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SCLC

SCLC. Dott. Andrea Ardizzoni UOC Oncologia Medica. Small Cell Lung Cancer (SCLC). Reduced incidence (from 25-30 to 13-15%) Still a ccounts for ~ 20-25,000 deaths yearly Strongly associated with cigarette smoking Neuroendocrine features High frequency of TP53 and RB gene mutations

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SCLC

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  1. SCLC Dott. Andrea Ardizzoni UOC Oncologia Medica

  2. 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)

  3. Neuroendocrine tumors of the lung Beasley et al. Human Pathol, 2003 Haruki et al. Jpn J can cerRes, 2000 Adapted from Swarts et al. BBA-Rev on Cancer,2012

  4. 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

  5. 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

  6. SCLC/LCNEC: What’s new in 2015 • Molecular profiling • Novel agents for relapsed disease • Role of TRT in ED • Role of surgery

  7. Reclassifying lung cancer Image from: CLCGP, Sci Transl Med, 2013

  8. Pembrolizumab for Extensive Stage SCLC: Efficacy and Relationship With PD-L1 Expression Patrick A. Ott,1 Elena Elez,2 Sandrine Hiret,3 Dong-Wan Kim,4Rebecca 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 3285 – Patrick A. Ott

  9. KEYNOTE-028 (NCT02054806): Phase 1b Multicohort Study of Pembrolizumab for PD-L1+ Advanced Solid Tumors Complete or partial response or stable disease Treat for 24 months or until progressiona or intolerable toxicity • Patients • 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 Pembrolizumab 10 mg/kg IV Q2W Confirmed progressive diseasea or unacceptable toxicity Discontinue pembrolizumab ResponseAssessment* *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 aIf clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan performed ≥4 weeks later.

  10. Analysis of PD-L1 Expression (KEYNOTE 028) Examples of PD-L1 Staining in SCLC Specimens from 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%) PD-L1 Negative PD-L1 Positive

  11. 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) 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.

  12. 100 % 80 , e n Change From Baseline in Tumor Size Over Timea 60 i l e 40 • Median DOR: 29.1 weeks (0.1+ to 29.1) • 6 of 7 responsesb are ongoing with patients still on treatment s a B 20 m 0 o r –20 F e –40 g n a –60 h C –80 –100 0 8 16 24 32 40 48 Time, weeks 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.

  13. CheckMate 032 Study Design Presented By Scott Antonia at 2015 ASCO Annual Meeting

  14. 17% RR 18% RR Tumor Responses (PD-L1 expression) Presented By Scott Antonia at 2015 ASCO Annual Meeting

  15. 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

  16. DLL3 Expression is highly expressed in SCLC Note: DLL3 appears to modulate NOTCH signaling Rovalpituzumab is a novel ADC directed against DLL3

  17. Results support biomarker-guided phase II studies Overall response rates Durability of Response at RP2D (0.3 mg/kg q6w): 182+ days †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

  18. 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 Ben Slotman Professor and Chair Department of Radiation Oncology VUmc, Amsterdam, The Netherlands

  19. CREST Trial design Chest Radiotherapy Extensive Stage Trial PCI + TRT (10 x 3 Gy) ES-SCLC No brain- /leptomeningeal mets No pleural mets No previous RTX brain/thorax Any response after 4-6 cycles of platinum-basedchemotherapy WHO 0-2 Age 18+ Encompassable volume Arm A • Stratification: • Residualintrathoracicdisease • Institution R Study treatment should start between 2 and 7 weeks after last chemotherapy PCI Arm B Slotman et al., Lancet 2015, 385, 36-42

  20. 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) Progression-free survival HR = 0.73 (95%CI 0.61-0.87) p=0.001 Slotman et al., Lancet 2015, 385, 36-42

  21. 95% CI Overall survival Overall Survival With residual intrathoracic disease P<0.05 Without residual intrathoracic disease N.S. Slotman et al., Lancet 2015, 385, 1292-3

  22. Overall survivalPts with residual intrathoracic disease HR =0.81 (95%CI 0.66-1.00) P<0.05

  23. Surgery in SCLC: should its role be re-evaluated • Survival analysis of 14179 SCLC-LD pts (863 surgically resected) belonging to the SEER registry (years 1988-2002) • Lobectomy had the best outcome Schreiber, Cancer 2010

  24. 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 ThoracOncol 2015; 10 (suppl 2): ORAL10.06

  25. 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 1.00 OS 0.75 Log-rank p-value <0.01 OS (Probability) 0.50 0.25 0.00 0 12 24 36 48 60 Time (months) Yang et al. J ThoracOncol 2015; 10 (suppl 2): ORAL10.06

  26. SCLC/LCNEC: What’s new in 2015 Conclusions • 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+)

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