sclc dott. andrea ardizzoni uoc oncologia medica
TRANSCRIPT
SCLC
Dott. Andrea ArdizzoniUOC Oncologia Medica
Small Cell Lung Cancer (SCLC)
• Reduced incidence (from 25-30 to 13-15%)
• Still accounts for ~ 20-25,000 deaths yearly
• Strongly associated with cigarette smoking
• Neuroendocrine features
• High frequency of TP53 and RB gene mutations
• Highly aggressive
• Often metastasized at the time of diagnosis
• Highly responsive to CT and RT
• High rate of early relapse/PD
• Poor cure-rate (10-20%) and overall prognosis (MS 9-12 months)
Neuroendocrine tumors of the lung
Carcinoid Atypical Carcinoid
LCNEC SCLC
Mitoses/2mm2
(10 HPF)<2 2-10 >10 >10
Smoking 33%(general population)
64% 98% 97%
5 YR OS 92-100% 61-88% 13-57% 5%
Prevalence 1-2% 0.1-0.2% 1.6-3% 15%
TP53 mutation 6% - 74% 90%
RB1 down-regulation 0% 21% 68% 87%
MEN mutation 18% 36% 0% 0%
Beasley et al. Human Pathol, 2003Haruki et al. Jpn J can cer Res, 2000Adapted from Swarts et al. BBA-Rev on Cancer,2012
SCLC/LCNEC: State of the art treatment
Platinum (either cis or carbo) combination chemotherapy (i.e cis/carbo-etoposide) x 4-6 courses q 3 weeks “standard of care” 1st line therapy for both LD and ED
Combined chemotherapy and thoracic radiotherapy (preferably early concurrent) standard of care for LD
Possible role of upfront surgery in very limited disease Frail pts should receive profilactic G-CSF +/- antibiotics 2a line therapy: Topotecan o CAV or PE-rechallenge
based on treatment-free interval (refractory vs sensitive disease)
PCI for pts with both LD or ED with good response to 1st line therapy
Standard treatment of Relapsed SCLC
Relapsed SCLC
•TFI < 60 days •60 < TFI < 180 days •TFI > 180 days
•BSC•Clinical trials•Taxanes
•Topotecan•CAV
•Topotecan•PE/CE re-induction
SCLC/LCNEC: What’s new in 2015
• Molecular profiling
• Novel agents for relapsed disease
• Role of TRT in ED
• Role of surgery
Reclassifying lung cancer
Image from: CLCGP, Sci Transl Med, 2013
Gene/pathway LCNEC- Miyoshi
LCNEC-Fernandez-Cuesta
TP53 74% 90%
RB1 29% 35%
AmpificationMYCMYCL1FGFR1
+++
+++
PI3K/AKT/MTOR pathwayPIK3CAPTENRICTORMTOR
40% 3%6%10%5%
RAS/MEK/ERKKRASHRAS
4%1%
OtherSTK11KEAP-1
25%20%
Pembrolizumab for Extensive Stage SCLC: Efficacy and Relationship With
PD-L1 Expression
3285 – Patrick A. Ott
Patrick A. Ott,1 Elena Elez,2 Sandrine Hiret,3 Dong-Wan Kim,4 Rebecca A. Moss,1 Tammy Winser,5 Sanatan Saraf,5 Marisa Dolled-Filhart,5
Jonathan Cheng,5 Bilal Piperdi,5 Janice M. Mehnert6
1Dana-Farber Cancer Institute, Boston, MA, USA; 2Vall d’Hebron Institute of Oncology, Barcelona, Spain; 3ICO René Gauducheau, Nantes, France; 4Seoul National University Hospital, Seoul, Republic of Korea;
5Merck & Co., Inc., Kenilworth, NJ, USA; 6Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
KEYNOTE-028 (NCT02054806): Phase 1b Multicohort Study of Pembrolizumab for PD-L1+ Advanced Solid Tumors
*Response assessment: Every 8 weeks for the first 6 months; every 12 weeks thereafter
Primary end points: ORR per RECIST v1.1 and safety
Secondary end points: PFS, OS, duration of response
Pembrolizumab Pembrolizumab
10 mg/kg IV 10 mg/kg IV Q2WQ2W
Complete or partial Complete or partial response or stable response or stable diseasedisease
Treat for 24 months Treat for 24 months or until progressionor until progressionaa
or intolerable or intolerable toxicitytoxicity
Confirmed Confirmed progressive diseaseprogressive diseaseaa or unacceptable or unacceptable toxicitytoxicity
Discontinue Discontinue pembrolizumabpembrolizumab
ResponseAssessment*
PatientsPatients•Small cell lung cancer•Failure of or inability to receive standard therapy•ECOG PS 0 or 1•≥1 measurable lesion•PD-L1 positivity•No autoimmune disease or interstitial lung disease
aIf clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan performed ≥4 weeks later.
Analysis of PD-L1 Expression (KEYNOTE 028)• Samples: archival or newly obtained core or excisional biopsy of a nonirradiated lesion• Immunohistochemistry: performed at a central laboratory using a prototype assay and the
22C3 antibody clone (Merck)• Positivity: membranous PD-L1 expression in ≥1% of tumor and associated inflammatory
cells or positive staining in stroma• SCLC cohort: of 147 evaluable samples, 42 PD-L1 positive (28.6%)
Examples of PD-L1 Staining in SCLC Specimens from KEYNOTE-028
PD-L1 Negative PD-L1 Positive
Best Overall Response n % 95% CI
Complete response 0 0 0.0-14.2
Partial response 7 29.2 12.6-51.1
Stable disease 1 4.2 0.1-21.1
Progressive disease 10 41.7 22.1-63.4
No assessmentb 6 25.0 9.8-46.7
aBoth confirmed and unconfirmed responses are included. Response was assessed by RECIST v1.1 per investigator review. bIncludes patients who died or discontinued for clinical progression before the first imaging assessment (n = 3) or who had not reached the first imaging assessment at data cutoff (n = 3). cPatients with CR, PR, or SD of any duration. Data cutoff date: June 24, 2015.
Antitumor Activitya (RECIST v1.1, Investigator Review)
Objective response rate: 29.2% (95% CI, 12.6–51.1)
Disease control ratec: 33.3% (95% CI, 15.6–55.3)
Change From Baseline in Tumor Size Over Timea
• Median DOR: 29.1 weeks (0.1+ to 29.1)• 6 of 7 responsesb are ongoing with patients
still on treatment
aIncludes patients with ≥1 evaluable postbaseline tumor assessment (n = 18). Response was assessed by RECIST v1.1 per investigator review. bIncludes confirmed and unconfirmed responses. Data cutoff date: June 24, 2015.
0 8 16 24 32 40 48–100
–80
–60
–40
–20
0
20
40
60
80
100
Time, weeks
Ch
ang
e F
rom
Bas
elin
e, %
CheckMate 032 Study Design
Presented By Scott Antonia at 2015 ASCO Annual Meeting
Tumor Responses (PD-L1 expression)
Presented By Scott Antonia at 2015 ASCO Annual Meeting
18% RR 17% RR
DLL3 is a dominant inhibitor of Notch signaling
• Normally expressed during development in the Golgi
• Aberrantly expressed in SCLC tumor-initiating cells
• Interacts with and inhibits Notch1 in cis
• May mediate Notch inhibition downstream of ASCL1
Kume et al., J Angiogen Res 2009
DLL3 Expression is highly expressed in SCLC
Rovalpituzumab is a novel ADC directed against DLL3
Note: DLL3 appears to modulate NOTCH signaling
Results support biomarker-guided phase II studies
Topotecan†
Rova-T; SC16LD6.5
All Pts & dose levels
DLL3+Ph 1b Cohorts
2nd Line 17% 22% 40%
3rd Line No Approved Drug 17% 38%
Sensitive to C/E 23% 24% 62%
Resistant to C/E 9% 14% 20%
Overall response rates
†Tabulated from published trial data with Topotecan: von Pawel (2014) JCO, Jotte (2011) JCO, O’Brien (2006) JCO, Huber (2006) Eur Respir J, von Pawel (1999) JCO, and Ardizzoni (1997) JCO
Durability of Response at RP2D (0.3 mg/kg q6w): 182+ days
Ben SlotmanProfessor and Chair
Department of Radiation OncologyVUmc, Amsterdam, The Netherlands
Which Patients with ES-SCLC Should Receive Thoracic Radiotherapy Routinely?
Ben Slotman, Corinne Faivre-Finn, Harm Van Tinteren, John Praag, Joost Knegjens, Sherif El Sharouni,
Matthew Hatton, Astrid Keijser, Suresh Senan
CREST Trial design
ES-SCLCNo brain- /leptomeningeal metsNo pleural metsNo previous RTX brain/thoraxAny response after 4-6 cycles of platinum-based chemotherapyWHO 0-2Age 18+Encompassable volume Arm B
PCI + TRT (10 x 3 Gy)
R
Arm A
PCI
Stratification:•Residual intrathoracic disease•Institution
Study treatment should start between 2 and 7 weeks after last chemotherapy
Slotman et al., Lancet 2015, 385, 36-42
C hestR adiotherapyE xtensiveS tageT rial
Overall and progression-free survival
Overall survival
HR = 0.84 (95%CI 0.69-1.01) p=0.066
12 m: 33% vs. 28%24 m: 13% vs. 3% (p=0.004)
Slotman et al., Lancet 2015, 385, 36-42
Time (mths)
PF
S P
rob
ab
ility
0 3 6 9 12 15 18 21 24
0.0
0.2
0.4
0.6
0.8
1.0
247 163 59 31 15 10 9 9 7 Thoracic RT
248 126 48 15 8 3 3 3 3 No Thoracic RT
Thoracic RT
No Thoracic RT
6 mos PFS - Thoracic RT : 24.3 ( 95% CI: 19.5 - 30.4 )
6 mos PFS - No Thoracic RT : 20.0 ( 95% CI: 15.6 - 25.7 )
ITT, events/n ( 239 / 248 - 231 / 247 )
HR= 0.73 ( 95% CI: 0.61 - 0.87 )
stratified log-rank p-value 0.001
Time (mths)
OS
Pro
ba
bility
0 6 12 18 24
0.0
0.2
0.4
0.6
0.8
1.0
247 147 67 26 14 Thoracic RT
248 160 61 17 5 No Thoracic RT
Thoracic RT
No Thoracic RT
12 mos OS - Thoracic RT : 32.7 ( 95% CI: 27.2 - 39.3 )
12 mos OS - No Thoracic RT : 27.6 ( 95% CI: 22.5 - 33.9 )
ITT, events/n ( 224 / 248 - 201 / 247 )
HR= 0.84 ( 95% CI: 0.69 - 1.01 )
stratified log-rank p-value 0.066
Progression-free survival
HR = 0.73 (95%CI 0.61-0.87) p=0.001
Overall survivalWith residual intrathoracic disease
Without residual intrathoracic disease
Overall Survival
P<0.05
95% CI
Slotman et al., Lancet 2015, 385, 1292-3
N.S.
Overall survivalPts with residual intrathoracic disease
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24
Months
Surv
ival P
robability
Thoracic RT
No Thoracic RT
215 184 132 94 59 35 22 15 11
219 188 138 82 50 26 14 5 4
Thoracic RTNo Thoracic RT
12 months OS - Thoracic RT : 32.5 ( 95% CI: 26.7 - 39.6 )
12 months OS - No Thoracic RT : 25.9 ( 95% CI: 20.6 - 32.6 )
HR= 0.81 ( 95% CI: 0.66 - 1 )
log-rank p-value 0.044
HR =0.81 (95%CI 0.66-1.00)P<0.05
Surgery in SCLC: should its role be re-evaluated
Schreiber, Cancer 2010
•Survival analysis of 14179 SCLC-LD pts (863 surgically resected) belonging to the SEER registry (years 1988-2002)•Lobectomy had the best outcome
ORAL10.06: Long-Term Survival after Surgery for Pathologic N1 and N2 Small Cell Lung Cancer: A Comparison with Nonoperative Management – Yang C-F et al
Study objective
•To test whether or not surgery, in the setting of modern adjuvant therapies, offers a survival advantage among patients with node-positive SCLC compared with non-operative management
Study design
•Patients were identified between 2003 and 2011 from the National Cancer Data Base:
– Patients had to have pT1–2 N1–2 M0 SCLC
– All patients underwent non-operative management (CT ± RT ≥45 Gy) or surgery (with adjuvant CT ± RT ≥45 Gy)
– Patients with a history of unrelated malignancy and palliative-intent treatment were excluded
•Data were assessed using Kaplan-Meier analyses and propensity score matching
Yang et al. J Thorac Oncol 2015; 10 (suppl 2): ORAL10.06
ORAL10.06: Long-Term Survival after Surgery for Pathologic N1 and N2 Small Cell Lung Cancer: A Comparison with Nonoperative Management – Yang C-F et al
• Key results
• Conclusions– Surgery + adjuvant CT ± RT was associated with better survival vs. non-
operative management in patients with node-positive SCLC– Results support the re-evaluation of the role of surgery for selected patients
Yang et al. J Thorac Oncol 2015; 10 (suppl 2): ORAL10.06
mOS, months Surgery No surgery p-value
pN1 36.2 17.1 <0.01
pN2 22.6 13.3 <0.01
OSO
S (
Pro
ba
bili
ty)
1.00
0.75
0.50
0.25
0.00
Time (months)0 12 24 36 48 60
Log-rank p-value <0.01
Median survival 5-year survival
Surgery 26.3 months 28.5%
No surgery
17.1 months 16.7%
SCLC/LCNEC: What’s new in 2015 Conclusions
31
• No practice-changing new data
• Thorough molecular profiling of SCLC/LCNEC with possible druggable target identified
• Promising novel agents for relapsed disease (immune check-point inhibitors
• Possible role of TRT in selected cases of ED
• Renewed interest for surgery in LD (including N+)