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+)