presentación de powerpoint - forodebateoncologia.net · imielinski, tcga, nature 2012 178 resected...
TRANSCRIPT
![Page 1: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/1.jpg)
Carcinoma escamoso: optimizacion de tratamiento
Noemi Reguart
Hospital Clínic Barcelona
![Page 2: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/2.jpg)
National Cancer Database (US)
1998-1999 2000-2003 2004-2007 2008-2011
SCC 35% 28% 26% 27%
Non SCC 65% 72% 75% 72%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Incidence of SCC
27%
M. Behera WCLC 2015
An oncology outcomes database administered by the American College of Surgeons and the American Cancer Society
![Page 3: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/3.jpg)
NSCLC Classification
![Page 4: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/4.jpg)
X40
Courtesy of J.C. Soria
![Page 5: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/5.jpg)
Imielinski, TCGA, Nature 2012
178 resected lung SqCC
The Cancer Genome Atlas (TCGA) initiative
Squamous NSCLC has a high somatic mutation burden and complex tumor genetic alterations
![Page 6: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/6.jpg)
TCGA : Focal copy number alterations in SCC
Amplifications Deletions
MYCL MCL1
REL NFE2L2
SOX2 PDGFRA
EGFR FGFR1
CCND1
CRKL
ERBB2
MDM2
LRP1B ERBB4 FOXP1
CSMD1
CDKN2A
PTEN
RB1
The Cancer Genome Atlas (TCGA) initiative Imielinski, TCGA, Nature 2012
![Page 7: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/7.jpg)
MINI13.05: Marc Ladanyi – Discussant
Cancer Discovery, April 30, 2015
• Comprehensive genomic profiling of 79 stage IV SQCLCs • 2 major SqCLC subtypes: FGFR1 amplified and PI3K aberrant. • PI3K-aberrant tumors had worse survival and more brain mets
PI3K and FGFR1 the 2 main pathways?
Paik P et al, Cancer Discovery 2015
![Page 8: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/8.jpg)
Mountain, Chest 1997
Most common Driver mutations in lung cancer
Lung Cancer Consortium, ASCO 2011; Perez-Moreno et al. Clin Cancer Res 2012; Y. Shi , WCLC 2015
Squamous cell Adenocarcinoma
Gene Lung ADC Lung Squamous Cell
EGFR 14%, most at known sites Amplification (7%), rare non-canonical mutation (L861Q)
KRAS 31% mutation 1%, HRAS more common
BRAF 10%, 2% (V600/601) 4%, (no V600/601)
PIK3CA 7% mutation 16% mutation
ERBB2 5% mutation 3% non-canonical, rare amplification (<5%)
FGFRs 2% mutation 10% amplification, 12% mutation, fusions
DDRs 3% mutation 4% mutation
![Page 9: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/9.jpg)
Schiller et al. N Engl J Med 2002
Study
arm
OS
(mo)
1 year
(%)
PCb 8.6 38
CV 8.1 36
Study arm
OS (mo)
1 year (%)
PC 7.8 31
GC 8.1 36
DC 7.4 31
PCb 8.1 34
Study
arm
OS
(mo)
1 year
(%)
PCb 9.9 43
GC 9.8 37
CV 9.5 37
Kelly et al. J Clin Oncol 2001 Scagliotti, et al. J Clin Oncol 2002
Pacli + carbo (PCb)
Cis + vin (CV)
Overa
ll surv
ival %
100
80
60
40
20
0
0
Months Months
Overa
ll surv
ival
30
Pacli + cis (PC)
Gem + cis (GC)
Doc + cis (DC)
Pacli + carbo (PCb)
5 10 15 20 25
Pacli + carbo (PCb)
Gem + cis (GC)
Cis + vin (CV)
Months
0
1.0
0.9
0.6
0.5
0.4
0.3
0.8
0.7
0.2
0.1
0
1.0
0.9
0.6
0.5
0.4
0.3
0.8
0.7
0.2
0.1
0
Overa
ll surv
ival
30 5 10 15 20 25 0 30 5 10 15 20 25
2002 2001 2002
First line Chemotherapy
N. Thatcher ELCC 2015
![Page 10: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/10.jpg)
New chemo standards?............ Probably not
Nab-Paclitaxel WJOG5208L
Nab-Paclitax. Carboplatin
Paclitaxel CBDCA
Docetaxel Nedaplatin
Docetaxel CDDP
N 229 221 172 168
ORR (%) 41 24* 55.8 53
PFS (mo) 5.6 5.7 4.9 4.5*
OS (mo) 10.7 9.5 13.6 11.4*
G3-5 AE (%) 70 68 92 90
* Statistically significant
M. Socinski, Ann Oncol 2013 – Takehito Shukuya, Lancet Oncology 2015
![Page 11: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/11.jpg)
♦ Primary objective: OS
♦ Patient selection not based on EGFR protein expression
♦ Mandatory tissue collection from archived tumor
Randomization stratified by: ECOG PS (0-1 vs. 2) and geographic region (North America, Europe, and Australia; vs. South America, South Africa, and India; vs. Eastern Asia)
Thatcher N. et al. Lancet Oncol 2015
PD
CRPRSD
PD
Neci + Gem-Cis q3w (N=545)
Necitumumab 800 mg D1, D8 Gemcitabine 1250 mg/m², D1, D8 Cisplatin 75 mg/m², D1
PD
Maximum of 6 cycles
First-line Stage IV Squamous-LC
ECOG PS 0-2
Neci q3w
800 mg D1, D8
Gem-Cis q3w (N=548)
Gemcitabine 1250 mg/m², D1, D8 Cisplatin 75 mg/m², D1
R
N=1093
.
• Necitumumab is a second-generation human IgG1 anti-EGFR monoclonal antibody
![Page 12: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/12.jpg)
Time Since Randomization (Months)
Ove
rall
Su
rviv
al (%
)
16.5%
42.8%
Patients / events:
Neci + Gem-Cis: 545 / 418
Gem-Cis: 548 / 442
19.9%
47.7%
1yr OS
2yr OS
• 16% reduction risk of death, 1.6 month absolute improvement in OS • Similar RR 31% vs 29% (p ns)
Thatcher N. et al. Lancet Oncol 2015
SQUIRE Primary Outcome: Overall Survival (ITT)
GC+N
N=545
GC
N=548
Stratified HR (95% CI) 0.84 (0.74, 0.96)
Stratified p-value (log-rank) 0.01
Median, months (95% CI) 11.5 (10.4, 12.6) 9.9 (8.9, 11.1)
![Page 13: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/13.jpg)
Thatcher et al. Lancet Oncol 2015; Paz-Ares Annals of Oncol 2016
EMA approved only in EGFR expressing tumours, IHC (DAKO PharmDx):
BUT only 5% tumors did not express EGFR (small sample size) OS H-Score >0 vs < 0: OS 11.7 vs 10 (HR 0.81)
SQUIRE Exploratory Analysis: EGFR H-Score
![Page 14: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/14.jpg)
1. Fossella 2000; 2. Shepherd 2000; 3. Hanna 2004; 4. Shepherd 2005
< 9 months
Second Line………….very poor outcomes
5.7 5.6
7.5
4.6
8.37.9
6.7
4.7
0
1
2
3
4
5
6
7
8
9
Docetaxel Ifosfamide or vinorelbine
Docetaxel BSC Pemetrexed Docetaxel Erlotinib Placebo
TAX320 TAX317 JMEI BR.21
Med
ian
OS
(m
on
ths)
5.7 5.6
7.5
4.6
8.37.9
6.7
4.7
0
1
2
3
4
5
6
7
8
9
Docetaxel Ifosfamide or vinorelbine
Docetaxel BSC Pemetrexed Docetaxel Erlotinib Placebo
TAX320 TAX317 JMEI BR.21
Med
ian
OS
(m
on
ths)
![Page 15: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/15.jpg)
Garon EB et al. Lancet 2014;384:665-73
• Primary endpoint: OS • Secondary: PFS, ORR, safety • Analysis by histology NOT preplanned
* Ramucirumab, a fully human monoclonal antibody that specifically binds VEGFR2
Squamous: 157 (25%)
Squamous: 171 (27%)
![Page 16: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/16.jpg)
REVEL Primary Outcome: Overall Survival (ITT)
• 14% reduction risk of death, 1 month improvement in OS
Garon EB et al. Lancet 2014
![Page 17: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/17.jpg)
REVEL: Overall Survival by Histology
Garon EB et al. Lancet 2014
* Subgroup analyses by histology in this study were not pre-planned
![Page 18: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/18.jpg)
REVEL: AEs of interests by histology
Nonsquamous Squamous
Treatment Emergent Adverse Events Grade
Ramucirumab (N=465)
Placebo (N=441)
Ramucirumab (N=157)
Placebo (N=170)
Bleeding/ Haemorrhage*
Any 145 (31.2)† 60 (13.6) 36 (22.9) 33 (19.4)
3/4/5 11 (2.4) 8 (1.8) 4 (2.5) 5 (2.9)
Epistaxis Any 97 (20.9)† 30 (6.8) 19 (12.1)† 9 (5.3)
3/4/5 2 (0.4) 0 (0.0) 0 (0.0) 0 (0.0)
Gastrointestinal haemorrhage* Any 14 (3.0) 7 (1.6) 3 (1 .9) 3 (1.8)
3/4/5 3 (0.6) 1 (0.2) 1 (0.6) 1 (0.6)
Pulmonary haemorrhage* Any 34 (7.3) 25 (5.7) 15 (9.6) 21 (12.4)
3/4/5 5 (1.1) 4 (0.9) 3 (1.9) 4 (2.4)
Haemoptysis Any 25 (5.4) 16 (3.6) 11 (7.0) 16 (9.4)
3/4/5 3 (0.6) 2 (0.5) 1 (0.6) 2 (1.2)
Hypertension* Any 54 (11.6)† 23 (5.2) 14 (8.9) 6 (3.5)
3/4/5 27 (5.8)† 13 (2.9) 8 (5.1)† 0 (0.0)
Infusion-related reaction* Any 18 (3.9) 20 (4.5) 5 (3.2) 8 (4.7)
3/4/5 4 (0.9) 3 (0.7) 1 (0.6) 1 (0.6)
Proteinuria Any 15 (3.2)† 5 (1.1) 6 (3.8)† 0 (0.0)
3/4/5 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)
†P value <0.05 between treatment groups, comparison based on Fisher’s exact tests *Consolidated AE category comprising synonymous MedDRA preferred terms.
Garon EB et al. Lancet 2014
![Page 19: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/19.jpg)
• *Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted †Dose reduction to 100 or 50 mg permitted
• ‡Tumor assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter
Key secondary endpoint
Overall survival
Other secondary endpoints: ORR, DCR,
tumor shrinkage, PRO, safety
1:1
Stratified by east Asian vs non-east Asian
Afatinib 40 mg* QD
Erlotinib 150 mg† QD
SCC of the lung (Stage IIIB/IV)1
Progressed after ≥4 cycles of a
first-line platinum-doublet
ECOG PS 0–1
Adequate organ function
Primary endpoint
PFS by
independent review‡
Soria, Lancet Oncol 2015
N=795
![Page 20: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/20.jpg)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
EstimatedPFSprobability
Timeofprogression-freesurvival(months)
0 3 6 9 12 15 18 21 24 27
Afatinib
n=398
Erlotinib
n=397
Median, months
(95% CI)
2.6
(2.0–2.9)1.9
(1.9–2.1)
HR (95% CI) 0.81 (0.69–0.96)
p value 0.0103
Afatinib
n=398
Erlotinib
n=397
Median, months
(95% CI)
7.9
(7.2–8.7)6.8
(5.9–7.8)
HR (95% CI) 0.81 (0.69–0.95)
p value 0.0077
3 6 9 12 15 3018 21 24 27
Timeofoverallsurvival(months)
0.2
0.4
0.6
0.8
1.0
0
EstimatedOSprobability
0
36.4%
28.2%22.0%
14.4%
LUX-Lung 8: Primary endpoint PFS
Soria, Lancet Oncol 2015
OS PFS
• 19% reduction risk of death, <1 month improvement in OS • Similar RR 6% vs 3% (p ns)
![Page 21: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/21.jpg)
Subgroup Aberration present (%) HR (95% CI)†
LL8
LL8 subset* (n=238)
0.82 (0.71–0.96)‡
0.73 (0.56–0.96)
EGFR No (94.1)
Yes (5.9)
0.72 (0.54–0.95)
1.04 (0.33–3.25)
TP53 No (12.2)
Yes (87.8)
0.54 (0.24–1.24)
0.74 (0.55–0.99)
LRP1B No (60.5)
Yes (39.5)
0.74 (0.52–1.05)
0.73 (0.47–1.13)
MLL2 No (67.2)
Yes (32.8)
0.68 (0.49–0.96)
0.83 (0.52–1.32)
CDKN2A No (71.4)
Yes (28.6)
0.75 (0.54–1.03)
0.68 (0.40–1.14)
FAT3 No (72.3)
Yes (27.7)
0.69 (0.50–0.96)
0.75 (0.44–1.27)
EGFR No (93.7)
Yes (6.3)
0.76 (0.57–1.01)
0.42 (0.12–1.43)
SOX2 No (56.3)
Yes (43.7)
0.78 (0.54–1.11)
0.70 (0.46–1.07)
KLHL6 No (59.7)
Yes (40.3)
0.76 (0.54–1.08)
0.72 (0.46–1.12)
PIK3CA No (63.0)
Yes (37.0)
0.72 (0.51–1.02)
0.78 (0.50–1.23)
MAP3K13 No (67.2)
Yes (32.8)
0.80 (0.57–1.11)
0.66 (0.40–1.08)
BCL6 No (68.9)
Yes (31.1)
0.74 (0.54–1.03)
0.79 (0.47–1.32)
FGF12 No (71.4)
Yes (28.6)
0.76 (0.55–1.04)
0.77 (0.45–1.32)
ERBB No (71.0)
Yes (29.0)
0.74 (0.54–1.03)
0.70 (0.42–1.16)
FGF No (41.2)
Yes (58.8)
0.69 (0.45–1.06)
0.76 (0.53–1.08)
LUX-Lung 8: Predictive analysis by OS
0.5 0 1.5 2.0 1.0 2.5
Favors afatinib Favors erlotinib
SVs
Predefined
families:
any aberration
CNAs
J.C. Soria WCLC 2015
• NONE Genetic Abnormality is predictive of benefit to afatinib treatment compared with erlotinib
• DO NOT not appear to be associated with longer PFS/OS
![Page 22: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/22.jpg)
Jan 2016 June 2016 June 2017
Case report by N.Reguart, N. Vilariño
Squamous, male, heavy smoker…I can’t believe it!
![Page 23: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/23.jpg)
Lawrence et al. Nature 2014
Lung adenoc 8.9 and SCC 8.1 mut/MB estimated from exome sequencing
Squamous cell lung cancer has a very high rate of somatic mutations
Squamous
LC
![Page 24: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/24.jpg)
TMB is higher in patients with smoking history
Govindan et al. Cell 2012
Smoking history
![Page 25: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/25.jpg)
Ock et al. Clin Cancer Res 2016
TME immuno type I common in lung tumors TILs+
PD-L1+
Type I
TILs-
PD-L1-
Type II
PD-L1-
TILs+
Type IV
PD-L1+
TILs-
Type III
EGFRmutantNSCLCALKrearrangedNSCLC
KRASNSCLCMELANOMA
![Page 26: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/26.jpg)
PDL-1 TPS and histology
Aggarwal C, ASCO 2017
* Data from KEYNOTE-001, -010, and -024
PD-L1 TPS ≥1%_67%
PD-L1 TPS ≥50%_ 28%
![Page 27: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/27.jpg)
CheckMate 017 - Study Design
• One pre-planned interim analysis for OS
• At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)
• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
Patients stratified by region
and prior paclitaxel use
Nivolumab
3 mg/kg IV Q2W
until PD or
unacceptable toxicity
n = 135
Docetaxel
75 mg/m2 IV Q3W
until PD or
unacceptable toxicity
n = 137
Ra
nd
om
ize
1:1
• Primary Endpoint:
– OS
• Additional Endpoints:
Investigator-assessed ORR
Investigator-assessed PFS
Correlation between PD-L1
expression and efficacy
Safety
Quality of life (LCSS)
• Stage IIIb/IV SQ NSCLC
• 1 prior platinum doublet-based
chemotherapy
• ECOG PS 0–1
• Pre-treatment (archival or
fresh) tumor samples required
for PD-L1 analysis
N = 272
LCSS = Lung cancer symptom scale
100% SqCC
J. Brahmer, et al. N Engl J Med. 2015
![Page 28: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/28.jpg)
CheckMate 017 in SCC: Primary endpoint OS
Based on August 2015 DBL. Symbols refer to censored observations.
1. J. Brahmer, et al. N Engl J Med. 2015; 2. Borghaei H et al. Poster presentation at ASCO 2016
Updated OS 2 years follow-up2
Nivolumab
Docetaxel
CheckMate 017: Squamous
Median OS Nivo = 9.2 months
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 24 30 332721
OS
(%
)
18-mo OS rate = 13%
Time (months)
18-mo OS rate = 28%
Overall Survival1
OS(%)
100
80
60
40
0
20
332724211815129630 30
Docetaxel
2-yrOS=23%
2-yrOS=8%Nivolumab
Time(months)
Nivolumab (n = 135)
Docetaxel (n = 137)
mOS mo, (95% CI)
9.2 (7.3–13.3)
6.0 (5.1–7.3)
# deaths 86 113
HR = 0.59 (95% CI: 0.44–0.79); P < 0.001
![Page 29: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/29.jpg)
CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC
Non-squamous (n = 74)
74 28 14 10 9 8 0 0 0
Years
1 y OS, 42%
2 y OS, 24%
3 y OS, 17% 5 y OS, 15% 20
40
60
80
100
0 0 1 2 3 4 5 6 7 8
Squamous (n = 54)
No. at Risk
54 20 12 10 8 8 3 0 1
OS
(%)
Years
1 y OS, 41%
2 y OS, 24%
3 y OS, 20% 5 y OS, 16%
20
40
60
80
100
0 0 1 2 3 4 5 6 7 8
Julie Brahmer, AACR 2017
![Page 30: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/30.jpg)
1. Brahmer J, et al. New Engl J Med. 2015;373:123–135. 2. Spigel DR, et al. Presented at ASCO 2015, Abstract 8009. 3. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109.
PD-L1 expression
OS
≥1%
<1%
≥5%
<5%
≥10%
<10%
NQa
PFS
≥1%
<1%
≥5%
<5%
≥10%
<10%
NQa
Squamous NSCLC (CheckMate 017)1,2
NOT PREDICTIVE
Unstratified HR
Interaction P-value
0.69 0.56
0.58
0.53 0.47
0.70
0.50 0.41
0.70
0.39
0.67 0.70
0.66
0.54 0.16
0.75
0.58 0.35
0.70
0.45
Non-squamous NSCLC (CheckMate 057)3
PREDICTIVE
PD-L1-positive expression NQ PD-L1-negative expression
0.25 1.0 2.0
Nivolumab Docetaxel
0.5 0.125 1.0 0.5 2.0 0.25
Nivolumab Docetaxel
Unstratified HR
Interaction P-value
0.59 0.0646
0.90
0.43 0.0004
1.01
0.40 0.0002
1.00
0.91
0.70 0.0227
1.19
0.54 <0.0001
1.31
0.52 0.0002
1.24
1.06
CheckMate 017: Nivolumab benefit by PD-L1
![Page 31: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/31.jpg)
KEYNOTE 010- Study Design
Herbst R, Lancet 16
N = 1034
22% SqCC
•Coprimary Endpoints:
–OS and PFS
* No staification by histology
![Page 32: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/32.jpg)
OS, PD-L1 TPS ≥1% (total population)
0 5 10 15 20 25 0
10
20
30
40
50
60
70
80
90
100
Time, months
O v e r a
l l S
u r v
i v a l , %
344 346 343
259 255 212
115 124 79
49 56 33
12 6 1
0 0 0
Treatment Arm Median
(95% CI), mo Rate at
1 y HRa
(95% CI)
P
Pembro 2 mg/kg 10.4 (9.4-11.9) 43.2% 0.71 (0.58-0.88) 0.0008
Pembro 10 mg/kg 12.7 (10.0-17.3) 52.3% 0.61 (0.49-0.75) <0.0001
Docetaxel 8.5 (7.5-9.8) 34.6% — —
Pembro 2 vs 10 mg/kg: HR 1.17, 95% CI 0.94-1.45
KEYNOTE-010: OS in ITT by PDL-1 expression
Herbst R, Lancet 16
0 5 10 15 20 25 0
10
20
30
40
50
60
70
80
90
100
Time, months
O v e
r a l l
S u
r v i v
a l , %
139
151
152
110
115
90
51
60
38
20
25
19
3
1
1
0
0
0
Treatment Arm Median
(95% CI), mo HRa
(95% CI)
P
Pembro 2 mg/kg 14.9 (10.4-NR) 0.54 (0.38-0.77) 0.0002
Pembro 10 mg/kg 17.3 (11.8-NR) 0.50 (0.36-0.70) <0.0001
Docetaxel 8.2 (6.4-10.7) — —
OS, PD-L1 TPS ≥50% stratum
Pembro 2 vs 10 mg/kg: HR 1.12, 95% CI 0.77-1.62
![Page 33: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/33.jpg)
KEYNOTE-010: 3 years OS
29.5%
22.1%
12.3%
Herbst RS, ASCO 2017
![Page 34: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/34.jpg)
0.1 1 10
Overall Sex
Male Female
ECOG performance status 0 1
Histology Squamous Adenoc
521/1033
332/634 189/399
149/348 367/678
128/222 333/708
0.67 (0.56-0.80)
0.65 (0.52-0.81) 0.69 (0.51-0.94)
0.73 (0.52-1.02) 0.63 (0.51-0.78)
0.74 (0.50-1.09) 0.63 (0.50-0.79)
Subgroups No. of Events/
No. of Patients Hazard Ratio (95% CI)
Favors Pembrolizumab Favors Docetaxel
PD-L1 tumor proportion score 50% 1%–49%
204/442 317/591
0.53 (0.40-0.70) 0.76 (0.60-0.96)
Age <65 years 65 years
317/604 204/429
0.63 (0.50-0.79) 0.76 (0.57-1.02)
Tumor sample Archival New
266/455 255/578
0.70 (0.54-0.89) 0.64 (0.50-0.83)
EGFR status Mutant Wild type
46/86 447/875
0.88 (0.45-1.70) 0.66 (0.55-0.80)
Roy S. Herbst, ESMO ASIA 2015; Lancet 2015 Analysis cut-off date: September 30, 2015.
KEYNOTE-010: OS by Subgroups
![Page 35: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/35.jpg)
KEYNOTE-010: Adjusted HR for OS (PD-L1 TPS ≥1%)
Herbst RS, ASCO 2017
Exploratory, post hoc, multivariate analyses
![Page 36: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/36.jpg)
Analysis of all 550 patients of antitumor activity of Pembrolizumab in advanced NSCLC enrolled in KEYNOTE-001
Hellmann – WCLC 2015
KEYNOTE-010: Subgroup analysis by PDL-1
![Page 37: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/37.jpg)
OAK- Study Design
Atezolizumab 1,200mg IV q3w Loss of clinical benefit
Docetaxel 75mg/m2 q3w
Locally advanced or metastatic previously
treated NSCLC
Locally advanced/metastatic
NSCLC
Tumour specimen available (FFPE)
1–2 prior lines of chemo including 1 line of platinum chemo
All PD-L1 status allowed
PD
R
1:1
Stratification factors Primary endpoints (first 850 enrolled patients)
Secondary endpoints
• PD-L1 IC expression (0 vs 1 vs 2 vs 3)
• Histology (squamous vs non-squamous)
• Prior chemotherapy regimens (1 vs 2)
• OS in ITT population
• OS in patients with ≥1% PD-L1 expression (TC1/2/3 or IC1/2/3)
• ORR, PFS, and DoR
• Safety
No crossover
Rittemeyer Lancet 17
26% SqCC
(N=850 enrolled)
![Page 38: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/38.jpg)
Rittemeyer Lancet 17
aStratified HR
Atezolizumab Docetaxel
55%
40%
41%
27%
18-mo OS
12-mo OS
Median 13.8 vs 9.6 mo HR, 0.73a (95% CI, 0.62, 0.87) P = .0003
Minimum follow-up = 19 months
Ove
rall
Surv
ival
, %
Months
OAK study: OS ITT (N = 850)
![Page 39: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/39.jpg)
Atezolizumab Docetaxel
Minimum follow-up 19 months
Landmark OS – 12 month 59% 46%
Landmark OS – 18 month 44% 31%
Median OS, mo (95% CI) 15.6 (13.3, 17.6) 11.2 (9.3, 12.6)
HR (95% CI) 0.73 (0.60, 0.89); P=0.0015
Atezolizumab Docetaxel
Minimum follow-up 19 months
Landmark OS – 12 month 42% 29%
Landmark OS – 18 month 30% 16%
Median OS, mo (95% CI) 8.9 (7.4, 12.8) 7.7 (6.3, 8.9)
HR (95% CI) 0.73 (0.54, 0.98); P=0.0383
Ove
rall s
urv
iva
l (%
)
Time(months)
Median 11.2 mo
(95% CI, 9.3, 12.6)
Median 15.6 mo
(95% CI, 13.3, 17.6)
Atezolizumab
Docetaxel
Atezolizumab
Docetaxel
Ove
rall s
urv
iva
l (%
)
Time(months)
Median 7.7 mo
(95% CI, 6.3, 8.9)
Median 8.9 mo
(95% CI, 7.4, 12.8)
non-squamous ITT (n=628) squamous ITT (n=222)
Rittmeyer, et al. Lancet 2016; Barlesi, et al. ESMO 2016 (abstr LBA44); Roche data on file
OAK: OS by histology
![Page 40: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/40.jpg)
OAK: OS HR by histology and PD-L1
Gadgeel, et al. WCLC 2016 (abstr PL04a.02)
0.35
n (%) Subgroup
96 (15%)
Non-squamous
Median OS, mo Atezolizumab Docetaxel
22.5 8.7
HR
TC3 or IC3
TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0
All non-squamous
Squamous
TC3 or IC3
TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0
All squamous
ITT
628 (100%)
188 (30%)
333 (53%)
290 (46%)
41 (18%)
222 (100%)
77 (35%)
130 (59%)
89 (40%)
0.61
0.72
0.75
0.73
0.57
0.76
0.71
0.82
0.73
18.7 11.3
17.6 11.3
14.0 11.2
15.6 11.2
17.5
10.4
11.6
9.9
9.7
7.6
8.7
8.9
7.1
7.7
13.8 9.6 0.73 850
0.2 20.2 1 2
In favour of docetaxel Hazard Ratio In favour of atezolizumab
![Page 41: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/41.jpg)
KEYNOTE-024: First Line Pembrolizumab
A Phase III, randomized, open-label study of pembrolizumab vs platinum-doublet chemotherapy as first-line therapy in patients with advanced or metastatic NSCLC that expresses PD-L1 in ≥50% of tumor cells
• Primary endpoint: PFS (RECIST v1.1 per blinded, independent central review)
• Secondary endpoints: ORR, OS, safety, and tolerability
• Exploratory endpoint: DOR
Key Inclusion Criteria
• Advanced, previously untreated NSCLC
• PD-L1+ tumor expression ≥50%
• No EGFR sensitizing mutation or ALK translocation
• ECOG PS ≤ 1
Pembrolizumab 200 mg Q3W
(2 years)
R
1:1
Investigator choice of platinum-based chemotherapy
For 4–6 cycles
Optional crossover after disease progression
N=305
Reck M et al. N Engl J Med. 2016
50%
19% SqCC
![Page 42: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/42.jpg)
Time (months)
62%
50%
0 3 6 9 12 15 18
0
20
40
60
80
100
PF
S,
%
48%
15%
80%
72%
0 3 6 9 12 15 18 21
0
20
40
60
80
100
Time (months)
OS
, %
70%
54%
KEYNOTE-024: PFS and OS (PD-L1 ≥50%)
Events,
n
Median,
mo
HR
(95% CI)
P
Pembro 73 10.3 0.50
(0.37-0.68) <0.001
Chemo 116 6.0
Events,
n
Median,
mo
HR
(95% CI)
P
Pembro 44 NR 0.60
(0.41-0.89) 0.005
Chemo 64 NR
Reck M et al. N Engl J Med. 2016
![Page 43: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/43.jpg)
KEYNOTE-024: PFS in Subgroups
Reck M et al. N Engl J Med. 2016
![Page 44: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/44.jpg)
New strategies for SqCC-NSCLC
Trial Eligibility N /EP Bio-marker Study Arms
Roche
IMpower-131
Stage IIIB/IV Squamous,
1200 PFS
All corners 1. Atezo+ Carbo/taxol_ Atezo man 2. Atezo+ Carbo/ Nab-paclitaxel_ Atezo
man 3. Carbo/ Nab-paclitaxel
MSD KN-407 Stage IV, Squamous
560 PFS/OS
All corners 1. Pembro + Carboplatin/ Nab-paclitaxel/taxol
2. Carboplatin/ Nab-paclitaxel/taxol
Roche IMpower-1103
Stage IIIB/IV, Chemonaïve SCC/non-SCC
570 PFS/OS
PD-L1 expression (TC or IC ≥ 1% [TC1/2/3 or IC1/2/3])
1. Atezo 2. Chemo
AZ MYSTIC Stage IIIB/IV SCC/non-SCC
675 PFS
Collected, not defined for eligibility
1. Durva + Treme 2. Durva 3. Chemo
AZ NEPTUNE Stage IIIB/IV SCC/non-SCC
800 OS
Collected, not defined for eligibility
1. Durva + Treme 2. Chemo
BMS CM-227 Stage IIIB/IV, SCC/non-SCC
1980 PFS/OS
PDL1 positive 1. Nivo 2. Nivo + Ipi 3. Nivo + Chemo 4. Chemo
NCT02451030 Phase I
Safety 1. Pembro + Necitumumab 48
![Page 45: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/45.jpg)
ESMO Guidelines for Advanced Stage IV SCC
Silvia Novello, ESMO Guidelines, Annals of Oncol 2016
![Page 46: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/46.jpg)
ESMO Guidelines for Advanced Stage IV SCC
Silvia Novello, ESMO Guidelines, Annals of Oncol 2016
![Page 47: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/47.jpg)
![Page 48: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/48.jpg)
* Nectimumumab and afatinib not recommended in updated NCCN
![Page 49: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/49.jpg)
New Algorism for SqCC Lung Cancer Treatment
Yi-Chen Zhang, ESMO open 2016
OS HR 0.35
HR 0.88
OS HR 0.59, 0.74, 0.73
Necitumumab???
OS HR 0.84
Afatinib???
OS HR 0.81
OS HR 0.35
HR 0.88
OS HR 0.59, 0.74, 0.73
![Page 50: Presentación de PowerPoint - forodebateoncologia.net · Imielinski, TCGA, Nature 2012 178 resected lung SqCC The Cancer Genome Atlas (TCGA) initiative Squamous NSCLC has a high somatic](https://reader031.vdocuments.net/reader031/viewer/2022040711/5e120ed517aab40b79798168/html5/thumbnails/50.jpg)
THANK YOU!!! [email protected]