1. Developed in association with the European Thoracic Oncology Platform

2. Letter from Prof Rolf Stahel
Dear Colleagues It is my pleasure to present this ETOP slide set which has been designed to highlight and summarise key findings in thoracic cancers from the major congresses in This slide set specifically focuses on the ESMO 2019 Congress and is available in 4 languages – English, French, Chinese and Japanese. The area of clinical research in oncology is a challenging and ever changing environment. Within this environment we all value access to scientific data and research which helps to educate and inspire further advancements in our roles as scientists, clinicians and educators. I hope you find this review of the latest developments in thoracic cancers of benefit to you in your practice. If you would like to share your thoughts with us we would welcome your comments. Please send any correspondence to I would like to thank our ETOP members Drs Solange Peters and Martin Reck for their roles as Editors – for prioritising abstracts and reviewing slide content. The slide set you see before you would not be possible without their commitment and hard work. Finally, we are also very grateful to Lilly Oncology for their financial, administrative and logistical support in the realisation of this complex yet rewarding activity. Yours sincerely, Rolf Stahel President, ETOP Foundation Council

3. ETOP Medical Oncology Slide Deck Editors 2019
Focus: advanced NSCLC (not radically treatable stage III & stage IV) and related biomarker data
Dr Solange Peters
Multidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland
Focus: early and locally advanced NSCLC (stage I–III) and related biomarker data plus other malignancies
Dr Martin Reck
Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany

4. Contents
Screening and biomarkers
Early stage and locally advanced NSCLC – Stages I, II and III
Advanced NSCLC – Not radically treatable stage III and stage IV
First line
Later lines
Other malignancies
SCLC, mesothelioma and thymic epithelial tumors

5. Screening and biomarkers

6. LBA17: Harmonization study of tumour mutational burden determination in non-small-cell lung cancer (NSCLC) – Garrido-Martin EM, et al
Study objective
To evaluate the performance of two gene panel assays for the detection of TMB, and investigate the correlation of calculated TMBs with PD-L1 expression in NSCLC
Methods
Tumour samples (n=100) were collected from patients with early stage NSCLC from 22 hospitals in Spain
TMB was assessed using two NGS panels (TSO500a and TMLb) and compared with the standard reference method (F1CDxc)
TMB was calculated as the total number of mutations (synonymous and non- synonymous) per exonic Mb
aSNVs and indels; bSNVs; cSNVs, indels, CNAs, select rearrangements
Garrido-Martin EM, et al. Ann Oncol 2019;30(suppl):Abstr LBA17

7. LBA17: Harmonization study of tumour mutational burden determination in non-small-cell lung cancer (NSCLC) – Garrido-Martin EM, et al
Key results
TMB values for 96 early stage NSCLC tumours
Total TMB (F1CDx)
Total TMB (TSO500 H12O)
100 80 60 40 20
R2= N=96
Total TMB (F1CDx)
Total TMB (TML HMS)
100 80 60 40 20
R2= N=96
Total TMB (TSO500 H12O)
Total TMB (TML HMS)
100 80 60 40 20
R2= N=96
F1CDx
Total TMB (muts/Mb)
100 80 60 40 20
N=96
TML
TSO500
Garrido-Martin EM, et al. Ann Oncol 2019;30(suppl):Abstr LBA17

8. LBA17: Harmonization study of tumour mutational burden determination in non-small-cell lung cancer (NSCLC) – Garrido-Martin EM, et al
Key results (cont.)
In tumours with PD-L1 <1% there was a high correlation of TMB values between the reference F1CDx panel and the TSO500 and TML panels (TSO500, R2=0.9120; TML, R2=0.8768; n=55)
Conclusions
In NSCLC tumour samples, the detection of TMB values performed through TSO500 and TML panels was comparable with that obtained with the standard F1CDx
F1DCx
TSO500
TML
Average of total TMB, muts/Mb 14 13
Median of total TMB, muts/Mb 10 9
Range of total TMB, muts/Mb
0–74
1–84
0–60
Total TMB ≥10 muts/Mb, % 47
42.2
46.1
Total TMB ≥13 muts/Mb, %
32.6
28.8
35.5
Total TMB ≥16 muts/Mb, %
25.9
19.2
22.1
Total TMB ≥20 muts/Mb, %
16.3
14.4
15.4
Garrido-Martin EM, et al. Ann Oncol 2019;30(suppl):Abstr LBA17

9. Early stage and locally advanced NSCLC – Stages I, II and III

10. 1459PD: Efficacy of durvalumab in patients with Stage III NSCLC who experience pneumonitis (PACIFIC) – Vansteenkiste JF, et al
Study objective
To evaluate the impact of pneumonitis on the efficacy of durvalumab in patients with stage III NSCLC in the PACIFIC study
Durvalumab 10 mg/kg q2w for up to 12 months
(n=476)
Key patient inclusion criteria
Stage III, locally advanced, unresectable NSCLC
Not progressed following platinum-based cCRT (≥2 cycles)
WHO PS 0–1
(n=713)
R 2:1
Stratification
Age, sex, smoking history
Placebo q2w for up to 12 months
(n=237)
Co-primary endpoints
PFS (BICR by RECIST v1.1), OS
Secondary endpoints
ORR (BICR), DoR (BICR), TTDM (BICR), PFS2, PROs, safety
Vansteenkiste JF, et al. Ann Oncol 2019;30(suppl):Abstr 1459PD

11. 1459PD: Efficacy of durvalumab in patients with Stage III NSCLC who experience pneumonitis (PACIFIC) – Vansteenkiste JF, et al
Key results
In the multivariate analysis adjusted for the time-dependant occurrence of pneumonitis, the OS, PFS and TTDM were consistent with the ITT population
No. of events/no. of patients (%)
HR (95%CI)a for durvalumab vs. placebo
Durvalumab
Placebo
Adjusted for the time-depended occurrence of pneumonitis
ITT population OS
Model 1
Model 2
183/476 (38.4)
116/237 (48.9)
0.70 (0.55, 0.88) 0.65 (0.51, 0.83)
0.68 (0.53, 0.87) -
PFS
243/476 (51.1)
173/237 (73.0)
0.54 (0.45, 0.66) 0.52 (0.42, 0.64)
0.51 (0.41, 0.63) -
TTDM
182/476 (38.2)
126/237 (53.2)
0.57 (0.45, 0.71) 0.53 (0.41, 0.67)
0.53 (0.41, 0.68) -
aCox-proportional hazards model adjusted for time-depended occurrence of pneumonitis using two sets of covariates: model 1 (age, sex, smoking history) and model 2 (model 1 factors plus stage, histology, best response to prior therapy, WHO PS, region, race)
Vansteenkiste JF, et al. Ann Oncol 2019;30(suppl):Abstr 1459PD

12. 1459PD: Efficacy of durvalumab in patients with Stage III NSCLC who experience pneumonitis (PACIFIC) – Vansteenkiste JF, et al
Key results (cont.)
Conclusions
In patients with unresectable, stage III NSCLC, improvements in OS, PFS and TTDM appear to be maintained with durvalumab vs. placebo, irrespective of on- study pneumonitis status
There was a similar incidence of grade 3–4 AEs and deaths observed in the durvalumab compared with placebo arm; however, SAEs, discontinuations and irAEs were more common in patients with pneumonitis
AEs by on-study pneumonitis status
Pneumonitis present
Pneumonitis absent
Durvalumab (n=161)
Placebo (n=58)
Durvalumab (n=314)
Placebo (n=176)
Any grade, all causality AEs, n (%)
Grade 3–4
Outcome of death
Leading to discontinuation
161 (100)
49 (30.4)
9 (5.6) 41 (25.5)
58 (100) 12 (20.7) 7 (12.1) 11 (19.0)
299 (95.2) 106 (33.8) 12 (3.8) 32 (10.2)
164 (93.2) 54 (30.7) 8 (4.5) 12 (6.8)
SAEs, n (%)
63 (39.1)
15 (25.9)
75 (23.9)
39 (22.2)
irAEs, n (%)
68 (42.2)
17 (29.3)
48 (15.3)
2 (1.1)
Vansteenkiste JF, et al. Ann Oncol 2019;30(suppl):Abstr 1459PD

13. Advanced NSCLC Not radically treatable stage III and stage IV
First line

14. LBA4_PR: Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis – Peters S, et al
Study objective
To evaluate the final OS endpoint of nivolumab + low-dose ipilimumab as a 1L treatment for patients with advanced NSCLC and PDL ≥1% in CheckMate 227
Nivolumab 3 mg/kg q2w +
ipilimumab 1 mg/kg q6w (n=187)
PD/ toxicity/ up to 2 years
PD-L1 exp. <1% (n=550) R
1:1:1
Nivolumab 360 mg q3w +
histology-based chemotherapy (n=177)
Key patient inclusion criteria
Stage IV or recurrent NSCLC
No prior systemic therapy
No known sensitising EGFR/ALK alterations
ECOG PS 0–1
Histology-based chemotherapy (n=186)
Nivolumab 3 mg/kg q2w +
ipilimumab 1 mg/kg q6w (n=396)
PD-L1 exp. ≥1% (n=1189) R
1:1:1
Nivolumab 240 mg q2w (n=396)
Stratification
Tumour histology (NSQ vs. SQ)
Histology-based chemotherapy (n=397)
Primary endpoints
OS in PD-L1 ≥1% population
PFS in high TMB (≥10 mut/Mb) population
Secondary endpoints
OS and PFS in patients with PD-L1 expression <1%, OS in patients with PD-L1 ≥50%
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr LBA4_PR

15. LBA4_PR: Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis – Peters S, et al
Key results
OS: PD-L1 ≥1%
OS: PD-L1 <1%
Nivo + Ipi (n=396)
Nivo (n=396)
CT (n=397)
mOS, months
17.1
15.7
14.9
HR (vs. CT)a CI
, 0.96b
, 1.04c
Nivo + Ipi (n=187)
Nivo + CT (n=177)
CT (n=186)
mOS, months
17.2
15.2
12.2
HR (vs. CT) CI
, 0.78c
, 1.02b
OS, %
100 80 60 40 3 6 9 12 15 33 36 45 18 21 24 27 30 39 42
OS, %
100 80 60 40 3 6 9 12 15 33 36 45 18 21 24 27 30 39 42
40%
36%
33%
40%
35%
23%
63%
57%
56%
60%
59%
51% 20
Nivo + Ipi
Nivo CT 20
Nivo + Ipi
Nivo + CT CT
No. at risk
Time, months
Time, months
Nivo
+Ipi
396
341
295
264
244
212 9 1
190
153
145 91 41
129
165
Nivo
+Ipi
187
165
142
120
110
100 8 2 87 73 69 34 19 59 80
Nivo
396
330
299
265
220
201 10 2
176
139
129 70 36
115
153
Nivo +CT
177
159
139
119
102 88 1 78 60 48 23 9 40 67 CT
397
358
306
250
218
190 6 1
166
126
112 57 22 93
141 CT
397
358
306
250
218
190 6 1
166
126
112 57 22 93
141
aHR 0.90 (95%CI 0.76, 1.07) for Nivo + Ipi vs. Nivo; b97.72%CI; c95%CI
From NEJM, Hellmann MD, et al, Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer, doi: /NEJMoa Copyright © (2019) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr LBA4_PR

16. LBA4_PR: Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis – Peters S, et al
Key results (cont.)
PD-L1 TPS ≥1%
Nivolumab + ipilimumab (n=396)
Chemotherapy (n=397)
Nivolumab (n=396)
Median PFS, months
5.1
5.6
4.2
HR (95%CI) vs. chemo
0.82 (0.69, 0.97)
0.99 (0.84, 1.17)
ORR, n (%)
142 (35.9)
119 (30.0)
109 (27.5)
Median DoR, months (95%CI)
23.2 (15.2, 32.2)
6.2 (5.6, 7.4)
15.5 (12.7, 23.5)
PD-L1 TPS <1%
Nivolumab + ipilimumab (n=187)
Chemotherapy (n=177)
Nivolumab + chemotherapy (n=186)
51 (27.3)
67 (37.9)
43 (23.1)
18.0 (12.4, 28.6)
4.8 (3.7, 5.8)
8.3 (5.9, 9.4)
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr LBA4_PR

17. LBA4_PR: Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis – Peters S, et al
Key results (cont.)
Median OS, months
Nivo + Ipi (n=583)
Chemo (n=583) HR
HR (95%CI)
Randomised groups
Stratified
PD-L1
All randomised (N=1166)
PD-L1 <1% (n=373)
PD-L1 ≥1% (n=793)
17.1
17.2
13.9
12.2
14.9
0.73
0.62
0.79a
Additional exploratory subgroups analysesb,c
Unstratified
PD-L1 1–49% (n=393)
PD-L1 ≥50% (n=397)
15.1
21.2
14.0
0.94
0.70
TMBd (mut/Mb)
low <10 (n=380)
high ≥10 (n=299)
16.2
23.0
12.6
16.4
0.75
0.68
0.25
0.5 1 2
aStratified HR 0.90 (97.72%CI 0.76, 1.07) for Nivo + Ipi vs. Nivo; bpatients not stratified by TMB or PD-L1, analyses therefore may be impacted by imbalances and should be interpreted with caution; cnot controlled by randomisation; dunstratified HR for Nivo + Ipi vs. chemo in TMB evaluable and non-evaluable patients was 0.74 (95%CI 0.61, 0.88) and 0.74 (95%CI 0.60, 0.92), respectively
From NEJM, Hellmann MD, et al, Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer, doi: /NEJMoa Copyright © (2019) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr LBA4_PR

18. Improvement of OS was observed independent of PD-L1 expression
LBA4_PR: Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis – Peters S, et al
Key results (cont.)
Conclusions
In patients with advanced NSCLC and PD-L1 ≥1, the combination of nivolumab + ipilimumab presented with a highly manageable safety profile, and showed significant improvement in OS vs. chemotherapy
Improvement of OS was observed independent of PD-L1 expression
TRAEs in all patients, %
Nivo + Ipi (n=576)
Chemotherapy (n=570)
Nivolumab (n=391)
Any grade
Grade 3–4
Any TRAEs 77 33 82 36 66 19
TRAEs leading to discontinuation 18 12 9 5 7
Most frequent TRAEs (≥15%)
Diarrhoea
Rash
Fatigue
Decreased appetite
Nausea
Anaemia
Constipation
Neutropenia
<1
<
<1 10
<1
<1 1 <1 0 <1 <1 0 0
Treatment-related deaths 1
<1
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr LBA4_PR

19. Comparator EGFR TKI* Gefitinib 250 mg/day or Erlotinib 150 mg/day
LBA5_PR: Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis – Ramalingam SS, et al
Study objective
To evaluate the final OS with osimertinib as a 1L treatment for patients with EGFRm advanced NSCLC in the FLAURA trial
Key patient inclusion criteria
Locally advanced or metastatic NSCLC
Ex19del/L858R
No prior EGFR TKI/systemic anti-cancer therapy
Stable CNS metastases allowed
WHO PS 0–1
(n=556)
Osimertinib 80 mg/day
(n=279) PD
Stratification
Mutation status (Ex19del/L858R)
Race (Asian/non-Asian) R
1:1
Comparator EGFR TKI* Gefitinib 250 mg/day or Erlotinib 150 mg/day
(n=277) PD
Primary endpoint
PFS (investigator-assessed RECIST v1.1)
Secondary endpoints
OS, ORR, DoR, DCR, depth of response, PROs, safety
*Crossover to osimertinib was permitted upon central confirmation of progression and T790M positivity
Ramalingam SS, et al. Ann Oncol 2019;30(suppl):Abstr LBA5_PR

20. LBA5_PR: Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis – Ramalingam SS, et al
Key results
Osimertinib
Comparator EGFR TKI
PFS OS
Probability of PFS
1.0
0.8
0.6
0.4
0.2 3 6 9 12 15 18 21 24 27
Time from randomisation, months
Probability of OS
1.0
0.8
0.6
0.4
0.2 3 12 18 24 33 39 45 51 6 9 15 21 27 30 36 42 48 54
89%
74%
83%
59%
54%
44%
Time from randomisation, months
No.at risk
Osimertinib
279
262
233
210
178
139 71 28 4
204
279
276
245
217
193
153
123 50 2
270
254
236
180
166
138 86 17
277
239
197
152
107 78
Comparator EGFR-TKI 37 10 2
277
263
219
182
148
121
101 40 2
252
239
205
165
138
131
110 72 17
Osimertinib
Comparator EGFR TKI
Median PFS, months (95%CI)
18.9 (15.2, 21.4)
10.2 (9.6, 11.1)
HR (95%CI)
0.46 (0.37, 0.57)
p-value
0.001
Osimertinib
Comparator EGFR TKI
Median OS, months (95%CI)
38.6 (34.5, 41.8)
31.8 (26.6, 36.0)
HR (95%CI)
0.799 (0.641, 0.997)
p-value
0.0462
Ramalingam SS, et al. Ann Oncol 2019;30(suppl):Abstr LBA5_PR

21. Favours comparator EGFR TKI
LBA5_PR: Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis – Ramalingam SS, et al
Key results (cont.)
OS across subgroups
Subgroup
Favours osimertinib
Favours comparator EGFR TKI
HR 95%CI
Overall (n=556)
Log-rank (primary)
Unadjusted Cox PH
Sex
Male (n=206)
Female (n=350)
Age at screening
<65 years (n=298)
≥65 years (n=258)
Race
Asian (n=357)
Non-Asian (n=209)
Smoking history
Yes (n=199)
No (n=357)
CNS metastases at trial entry
Yes (n=116)
No (n=440)
WHO PS
0 (n=228)
1 (n=327)
EGFR mutation at randomisation
Ex19del (n=349)
L858R (n=207)
EGFR mutation by ctDNA
Positive (n=359)
Negative (n=124)
, 0.996
, 0.983
, 1.135
, 1.037
, 0.969
, 1.215
, 1.139
, 0.772
, 1.002
, 1.118
, 1.298
, 1.014
, 1.366
, 0.913
, 0.904
, 1.404
, 0.995
, 1.359
HR for death (95%CI)
0.1
1.0
10.0
2.0
0.2
0.3
0.4
0.6
0.8
Ramalingam SS, et al. Ann Oncol 2019;30(suppl):Abstr LBA5_PR

22. LBA5_PR: Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis – Ramalingam SS, et al
Key results (cont.)
In the comparator EGFR TKI arm, 85/180 (47%) patients who received subsequent treatment crossed over to osimertinib
Grade ≥3 AEs that were possibly treatment-related occurred in 51/279 (18%) patients receiving osimertinib and 79/277 (29%) patients receiving a comparator EGFR TKI, with diarrhoea (3%) and anorexia (3%) being the most frequently reported grade ≥3 AEs in the osimertinib arm
Conclusions
In patients with EGFRm advanced NSCLC, osimertinib showed a statistically significant improvement in OS vs. comparator EGFR TKI as 1L treatment, with a favourable toxicity profile
No difference in OS was seen in Asian patients and patients with Exon 21 mutation – these findings require further research
Time to first subsequent therapy or death
Events
Median, months (95%CI)
HR (95%CI)
p-value
Osimertinib
194
25.5 (22.0, 29.1)
(0.393, 0.581)
0.0001
Comparator EGFR TKI
242
13.7 (12.3, 15.7)
Ramalingam SS, et al. Ann Oncol 2019;30(suppl):Abstr LBA5_PR

23. LBA78: IMpower110: Interim overall survival (OS) analysis of a Phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC – Spigel D, et al
Study objective
To evaluate the efficacy and safety of atezolizumab monotherapy as 1L treatment in patients with PD-L1 positive NSCLC
Atezolizumab mg q3w
Atezolizumab mg q3w
Key patient inclusion criteria
Squamous or non-squamous stage IV NSCLC
Chemotherapy-naïve
PD-L1 ≥1
(n=572)
PD/ loss of clinical benefit
Stratification
Sex, ECOG PS, PD-L1 expression, histology R
1:1
NSQ: Cisplatin/carboplatin + pemetrexeda SQ: Cisplatin/carboplatin + gemcitabineb
NSQ: pemetrexed SQ: BSC PD
Primary endpoint
OS (tested in a hierarchical manner according to PD-L1 expression status)
Secondary endpoints
PFS (investigator assessed), ORR, DoR
aCisplatin 75 mg/m2 or carboplatin AUC6 + pemetrexed 500 mg/m2 q3w; bcisplatin 75 mg/m2 + gemcitabine 1250 mg/m2 or carboplatin AUC5 + gemcitabine 1000 mg/m2 q3w
Spigel D, et al. Ann Oncol 2019;30(suppl):Abstr LBA78

24. LBA78: IMpower110: Interim overall survival (OS) analysis of a Phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC – Spigel D, et al
Key results
OS: TC3 or IC3 WT
TC3 or IC3 WT*
Atezolizumab (n=107)
Chemotherapy (n =98)
6-mo OS, % (95%CI)
76.3 (68.2, 84.4)
70.1 (60.8, 79.4)
12-mo OS, % (95%CI)
64.9 (55.4, 74.4)
50.6 (40.0, 61.3)
mOS, months (95%CI)
20.2 (16.5, NE)
13.1 (7.4, 16.5)
HR (95%CI)
0.59 (0.40, 0.89)
p-value
0.0106
Time, months
OS, %
100 80 60 40 20
No. at risk 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 36 38
Median follow-up, 15.7 mo (range 0–35) 34
Atezolizumab
107 94 85 80 66 61 48 40 34 25 18 16 11 7 6 5 2
Chemotherapy 98 89 75 65 50 40 33 28 19 12 9 7 6 4 3 3 3 1
*PD-L1 expression evaluated with VENTANA SP142 IHC assay. TC3: TC≥ 50% PD-L1+ and IC3: IC ≥10% PD-L1+
Spigel D, et al. Ann Oncol 2019;30(suppl):Abstr LBA78

25. LBA78: IMpower110: Interim overall survival (OS) analysis of a Phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC – Spigel D, et al
Key results (cont.)
PFS: TC3 or IC3 WT
TC3 or IC3 WT*
Atezolizumab (n=107)
Chemotherapy (n=98)
6-mo PFS, % (95%CI)
59.8 (50.4, 69.2)
38.3 (28.5, 48.1)
12-mo PFS, % (95%CI)
36.9 (27.0, 46.9)
21.6 (12.6, 30.6)
mPFS, months (95%CI)
8.1 (6.8, 11.0)
5 (4.2, 5.7)
HR (95%CI)
0.63 (0.45, 0.88)
Time, months
PFS, %
100 80 60 40 20
No. at risk 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 36 38 34
Atezolizumab
107 82 72 60 45 31 25 21 16 13 10 8 4 4 4 2
Chemotherapy 98 74 62 36 26 16 13 8 5 5 1 1 1
*PD-L1 expression evaluated with VENTANA SP142 IHC assay. TC3: TC≥ 50% PD-L1+ and IC3: IC ≥10% PD-L1+
Spigel D, et al. Ann Oncol 2019;30(suppl):Abstr LBA78

26. LBA78: IMpower110: Interim overall survival (OS) analysis of a Phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC – Spigel D, et al
Key results (cont.)
ORR and DoR: TC3 or IC3 WT
Chemotherapy
Atezolizumab
Median DoR, months (range)
NE (1.8*–29.3*)
6.7 (2.6–23.9*)
Response, % 60 50 40 30 20 10
38.3%
28.6% PR CR
*Censored
Spigel D, et al. Ann Oncol 2019;30(suppl):Abstr LBA78

27. In patients with TC2/3 or IC 2/3, significant OS benefit was not met
LBA78: IMpower110: Interim overall survival (OS) analysis of a Phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC – Spigel D, et al
Key results (cont.)
Conclusions
In patients with TC3 or IC3 WT NSCLC, there were significant improvements in OS, PFS, ORR and DoR with 1L atezolizumab monotherapy compared with chemotherapy and there were no new safety signals
In patients with TC2/3 or IC 2/3, significant OS benefit was not met
n, %
Atezolizumab (n=286)
Chemotherapy (n=263)
Pembrolizumab
Gemcitabine
Carboplatin
Cisplatin
Median treatment duration, months (mix-max)
5.3 (0–33)
3.5 (0–20)
2.6 (0–5)
2.3 (0–5)
2.1 (0–5)
Any cause AEs
258 (90.2)
249 (94.7)
Grade 3–4 AEs
91 (31.8)
141 (53.6)
SAEs
81 (28.3)
75 (28.5)
Grade 5 AEs
11 (3.8)
11 (4.2)
AEs leading to treatment withdrawal
18 (6.3)
43 (16.3)
Atezolizumab AE of special interest
Grade 3–4 Atezolizumab AE of special interest
115 (40.2) 19 (6.6)
44 (16.7) 4 (1.5)
AEs requiring use of corticosteroids
22 (7.7)
1 (0.4)
Spigel D, et al. Ann Oncol 2019;30(suppl):Abstr LBA78

28. LBA81_PR: Phase II/III Blood First Assay Screening Trial (BFAST) in patients (pts) with treatment-naïve NSCLC: initial results from the ALK+ cohort – Gadgeel SM, et al
Study objective
To prospectively evaluate the clinical utility of predictive blood-based biomarkers in patients with treatment-naïve advanced or metastatic NSCLC treated with targeted therapy or immunotherapy
ALK+
Alectinib 600 mg BID (n=87)
PD/ toxicity/ withdrawal/ death
Key patient inclusion criteria
Unresectable, stage IIIb/IV NSCLC
Treatment-naïve
Measureable disease
Blood sample positive for BFAST alteration
ECOG PS 0–2
RET+
Alectinib 900/1200/750 mg BID PD
bTMB+
Atezolizumab 1200 mg or chemotherapy
PD/ loss of clinical benefit
ROS1+
Entrectinib 600 mg BID PD
Primary endpoint
ORR (investigator assessed)
Secondary endpoints
ORR (BICR), DoR and PFS (investigator and BICR), safety
Gadgeel SM, et al. Ann Oncol 2019;30(suppl):Abstr LBA81_PR

29. No baseline CNS mets (n=52)
LBA71_PR: Phase II/III Blood First Assay Screening Trial (BFAST) in patients (pts) with treatment-naïve NSCLC: initial results from the ALK+ cohort – Gadgeel SM, et al
Key results
6-month DoR was 90.4% (95%CI 83.7, 97.2) among confirmed responders
2-month PFS was 78.38% (95%CI 69.07, 87.69)
ORR
ORR: with or without CNS mets
Response, %
INV
BICR
84.1, 96.7
78.5, 93.5
95%CI
Median duration of follow-up: months
Response, %
Baseline
CNS
No baseline
(n=52)
(n=35)
Response, n (%) [95%CI]
INV (n=87)
BICR (n=87) CR
0 [0.00, 4.15]
11 (12.6) [6.48, 21.50] PR
76 (87.4) [78.50, 93.52]
69 (79.3) [69.29, 87.25] PD
1 (1.1) [0.03, 6.24]
Response*, n (%) [95%CI]
Baseline CNS mets (n=35)
No baseline CNS mets (n=52) CR
0 [0.00, 10.00]
0 [0.00, 6.85] PR
32 (91.4) [76.94, 98.20]
44 (84.6) [71.92, 93.12] PD
1 (2.9) [0.07, 14.92]
*Investigator assessed
Gadgeel SM, et al. Ann Oncol 2019;30(suppl):Abstr LBA81_PR

30. LBA81_PR: Phase II/III Blood First Assay Screening Trial (BFAST) in patients (pts) with treatment-naïve NSCLC: initial results from the ALK+ cohort – Gadgeel SM, et al
Key results (cont.)
Conclusions
This study assigned treatment through the results of blood-based NGS testing alone. In the cohort of patients with advanced or metastatic NSCLC identified as ALK+, treatment with alectinib resulted in an ORR of 87.4% and demonstrates the utility of blood-based NGS testing
AEs, n (%)
ALK+ cohort (n=87)
Total number of all-grade AEs
716
Patient with at least one AE
SAEs
Grade 3–4 AEs
Treatment-related SAEs
Fatal AEs
87 (100) 21 (24) 30 (35) 5 (6) 1 (1)
AEs leading to
Treatment discontinuation
Dose reduction
Dose interruption
6 (7) 7 (8) 27 (31)
Gadgeel SM, et al. Ann Oncol 2019;30(suppl):Abstr LBA81_PR

31. LBA82: Pembrolizumab (pembro) + chemotherapy (chemo) in metastatic squamous NSCLC: final analysis and progression after the next line of therapy (PFS2) in KEYNOTE-407 – Paz-Ares L, et al
Study objective
To update the final efficacy and PFS2 of pembrolizumab + chemotherapy in patients with metastatic squamous NSCLC in KEYNOTE-407
Pembrolizumab 200 mg q3w + carboplatin AUC6 q3w +
paclitaxel 200 mg/m2 q3w OR nab-paclitaxel 100 mg/m2 q1w (4 cycles) (n=278)
Pembrolizumab 200 mg q3w up to 31 cycles
Key patient inclusion criteria
Stage IV squamous NSCLC
Treatment naïve
No symptomatic brain metastases
ECOG PS 0–1
(n=559)
Stratification
Taxane (paclitaxel vs. nab-paclitaxel)
PD-L1 expression (TPS <1% vs. ≥1%)
Geographical region (East Asia vs. rest of world) R
1:1
Placebo q3w + carboplatin AUC6 q3w +
paclitaxel 200 mg/m2 q3w OR nab-paclitaxel 100 mg/m2 q1w (4 cycles) (n=281)
Placebo q3w up to 31 cycles*
Co-primary endpoints
PFS (BIRC), OS
Secondary endpoints
PFS2, ORR, DoR, safety
*Optional crossover to pembrolizumab (up to 35 cycles) permitted after PD
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA82

32. Pembrolizumab + CT (n=278)
LBA82: Pembrolizumab (pembro) + chemotherapy (chemo) in metastatic squamous NSCLC: final analysis and progression after the next line of therapy (PFS2) in KEYNOTE-407 – Paz-Ares L, et al
Key results
PFS2
Updated survival outcomes
Pembrolizumab + CT (n=278)
Placebo + CT (n=281)
Median OS, months (95%CI)
17.1 (14.4, 19.9)
11.6 (10.1, 13.7)
HR (95%CI)
0.71 (0.58, 0.88)
Median PFS, months (95%CI)
8.0 (6.3, 8.4)
5.1 (4.3, 6.0)
0.57 (0.47, 0.69)
ORR, %
62.6
38.4
Median DoR, months (range)
8.8 (1.3+ –28.4+)
4.9 (1.3+ –28.3+)
Median, months (95%CI) 13.8 (12.2, 15.9) 9.1 (8.2, 10.2)
HR 0.59 (95%CI 0.49, 0.72)
PFS2, %
No. at risk
Time, months
100 80 60 40 20
Pembrolizumab + CT
278
256
227
189
157
127 98 10 4 67 39
81.7% 3 6 9 12 15 18 21 24 27 30 33
69.5%
Placebo + CT
281
241
193
142 99 74 62 2 42
+No progressive disease before data cut-off date
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA82

33. Pembrolizumab + CT (n=278)
LBA82: Pembrolizumab (pembro) + chemotherapy (chemo) in metastatic squamous NSCLC: final analysis and progression after the next line of therapy (PFS2) in KEYNOTE-407 – Paz-Ares L, et al
Key results (cont.)
Conclusions
In patients with metastatic squamous NSCLC, the combination of pembrolizumab with chemotherapy as 1L treatment demonstrated consistent improved outcomes in terms of OS, PFS, ORR and PFS2, with a manageable safety profile
AEs, n (%)
Pembrolizumab + CT (n=278)
Placebo + CT (n=280)
Any AE
Grade 3–5
Leading to discontinuation
Any treatment
All treatments
Leading to death
Treatment-related
274 (99) 206 (74) 76 (27) 45 (16) 31 (11) 12 (4)
275 (98) 195 (70) 37 (13) 20 (7) 19 (7) 5 (2)
Immune-related AEs and infusion reaction
98 (35) 37 (13)
25 (9) 9 (3)
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA82

34. PD/toxicity/ loss of benefit
LBA83: Final efficacy results from B-F1RST, a prospective Phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC) – Socinski M, et al
Study objective
To evaluate the final efficacy of atezolizumab as a 1L treatment for patients with NSCLC
Key patient inclusion criteria
Stage IIIB/IVB locally advanced or metastatic NSCLC
Immunotherapy naïve
PD-L1 unselected
Blood samples provided
ECOG PS 0–1
(n=152)
Atezolizumab 1200 mg q3w
PD/toxicity/ loss of benefit
Co-primary endpoints
ORR (investigator assessed)
PFS (investigator assessed)
Secondary endpoints
DoR, OS, safety
Socinski M, et al. Ann Oncol 2019;30(suppl):Abstr LBA83

35. LBA83: Final efficacy results from B-F1RST, a prospective Phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC) – Socinski M, et al
Key results
mOS in bTMB <16 group was 13.4 months (95%CI 11.7, 18.0) and in bTMB ≥16 group was 23.9 months (95%CI 8.8, NE) with HR 0.66 (90%CI 0.40, 1.10)
ORR
PFS
bTMB subgroups
bTMB ≥16 (n=28)
bTMB <16 (n=91)
mPFS, months (95%CI)
5.0 (1.6, 10.8)
3.5 (2.6, 4.3)
HR (90%CI)
0.80 (0.54, 1.18)
p-value
0.35
bTMB high
bTMB Low
≥10 cut-off
≥16 cut-off
≥20 cut-off
p<0.0001
100
p<0.0001
47.7% 80
bTMB ≥16
bTMB <16 PR
35.7% CR
p=0.033 60
PFS, %
ORR, %
20.4% 40
17.1%
12.6% 20
7.1%
5.5%
6.0%
ITT
(n=152)
BEP
(n=119)
n=49
n=70
n=28
n=91
n=19
n=100 3 9 12 15 18 24 27 30 33
No. at risk
Time, months 28 27 18 15 14 12 11 9 7 5 4 3 2 1
≥16
<16 91 86 56 44 39 28 25 19 15 12 8 6 3 2
Socinski M, et al. Ann Oncol 2019;30(suppl):Abstr LBA83

36. No additional safety findings were observed
LBA83: Final efficacy results from B-F1RST, a prospective Phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC) – Socinski M, et al
Key results (cont.)
Conclusions
In patients with NSCLC receiving 1L atezolizumab monotherapy, bTMB ≥16 confirmed favourable clinical outcomes in terms of PFS and ORR
No additional safety findings were observed
AEs, n (%)
ITT population
All grade AEs, any cause
TRAEs
152 (100) 116 (76)
All grade SAEs, any cause
Treatment-related SAEs
81 (53) 22 (14)
Grade 3–4 AEs, any cause
Grade 3–4 TRAEs
86 (57) 30 (20)
Grade 5 AEs, any cause
Grade 5 TRAEs
10 (7) 1 (1)
AEs leading to treatment discontinuation
27 (18)
AEs of special interest (immune-related)
66 (43)
Socinski M, et al. Ann Oncol 2019;30(suppl):Abstr LBA83

37. Nivolumab 480 mg q4w up to 1 year
1457PD: Efficacy evaluation of concurrent nivolumab addition to a first-line, concurrent chemo-radiotherapy regimen in unresectable locally advanced NSCLC – Results from the European Thoracic Oncology Platform (ETOP 6-14) NICOLAS phase II trial – Peters S, et al
Study objective
To evaluate the efficacy of nivolumab combined with 1L concurrent chemoradiotherapy in patients with unresectable locally advanced NSCLC
Key patient inclusion criteria
Unresectable locally advanced stage IIIA/B NSCLC
Nodal status N2 or N3
ECOG PS 0–1
(n=79)
Platinum-based chemotherapy* + radiotherapy 66 GY/33 fractions for 3 cycles + 4 doses nivolumab 360 mg q3w
Nivolumab 480 mg q4w up to 1 year
Primary endpoints
Grade ≥3 pneumonitis-free rate, 1-year PFS rate
Secondary endpoints
Time to first grade ≥3 pneumonitis, ORR, OS, time-to-treatment failure, safety
*Cisplatin + vinorelbine/etoposide/pemetrexed
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr 1457PD

38. 1457PD: Efficacy evaluation of concurrent nivolumab addition to a first-line, concurrent chemo-radiotherapy regimen in unresectable locally advanced NSCLC – Results from the European Thoracic Oncology Platform (ETOP 6-14) NICOLAS phase II trial – Peters S, et al
Key results
PFS: Stage
PFS: Histology
Stage
PFS events, n (%)
12-mo PFS, % (95%CI)
Median, months (95%CI)
Log-rank p-value
IIIA
13 (46.4)
66.3 (45.2, 88.9)
27.4 (7.3, NE)
0.11
IIIB
33 (66.0)
50.0 (35.6, 62.8)
12.1 (8.9, 17.8)
Histology
PFS events, n (%)
12-mo PFS, % (95%CI)
Median, months (95%CI)
Log-rank p-value SQ
19 (67.9)
56.3 (35.9, 72.3)
13.5 (10.1, 22.0)
0.68
NSQ
26 (55.3)
54.5 (39.1, 67.5)
12.9 (7.2, NE)
Time, months
PFS, %
100 80 60 40 20 6 2 4 8 10 12 14 16 18 22 24 26
No. at risk 28 27 21 19 9 3
IIIA 50 46 41 38 34 30 25 17 13 11 7 1
IIIB
100 80 60
PFS, % 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26
Time, months 28 27 25 23 21 19 15 11 10 9 8 1 SQ 47 43 39 35 30 27 25 19 12 10 8 6 4 3
NSQ
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr 1457PD

39. 1457PD: Efficacy evaluation of concurrent nivolumab addition to a first-line, concurrent chemo-radiotherapy regimen in unresectable locally advanced NSCLC – Results from the European Thoracic Oncology Platform (ETOP 6-14) NICOLAS phase II trial – Peters S, et al
Key results (cont.)
Overall, pneumonitis was reported by 34 patients (7 grade 3, 1 grade 5), oesophagitis by 24 patients (5 grade 3) and dyspnoea by 27 patients (2 grade 3)
In total, 240 nivolumab TRAEs were reported; 26 grade 3, 5 grade 4 and 4 grade 5 (colitis, pulmonary fibrosis, autoimmune disorder, pneumonitis). Of these, 7% (17/240 TRAEs) led to permanent discontinuation
Conclusions
In patients with unresectable locally advanced NSCLC combining nivolumab with concurrent chemoradiation is feasible, without any unexpected safety signal
The PFS observed for combining nivolumab with concomitant definitive chemoradiation as 1L therapy compares favourably to other studies in the same patient population
Peters S, et al. Ann Oncol 2019;30(suppl):Abstr 1457PD

40. 1484PD: Final PFS, updated OS and safety data from the randomised, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC – Mok TSK, et al
Study objective
To evaluate the final efficacy and safety of alectinib as a 1L treatment for patients with ALK+ NSCLC in the ALEX study
Alectinib 600 mg BID
(n=152)
Key patient inclusion criteria
Stage IIIB/IV ALK+ NSCLC
Treatment naive
CNS metastases permitted if asymptomatic
ECOG PS 0–2
(n=303)
PD/ toxicity/ withdrawal
R 1:1
Stratification
ECOG PS, ethnicity, CNS metastases at baseline
Crizotinib 250 mg BID
(n=151)
PD/ toxicity/ withdrawal
Primary endpoint
PFS (investigator assessed)
Secondary endpoints
PFS (IRC), ORR, time to CNS progression, DoR, OS, safety
Mok TSK, et al. Ann Oncol 2019;30(suppl):Abstr 1484PD

41. PFS event-free rate: with CNS metastases
1484PD: Final PFS, updated OS and safety data from the randomised, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC – Mok TSK, et al
32.5
Alectinib 36 32 24 1
No. at risk
Crizotinib 17 3 NE
PFS event-free rate: with CNS metastases
PFS, %
Key results
PFS
Alectinib (n=152) Crizotinib (n=151)
100 80 60 40 20
HR 0.43 (95%CI 0.32, 0.58) p<0.0001
PFS, %
34.8
10.9
PFS event-free rate: without CNS metastases 6 12 18 24 30 36 42 48
57.2
Time, months
No. at risk
PFS, %
Alectinib
152
135
113
109 98 84 81 79 61 49 39 14 3 76 69 68 NE
Crizotinib
151
132
104 83 65 48 43 36 33 17 13 11 6 29 19
Alectinib 62 47 37 2
No. at risk
Crizotinib 48 30 16 NE
Mok TSK, et al. Ann Oncol 2019;30(suppl):Abstr 1484PD

42. 1484PD: Final PFS, updated OS and safety data from the randomised, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC – Mok TSK, et al
Key results (cont.)
Conclusions
In patients with ALK+ NSCLC, alectinib demonstrated consistent superior efficacy vs. crizotinib as 1L treatment, regardless of baseline CNS metastases and with a favourable safety profile
AEs, n, %
Alectinib (n=152)
Crizotinib (n=151)
All grade AEs
147 (97)
SAEs
54 (36)
48 (32)
Grade 3–5 AEs
74 (49)
83 (55)
Fatal AE
6 (4)
7 (5)
AEs leading to treatment discontinuation
21 (14)
22 (15)
AEs leading to dose reduction
29 (19)
30 (20)
AEs leading to dose interruption
38 (25)
39 (26)
Mok TSK, et al. Ann Oncol 2019;30(suppl):Abstr 1484PD

43. Advanced NSCLC Not radically treatable stage III and stage IV
Later lines

44. KEYNOTE-042 Pembrolizumab 200 mg q3w or platinum-based chemotherapy
LBA79: Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials – Herbst RS, et al
Study objective
To evaluate the association between tTMB levels and outcomes in the KEYNOTE-010 and KEYNOTE-042 trials
tTMB assessment by whole exome sequencing of tumour tissue
Outcomes (OS, PFS, ORR) association with tTMB assessed
KEYNOTE-010 Pembrolizumab 2 or 10 mg/kg q3w or docetaxel 75 mg/m2 q3w (n=1034)
Key patient inclusion criteria
Advanced NSCLC
PD-L1-positive
PD-L1 TPS ≥1%
≥1 DNA samples
KEYNOTE-042 Pembrolizumab 200 mg q3w or platinum-based chemotherapy
(n=1275)
aPre-specified cut-points of 175 mut/exome; assessed as continuous log10-transformed variable
Herbst RS, et al. Ann Oncol 2019;30(suppl):Abstr LBA79

45. AUROC of ORR for tTMB (95%CI) AUROC of ORR for tTMB (95%CI)
LBA79: Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials – Herbst RS, et al
Key results
Association of tTMB with efficacy
KEYNOTE-010
AUROC of ORR for tTMB (95%CI)
Pembrolizumab
0.61 (0.50, 0.71)
Chemotherapy
0.40 (0.21, 0.58)
KEYNOTE-042
AUROC of ORR for tTMB (95%CI)
Pembrolizumab
0.67 (0.61, 0.73)
Chemotherapy
0.57 (0.50, 0.63)
1–Specificity
Sensitivity
1.0
0.8
0.6
0.4
0.2
1–Specificity
Sensitivity
1.0
0.8
0.6
0.4
0.2
Nominal p-valuea
Pembrolizumab (n=164)
Chemotherapy (n=89) OS
0.006b
0.410c
PFS
0.001b
0.579c
ORR
0.009b
0.330c
Nominal p-valuea
Pembrolizumab (n=414)
Chemotherapy (n=379) OS
<0.001b
0.060c
PFS
0.174c
ORR
0.035c
aWald test; bone-sided; ctwo-sides; statistical significance determined at 0.05 level without multiplicity adjustment
Herbst RS, et al. Ann Oncol 2019;30(suppl):Abstr LBA79

46. LBA79: Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials – Herbst RS, et al
Key results (cont.)
There was no association between tTMB and PD-L1 in KEYNOTE-010 (pembrolizumab r=0.16; chemotherapy r=0.18) or KEYNOTE-042 (pembrolizumab r=0.05; chemotherapy r=0.04)
Conclusions
In previously treated or untreated patients with PD-L1+ NSCLC, high tTMB levels were associated with improved clinical outcomes in those receiving pembrolizumab monotherapy, suggesting a possible clinical use of tTMB as a predictive biomarker
Herbst RS, et al. Ann Oncol 2019;30(suppl):Abstr LBA79

47. Pembrolizumab 200 mg/kg q3w + carboplatin + pemetrexed 500 mg/m2 q3w
LBA80: Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407 – Paz-Ares L, et al
Study objective
To evaluate the association of tTMB with efficacy of pembrolizumab + platinum- based chemotherapy vs. platinum-based chemotherapy alone
tTMB assessment by whole exome sequencing of tumour tissue
Outcomes (OS, PFS, ORR) association with tTMB assessed
KEYNOTE-021 (Cohort C)
Pembrolizumab 2 or 10 mg/kg q3w + carboplatin + pemetrexed 500 mg/m2 q3w
(n=24)
Key patient inclusion criteria
Untreated stage IIIB/IV, squamous or non-squamous NSCLC
ALK or EGFR negative
ECOG PS 0–1
KEYNOTE-021 (Cohort G)
Pembrolizumab 200 mg/kg q3w + carboplatin + pemetrexed 500 mg/m2 q3w
(n=123)
KEYNOTE-189
Pembrolizumab 200 mg q3w or placebo + carboplatin/cisplatin + pemetrexed 500 mg/m2 q3w (n=616)
KEYNOTE-407
Pembrolizumab 200 mg q3w or placebo + carboplatin + paclitaxel/nab-paclitaxel q3w (n=559)
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA80

48. There was no association between tTMB and efficacy
LBA80: Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407 – Paz-Ares L, et al
Key results
There was no association between tTMB and efficacy
The ROC curve analysis for the association of tTMB with ORR suggested limited ability of tTMB to predict the treatment response, either with pembrolizumab + chemotherapy or chemotherapy alone, in all studies
Pembrolizumab + chemotherapy had OS, PFS and ORR benefit vs. chemotherapy in both tTMB-high (≥175 mt/exome) and tTMB-low (<175 mut/exome) subgroups
Nominal p-valuea
KEYNOTE-021 C and G
KEYNOTE-189
KEYNOTE-407
Pembrolizumab + CT (n=44)
CT alone (n=26)
Pembrolizumab + CT (n=207)
Placebo + CT (n=86)
Pembrolizumab + CT (n=143)
Placebo + CT (n=169)
ORR
0.180
0.279
0.072
0.434
0.393
0.086
PFS
0.187
0.409
0.075
0.055
0.052
0.560 OS
0.081
0.475
0.174
0.856
0.160
0.818
aP-values were values calculated using the Wald test and are one-sided for pembrolizumab + chemotherapy and two-sided for chemotherapy alone and placebo + chemotherapy
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA80

49. LBA80: Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407 – Paz-Ares L, et al
Conclusions
In patients with squamous and non-squamous NSCLC, no significant association between tTMB and efficacy was demonstrated for any treatment group
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA80

50. Without brain metastases
1482O: Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042 – Mansfield AS, et al
Study objective
To evaluate the efficacy and safety of pembrolizumab in patients with PD-L1- positive NSCLC and stable pretreated brain metastases at baseline in a post- hoc analysis of data pooled from KEYNOTE-001, -010, -024 and -042
Pembrolizumab* (n=199)
Key patient inclusion criteria
Advanced NSCLC
Previously treated or treatment naive
PD-L1 TPS ≥1%
Data pooled from KEYNOTE-001, -010, -024 and -042
(n=3170)
With brain metastases
(n=293)
Chemotherapy* (n=94)
Pembrolizumab* (n=1754)
Without brain metastases
(n=2877)
Chemotherapy* (n=1123)
*KEYNOTE-001: pembrolizumab 2 or 10 mg/kg q3w or 10mg/kg q2w; KEYNOTE-010: pembrolizumab 2 or 10 mg/kg q3w vs. docetaxel 75 mg/m2 q3w; KEYNOTE-024: pembrolizumab 200 mg q3w vs. platinum chemotherapy; KEYNOTE-042: pembrolizumab 200 mg
q3w vs. platinum chemotherapy
Mansfield AS, et al. Ann Oncol 2019;30(suppl):Abstr 1482O

51. Without brain metastases
1482O: Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042 – Mansfield AS, et al
Key results
With brain metastases
Without brain metastases
Pembrolizumab
Chemotherapy
PD-L1 TPS ≥50%, n
112 48
842
598
mOS, months (95%CI)
HR (95%CI)
19.7 (12.1, 31.4)
0.78 (0.71, 0.85)
9.7 (7.2, 19.4)
19.4 (17.0, 22.4)
0.66 (0.58, 0.76)
11.7 (10.1, 13.1)
PFS, months (95%CI)
4.1 (2.3, 10.6)
0.70 (0.47, 1.03)
4.6 (3.5, 8.4)
6.5 (6.1, 8.1)
0.69 (0.62, 0.78)
6.1 (5.8, 6.2)
ORR, n (%)
38 (33.9)
7 (14.6)
321 (38.1)
156 (26.1)
Median DoR, months (range)
NR (4.0+–41.7+)
7.6 (2.9+–28.6+)
33.9 (1.4+–49.3+)
8.2 (1.6+–30.4+)
DoR ≥12 months, n (%)
28 (91.7)
1 (25.0)
173 (74.0)
27 (38.1)
PD-L1 TPS ≥1%, n
199 94
1754
1123
13.4 (10.4, 18.0)
0.83 (0.62, 1.10)
10.3 (8.1, 13.3)
14.8 (13.4, 16.1)
11.3 (10.2, 12.0)
2.3 (2.1, 3.9)
0.96 (0.73, 1.25)
5.2 (4.2, 8.3)
4.3 (4.2, 5.1)
0.91 (0.84, 0.99)
6.1 (6.0, 6.3)
52 (26.1)
17 (18.1)
452 (25.8)
249 (22.2)
NR (3.3–46.2+)
8.3 (2.0+–28.6+)
30.4 (1.4+–49.3+)
8.1 (1.1+–30.4+)
36 (83.9)
3 (39.3)
245 (71.2)
39 (33.9)
Mansfield AS, et al. Ann Oncol 2019;30(suppl):Abstr 1482O

52. 1482O: Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042 – Mansfield AS, et al
Key results (cont.)
Conclusions
In patients with PD-L1+ NSCLC, the OS and PFS benefit of pembrolizumab was similar regardless of pretreated brain metastasis status at baseline and pembrolizumab improved clinical outcomes compared with chemotherapy alone in those with and without brain metastases
Pembrolizumab monotherapy showed a manageable safety profile both in patients with and without brain metastases and no new safety signals were identified
Pembrolizumab
Chemotherapy
With brain metastases (n=196)
Without brain metastases (n=1743)
With brain metastases (n=90)
Without brain metastases (n=1066)
Median treatment duration, months (range)
2.8 (0.03–39.6)
4.7 (0.03–75.9)
2.9 (0.03–29.5)
3.5 (0.03–34.8)
TRAEs, %
Grade 3–5
Led to death
Led to discontinuation
Affecting CNS
Immune-mediated AEs and infusion reactions, % 21 25 9 8
Mansfield AS, et al. Ann Oncol 2019;30(suppl):Abstr 1482O

53. 1483PD: Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407 – Powell SF, et al
Study objective
To evaluate the efficacy and safety of pembrolizumab + chemotherapy in patients with advanced/metastatic NSCLC and stable pretreated or asymptomatic brain metastases at baseline in a post-hoc analysis of data pooled from KEYNOTE- 021, -189 and -407
Pembrolizumab + Chemotherapy* (n=105)
With brain metastases
(n=171)
Key patient inclusion criteria
Advanced NSCLC
Treatment naive
Data pooled from KEYNOTE-021, -189 and -407
(n=1298)
Chemotherapy* (n=66)
Pembrolizumab + Chemotherapy* (n=643)
Without brain metastases
(n=1127)
Chemotherapy* (n=484)
*KEYNOTE-021: pembrolizumab 200 mg q3w + pemetrexed-carboplatin vs. pemetrexed-carboplatin; KEYNOTE-189: pembrolizumab 200 mg q3w + pemetrexed-platinum vs. placebo + pemetrexed-platinum; KEYNOTE-407: pembrolizumab 200 mg q3w + carboplatin-paclitaxel/nab-paclitaxel vs. placebo + carboplatin-paclitaxel/nab-paclitaxel
Powell SF, et al. Ann Oncol 2019;30(suppl):Abstr 1483PD

54. 1483PD: Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407 – Powell SF, et al
Key results
Patients with brain metastases OS
PFS
OS, %
No. at risk
Time, months
Pembro + CT
105 92 82 71 58 53 44 9 2 1 31 20
100 80 60 40
34.9%
62.9% 3 6 12 15 18 21 24 27 30 33 CT 66 52 37 28 19 14 8
Median, month (95%CI)
18.8 (13.8, 25.9)
7.6 (5.4, 10.9)
643
598
507
420
333
264
234 10
154 90
53.6%
70.2%
484
435
344
231
168
123 98 23 68
Median, month (95%CI) (19.8, 25.2)
13.5 (11.3, 15.8)
Events, %
HR (95%CI)
Pembro + CT
53.3
0.48 (0.32, 0.70) CT
74.2
PFS, %
No. at risk
Time, months
Pembro + CT
105 77 57 37 26 21 16 2 9 3
100 80 60 40 20
6.6%
29.9% 6 12 15 18 24 27 30 CT 66 35 7 4 1
Median, month (95%CI) 6.9 (5.7, 8.9)
4.1 (2.3, 4.6)
Events, %
HR (95%CI)
Pembro + CT
78.1
0.44 (0.31, 0.62) CT
93.9
Patients without brain metastases
PFS, %
No. at risk
Time, months
Pembro + CT
643
525
394
249
171
126 97 16 3 63 39
100 80 60 40 20
20.1%
39.2% 6 9 12 15 18 21 24 27 30 33 CT
484
340
193 96 59 37 5 13 8
Median, month (95%CI) 8.8 (8.1, 9.5)
5.3 (4.8, 6.1) OS
PFS
Events, %
HR (95%CI)
Pembro + CT
41.1
0.63 (0.53, 0.75) CT
51.7
Events, %
HR (95%CI)
Pembro + CT
62.5
0.55 (0.48, 0.63) CT
76.0
Powell SF, et al. Ann Oncol 2019;30(suppl):Abstr 1483PD

55. Safety profile was tolerable, regardless of brain metastases status
1483PD: Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407 – Powell SF, et al
Key results (cont.)
Conclusions
In patients with advanced squamous and non-squamous NSCLC, with or without pretreated or asymptomatic brain metastases, pembrolizumab combined with platinum-based chemotherapy improved outcomes vs. chemotherapy alone
Safety profile was tolerable, regardless of brain metastases status
Pembro + CT CT
With brain metastases (n=102)
Without brain metastases (n=640)
With brain metastases (n=64)
Without brain metastases (n=480)
Median treatment duration, months (range)
7.0 (0.03–29.1)
6.9 (0.03–30.4)
4.2 (0.03–18.5)
4.3 (0.03–30.7)
TRAEs, %
Grade 3–5
Led to death
Led to discontinuation
Affecting CNS
Immune-mediated AEs and infusion reactions, %
Grade 3–5, %
25.5
13.7
27.8
9.7
9.4
1.6
10.6
3.8
Powell SF, et al. Ann Oncol 2019;30(suppl):Abstr 1483PD

56. 1478O & 390O: Results of the ASCEND-7 phase II study – Chow LQ, et al & Barlesi F, et al
Study objective
To investigate the efficacy and safety of ceritinib in patients with ALK+ NSCLC and brain or leptomeningeal metastases
Arm 1: Prior brain radiotherapy and prior crizotinib (n=42)
Key patient inclusion criteria
NSCLC
ALK+ (FISH)
Active brain metastases either newly diagnosed or progressive + ≥1 extra-cranial measurable lesion
WHO PS 0–2
Arm 2: No prior brain radiotherapy and prior crizotinib (n=40)
Arm 3: Prior brain radiotherapy and no prior ALKi (n=12)
Ceritinib 750 mg/day
Arm 4: No prior brain radiotherapy and no prior ALKi (n=44)
Arm 5: Leptomeningeal carcinomatosis with or without active metastases (n=18)
Primary endpoint
ORR (whole body; RECIST v1.1)
Secondary endpoints
DCR, intra- and extra-cranial response, safety
Chow LQ, et al. Ann Oncol 2019;30(suppl):Abstr 1478O
Barlesi F, et al. Ann Oncol 2019;30(suppl):Abstr 390O

57. 1478O & 390O: Results of the ASCEND-7 phase II study – Chow LQ, et al & Barlesi F, et al
Key results
Whole body response, % (95%CI)
Arm 1 (n=42)
Arm 2 (n=40)
Arm 3 (n=12)
Arm 4 (n=44)
Arm 5 (n=18)
ORR
35.7 (21.6, 52.0)
30.0 (16.6, 46.5)
50.0 (21.1, 78.9)
59.1 (43.2, 73.7)
16.7 (3.6, 41.4)
DCR
66.7 (50.5, 80.4)
82.5 (67.2, 92.7)
66.7 (34.9, 90.1)
70.5 (54.8, 83.2)
66.7 (41.0, 86.7)
Intracranial response, % (95%CI)
Arm 1 (n=28)
Arm 2 (n=29)
Arm 3 (n=7)
Arm 4 (n=33)
39.3 (21.5, 59.4)
27.6 (12.7, 47.2)
28.6 (3.7, 71.0)
51.5 (33.5, 69.2)
5.6 (0.1, 27.3)
75.0 (55.1, 89.3)
82.8 (64.2, 94.2)
85.7 (42.1, 99.6)
75.8 (57.7, 88.9)
Extracranial response, % (95%CI)
31.0 (17.6, 47.1)
42.5 (27.0, 59.1)
41.7 (15.2, 72.3)
61.4 (45.5, 75.6).
22.2 (6.4, 47.6)
69.0 (52.9, 82.4)
92.5 (79.6, 98.4)
72.7 (57.2, 85.0)
72.2 (46.5, 90.3)
Chow LQ, et al. Ann Oncol 2019;30(suppl):Abstr 1478O
Barlesi F, et al. Ann Oncol 2019;30(suppl):Abstr 390O
ORR (CR + PR); DCR (CR + PR + SD)

58. No new safety signals were observed
1478O & 390O: Results of the ASCEND-7 phase II study – Chow LQ, et al & Barlesi F, et al
Key results (cont.)
Conclusions
In patients with ALK+ NSCLC and active brain or leptomeningeal metastases, ceritinib demonstrated whole body, intra- and extracranial activity, regardless of prior treatment
No new safety signals were observed
Arm 1 (n=42)
Arm 2 (n=40)
Arm 3 (n=12)
Arm 4 (n=44)
Arm 5 (n=18)
AEs, n (%)
All AEs
Grade 3–4
AEs suspected to be drug-related
Grade 3–4 AEs suspected to be drug-related
42 (100) 34 (81.0) 41 (97.6) 20 (47.6)
40 (100) 32 (80.0) 40 (100) 25 (62.5)
11 (91.7) 7 (58.3) 10 (83.3) 4 (33.3)
43 (97.7) 34 (77.3) 39 (88.6) 25 (56.8)
18 (100)
16 (88.9)
9 (50.0)
SAEs, n (%)
All SAEs
Grade 3–4 SAEs
SAEs suspected to be drug-related
Grade 3–4 SAEs suspected to be drug-related
28 (66.7) 21 (50.0) 4 (9.5) 3 (7.1)
17 (42.5) 10 (25.0) 3 (7.5) 2 (5.0)
4 (33.3) 4 (33.3) 2 (16.7) 1 (8.3)
15 (34.1) 12 (27.3) 3 (6.8) 3 (6.8)
11 (61.1)
1 (5.6)
AEs leading to discontinuation, n (%)
2 (4.8)
2 (5.0)
2 (16.7)
7 (15.9)
6 (33.3)
AEs requiring dose adjustments or interruption, n (%)
33 (78.6)
35 (87.5)
11 (91.7)
33 (75.0)
12 (66.7)
Chow LQ, et al. Ann Oncol 2019;30(suppl):Abstr 1478O
Barlesi F, et al. Ann Oncol 2019;30(suppl):Abstr 390O

59. SCLC, mesothelioma and thymic epithelial tumors
Other malignancies
SCLC, mesothelioma and thymic epithelial tumors

60. LBA89: PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN – Paz-Ares L, et al
Study objective
To evaluate the patterns of progression and PROs of durvalumab + platinum- etoposide in patients with extensive-stage SCLC
Durvalumab 1500 mg + etoposide-platinum* q3w up to 4 cycles
(n=268)
Durvalumab mg q4w PD
Key patient inclusion criteria
Extensive-stage SCLC
Treatment naïve
Asymptomatic or treated and stable brain metastases permitted
WHO PS 0–1
(n=805)
Etoposide-platinum* q3w up to 6 cycles
(n=269)
Optional PCI
R 1:1:1
Durvalumab 1500 mg + tremelimumab 75 mg + etoposide-platinum*
q3w up to 4 cycles
Durvalumab mg q4w PD
Stratification
Platinum agent (carboplatin vs. cisplatin)
Primary endpoint OS
Secondary endpoints
PFS, ORR, PROs, safety
*Etoposide 80–100 mg/m2 + carboplatin AUC5–6 or cisplatin 75–80 mg/m2
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA89

61. PD-L1 was evaluable* in 277 (51.6%) patients across both arms
LBA89: PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN – Paz-Ares L, et al
Key results
Median OS was 13.0 months (95%CI 11.5, 14.8) for durvalumab + EP and months (95%CI 9.3, 11.2) for EP alone (HR 0.73 [95%CI 0.591, 0.909])
PD-L1 was evaluable* in 277 (51.6%) patients across both arms
94.9% had TC PD-L1 <1% and 77.6% had IC PD-L1 <1%
No significant impact of PD-L1 expression was observed on OS, PFS or ORR
ITT (n=537)
PD-L1 evaluable (n=277)
IC <1 (n=215)
IC ≥1 (n=62)
TC <1 (n=263)
TC ≥1 (n=14)
HR (95%CI)
0.73 (0.591, 0.910)
0.65 (0.482, 0.864)
0.64 (0.462, 0.897)
0.69 (0.370, 1.283)
0.66 (0.491, 0.896)
0.46 (0.119, 1.793)
0.10
0.25
0.5
1.0
2.0
Favours durvalumab + EP
Favours EP
OS based on PD-L1 expression
*PD-L1 assessed using the VENTANA PD-L1 (SP263) assay
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA89

62. LBA89: PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN – Paz-Ares L, et al
Global health status/QoL(QLQ-C30)*
Key results (cont.)
0.2
1.0
0.8
0.6
0.4 3 6 9 12 15 18 21 24
Durvalumab + EP EP
HR 0.81
(95%CI 0.626, 1.054)
Time to deterioration
Probability of not worsening
No. at risk
Time from randomisation, months
D + EP
238
183
125 74 41 20 12 1 EP
232
147 77 40 16 5
Physical functioning (QLQ-C30)*
Cognitive functioning (QLQ-C30)*
0.2
1.0
0.8
0.6
0.4 3 6 9 12 15 18 21 24
Durvalumab + EP EP
HR 0.61
(95%CI 0.472, 0.776)
Probability of
not worsening
0.2
Probability of
not worsening
1.0
0.8
0.6
0.4 3 6 9 12 15 18 21 24
Durvalumab + EP EP
HR 0.75
(95%CI 0.581, 0.970)
No. at risk
Time from randomisation, months
Time from randomisation, months
D + EP
243
173
123 73 37 19 13 1
D + EP
244
181
126 72 38 17 10 EP
240
145 75 40 16 6 EP
242
142 69 32 12 2
*Patients with baseline scores ≥10
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA89

63. Durvalumab + EP showed improved disease-progression outcomes
LBA89: PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN – Paz-Ares L, et al
Key results (cont.)
Conclusions
In patients with extensive-stage NSCLC, a statistically significant improvement OS was observed with 1L durvalumab +EP vs. EP alone (p=0.0047), and there was no significant interaction with PD-L1 expression
Durvalumab + EP showed improved disease-progression outcomes
Types of progression
Durvalumab + EP (n=268)
EP (n=269)
Total progression events, n (%)
226 (84.3)
233 (86.6)
RECIST-defined progression, n (%)
Target lesions
Non-target lesions
New lesions
192 (71.6) 115 (42.9) 66 (24.6) 111 (41.4)
194 (72.1) 106 (39.4) 61 (22.7) 127 (47.2)
Death in absence of progression, n (%)
34 (12.7)
39 (14.5)
Sites of new lesions (>5% patients)
Durvalumab + EP (n=268)
EP (n=269)
New lesions, n (%)
Lung
Brain/CNS
Liver
Bone
Regional Lymph nodes
111 (41.4) 23 (8.6) 31 (11.6) 15 (5.6) 12 (4.5) 15 (5.6)
127 (47.2) 41 (15.2) 31 (11.5) 24 (8.9) 19 (7.1) 12 (4.5)
Paz-Ares L, et al. Ann Oncol 2019;30(suppl):Abstr LBA89

64. 1736O: IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) – Reck M, et al
Study objective
To update the OS findings with atezolizumab + carboplatin + etoposide as a 1L treatment for patients with extensive-stage SCLC in IMpower133
Key patient inclusion criteria
Measureable extensive-stage SCLC
No prior systemic therapy
Treated asymptomatic brain metastases were eligible
ECOG PS 0–1
(n=403)
Atezolizumab 1200 mg IV q3w + carboplatin + etoposide
(n=201)
Atezolizumab maintenance
PD/ loss of benefit
Stratification
Sex (male vs. female)
ECOG PS (0 vs. 1)
Brain metastases (yes vs. no) R
1:1
Placebo + carboplatin + etoposide
(n=202)
Placebo
PD/ loss of benefit
Endpoints
Updated OS in ITT, and by PD-L1 subgroups
Updated DoR/ORR in ITT
Updated safety
Updated biomarker analysis
Carboplatin AUC 5 mg/mL/min IV q3w; etoposide 100 mg/m2 IV D1–3 q3w
Reck M, et al. Ann Oncol 2019;30(suppl):Abstr 1736O

65. 1736O: IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) – Reck M, et al
Key results OS
Response
Atezo + CP/ET
64.4
Time, months
OS, %
100 80 60 40 20 2 4 6 8 10 12 14 16
No.at risk 18 22 26 28 30 32 24
12-month OS
18-month OS
202
183
160
131 97 74 58 49 39
Placebo + CP/ET 33 3
189
21.0%
39.0%
60.2
Placebo + CP/ET
Atezo + CP/ET
201
180
159
130
109 93 86 75 61 51 28 21 8 1
187
51.9%
34.0%
Response, %
20.9
21.3
6.9
3.5
1.0
Atezo + CP/ET (n=201)
Placebo + CP/ET (n=202)
Median OS, months (95%CI)
12.3 (10.8, 15.8)
10.3 (9.3, 11.3)
HR (95%CI)
0.76 (0.60, 0.95)
p-value
0.0154
Atezo + CP/ET (n=121)
Placebo + CP/ET (n=130)
DoR, months (range)
4.2 (1.4+–24.3+)
3.9 (2.0–24.2+)
Patients with ongoing response, n (%)
11 (9.1)
3 (2.3)
Reck M, et al. Ann Oncol 2019;30(suppl):Abstr 1736O

66. PD-L1* was evaluable in 137/403 (34%) of the ITT population
1736O: IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) – Reck M, et al
Key results (cont.)
PD-L1* was evaluable in 137/403 (34%) of the ITT population
Conclusions
In patients with extensive-stage NSCLC, updated survival outcomes continue to favour use of 1L atezolizumab + carboplatin + etoposide over chemotherapy alone
Efficacy was not related to PD-L1 expression (1% or 5% threshold) or bTMB (10 or 16 thresholds)
Median OS (months)
OS HRa
(95%CI)
Subgroup
Atezo + CP/ET
Placebo + CP/ET
0.25
0.5
1.0
1.5
Hazard ratioa
Favours Atezo + CP/ET
Favours Placebo + CP/ET
ITT (N=403)
12.3
10.3
0.76 (0.61, 0.96)
ITT-BEP (n=137)
Non-BEP (n=266)
PDL-1 expression 1% TC or IC
<1% PD-L1 (n=65)
≥1% PD-L1 (n=72)
PDL-1 expression 5% TC or IC
<5% PD-L1 (n=108)
≥5% PD-L1 (n=29)
9.9
14.6
10.2
9.7
9.2
21.6
8.9
11.2
8.3
10.6
9.2
0.70 (0.48, 1.02)
0.81 (0.61, 1.08)
0.51 (0.30, 0.89)
0.87 (0.51, 1.49)
0.77 (0.51, 1.17)
0.60 (0.25, 1.46)
*PD-L1 assessed by VENTANA SP 263 assay of slide sections ≤1 year old; aHR stratified for ITT, unstratified for subgroups
Reck M, et al. Ann Oncol 2019;30(suppl):Abstr 1736O

67. Pembrolizumab 200 mg q3w (n=73)
LBA91_PR: A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM) – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial – Popat S, et al
Study objective
To evaluate the efficacy of pembrolizumab vs. platinum-based chemotherapy in patients with advanced MPM
Pembrolizumab 200 mg q3w (n=73)
Key patient inclusion criteria
MPM
Progression on platinum-based chemotherapy
ECOG PS 0–1
(n=144)
Stratification
Histology (epithelioid vs. non-epithelioid) R
1:1 PD
(max 2 years)
Chemotherapya
Gemcitabine 1000 mg/m2 q3w or vinorelbine 30 mg/m2 q3w or vinorelbine 60/80 mg/m2 q3w
(n=71)
Primary endpoint
PFS (BICR)
Secondary endpoints
ORR, TTF, OS, PFS (investigator-assessed), safety
aCrossover to pembrolizumab was allowed at progression
Popat S, et al. Ann Oncol 2019;30(suppl):Abstr LBA91_PR

68. LBA91_PR: A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM) – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial – Popat S, et al
Key results
PFS
100
Events/N
mPFS, months
(95%CI)
6-month PFS, % (95%CI) CT
56/71
3.4 (2.2, 4.3)
27.4 (17.1, 38.7)
Pembro
62/73
2.5 (2.1, 4.2)
25.0 (15.5, 35.6) 80 60
PFS, %
HR 1.06 (95%CI 0.73, 1.53); p=0.76a 40 20 2 4 6 8 10 12 14
No. at risk
Time, months CT 9 16 29 55 71 4
Pembro 11 17 33 50 73 3 6
aStratified by histological subtype
Popat S, et al. Ann Oncol 2019;30(suppl):Abstr LBA91_PR

69. LBA91_PR: A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM) – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial – Popat S, et al
Key results (cont.) OS
Deaths/N
mOS, months
(95%CI)
6-month OS, % (95%CI) CT
34/71
11.7 (7.4, NE)
72.9 (60.8, 81.7)
Pembro
37/73
10.7 (7.6, NE)
68.5 (56.5, 77.8)
100 80 60
HR 1.04 (95%CI 0.66, 1.67); p=0.85a
OS, % 40 20 2 4 6 8 10 12 14 16
No. at risk
Time, months CT 39 51 58 64 71 8 15 26 1
Pembro 39 50 55 66 73 17 27 9 3
aStratified by histological subtype
Popat S, et al. Ann Oncol 2019;30(suppl):Abstr LBA91_PR

70. LBA91_PR: A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM) – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial – Popat S, et al
Key results (cont.)
ORR was significantly improved with pembrolizumab vs. chemotherapy (22% [95%CI 13, 33] vs. 6% [95%CI 2, 14], respectively; p=0.004)
Median DoR was 4.6 months (95%CI 2.2, 10.3) for pembrolizumab and months (95%CI 6.2, 15.3) for chemotherapy
Median TTF was similar in the two treatment arms; 2.8 months (95%CI 2.1, 4.2) vs. 2.3 months (95%CI 2.1, 3.9) for pembrolizumab vs. chemotherapy, respectively
Popat S, et al. Ann Oncol 2019;30(suppl):Abstr LBA91_PR

71. No new safety signals were observed
LBA91_PR: A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM) – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial – Popat S, et al
Key results (cont.)
The most frequent pembrolizumab-related AEs were dry skin (13.9%), pruritus (12.5%) and maculopapular rash (12.5%)
Conclusions
In pre-treated patients with advanced MPM, pembrolizumab failed to demonstrate PFS and OS superiority vs. platinum-based chemotherapy, despite a significantly improved ORR
No new safety signals were observed
AEs, n (%)
Pembrolizumab (n=72)
Placebo + CP/ET (n=70)
Any AEs
70 (97.2)
65 (92.9)
Any TRAEs
50 (69.4)
51 (72.9)
Grade 3–5 TRAEs
14 (19.4)
17 (24.3)
TRAEs leading to discontinuation
6 (8.3)
5 (7.1)
TRAEs leading to death
1 (1.4)
Popat S, et al. Ann Oncol 2019;30(suppl):Abstr LBA91_PR

72. Nivolumab 3 mg/kg IV q2w + ipilimumab 1 mg/kg IV q6w
1841O: 2nd/3rd-line nivolumab vs nivo plus ipilimumab in malignant pleural mesothelioma: Long-term results of IFCT-1501 MAPS2 phase 2R trial with a focus on hyperprogression (HPD) – Zalcmann G, et al
Study objective
To evaluate the long-term efficacy and safety of nivolumab ± ipilimumab as a 2L or 3L treatment for patients with MPM
Key patient inclusion criteria
Histological diagnosis of MPM
Unresectable cancer with documented progression after 1 or 2 lines of chemotherapy including a pemetrexed/ platinum doublet
ECOG PS 0−1
(n=125)
Nivolumab 3 mg/kg IV q2w
(n=63)
PD/ toxicity
R 1:1
Nivolumab 3 mg/kg IV q2w + ipilimumab 1 mg/kg IV q6w
(n=62)
PD/ toxicity
Primary endpoint
DCR at 12 weeks in first 54 accrued patients in each group
Secondary endpoints
PFS, OS, QoL, safety
Zalcmann G, et al. Ann Oncol 2019;30(suppl):Abstr 1841O

73. 1841O: 2nd/3rd-line nivolumab vs nivo plus ipilimumab in malignant pleural mesothelioma: Long-term results of IFCT-1501 MAPS2 phase 2R trial with a focus on hyperprogression (HPD) – Zalcmann G, et al
Key results
OS: Nivolumab
OS: Nivolumab + Ipi
OS, %
100 80 60 40 20 15 10 5 25
Time, months 30 35
Events=52, censored=11
OS, %
100 80 60 40 20 15 10 5 25
Time, months 30 35
Events=49, censored=13
Nivolumab (n=63)
Nivolumab + Ipi (n=62)
2-years OS, % (95%CI)
25.4 (15.5, 36.6)
31.7 (20.5, 43.4)
mOS, months (95%CI)
11.9 (6.7, 17.5)
15.9 (10.7, 22.2)
Zalcmann G, et al. Ann Oncol 2019;30(suppl):Abstr 1841O

74. 1841O: 2nd/3rd-line nivolumab vs nivo plus ipilimumab in malignant pleural mesothelioma: Long-term results of IFCT-1501 MAPS2 phase 2R trial with a focus on hyperprogression (HPD) – Zalcmann G, et al
Key results (cont.)
The correlation of HPD status with OS was evaluated according to tumour growth rate (TGR) or tumour growth kinetics (TGK) methods; despite a negative result with TGR, TGK revealed an impact of HPD on the OS in both study arms (p<0.0001)
Conclusions
In patients with MPM, both nivolumab or nivolumab + ipilimumab demonstrated a favourable survival outcome compared with chemotherapy
In fast-progressing MPM patients who are receiving immunotherapy, it is recommended to be cautious and requires early evaluation
Zalcmann G, et al. Ann Oncol 2019;30(suppl):Abstr 1841O

75. PD/ toxicity/ withdrawal
1843O: SAKK 17/16: Lurbinectedin as second or third line palliative chemotherapy in malignant pleural mesothelioma (MPM): A multi-center, single-arm Phase II trial – Metaxas Y, et al
Study objective
To evaluate the efficacy and safety of lurbinectedin in patients with progressive MPM
Key patient inclusion criteria
Confirmed MPM
Progression after 1L platinum-pemetrexed chemotherapy ± immunotherapy
ECOG PS 0–1
(n=42)
Lurbinectedin 3.2 mg/m2 q3w
(n=42)
PD/ toxicity/ withdrawal
Primary endpoint
PFS at 12 weeks
Secondary endpoints
PFS, OS, safety
Metaxas Y, et al. Ann Oncol 2019;30(suppl):Abstr 1843O

76. 1843O: SAKK 17/16: Lurbinectedin as second or third line palliative chemotherapy in malignant pleural mesothelioma (MPM): A multi-center, single-arm Phase II trial – Metaxas Y, et al
Key results
PFS OS 9 6 3 12 15 18
Survival probability
1.00
0.75
0.50
0.25
Time, months
No. at risk
58.4%
(95%CI 41.8, 71.7)
30.54%
(95%CI 17.1, 44.9)
12.7%
(95%CI 4.7, 24.9) 42 4 23 1 9 6 3 12 15 18
Survival probability
1.00
0.75
0.50
0.25
Time, months
No. at risk
73.8%
(95%CI 57.7, 84.67)
44.9%
(95%CI 28.1, 60.3) 42 25 31 40 13 5
Lurbinectedin (n=42)
Simon’s first-stage
11/21
12-week PFS, % (90%CI)
52.4 (38.7, 63.5)
mPFS, months (95%CI)
4.1 (2.6, 5.5)
Lurbinectedin (n=42)
No. of events (death) 26
mOS, months (95%CI)
11.1 (8.8, 14.7)
Metaxas Y, et al. Ann Oncol 2019;30(suppl):Abstr 1843O

77. Grade 3–4 AEs occurred in 32/42 (76.2%) patients
1843O: SAKK 17/16: Lurbinectedin as second or third line palliative chemotherapy in malignant pleural mesothelioma (MPM): A multi-center, single-arm Phase II trial – Metaxas Y, et al
Key results (cont.)
Neither histological types (epithelioid and non-epithelioid) nor prior immunotherapy affected the PFS and OS outcomes
Grade 3–4 AEs occurred in 32/42 (76.2%) patients
Grade 3–4 TRAEs occurred in 20/42 (47.6%) patients
The most frequent grade 3–4 TRAEs were neutropenia, fatigue and febrile neutropenia (23.8%, 16.7% and 9.5%, respectively)
Conclusions
In patients with progressive MPM, lurbinectedin showed clinical activity and had a manageable safety profile
Metaxas Y, et al. Ann Oncol 2019;30(suppl):Abstr 1843O

78. 1844O: Durable anti-tumor activity of the multi-targeted inhibitor lenvatinib in patients with advanced or metastatic thymic carcinoma; Preliminary results from a multicenter phase II (REMORA) trial – Itoh S, et al
Study objective
To evaluate the efficacy and safety of lenvatinib, a multi-targeted inhibitor of VEGFR kinases, in patients with advanced or metastatic thymic carcinoma
Key patient inclusion criteria
Advanced or metastatic thymic carcinoma
Progression after ≥1 prior platinum-based chemotherapy
ECOG PS 0–1
(n=42)
Lenvatinib 24 mg/day
PD/ toxicity
Primary endpoint
ORR
Secondary endpoints
PFS, OS, DCR, safety
Itoh S, et al. Ann Oncol 2019;30(suppl):Abstr 1844O

79. Maximum % change from baseline
1844O: Durable anti-tumor activity of the multi-targeted inhibitor lenvatinib in patients with advanced or metastatic thymic carcinoma; Preliminary results from a multicenter phase II (REMORA) trial – Itoh S, et al
Key results
The median PFS was 9.3 months (95%CI 7.7, 13.9), while median OS was not reached (95%CI 16.1, NR)
ORR (BICR)
Maximum % change from baseline 20 10
–10
–20
–30
–40
–50
–60
–80
–70
Lenvatinib (n=42)
Best overall response, n (%) PR SD PD
16 (38.1)
24 (57.1)
2 (4.8)
ORR, % (90%CI)
38.1 (25.6, 52.0)
DCR, % (95%CI)
95.2 (83.8, 99.4)
Median DoR, n/N months (95%CI)
16/ (5.8, 18.0)
Best overall response
PR (n=16)
SD (n=24)
PD (n=2)
Itoh S, et al. Ann Oncol 2019;30(suppl):Abstr 1844O

80. 1844O: Durable anti-tumor activity of the multi-targeted inhibitor lenvatinib in patients with advanced or metastatic thymic carcinoma; Preliminary results from a multicenter phase II (REMORA) trial – Itoh S, et al
Key results (cont.)
Of the patients 20/42 (47.6%) discontinued the treatment due to disease progression and 7/42 (16.7%) due to TRAEs
AEs that led to discontinuation were all grade 3 and included arthralgia, intestine perforation, left ventricular dysfunction, pneumonitis and pneumothorax
Conclusions
In patients with advanced or metastatic thymic carcinoma, lenvatinib showed clinical efficacy with a tolerable safety profile
Itoh S, et al. Ann Oncol 2019;30(suppl):Abstr 1844O