ESMO 2018 CONGRESS

Supported by Eli Lilly and Company.

Eli Lilly and Company has not influenced the content of this publication

Developed in association with theEuropean Thoracic Oncology Platform

19–23 October 2018

Munich, Germany

ESMO 2018 CONGRESS

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 2018. This slide

set specifically focuses on the ESMO 2018 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 [email protected].

I would like to thank our ETOP members 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 activity.

Yours sincerely,

Rolf Stahel

President, ETOP Foundation Council

mailto:[email protected]

ETOP Medical Oncology Slide Deck Editors 2018

Focus: advanced NSCLC (not radically treatable stage III & stage IV)

Dr Solange Peters

Multidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland

Focus: other malignancies, SCLC, mesothelioma, rare tumours

Dr Martin Reck

Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany

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 tumours

Screening and biomarkers

65PD: High tumor mutational burden (TMB) and PD-L1 have similar predictive

utility in 2L+ NSCLC patients (pts) treated with anti-PD-L1 and anti-CTLA-4

– Higgs BW, et al

• Study objective

– To compare the utility of high TMB and PD-L1 to predict outcomes in patients

with non-squamous NSCLC who were treated with durvalumab and

tremelimumab

• Methods

– Immunotherapy-naïve patients (n=213) with non-squamous EGFR and ALK wild-

type NSCLC who had progressed after one prior platinum-based therapy were

enrolled to durvalumab 20 mg/kg q4w for up to 12 months with tremelimumab

1 mg/kg q4w for 4 cycles

– Tumour PD-L1 expression classified as ≥25% or <25% using the Ventana PD-L1

(SP263) assay

– DNA sequencing was performed on 106 of 200 (53%) available tumour biopsies

and TMB high defined as the top tertile of values (11 mut/Mb)

Higgs BW, et al. Ann Oncol 2018;29(suppl 5):Abstr 65PD



– Higgs BW, et al

• Key results

– There was no appreciable correlation between TMB and PD-L1


Low linear correlation

between PD-L1 levels and TMB

PD-L1 vs. TMB

status overlap

PD

-L1

TC

, %

TMB, mutations/Mb

30

40

50

60

70

80

90

100

20

10

00 5 10 20 25 30 35 5540 45 5015

rho=0.3

PD-L1

≥25%

n=16

16%

TMB

high

n=17

17%

n=18

17%

PD-L1 <25%/

TMB low

n=52

50%



– Higgs BW, et al

• Key results

• Conclusions

– In this study of patients with non-squamous NSCLC TMB and PD-L1 expression

were not correlated

– Patients who were TMB high (≥11 mut/Mb) had improved ORR, PFS and OS


TMB

≥11 mut/Mb

(n=37)

TMB

<11 mut/Mb

(n=69)

PD-L1

≥25%

(n=57)

PD-L1

<25%

(n=136)

Total*

(N=213)

PFS

Median, months (95%CI) 7.1 (1.7, 9.1) 1.7 (1.6, 3.6) 7.1 (3.5, 9.2) 3.3 (1.7, 3.6) 3.5 (1.8, 4.0)

12-month PFS, % (95%CI) 26.8 (13.8, 41.6) 12.6 (5.6, 22.6) 34.2 (21.9, 46.8) 10.0 (4.8, 17.5) 17.6 (12.4, 23.6)

OS

Median, months (95%CI) NE (7.9, NE) 8.9 (4.8, NE) 15.5 (15.4, NE) 9.5 (6.7, NE) 15.4 (10.0, NE)

12-month OS, % (95%CI) 61.2 (42.4, 75.5) 43.0 (30.4, 55.0) 71.6 (57.3, 81.9) 47.3 (38.2, 55.9) 53.8 (46.4, 60.6)

*20 patients had unknown PD-L1 expression; NE, not estimable

1136PD: Discrepancy of tumor neoantigen burden between primary lesions and

matched metastases in lung cancer – Jiang T, et al

• Study objective

– To compare neoantigen landscapes in primary tumours and metastases in patients with

lung cancer

• Key result

• Conclusion

– Neoantigen landscapes were similar in primary tumours and metastases, however, only

20% of neoantigens were shared

Jiang T, et al. Ann Oncol 2018;29(suppl 5):Abstr 1136PD

Comparison of neoantigens in primary tumours and metastases by baseline characteristics

0

400

800

1200

1600

2000

53 61 69 62 68 57 45 58 54 87 51 61 60 47

Primary

Female

Yes

SCLC

Metastasis

Male

No

LUAD

Ne

oa

ntig

en c

oun

ts

Age, years

Gender

Smoking

Histology

LM

15

LM

18

LM

21

LM

14

LM

10

LM

08

LM

13

LM

16

LM

11

LM

19

BM

12

BM

14

BM

18

BM

15

LUSC

Gender

Smoking

Histology

Early stage and locally advanced

NSCLC – Stages I, II and III

LBA48_PR: CTONG 1103: Erlotinib versus gemcitabine plus cisplatin as neo-

adjuvant treatment for stage IIIA–N2 EGFR-mutation non-small-cell lung cancer

(EMERGING): a randomised study – Zhong W, et al

• Study objective

– To investigate the efficacy of erlotinib vs. gemcitabine + cisplatin as neoadjuvant/

adjuvant treatment in patients with locally advanced EGFR mutant NSCLC

Zhong W, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA48_PR

Primary endpoint

• ORR

Secondary endpoints

• Downstaging rates of pathological lymph nodes,

pCR, PFS, OS, safety

R

1:1

Stratification

• Lymph node status

• Histology

• Smoking

• Sex

Key patient inclusion criteria

• Treatment naïve IIIA-N2

NSCLC

• EGFR activating mutation

• ECOG PS 0–1

(n=72)Gemcitabine +

cisplatin* q3w

for 2 cycles

(n=35)

Erlotinib 150 mg/day

for 42 days

(n=37)

*Gemcitabine 1250 mg/m2 D1, 8; cisplatin 75 mg/m2 D1

Gemcitabine +

cisplatin* q3w

for 2 cycles

Erlotinib 150 mg/day

for 12 months

S

U

R

G

E

R

Y

Non-PD




• Key results

– ORR in the ITT population was 54.1% (95%CI 37.2, 70.9) with erlotinib vs.

34.3% (95%CI 17.7, 50.8) with gemcitabine + cisplatin (OR 2.26 [95%CI 0.87,

5.84], p=0.092)

Zhong W, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA48_PR

Erlotinib

(n=37)

Gemcitabine +

cisplatin

(n=35) p-value

Surgery, n (%) 31 (83.8) 24 (68.6) 0.129

Complete resection, n (%)

R0

R1

R2

27 (73.0)

27 (73.0)

1 (2.7)

3 (8.1)

22 (62.9)

22 (62.9)

1 (2.9)

1 (2.9)

0.358

Lymph node downstage, n (%)

N2pN0

N2pN1

N2pN2

4 (10.8)

3 (8.1)

1 (2.7)

27 (73.0)

1 (2.9)

1 (2.9)

0 (0)

23 (65.7)

0.185




• Key results

• Conclusion

– Erlotinib in the neoadjuvant setting for EGFRm NSCLC improved ORR, MPR,

R0 resection and lymph node downstaging and the safety profile was in line with

previous reportsZhong W, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA48_PR

100

80

60

40

20

0

Pro

gre

ssio

n-f

ree s

urv

iva

l, %

0

37

35

6

28

20

12

21

13

18

16

4

24

7

3

30

2

1

36

0

0

42

Time, months

76.7%

49.0% 36.4%

14.4%

Group Events mPFS, months (95%CI)

Erlotinib (n=37) 20 21.5 (19.3, 23.6)

Gemcitabine +

cisplatin (n=35)26 11.9 (9.1, 14.7)

HR 0.42 (95%CI 0.23, 0.76), p=0.003

No.at risk

Erlotinib

Gemcitabine

+ cisplatin

PFS (ITT population)

LBA49: Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for

resectable non-small cell lung cancer (NSCLC) – Cascone T, et al

• Study objective

– To investigate the efficacy and safety of nivolumab alone or in combination with

ipilimumab in patients with untreated resectable NSCLC

Cascone T, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA49

Primary endpoint

• Major pathological response (MPR)

Secondary endpoints

• Safety, perioperative mortality and

morbidity, ORR, RFS, OS, complete

resection rate, pCR

R

1:1

Stratification

• Stage


• Stage I–IIIA NSCLC

• Eligible for surgery

(n=44) Ipilimumab 1 mg/kg D1

+ nivolumab 3 mg/kg

D1, 15, 29

(n=18)

Nivolumab 3 mg/kg

D 1, 15, 29

(n=18)

SurgeryAdjuvant

therapy

SurgeryAdjuvant

therapy



• Key results


Total NivolumabNivolumab +

ipilimumab

Evaluable (resected) n=26 n=14 n=12

MPR + pCR, n (%) 8 (31) 4 (28) 4 (33)

0% viable tumour cells (pCR), n (%) 5 (19) 2 (14) 3 (25)

1–10% viable tumour cells, n (%) 3 (11) 2 (14) 1 (8)

Overall (resected + unresectable) n=31 n=16 n=15

MPR + pCR, n (%) 8 (26) 4 (25) 4 (27)

0% viable tumour cells (pCR), n (%) 5 (16) 2 (13) 3 (20)

1–10% viable tumour cells, n (%) 3 (10) 2 (13) 1 (7)

–21



• Key results (cont.)

• Conclusions

– In resected patients with NSCLC, neoadjuvant nivolumab or nivolumab +

ipilimumab induced an MPR rate of 31%

– Greater TIL proliferation and activation was demonstrated with neoadjuvant

nivolumab and nivolumab + ipilimumab compared with untreated tumours


Evaluable

Total

(n=32)

Nivolumab

(n=16)

Nivolumab +

ipilimumab

(n=16)

Response,

n (%)

CR

PR

SD

PD

1 (3)

6 (19)

19 (59)

6 (19)

0 (0)

5 (31)

8 (50)

3 (19)

1 (6)

1 (6)

11 (69)

3 (19)

ORR, n/N

(%)

7/32

(22)

5/16

(31)

2/16

(12)

-100

-80

-60

-40

-20

0

20

40

*

*

Overa

ll %

change in t

um

our

siz

e f

rom

baselin

e

Nivolumab (evaluable)

(n=16)

-100

-80

-60

-40

-20

0

20

40

Nivolumab + ipilimumab

(evaluable) (n=16)

*

*

21 1413

7 4 3 2 0 0

–2–12

–30–34

–39 –39–45

2214 12 10

40

–6

–16–17–18–19

–31

–100

–20

35

*Considered SD in target lesion but overall PD due to new

radiographic lesions

Radiographic responses

1363O: Efficacy and safety evaluation based on time from completion of

radiotherapy to randomization with durvalumab or placebo in pts from PACIFIC

– Faivre-Finn C, et al

• Study objective

– To investigate the efficacy and safety outcomes of durvalumab in the PACIFIC

trial based on PD-L1 expression and the components of chemoradiation

received prior to durvalumab or placebo

Faivre-Finn C, et al. Ann Oncol 2018;29(suppl 5):Abstr 1363O

Primary endpoints

• PFS by BICR, OS

Secondary endpoints

• ORR, DoR and TTDM by BICR, PFS2

by investigator, safety, PROs

Stratification

• Age

• Sex

• Smoking history


• Stage III NSCLC

• No progression after ≥2 cycles of

platinum-CRT

• Pre-cCRT tumour tissue for PD-L1

testing if available

• WHO PS 0–1

(n=713)

Placebo q2w

(n=237)

Durvalumab 10 mg/kg q2w

(n=476)

R

1:1




• Key results

– Median OS in the PD-L1 TC ≥1% was NR (95%CI NR, NR) with durvalumab

and 29.1 months (95%CI 17.7, NR) for placebo; HR 0.53 (95%CI 0.36, 0.77)

– Median OS in the PD-L1 TC <1% was NR (95%CI 20.8, NR) with durvalumab

and NR (95%CI 27.3, NR) for placebo; HR 1.36 (95%CI 0.79, 2.34)

Events/

patients (%)

Median PFS,

months

(95%CI)

Durvalumab 84/212 (39.6) 17.8 (16.9, NR)

Placebo 59/91 (64.8) 5.6 (3.6, 11.0)

HR 0.46 (95%CI 0.33, 0.64)

PFS (BICR) by PD-L1 TC ≥1% PFS (BICR) by PD-L1 TC <1%

Events/

patients (%)

Median PFS,

months

(95%CI)

Durvalumab 49/90 (54.4) 10.7 (7.3, NR)

Placebo 40/58 (69.0) 5.6 (3.7, 10.6)

HR 0.73 (95%CI 0.48, 1.11)

Pro

ba

bili

ty o

f P

FS

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 21 24 2718Time from randomisation, months

212

91

174

59

143

39

127

34

82

20

52

13

14

4

1

3

0

0

30

8

No. at risk

Durvalumab

PlaceboP

rob

ab

ility

of P

FS

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 21 24 2718Time from randomisation, months

90

58

70

45

51

25

42

21

23

14

9

8

1

0

0

0

0

0

4

5

No. at risk

Durvalumab

Placebo

Faivre-Finn C, et al. Ann Oncol 2018;29(suppl 5):Abstr 1363O





• Conclusions

– Durvalumab led to improvement in PFS and OS in the PD-L1 ≥1% subgroup

and PFS in the <1% PD-L1 subgroup

– Durvalumab improved PFS and OS regardless of chemoradiation received prior

to therapyFaivre-Finn C, et al. Ann Oncol 2018;29(suppl 5):Abstr 1363O

Events / patients (%)

HR (95%CI) Durvalumab Placebo

Induction

chemotherapy

Yes

No

59/123 (48.0)

155/353 (43.9)

49/68 (72.1)

108/169 (63.9)

Platinum Cisplatin

Carboplatin

115/266 (43.2)

91/199 (45.7)

87/129 (67.4)

65/102 (63.7)

Taxane Yes

No

97/207 (46.9)

117/269 (43.5)

72/112 (64.3)

85/125 (68.0)

Etoposide Yes

No

49/117 (41.9)

165/359 (46.0)

34/52 (65.4)

123/185 (66.5)

Vinorelbine Yes

No

58/124 (46.8)

156/352 (44.3)

42/59 (71.2)

115/178 (64.6)

Dose of

radiotherapy

<60 Gy

60–66 Gy

>66 Gy

16/38 (42.1)

187/407 (45.9)

10/30 (33.3)

11/15 (73.3)

130/202 (64.4)

15/19 (78.9)

Placebo betterDurvalumab better

0.25 0.5 1 2

PFS (BICR)

Advanced NSCLCNot radically treatable stage III and stage IV

First line

LBA10: Primary results of ALESIA: A randomised, phase III, open-label study of

alectinib vs crizotinib in Asian patients with treatment-naïve ALK+ advanced

NSCLC – Zhou C, et al

• Study objective

– To investigate safety and efficacy of 1L alectinib vs. crizotinib in Asian patients

with ALK+ NSCLC in the ALESIA study

Zhou C, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA10

Primary endpoint

• PFS (investigator-assessed)

Secondary endpoints

• PFS by IRC, time to CNS progression,

ORR and DoR (investigator-assessed),

OS, CNS ORR, safety, QoL, PK

Stratification

• ECOG PS (0/1 vs. 2)

• Baseline brain metastases


• Asian patients with stage IIIB/IV

ALK+ NSCLC

• Treatment naïve

• ECOG PS 0–2

(n=187)Crizotinib 250 mg bid

(n=62)

Alectinib 600 mg bid

(n=125)

R

2:1




• Key result

Zhou C, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA10

Alectinib

(n=125)

Crizotinib

(n=62)

Patients with event, n (%) 26 (20.8) 37 (59.7)

Median PFS, months (95%CI) NE (20.3, NE) 11.1 (9.1, 13.0)

HR (95%CI); p-value (log-rank test) 0.22 (0.13, 0.38); <0.0001

Pro

gre

ssio

n-f

ree s

urv

iva

l, %

Time, months

100

80

60

40

20

00 3 6 9 12 15 18 21

Alectinib

Crizotinib

NE

11.1 months

Cause-specific HR

p-value (log-rank test)

0.14 (95%CI 0.06, 0.30)

<0.0001C

um

ula

tive

incid

en

ce*,

%

Time, months

60

40

20

0

0 3 6 9 12 15 18 21

Alectinib

Crizotinib

7.3%

35.5% (95%CI 23.5, 47.8)

(95%CI 3.6, 12.8)

PFS (investigator-assessed) Time to CNS progression (IRC-assessed)

*Cumulative incidence of CNS progression without prior

non-CNS progression or death




• Key result (cont.)

• Conclusions

– Alectinib led to a significant improvement in PFS and showed benefits in

regards to ORR, DoR and time to CNS progression compared with crizotinib

– The safety profile of alectinib in Asian patients was consistent with the previous

findingsZhou C, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA10

DoR

(un

co

nfirm

ed)

,%

Time, months

100

80

60

40

20

00 3 6 9 12 15 18 21

Alectinib

Crizotinib

NE

9.3 months

Response, n (%)

Alectinib

(n=125)

Crizotinib

(n=62)

ORR 114 (91.2) 48 (77.4)

CR 5 (4.0) 3 (4.8)

PR 109 (87.2) 45 (72.6)

SD 7 (5.6) 8 (12.9)

PD 2 (1.6) 4 (6.5)

Missing or

unevaluable2 (1.6) 2 (3.2)

Alectinib

(n=114)

Crizotinib

(n=48)

Median DoR, months (95%CI) NE (18.4, NE) 9.3 (7.4, NE)

HR (95%CI), p-value (log-rank test) 0.22 (0.12, 0.40); p<0.0001

DoR (investigator-assessed)

LBA50: Mechanisms of acquired resistance to first-line osimertinib: preliminary

data from the phase III FLAURA study – Ramalingam SS, et al

• Study objective

– To investigate the mechanisms of acquired resistance to osimertinib and

standard of care (gefitinib + erlotinib) in patients who progressed or discontinued

treatment in the FLAURA study

• Methods

– Patients in the FLAURA study had EGFR+ (ex19del or L858R) locally advanced

or metastatic NSCLC and were treated with osimertinib or gefitinib + erlotinib

until progression

– Paired plasma samples were taken from patients at baseline and at

progression/discontinuation for ctDNA genomic profiling

– NGS was conducted using the Guardant360 assay or GuardantOMNI assay

– Analysis set of valid paired NGS data were available for 272 patients

• Osimertinib: 113/279 (41%)

• Gefitinib + erlotinib: 159/277 (57%)

Ramalingam SS, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA50

LBA50: Mechanisms of acquired resistance to first-line osimertinib: preliminary

data from the phase III FLAURA study – Ramalingam SS, et al

• Key results

– The most common acquired resistance mechanisms in the osimertinib arm

(n=91) were:

• MET amplification (15%) and EGFR C797S mutation (7%)

• There was no evidence of acquired T790M

– The most common acquired resistance mechanisms in the gefitinib + erlotinib

arm (n=129) were:

• T790M (47%), MET amplification (4%) and HER2 amplification (2%)

• Conclusions

– There was no evidence of acquired resistance through T790M in the

osimertinib-treated patients, while MET amplification and EGFR C797S

mutations were the most common

– New mechanisms that may lead to aggressive disease biology were not

identified

Ramalingam SS, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA50

LBA51: Analysis of resistance mechanisms to osimertinib in patients with EGFR

T790M advanced NSCLC from the AURA3 study – Papadimitrakopoulou VA, et al

• Study objective

– To investigate the mechanisms of acquired resistance to osimertinib in patients

who progressed or discontinued treatment in the AURA3 study

• Methods

– Patients in the AURA3 study had T790M+ locally advanced or metastatic

NSCLC and were treated with osimertinib or platinum-pemetrexed until

progression

– Paired plasma samples were taken from patients at baseline and at

progression/discontinuation for ctDNA genomic profiling

– NGS was undertaken using the Guardant360 assay

– Analysis set of valid paired NGS data were available for 113 patients

• Osimertinib: 83/279 (30%)

• Platinum-pemetrexed: 30/140 (21%)

Papadimitrakopoulou VA, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA51

LBA51: Analysis of resistance mechanisms to osimertinib in patients with EGFR

T790M advanced NSCLC from the AURA3 study – Papadimitrakopoulou VA, et al

• Key results

– Loss of T790M was seen in 49%

of patients

– Acquired EGFR mutations were

observed in 21% of patients; the

most common was C797S (14%)

– Other mutations included:

MET amplification (19%);

cell cycle gene alterations (12%);

HER2 amplification (5%);

PIK3CA amplification/mutation (5%);

oncogenic fusion (4%),

BRAF V600E (3%)

– All cases of C797X mutations were in

the cis position when co-occurring with T790M

• Conclusion

– EGFR mutations and MET amplifications were the most common acquired

resistance mechanisms to osimertinib among a diverse mixture, consistent with

previous reports Papadimitrakopoulou VA, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA51

Acquired EGFR mutations with osimertinib

(represents 21% of total patients)

C797X: 15%

(10 C797S, 1 C797G)

L792H/F

+ C797S: 1%

L792H: 1%

G796S: 1%

L718Q: 1%

Ex20ins: 1%

LBA52: Results of the GEOMETRY mono-1 phase II study for evaluation of the

MET inhibitor capmatinib (INC280) in patients (pts) with METΔex14 mutated

advanced non-small cell lung cancer (NSCLC) – Wolf J, et al

• Study objective

– To investigate the efficacy and safety of capmatinib, a selective MET inhibitor, in

patients with METΔex14 mutated advanced NSCLC

Wolf J, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA52

Primary endpoint

• ORR by BIRC

Secondary endpoints

• DoR by BIRC

Cohort 4:

Previously treated (1–2 prior lines) for

advanced stage

Capmatinib 400 mg bid

(n=69)


• Stage IIIB/IV NSCLC

• METΔex14 determined

centrally

• EGFR wt and ALK negative

• ≥1 measureable lesion

• ECOG PS 0–1

Cohort 5b:

Treatment-naïve for advanced stage

Capmatinib 400 mg bid

(n=28)




• Key results

– ORR (BIRC) in Cohort 4 (pre-treated) was 39.1% (95%CI 27.6, 51.6)

– ORR (BIRC) in Cohort 5b (treatment naïve) was 72.0% (95%CI 50.6, 87.9)


Be

st %

ch

an

ge

fro

m b

ase

line *

* * * * **

* * **

0

–25

–50

–75

–100

n=24†/25 PR SD PD NE

-100

-75

-50

-25

0

25

n=60†/69

*

** *

* * * * ** *

*

*Cohort 5b (treatment naïve)

Cohort 4 (pre-treated)

Be

st %

ch

an

ge

fro

m b

ase

line

*Patients still on treatment; †number of patients with measurable

disease at baseline and ≥1 post-baseline assessment




• Key results

• Conclusions

– In patients with METΔex14 advanced NSCLC, capmatinib shows promising

results

– The differential benefit of 1L over later-line treatment highlights the need for

prompt targeted treatment in this patient group


AE, n (%)

Cohort 4 (pre-treated)

(n=69)

Cohort 5b (treatment naive)

(n=28)

All patients

(N=302)

All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4

Any 60 (87.0) 33 (47.8) 27 (96.4) 14 (50.0) 253 (83.8) 100 (33.1)

Peripheral oedema 31 (44.9) 10 (14.5) 18 (64.3) 1 (3.6) 122 (40.4) 19 (6.3)

Nausea 24 (34.8) 0 11 (39.3) 0 99 (32.8) 5 (1.7)

Vomiting 13 (18.8) 0 4 (14.3) 0 58 (19.2) 6 (2.0)

Blood creatinine increased 15 (21.7) 0 7 (25.0) 0 58 (19.2) 0

Fatigue 9 (13.0) 4 (5.8) 2 (7.1) 1 (3.6) 40 (13.2) 10 (3.3)

Decreased appetite 10 (14.5) 1 (1.4) 5 (17.9) 0 40 (13.2) 3 (1.0)

Diarrhoea 8 (11.6) 0 3 (10.7) 0 35 (11.6) 0

LBA53: IMpower130: Progression-free survival (PFS) and safety analysis from a

randomised phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without

atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous

NSCLC – Cappuzzo F, et al

• Study objective

– To investigate the efficacy and safety of atezolizumab combined with carboplatin

+ nab-paclitaxel vs. carboplatin + nab-paclitaxel in chemotherapy-naïve patients

with stage IV non-squamous NSCLC

Cappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53

Co-primary endpoints

• Investigator-assessed PFS and OS

(ITT-WT* population)

Secondary endpoints

• OS and PFS (ITT population and by

PD-L1 expression), ORR, safety

R

2:1

PD/

toxicity

Loss of

clinical

benefit/

toxicity

Stratification

• Sex

• Baseline liver metastases

• PD-L1 tumour expression

Key patient inclusion

criteria

• Stage IV non-

squamous NSCLC

• Chemotherapy-naïve

• Pre-treated EGFR

mutated or ALK

translocation (TKI)

(n=723; ITT-WT* n=679)

Carboplatin AUC 6 q3w +

nab-paclitaxel 100 mg/m2 q3w

Atezolizumab 1200 mg q3w +

carboplatin AUC 6 q3w +

nab-paclitaxel 100 mg/m2 q3w

*ITT-WT population, randomised patients excluding

those with EGFR or ALK mutations

Best supportive care

or pemetrexed q3w

Atezolizumab

Induction treatment (4 or 6 cycles) Maintenance treatment

OS rate, % 1-year 2-year

Atezolizumab

+ CnP63.1 39.6

CnP 55.5 30.0





• Key results

Cappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53

PFS rate, % 6-month 12-month

Atezolizumab

+ CnP56.1 29.1

CnP 42.5 14.1

Investigator-assessed PFS (ITT-WT)

PF

S, %

Months after randomisation

1.0

0.8

0.6

0.4

0.2

0.0

0

451

228

1

432

214

2

383

174

3

351

150

4

329

136

5

281

110

30

No. at risk

Atezo + CnP

Chemo

6

242

90

7

213

75

8

183

61

9

157

48

10

138

40

11

132

35

12

119

29

13

108

23

14

83

18

15

78

15

16

62

7

17

60

6

18

41

5

19

36

5

20

29

3

21

23

3

22

13

2

23

12

2

24

7

1

25

4

1

26

1

27 28 29

Median follow-up: ~19 months

HR 0.64

(95%CI 0.54, 0.77)

p<0.0001

OS (ITT-WT)

OS

, %

Months after randomisation

1.0

0.8

0.6

0.4

0.2

0.0

0

451

228

1

435

218

2

422

206

3

400

190

4

384

176

5

365

167

30

4

No. at risk

Atezo + CnP

Chemo

6

351

161

7

333

154

8

315

147

9

305

136

10

294

132

11

284

124

12

268

119

13

253

109

14

217

96

15

194

90

16

167

75

17

147

65

18

129

58

19

103

49

20

88

39

21

75

31

31

2

22

59

24

32

1

23

49

17

3324

40

13

3425

29

9

26

19

8

27

12

3

28

10

1

29

6

HR 0.79

(95%CI 0.64, 0.98)

p=0.033

Median: 5.5 mo

(95%CI 4.4, 5.9)

Median: 7.0 mo

(95%CI 6.2, 7.3)

Median: 13.9 mo

(95%CI 12.0, 18.7)

Median: 18.6 mo

(95%CI 16.0, 21.2)






• Conclusions

– In the ITT-WT population atezolizumab + chemotherapy showed benefit in PFS

and OS, which was maintained across all PD-L1 subgroups

– No new safety signals were observed with the combination of atezolizumab +

chemotherapyCappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53

PFS by baseline PD-L1 status (ITT-WT)

Atezo + CnP

(n=88)

CnP

(n=42)

Median PFS,

mo (95%CI)

6.4

(5.49, 9.76)

4.6

(3.22, 7)

HR (95%CI) 0.51 (0.34, 0.77)

Atezo + CnP

(n=128)

CnP

(n=65)

Median PFS,

mo (95%CI)

8.3

(7.16, 10.35)

6.0

(5.29, 6.93)

HR (95%CI) 0.61 (0.43, 0.85)

Atezo + CnP

(n=235)

CnP

(n=121)

Median PFS,

mo (95%CI)

6.2

(5.52, 7.16)

4.7

(4.11, 5.72)

HR (95%CI) 0.72 (0.56, 0.91)

PF

S, %

100

80

60

40

20

0

0

88

42

2

76

32

4

64

23

No. at risk

Atezo+CnP

Chemo

6

43

18

8

34

11

10

28

9

12

22

4

14

17

1

16

12

18

8

20

6

22

4

24

3

26 28

PD-L1-high

TC3 or IC3

Time, months

30

PD-L1-low

TC1/2 or IC1/2

PF

S, %

100

80

60

40

20

0

0

128

65

2

113

49

4

103

42

6

83

30

8

64

20

10

51

12

12

42

9

14

28

5

16

16

3

18

9

1

20

6

22

4

24

2

26 28

Time, months

30

PD-L1-negative

TC0 and IC0

PF

S, %

100

80

60

40

20

0

0

235

121

2

194

93

4

162

71

306

116

42

8

85

30

10

59

19

12

55

16

14

38

9

16

34

4

18

24

4

20

17

3

22

5

2

24

2

1

26

1

28

Time, months

LBA54: IMpower132: efficacy of atezolizumab (atezo) + carboplatin

(carbo)/cisplatin (cis) + pemetrexed (pem) as 1L treatment in key subgroups with

stage IV non-squamous non-small cell lung cancer (NSCLC) – Barlesi F, et al

• Study objective

– To investigate the PFS benefit of atezolizumab combined with carboplatin or

cisplatin + pemetrexed in patients from IMpower132 in an exploratory analysis

stratified by race, age, smoking history or liver metastasis at baseline

Barlesi F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA54

Exploratory endpoints

• Clinical and biomarker subgroup analysis

R

1:1

PD/

loss of

clinical

benefit

Stratification

• Sex

• Smoking status

• ECOG PS

• Chemotherapy regimen

Key patient inclusion

criteria

• Stage IV non-

squamous NSCLC

• Chemotherapy-naïve

• Without EGFR or ALK

genetic alteration

(n=578) Carboplatin or cisplatin +

pemetrexed*

Atezolizumab +

carboplatin or cisplatin +

pemetrexed*

Pemetrexed*

Atezolizumab +

pemetrexed*

Induction therapy (4 or 6 cycles) Maintenance therapy

*Atezolizumab 1200 mg IV q3w; carboplatin AUC 6 mg/mL/min IV q3w;

cisplatin 75 mg/m2 IV q3w; pemetrexed 500 mg/m2 IV q3w

PD/

loss of

clinical

benefit

LBA54: IMpower132: efficacy of atezolizumab (atezo) + carboplatin

(carbo)/cisplatin (cis) + pemetrexed (pem) as 1L treatment in key subgroups with

stage IV non-squamous non-small cell lung cancer (NSCLC) – Barlesi F, et al

• Key results

• Conclusion– Atezolizumab added to carboplatin/cisplatin + pemetrexed improved PFS across several

subgroups including patients from Asia, never smokers, those who were older and those

without liver metastases at baseline, but currently has not shown improvement in OSBarlesi F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA54

PF

S, %

Time, months

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2019 21 22

Median PFS (95%CI), mos

HR (95%CI)

Non-Asian patients

Atezolizumab + PP

6.9 (5.9, 8.1)

PP

5.0 (4.2, 5.7)0.65 (0.53, 0.81)

Atezolizumab + PP (n=221)

PP (n=221)

PF

S, %

Time, months

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2019 21 22


HR (95%CI)

Asian patients

Atezolizumab + PP

10.2 (8.3, 15.3)

PP

5.3 (4.3, 6.7)

0.42 (0.28, 0.63)


PP (n=65)

PF

S, %

Time, months

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2019 21 22


HR (95%CI)

Former/current smokersAtezolizumab + PP

7.5 (6.3, 8.4)

PP

5.1 (4.3, 5.6)

0.61 (0.50, 0.74)


PP (n=226)

PF

S, %

Time, months

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2019 21 22


HR (95%CI)

Never smokersAtezolizumab + PP

8.6 (6.5, 15.4)

PP

5.5 (4.0, 8.3)

0.49 (0.28, 0.87)


PP (n=30)

LBA55: Primary 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 nonsmall cell lung cancer (NSCLC)

– Kim ES, et al

• Study objective

– To investigate the use of bTMB as a predictive biomarker for atezolizumab

monotherapy in 1L NSCLC

Kim ES, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA55

Co-primary endpoints

• Investigator-assessed ORR and PFS

(using pre-specified bTMB cut-off of 16)

Secondary endpoints

• Safety, investigator-assessed DoR and OS

Atezolizumab 1200 mg q3w

(biomarker evaluable

population n=119)

PD/toxicity/

loss of

benefit


• Stage IIIB/IVA locally advanced

or metastatic NSCLC

• Immunotherapy naïve

• PD-L1 unselected

• ECOG PS 0–1

(n=152)




– Kim ES, et al

• Key results

Kim ES, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA55

ORR per RECIST v1.1

bTMB subgroups

14.5%16.3%

28.6%

36.8%

10.1%

5.7% 4.4% 5%

0

5

10

15

20

25

30

35

40

Ove

rall

resp

on

se r

ate

, %

ITT

(N=152)

BEP

(n=119)

High

(n=49)

Low

(n=70)

High

(n=28)

Low

(n=91)

High

(n=19)

Low

(n=100)

PR CR

≥10 cut-off ≥16 cut-off ≥20 cut-off

p<0.0001

p=0.0002

p=0.0595




– Kim ES, et al


• Conclusion

– In patients with NSCLC treated with atezolizumab monotherapy a numerical

improvement in outcomes was seen in those with a bTMB cut-off of ≥16 Kim ES, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA55

bTMB high

(n=28)

bTMB low

(n=91)

Median PFS,

months (90%CI)4.6 (1.6, 11.0) 3.7 (2.6, 4.3)

HR (90%CI) 0.66 (0.42, 1.02)

p-value 0.12

PFS in bTMB high (≥16) vs. low (<16) subgroups

Pro

gre

ssio

n-f

ree s

urv

iva

l, %

Time, months

100

80

60

40

20

0

0

28

91

1

27

86

2

17

56

3

14

43

No. at risk

High (≥16)

Low (<16)

High, ≥16 (n=28)

Low, <16 (n=91)

6-month PFS

41.6% vs. 32.8%

9-month PFS

37.4% vs. 9.7%

4

14

39

5

13

28

6

11

21

7

8

11

8

8

5

9

8

4

10

5

3

11

4

3

12

3

1

13

2

14

1

LBA58: Intracranial efficacy of brigatinib (BRG) vs crizotinib (CRZ) in the

phase 3 ALTA-1L trial – Popat S, et al

• Study objective

– To investigate the intracranial efficacy of brigatinib vs. crizotinib in ALK inhibitor-

naïve patients with advanced ALK+ NSCLC in the ATLA-1L study

Popat S, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA58

PD/toxicity/

discontinuation

Stratification

• Brain metastases at baseline

• Prior chemotherapy


• Stage IIIb/IV NSCLC

• ALK+ (based on local ALK

testing)

• No prior ALK inhibitor

• ≤1 prior systemic therapy

• Brain metastases were

allowed

(n=275)

Crizotinib 250 mg bid

(n=138)

Brigatinib 180 mg/day

(90 mg/day for 7 day lead-in)

(n=137)

Primary endpoint

• PFS (BIRC-assessed)

Secondary endpoints

• ORR, intracranial ORR, intracranial PFS,

OS, safety

PD*/toxicity/

discontinuation

*Crossover to brigatinib permitted at PD

R

1:1

LBA58: Intracranial efficacy of brigatinib (BRG) vs crizotinib (CRZ) in the

phase 3 ALTA-1L trial – Popat S, et al

• Key results

• Conclusion

– In patients with advanced ALK+ NSCLC, brigatinib demonstrated superior intracranial

efficacy vs. crizotinib, with significantly higher intracranial response and improved

intracranial PFS in those with brain metastasesPopat S, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA58

Whole body BIRC-assessed PFS by brain metastases at baseline

Treatment

Pts with

events, n (%)

Median PFS,

months

(95%CI)

1-year PFS rate,

% (95%CI)

Brigatinib (n=40) 8 (20) NR 75 (56, 87)

Crizotinib (n=41) 24 (59) 5.6 (3.8, 11.1) 25 (8, 46)

With brain metastases

PF

S,

% o

f p

atie

nts

Time, months

100

80

60

40

20

00 3 6 9 12 15 18

HR 0.20 (95%CI 0.09, 0.46)

p<0.0001 by log-rank test

Brigatinib (n=40)

Crizotinib (n=41)

Treatment

Pts with

events, n (%)

Median PFS,

months

(95%CI)

1-year PFS rate,

% (95%CI)

Brigatinib (n=97) 28 (29) NR 63 (50, 74)

Crizotinib (n=41) 39 (40) 11.1 (9.2, NR) 49 (36, 61)

PF

S,

% o

f p

atie

nts

Time, months

100

80

60

40

20

00 3 6 9 12 15 18

HR 0.72 (95%CI 0.44, 1.18)

p=0.20 by log-rank test

Brigatinib (n=97)

Crizotinib (n=97)

Without brain metastases

1377O: Phase 2 study of tepotinib + gefitinib (TEP+GEF) in MET-positive

(MET+)/epidermal growth factor receptor (EGFR)-mutant (MT) non-small lung

cancer (NSCLC) – Wu Y, et al

• Study objective

– To investigate the efficacy and safety of tepotinib + gefitinib vs. chemotherapy in

Asian patients with advanced MET+/EGFR+T790M- NSCLC

Wu Y, et al. Ann Oncol 2018;29(suppl 5):Abstr 1377O

Primary endpoint

• PFS (investigator-assessed)

Secondary endpoints

• ORR, safety

R*

PD/

toxicity

PD/

toxicity

Stratification

• MET+ type (IHC2+, IHC3+ or MET amplification)

• Prior EGFR-TKI therapy


• Locally-advanced/metastatic IV

NSCLC

• EGFR+, T790M–, MET+

• Asian

• Resistance to prior EGFR TKI

• No prior HGF/MET pathway-

directed therapy

(n=55)

Chemotherapy:

Pemetrexed 500 mg/m2 q3w+

cisplatin 75 mg/m2 or

carboplatin AUC 5 or 6 q3w

(n=24)

Tepotinib 500 mg/day

+ gefitinib 250 mg/day

(n=31)

*Initially 1:1 and changed to 2:1 at protocol amendment (30 Sept 2016)




• Key results

– In the MET IHC3+ subgroup (n=34) median PFS was 8.3 months with tepotinib + gefitinib

and 4.4 months with chemotherapy (HR 0.35 [95%CI 0.17, 0.74])

– In the MET amplification subgroup (n=19) median PFS was 21.2 months with tepotinib +

gefitinib and 4.2 months with chemotherapy (HR 0.17 [95%CI 0.05, 0.57])


Tepotinib + gefitinib

(n=31)

Chemotherapy

(n=24)

Events 23 19

Median PFS, months (90%CI) 4.9 (3.9, 6.9 4.4 (4.2, 6.8)

Stratified HR (90%CI) 0.71 (0.36, 1.39)

KM

estim

ate

fo

r P

FS

Time, months

1.0

0.8

0.6

0.4

0.2

0.0

0

31

24

3

20

16

6

11

7

12

1

0

18

1

0

24

0

0

30

0

0

No. at risk

Tep + gef

Chemo

Investigator-assessed PFS (ITT population)

Tepotinib + gefitinib

Chemotherapy




• Key results

– Tepotinib + gefitinib was generally well tolerated, with TEAEs leading to discontinuation in

9.7% of patients compared with 4.3% in the chemotherapy group

• Conclusion

– In patients with advanced NSCLC and MET amplifications, improvements in PFS were

observed with tepotinib + gefitinib, indicating that MET may be considered as a biomarker

for treatment with tepotinib


Tepotinib + gefitinib Chemotherapy

Odds ratio

(90%CI)

Responders*

n/N

ORR, %

(90%CI)

Responders*

n/N

ORR, %

(90%CI)

Overall (n=55) 14/3145.2

(29.7, 61.3) 8/24

33.3

(17.8, 52.1)

1.99

(0.56, 6.87)

MET IHC3+ (n=34) 13/1968.4

(47.0, 85.3)5/15

33.3

(14.2, 57.7)

4.33

(1.03, 18.33)

MET amplification (n=19) 8/1266.7

(39.1, 87.7)3/7

42.9

(12.9, 77.5)

2.67

(0.37, 19.56)

*No confirmation required

1379PD: Impact of the EML4-ALK variant on the efficacy of alectinib (ALC) in

untreated ALK+ advanced NSCLC (aNSCLC) in the global phase III ALEX study

– Dziadziuszko R, et al

• Study objective

– To assess efficacy of alectinib vs. crizotinib in the ALEX trial in patients with

ALK+ advanced NSCLC stratified by EML4-ALK fusion variants

• Methods

– FOUNDATIONACT and FOUNDATIONONE NGS platforms were used to

determine the ALK fusion variants in plasma and tissue BEP subgroups

Dziadziuszko R, et al. Ann Oncol 2018;29(suppl 5):Abstr 1379PD


• ALK+ NSCLC

• No prior treatment for

NSCLC

• ECOG PS 0–2

(n=303)

Crizotinib 250 mg

bid

Alectinib 600 mg

bid

PD/death/

withdrawal

PD/death/

withdrawal

R

1:1

1379PD: Impact of the EML4-ALK variant on the efficacy of alectinib (ALC) in

untreated ALK+ advanced NSCLC (aNSCLC) in the global phase III ALEX study

– Dziadziuszko R, et al

• Key results

• Conclusion

– In patients with ALK+ NSCLC alectinib demonstrated greater efficacy than

crizotinib, regardless of EML4-ALK variant

Dziadziuszko R, et al. Ann Oncol 2018;29(suppl 5):Abstr 1379PD

PFS (investigator-assessed)

Plasma BEP subgroup Tissue BEP subgroup

ALK V1 ALK V2 ALK V3a/b

Su

rviv

al p

rob

ab

ility

1.0

0.8

0.6

0.4

0.2

3 6 12 15 18 21 2490

0.0

Time, months

EML4-ALK V1: 7.4

EML4-ALK V2: 8.8

EML4-ALK V3a/b: 9.1

Median PFS, months

Crizotinib

1.0

0.8

0.6

0.4

0.2

0.0

Time, months

EML4-ALK V1: NE

EML4-ALK V2: 14.9

EML4-ALK V3a/b: NE

Median PFS, months

Alectinib

3 6 1215 18212490 2730

1.0

0.8

0.6

0.4

0.2

3 6 12 15 18 21 2490

0.0

Time, months

EML4-ALK V1: 12.9

EML4-ALK V2: 8.8

EML4-ALK V3a/b: 14.6

Median PFS, months

Crizotinib

1.0

0.8

0.6

0.4

0.2

0.0

EML4-ALK V1: NE

EML4-ALK V2: 11.5

EML4-ALK V3a/b: NE

Median PFS, months

Alectinib

Time, months

3 6 1215 18212490 2730

1380PD: Efficacy of lorlatinib in patients (pts) with ROS1-positive advanced

non-small cell lung cancer (NSCLC) and ROS1 kinase domain mutations

– Solomon BJ, et al

• Study objective

– To investigate molecular profiling of patients with ROS1+ advanced NSCLC in

the B7461001 study of lorlatinib

• Methods

– Patients with locally advanced or metastatic NSCLC with ROS1 rearrangements

were enrolled in the phase 1/2 study

• Patients were treatment-naïve in the advanced setting of PD after ≥1 prior ROS1

inhibitor (phase 1) or any number of prior therapies (phase 2)

– Lorlatinib was orally administered in continuous 21-day cycles with escalating

doses (10 mg/day to 100 mg bid) in phase 1 and 100 mg/day in phase 2

– Molecular profiling of tumour tissue and blood was performed

• All patients had tissue samples collected before enrolment and tissue collection was

encouraged on PD; tumour tissue was analysed with a ROS1 kinase domain mutation-

focused NGS panel

• Blood samples were collected at screening, at the beginning of cycle 3, and at the end-

of-treatment visit for circulating-free DNA (cfDNA) analysis using an NGS panel or

digital PCR

Solomon BJ, et al. Ann Oncol 2018;29(suppl 5):Abstr 1380PD

1380PD: Efficacy of lorlatinib in patients (pts) with ROS1-positive advanced

non-small cell lung cancer (NSCLC) and ROS1 kinase domain mutations

– Solomon BJ, et al

• Key results

• Conclusions

– ROS1 kinase domain mutations occurred in 10–14% of samples

– In patients with ROS1 kinase domain resistance mutations, lorlatinib exhibited

some anti-tumour activitySolomon BJ, et al. Ann Oncol 2018;29(suppl 5):Abstr 1380PD

ORR by presence of ROS1 mutations

Percentage change in tumour size from baseline

in patients with ≥1 ROS1 kinase domain mutation

ROS1 TKI-naïve

(n=17)

Prior crizotinib

(n=36)*

Prior non-

crizotinib TKI

or ≥2 TKIs

(n=5)

No

mutation

(n=17)

≥1

mutation

(n=0)

No

mutation

(n=27)

≥1

mutation

(n=8)

No

mutation

(n=4)

≥1

mutation

(n=1)

Best overall response, n (%)

CR 2 (11.8) – 1 (3.7) 0 0 0

PR 9 (52.9) – 8 (29.6) 2 ( 25.0) 0 0

SD 5 (29.4) – 8 (29.6) 5 (62.5) 3 (75.0) 1 (100)

PD 1 (5.9) – 3 (11.1) 1 (12.5) 1 (25.0) 0

Indeterminate 0 – 7 (25.9) 0 0 0

Responders, n (%) 11 (64.7) – 9 (33.3) 2 (25.0) 0 0

*One patient had a non-analysable or uninformative sample-100

-80

-60

-40

-20

0

20

40

60

80

100

Best perc

enta

ge c

hange fro

m b

aselin

e

Partial response

Stable disease

Progressive disease

Best overall response

ROS1 kinase domain mutation in:

cfDNA

Tumour tissue

Both cfDNA and tumour tissue

1381PD Gefitinib with or without pemetrexed in nonsquamous non-small cell

lung cancer with EGFR mutation: Final overall survival results from a

randomized phase II study – Chih-Hsin Yang J, et al

• Study objective

– To investigate the efficacy and safety of pemetrexed + gefitinib vs. gefitinib in

non-squamous NSCLC with EGFR mutations

Chih-Hsin Yang J et al. Ann Oncol 2018;29(suppl 5):abstr 1381PD


• Stage IV or recurrent non-squamous

NSCLC

• Activating EGFR mutations

• East Asian ≥18 years (≥20 years in Japan

and Taiwan)

• No prior systemic therapy for stage IV or

recurrent NSCLC

• ECOG PS 0–1

(n=191)

Gefitinib 250 mg/day

(n=65)

Pemetrexed 500 mg/m2 q3w

+ gefitinib 250 mg/day

(n=126)

Primary endpoint

• PFS

Secondary endpoints

• OS, time to progressive disease, tumour response rates,

DoR, QoL, biomarker analysis, safety

R

2:1

1381PD Gefitinib with or without pemetrexed in nonsquamous non-small cell

lung cancer with EGFR mutation: Final overall survival results from a

randomized phase II study – Chih-Hsin Yang J, et al

• Key results

– 36 (28.6%) patients had TEAEs in the pemetrexed + gefitinib group and

7 (10.8%) in gefitinib group

• Conclusion

– In patients with EGFR+ advanced NSCLC pemetrexed + gefitinib significantly

prolonged PFS, with a numerically longer, but not statistically significant,

improvement in OSChih-Hsin Yang J et al. Ann Oncol 2018;29(suppl 5):abstr 1381PD

Updated PFSOS

Time, months

Pro

babili

ty

1.0

0.8

0.6

0.4

0.2

0.0

0

126

65

6

118

64

12

106

53

18

92

45

24

79

36

30

66

27

36

58

26

42

51

19

48

43

15

54

30

8

60

3

2

66

1

0

72

0

0

No.at risk

P+G

G

Median OS, months (95%CI)43.4 months (33.4, 50.8)

36.8 months (26.7, 42.6)

Pemetrexed + gefitinib

Gefitinib

Adjusted HR 0.77 (95%CI 0.5, 1.2)

1-sided p=0.105

Time, months

Pro

babili

ty

1.0

0.8

0.6

0.4

0.2

0.0

0

126

65

6

98

51

12

70

29

18

50

18

24

29

9

30

19

6

36

14

4

42

12

2

48

7

2

54

5

1

60

0

0

No.at risk

P+G

G

Median PFS, months (95%CI)

16.2 months (12.6, 18.7)

11.1 months (9.7, 13.8)

Pemetrexed + gefitinib

Gefitinib

Adjusted HR 0.67 (95%CI 0.5, 0.9)

1-sided p=0.009

1382PD: Phase III study of gefitinib (G) versus gefitinib+carboplatin+pemetrexed

(GCP) as 1st-line treatment for patients (pts) with advanced non-small cell lung

cancer (NSCLC) with EGFR mutations (NEJ009) – Seike M, et al

• Study objective

– To investigate the efficacy and safety of gefitinib + carboplatin + pemetrexed vs.

gefitinib in patients with non-squamous NSCLC

Seike M, et al. Ann Oncol 2018;29(suppl 5):Abstr 1382PD

Primary endpoints

• PFS, PFS2, OS

Secondary endpoints

• ORR, safety, QoL

Gefitinib +

pemetrexed

q3w

Platinum-

based regimen

Stratification

• Sex

• EGFR mutation

• Smoking history


• Treatment naïve patients

with non-squamous IIIB/IV

NSCLC

• EGFR+

• PS 0–1

(n=345) Gefitinib 250 mg/day

Gefitinib 250 mg/day +

carboplatin AUC6 +

pemetrexed 500 mg/m2

R

1:1

Induction phase Maintenance phase

1382PD: Phase III study of gefitinib (G) versus gefitinib+carboplatin+pemetrexed

(GCP) as 1st-line treatment for patients (pts) with advanced non-small cell lung

cancer (NSCLC) with EGFR mutations (NEJ009) – Seike M, et al

• Results

• Conclusions

– PFS and OS were significantly improved in patients treated with combination

therapy of gefitinib + carboplatin + pemetrexed

– There was no difference in PFS2

Seike M, et al. Ann Oncol 2018;29(suppl 5):Abstr 1382PD

PFS

Gefitinib Gefitinib + carb + pem

Median PFS, months (95%CI) 11.2 (9.0, 13.4) 20.9 (18.0, 24.0)

HR (95%CI); p-value 0.490 (0.388, 0.620); <0.001

Gefitinib Gefitinib + carb + pem

mOS, months (95% CI) 38.8 (31.1, 47.3) 50.9 (41.8, 62.5)

HR (95%CI); p-value 0.72 (0.58, 0.95); 0.02

Updated OS

Overa

ll surv

ival, %

Time, months

100

80

60

40

20

0

0

172

170

12

153

162

24

115

131

36

86

106

48

62

77

60

26

29

No. at risk

Gefitinib

Gef + carb + pem

Pro

gre

ssio

n-f

ree s

urv

ival, %

Time, months

100

80

60

40

20

0

0

172

169

12

78

123

24

29

68

36

11

37

48

2

10

60

0

2

No. at risk

Gefitinib

Gef + carb + pem

1385PD: A randomised phase III trial evaluating the addition of denosumab to

standard first-line treatment in advanced NSCLC – the ETOP and EORTC

SPLENDOUR trial – Peters S, et al

• Study objective

– To investigate the efficacy of denosumab as an add-on to standard 1L doublet

chemotherapy + BSC in patients with NSCLC in the SPLENDOUR study

Peters S, et al. Ann Oncol 2018;29(suppl 5):Abstr 1385PD

Primary endpoint

• OS

Secondary endpoints

• PFS, OS by bone metastases, safety

Stratification

• Bone metastases

• PS

• Histology

• Region


• Stage IV NSCLC

(n=514)

Chemotherapy (4–6 cycles) + BSC*

(n=259)

Denosumab 120 mg every 3–4 weeks

+ chemotherapy (4–6 cycles)

(n=255)

*Zoledronic acid in case of skeletal involvement

R

1:1




• Key results


Non-parametric Cox model

Treatment

Events/

patients

Median, years

(95%CI)

1 year, %

(95%CI)

HR

(95%CI)

p-value

(Score test)

Denosumab 177/2580.68

(0.62, 0.87)

40.2

(33.8, 46.5)

0.96

(0.78, 1.18)

BSC 178/2550.73

(0.63, 0.92)

40.2

(33.8, 46.5)1.00 0.689

OS PFS


Treatment

Events/

patient

Median, years

(95%CI)

1 year, %

(95%CI)

HR

(95%CI)

p-value

(Score test)


(0.35, 0.44)

13.1

(9.1, 17.9)

0.97

(0.81, 1.17)

BSC 227/2540.39

(0.34, 0.44)

9.3

(6.0, 13.6)1.00 0.777

OS

, %

100

80

60

40

20

00 2 3 41

29

23

2

0

83

82

259

255

Years

PF

S, %

100

80

60

40

20

00 20 28 3612

6

5

4

2

29

19

259

254

Months

4 24 3216

5

4

0

1

13

10

140

138

8

55

50

Denosumab

BSC

Denosumab

BSC

No. at risk

Denosumab

BSC

No. at risk

Denosumab

BSC





• Conclusions

– Denosumab added to 1L platinum-based chemotherapy did not improve OS

– There were no safety concerns with denosumab



Treatment

Events/

patients

Median, years

(95%CI)

1 year, %

(95%CI)

HR

(95%CI)

p value

(Score test)


(0.46, 0.73)

34.4

(26.1, 43.0)

1.03

(0.78, 1.37)

BSC 98/1370.61

(0.51, 0.82)

35.8

(27.5, 44.2)1.00 0.816

OS

Bone metastases

OS

No bone metastases


Treatment

Events/

patients

Median (years)

(95%CI)

1 year, %

(95%CI)

Hazard Ratio

(95%CI)

P-Value

(Score test)


(0.67, 1.35)

46.9

(37.2, 55.9)

0.89

(0.65, 1.22)

BSC 80/1180.92

(0.71, 1.05)

45.4

(35.7, 54.6)1.00 0.483

OS

, %

100

80

60

40

20

00 20 28 4012

20

15

14

7

36

41

N

138

137

Months

4 24 3216

17

13

5

3

27

25

87

95

8

50

53

36

2

0

OS

, %

100

80

60

40

20

00 20 28 3612

19

14

7

6

47

41

N

121

118

Months

4 24 3216

12

10

2

2

35

24

95

87

8

65

66

Denosumab

BSCDenosumab

BSC

No. at risk

Denosumab

BSC

No. at risk

Denosumab

BSC

Advanced NSCLCNot radically treatable stage III and stage IV

Later lines

LBA63: Long-term survival in patients (pts) with advanced NSCLC in the

KEYNOTE-010 study overall and in pts who completed 2 years of

pembrolizumab (pembro) – Herbst RS, et al

• Study objective

– Long-term follow-up of KEYNOTE-010 investigating pembrolizumab vs.

docetaxel in patients with advanced NSCLC and PD-L1 TPS ≥1% who had

progressed after platinum-containing chemotherapy

Herbst RS, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA63

Endpoints in TPS ≥50%

and ≥1% populations

• OS, PFS

• ORR, DoR, safety

Stratification

• ECOG PS (0 vs. 1)

• Region (East Asia vs. non-East Asia)

• PD-L1 status (TPS ≥50% vs. 1–49%)

Pembrolizumab 10 mg/kg q3w

for 24 months

R

1:1:1

Docetaxel 75 mg/m2 q3w

Pembrolizumab 2 mg/kg q3w

for 24 monthsKey patient inclusion criteria

• Advanced NSCLC

• PD-L1 TPS ≥1%

• Progression after ≥1 line of

chemotherapy

• No active brain metastases




• Key results

Herbst RS, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA63

Ove

rall

su

rviv

al, %

100

80

60

40

20

00

290

152

5

229

97

10

178

58

15

149

39

20

131

29

25

115

23

35

94

18

40

50

10

45

26

8

50

1

1

55

0

0

60

0

0

30

101

21

Time, months

35%

13%

N

Events,

n (%)

Median OS,

mo (95%CI)

HR (95%CI);

p-value

Pembrolizumab 290 199 (69) 16.9 (12.3, 21.4)0.53 (0.42, 0.66);

<0.00001Docetaxel 152 127 (84) 8.2 (6.4, 9.8)

PD-L1 TPS ≥50% population

Ove

rall

su

rviv

al, %

100

80

60

40

20

00

690

343

5

523

226

10

374

135

15

295

90

20

248

57

25

211

44

35

151

35

40

86

20

45

45

13

50

5

2

55

0

0

60

0

0

30

171

40

Time, months

23%

11%

N

Events,

n (%)

Median OS,

mo (95%CI)

HR (95%CI);

p-value

Pembrolizumab 690 548 (79) 11.8 (10.4, 13.1)0.69 (0.60, 0.80);

<0.00001Docetaxel 343 295 (86) 8.4 (7.6, 9.5)

PD-L1 TPS ≥1% population

OS

No. at risk

Pembro

Docetaxel

No. at risk

Pembro

Docetaxel





– Overall, median treatment duration was 3.5 months (range 0.03–31.7) in the

pembrolizumab group (n=682) and 2.0 months (range 0.03–26.4) in the docetaxel

group (n=309)

– 79 patients completed 35 cycles or 2 years of pembrolizumab with a median

follow-up of 43.4 months (range 35.7–49.8)

• 75/79 (95%) patients had a CR or PR

– 48/75 (64%) patients had ongoing response, median DoR NR (range 4–46+ months)

• Median OS was NR (95%CI NR, NR)

– The Kaplan-Meier estimate of 36-month OS rate was 98.7% (95%CI 91.2, 99.8)

• 25/79 (32%) patients had PD after stopping 35 cycles or 2 years of pembrolizumab

– In 14 patients who received a second course of pembrolizumab after 35 cycles or

2 years of treatment and subsequent PD, 6 (43%) had PR and 5 (36%) had SD

• Conclusions

– In patients with PD-L1-expressing advanced NSCLC, pembrolizumab continued

to prolong OS compared with docetaxel

– In patients who completed 2 years of pembrolizumab AEs were manageable and

responses were durable Herbst RS, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA63

1378O: ARCTIC: durvalumab + tremelimumab and durvalumab monotherapy vs

SoC in ≥3L advanced NSCLC treatment – Kowalski DM, et al

• Study objective

– To investigate the efficacy and safety of durvalumab vs. SoC and the combination of

durvalumab + tremelimumab vs. SoC in subgroups based on PD-L1 expression (≥25% or

<25%) in the ARCTIC study

Kowalski DM, et al. Ann Oncol 2018;29(suppl 5):Abstr 1378O

Stratification

• Planned SoC, histology

Study A

PD-L1 TC

≥25%

(n=126)

Study B

PD-L1 TC

<25%

(n=469)

R

1:1 SoC*

(n=64)

Durvalumab 10 mg/kg q2w for up to 12 mo

(n=62)


• Stage IIIB/IV NSCLC

• ≥2 prior treatments

• Immunotherapy-naïve

• EGFR/ALK wild-type

• WHO PS 0/1 SoC*

(n=118)

Durvalumab 20 mg/kg + tremelimumab 1 mg/kg q4w for 12 weeks then durvalumab

10 mg/kg for 34 weeks (n=174)

Tremelimumab 10 mg/kg q4w for 24 weeks

then q12w for 24 weeks (n=60)

R

3:2:2:1

*Erlotinib, gemcitabine, or vinorelbine

Durvalumab 10 mg/kg q2w for up to 12 mo

(n=117)

Primary endpoint

• OS, PFS (investigator assessed

Secondary endpoints

• 1-year OS and PFS rates, ORR, safety



• Key results

Kowalski DM, et al. Ann Oncol 2018;29(suppl 5):Abstr 1378O

Durvalumab

(n=62)

SoC

(n=64)

Events, n (%) 48 (77.4) 55 (85.9)

Median OS,

months (95%CI)

11.7

(8.2, 17.4)

6.8

(4.9, 10.2)

HR (95%CI) 0.63 (0.42, 0.93)Pro

babili

ty o

f O

S

Time from randomisation, months

1.0

0.8

0.6

0.4

0.2

0.0

0

62

64

3

53

45

6

45

35

9

37

27

No. at risk

Durvalumab

SoC

Durvalumab

SoC

12

30

19

15

25

15

18

21

12

21

18

10

24

16

8

27

6

4

30

3

0

33

0

OS (PD-L1 TC ≥25%)

31.3%

49.3%

Durvalumab

(n=62)

SoC

(n=64)

Events, n (%) 58 (93.5) 58 (90.6)

Median PFS,

months (95%CI)

3.8

(1.9, 5.6)

2.2

(1.9, 3.7)

HR (95%CI) 0.71 (0.49, 1.04)

Pro

babili

ty o

f P

FS


1.0

0.8

0.6

0.4

0.2

0.0

0

62

64

3

34

25

6

22

14

9

18

10

No. at risk

Durvalumab

SoC

Durvalumab

SoC

12

12

5

15

10

2

18

7

2

21

5

2

24

5

1

27

1

0

30

0

0

33

PFS (PD-L1 TC ≥25%)

9.9%

19.4%

Study A




• Conclusions

– Clinically meaningful improvement in OS was seen with durvalumab vs. SoC in

the PD-L1 TC ≥25% subgroup

– Combination therapy led to non-significant improvement in OS vs. SoC in PD-L1

TC <25% subgroupKowalski DM, et al. Ann Oncol 2018;29(suppl 5):Abstr 1378O

Pro

babili

ty o

f O

S


1.0

0.8

0.6

0.4

0.2

0.0

0

174

118

3

137

97

6

111

70

9

93

55

No. at risk

D + T

SoC

Durvalumab + tremelimumab

SoC

12

82

44

15

67

35

18

56

27

21

33

14

24

21

6

27

7

1

30

0

0

33

0

0

OS (PD-L1 TC <25%)

38.8%

49.5%Durvalumab + tremelimumab

SoC

Pro

babili

ty o

f O

S


0.8

0.6

0.4

0.2

0.0

0

174

118

3

90

51

6

49

25

9

41

13

No. at risk

D + T

SoC

12

31

6

15

23

3

18

17

3

21

11

1

24

9

0

27

1

0

30

0

0

8.0%20.6%

D + T (n=174) SoC (n=118)

Events, n (%) 118 (67.8) 90 (76.3)

mOS, months (95%CI) 11.5 (8.7, 14.1) 8.7 (6.5, 11.7)

HR (95%CI) 0.80 (0.61, 1.05), p=0.109

D + T (n=174) SoC (n=118)

Events, n (%) 146 (83.9) 92 (78.0)

mPFS, months (95%CI) 3.5 (2.3, 4.6) 3.5 (1.9, 3.9)

HR (95%CI) 0.77 (0.59, 1.01), p=0.056

PFS (PD-L1 TC <25%)Study B1.0

Other malignancies

SCLC, mesothelioma and thymic epithelial tumours

1664O: A randomized non-comparative phase II study of anti–PD-L1

atezolizumab or chemotherapy as second-line therapy in patients with small

cell lung cancer: results from the IFCT-1603 Trial – Pujol J, et al

• Study objective

– To investigate the activity of atezolizumab as systemic therapy in patients with

SCLC who have progressed after 1L platinum-based chemotherapy

Pujol J, et al. Ann Oncol 2018;29(suppl 5):Abstr 1664O

Primary endpoint

• ORR at 6 weeks (investigator assessed)

R

2:1

PD

PD

Stratification

• Sensitive vs. refractory disease

• PS (0–1 vs. 2)

• Limited vs. extensive disease

• Gender


• ED or LD SCLC

• Progressive disease after

1L chemotherapy

• No brain metastases

• PS 0–2

(n=73)

Chemotherapy:

topotecan (oral or IV) q3w or

carboplatin-etoposide q3w*

(n=24)

Atezolizumab 1200 mg q3w

(n=49)

*Maximum 6 cycles




• Key results


Atezolizumab

(n=43)

Chemotherapy

(n=20)

Total

(n=64)

ORR at 6 weeks, n (%)

[95%CI]

1 (2.3)

[0.0, 6.8]

2 (10)

[0.0, 23.1]

3 (4.8)

[0.0, 9.9]

DCR, n (%)

[95%CI]

9 (20.9)

[8.8, 33.1]

13 (65)

[44.1, 85.9]

22 (34.9)

[23.1, 46.7]

Progression, n (%)

[95%CI]

30 (69.8)

[56.0, 83.5]

6 (30)

[9.9, 50.1]

36 (57.1)

[44.9, 69.4]

Not done/not evaluable,

n (%) [95%CI]

4 (9.3)

[0.6, 18.0]

1 (5.0)

[0.0, 14.6]

5 (7.9)

[1.3, 14.6]





• Conclusions

– In pre-treated patients with progressive SCLC, the efficacy of atezolizumab was

inferior to chemotherapy

– ORR at 6 weeks with atezolizumab monotherapy was 2.3% and median PFS

was 1.4 months

– Therefore, the planned phase 3 portion of the study was not activated


HR (adjusted) atezolizumab group = 2.26 (95%CI 1.30, 3.93); p=0.004

PFS (ITT population)

Time, months0 1 2 3 5 6 7 8 94

Median follow-up: 13.7 months (95%CI 12.7, NR)

Chemotherapy (n=24): 4.3 (1.5, 5.9); 21 events, 3 censored

Atezolizumab (n=49): 1.4 (1.2, 1.5); 46 events, 3 censored

6-month PFS rate for atezolizumab group: 6.3% [0.0, 13.1]

Pro

gre

ssio

n-f

ree s

urv

ival

1.0

0.8

0.6

0.4

0.2

0

Median PFS, months (95%CI)

1665PD: Preliminary efficacy of durvalumab plus tremelimumab in platinum-

refractory/resistant EDSCLC from arm A of the phase II BALTIC study

– Bondarenko I, et al

• Study objective

– To determine the efficacy and safety of durvalumab + tremelimumab in patients

from the BALTIC study with extensive-disease (ED) SCLC who have platinum-

refractory or -resistant disease

Primary endpoint

• ORR

Secondary endpoints

• DCR at 12 weeks, DoR, TTR, PFS, OS,

safety

Cohort A:

Durvalumab 1500 mg +

tremelimumab 75 mg q4w

for up to 4 months, then

durvalumab 1500 mg q4w

(n=10)

Interim

analysis*


• ED-SCLC

• Refractory or resistant to 1L

chemotherapy

• Life expectancy ≥8 weeks

• No prior exposure to immunotherapy

• WHO/ECOG PS 0–1

Bondarenko I, et al. Ann Oncol 2018;29(suppl 5):Abstr 1665PD*Interim ORR analysis followed by expansion stage with n=20

1665PD: Preliminary efficacy of durvalumab plus tremelimumab in platinum-

refractory/resistant EDSCLC from arm A of the phase II BALTIC study

– Bondarenko I, et al

• Key results

– Confirmed ORR was 9.5% (95%CI 1.2, 30.4) with PR in 2 patients

– Median PFS was 1.9 months (95%CI 1.8, 4.3)

– Median OS was 6.0 months (95%CI 1.9, 12.0)

• Conclusion

– In patients with platinum-refractory ED-SCLC, durvalumab + tremelimumab

showed promising activity, with a safety profile consistent with previous reports

Bondarenko I, et al. Ann Oncol 2018;29(suppl 5):Abstr 1665PD

Maximum percentage change in target lesion size

Be

st ch

an

ge

fro

m b

ase

line

in t

arg

et le

sio

n s

ize

, %

100

80

60

40

20

–20

–40

–60

–80

–100

Non-response

Response

0

1667PD: Impact of early prophylactic cranial irradiation with hippocampal

avoidance on neurocognitive function in patients with limited disease small-cell

lung cancer. A multicenter phase II trial (SAKK 15/12) – Vees H, et al

• Study objective

– To investigate the neurocognitive function (NCF) in patients with limited-disease

SCLC treated with prophylactic cranial irradiation (PCI) concomitant with

chemotherapy and thoracic radiotherapy (tRT) in the SAKK 15/12 study

• Methods

– Patients received hippocampal avoidance PCI at the start of the 2nd cycle of

chemotherapy (cisplatin or carboplatin and etoposide) and tRT (total of 6 cycles

of chemotherapy)

– NCF was tested prior to PCI and at weeks 11, 29 and 53

• Memory was assessed using Hopkins Verbal Learning Test Revised (HVLT-R);

language and verbal fluency was assessed using Controlled Oral Word Association

Test (COWAT); visual search, scanning, speed of processing and executive function

was assessed using Trail Making Tests A and B (TMT A&B)

– NCF decline was defined as a decrease of 1 SE of measurement in any test

• A rate of ≤30% in patients with no NCF decline was assumed unpromising and a rate of

≥50% in patients with no NCF decline was assumed promising

Vees H, et al. Ann Oncol 2018;29(suppl 5):Abstr 1667PD

1667PD: Impact of early prophylactic cranial irradiation with hippocampal

avoidance on neurocognitive function in patients with limited disease small-cell

lung cancer. A multicenter phase II trial (SAKK 15/12) – Vees H, et al

• Key result

– No brain metastases were observed during 6 months

– OS was 87% (95%CI 72, 94)

– Overall 7 patients died: 4 due to disease progression, 1 due to respiratory failure, 1 due to

haemorrhage and 1 for unknown reason

– The most common grade ≥3 AEs were: anaemia (21%), febrile neutropenia (19%) and

fatigue (14%)

• Conclusion

– The proportion of patients with no decline in NCF at 6 months is similar to that in those

receiving sequential PCI

Vees H, et al. Ann Oncol 2018;29(suppl 5):Abstr 1667PD

Deterioration of NCF by cognitive test

1310

79 9 9

25

0

5

10

15

20

25

30

HVLT-R totalrecall

HVLT-Rdelayed recall

HVLT-R RDI COWAT TMT-A TMT-B Deteriorationin at least one

test

Deterioration of NCF n (%) 90%CI

No 13 (34.2) 21.6, 48.8

Yes 25 (65.8)

Nu

mb

er

of p

atie

ntsDeterioration of NCF at 6 months

Documents

ESMO 2018 CONGRESS