of adult patients with
metastatic SCLC whose disease progressed on or after platinum-based chemotherapy
‒ Administration/dose: 3.2 mg/m2 every 21 days
‒ Consider premedication with corticosteroids and serotonin antagonists
‒ Monitor blood counts prior to each administration; monitor LFTs prior to initiation
and periodically during treatment
‒ Management of AEs may require temporary interruption, dose reduction, or
discontinuation
 Approval based on ORR and DoR data from single-arm, multicohort, phase II
PM1183-B-005-14 trial