Small cell Lung cancer New Chemotherapy options. Nicolas Mach, MD,PD

Transcription

1 Small cell Lung cancer New Chemotherapy options Nicolas Mach, MD,PD

2 > 40 negative Phase III trials List of unsucessful drugs Pemetrexed, imatinib, bevacizumab, bcl-2 antagonist, ASCT,

3 CASE PRESENTATION 48 years old woman, smoker, no comorbidities, SOB, neck-face swelling over the last 4 weeks Hypoxemia, RR:25, Pulse:135/min O2 + steroids + pleural tap, Cardiac US and mediastinal biopsy..

4 CASE PRESENTATION Histology from percutaneous biopsy: SCLC Cytology from pleural tap: SCLC No distant metastasis / No supraclavicular node (brain + thoraco-abdominal CT) No hypercalcemia, hyponatremia, LDH: normal Emergency treatment Immediate chemotherapy with Cisplatin / Etoposide Evolution.

5 STATEMENTS ABOUT SCLC 15-20% of all lung cancers 95% of SCLC patients are smokers <30% diagnosed at early stage Chemo-Radiosensitive tumor Median OS: 12 months No predictive molecular markers Very limited progress in the last 20 years Typical paraneoplastic syndromes

6 MILESTONE N 1 IN TREATMENT OF SCLC

7 MILESTONE N 2 IN TREATMENT OF SCLC NEJM 1999

8 MILESTONE N 3 IN TREATMENT OF SCLC Change in Staging and Guidelines TNM staging

9 J. Thorac. Oncol 2007

10 Treatment modalities > 40 negative Phase III trials List of unsucessful drugs Pemetrexed, imatinib, bevacizumab, bcl-2 inhibitors, ASCT, irinotecan, picoplatin, SCLC curative stage Chemo-radiotherapy (EP better than VAC / bi-fractionnated better than once day) Surgery followed by chemotherapy (for T1-T2 N0 M0) Nothing is better than Cisplatin /Etoposide as chemotherapy

11 Curative setting: 1st line chemo: Cisplatin / Etoposide with RTX Palliative setting: 1st line Carboplatin /Etoposide + BSC

12 First line M+ Nothing is better than Platin/Etoposide Carboplatine / Etoposide +/- Bevacizumab JCO 2011

13 First line M+ Nothing is better than Platin/Etoposide Carboplatine / Etoposide +/- Bevacizumab after 2 cycles of chemotherapy

14 Potential drug targets in SCLC

15 List of unsucessful drugs Pemetrexed, imatinib, bevacizumab, bcl-2 inhibitors, ASCT, irinotecan, picoplatin, Single agent :Imatinib, gefitinib, vandetanib, dasatinib, temsirolimus, bevacizumab, Cediranib, sorafenib, sunitinib,bi 2536, Panobinostat, Bortezomib, pazopanib, ipilimumab Tested in combination with chemotherapy :Imatinib, simvastatin, bevacizumab, Cediranib, sorafenib, sunitinib, oblimersen, BI2536, Ipilimumab, vismodegib, figitumumab, Everolimus, buparlisib, veliparib, carfilzomib, anti-ganglioside vaccination,

16 Maintenance post 1 st line Failed for chemotherapy Failed for TKI Failed for biologics (INF, vaccines) Failed for anti-angiogenic (Marimastat, VEGFR inhibitors, thalidomide)

17 OS Phased CT followed by Ipi OS Concomittant CT + Ipi

18 Second lines Treatment Taxanes, 25% Irinotecan, 33 Vinorelbine 14%, Gemcitabine. 10% Temozolomide 15% Bendamustine 26% Amrubicin 31% ORR but negative OS comared to topotecan Only approved drug Topotecan Re-treatment with 1 st line regimen if prolonged response observed Ongoing trials: paclitaxel-everolimus carfilzomib /Irinotecan Carbet + vesmodegib

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20 CASE PRESENTATION 48 years old woman Locally advanced, M1a 2 cycles of Cisplatin / Etoposide Very good partial response after 2 cycles Multidisciplinary panel: Continue chemotherapy up to 6 no concomittant RTX (advanced M1a disease)

21 CASE PRESENTATION After 3rd cycles: severe tinnitus and moderate hear loss (audiogram), switch to carboplatin After 4 cycles of Platin / Etoposide After 6 cycles of Platin / Etoposide

22 CASE PRESENTATION Tumorboard: Good partial response, ametabolic pleural effusion OK for thoracic RTX + PCI (if brain MRI ok and pleural effusion resolves) 6 weeks after last chemotherapy Thoracic RTX : mediastinum and remaining pleural nodules 30Gy in 10 fractions VMAT PCI: 25Gy in 10 fractions 2 months after RTX : Nausea, vomiting, gait disturbance Otoneurologic examaniation: OK Brain MRI: OK Cause?

23 CASE PRESENTATION October months since diagnosis 12 months post last chemotherapy 10 months post end of RTX (thorax and PCI) Before Know

24 Hope for the future?? ONLY IN CLINICAL TRIALS 409 open trials recruiting patients 12 studies with pembrolizumab 13 studies with nivolumab 7 studies with ipilimumab Risk of acute / late auto-immune side effects

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27 Hope for the future?? Science Translational Medicine 2015 aug

28 Bioscience report 2015

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31 Abstract no: LBA 7. Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC), in small cell lung cancer (SCLC), Presidential session III DLL-3 is highly expressed on neuroendocrine tumor cells 79 SCLC pts progressing after 1-2 lines were included 29 DLL-3 high pts 34% (10) responded and 31% had stable disease(9) Duration of response 178 days

32 CONCLUSIONS Small cell Lung cancer?? New Chemotherapy options?? Very challenging disease No major proven breakthrough in the last 20 years Best chance is with prevention of smoking Some new therapeutics strategies in the future (I-O, ADC) Nicolas Mach, MD,PD

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