1 / 32

Outline

WCLC 2013: Update On SCLC Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester Manchester, UK raffaele.califano@christie.nhs.uk. Outline. Background Key studies Conclusion. Background. Aggressive disease Poor prognosis

trynt
Télécharger la présentation

Outline

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. WCLC 2013:Update On SCLCRaffaele CalifanoDepartment of Medical Oncology The Christie and University Hospital of South ManchesterManchester, UKraffaele.califano@christie.nhs.uk

  2. Outline Background Key studies Conclusion

  3. Background Aggressive disease Poor prognosis Targeted agents have all failed so far... No real progress in 20 years

  4. Key Studies First-line treatment: Seckl et al (Abs O21.01) Glisson et al (Abs O21.05) Pre-treated patients: Havel et al (Abs O21.06)

  5. LungSt r Multicentre Phase III Randomised Double Blind Placebo Controlled Trial of Pravastatin added to First Line Standard Chemotherapy in SCLC Michael J Seckl on behalf of the LungStar collaborators

  6. Rationale Statins: Kill SCLC in vitro +in vivo/additive with chemo May prevent cancer Danish study: Longer OS for ca pts on statins HCC: Pravastatin doubles survival

  7. Pravastatin 40 mg OD Previously untreated LS/ ES SCLC, PS 0-3 No statins < 12m (n=846) Platinum/Etoposide plus placebo Platinum/Etoposide plus pravastatin 40 mg OD Placebo R Study Design For 2 years 1:1 Primary endpoint: OS

  8. Statistics • Original sample size: • 1300 patients (90% power, 5% significance level) to detect an increase from 10% to 15% in 2-yr survival with pravastatin • Equivalent to a median survival increase from 9 to 11 months in ES and 15 to 19 months in LS • Revised sample size: • Reduced to 80% power, 5% significance level • 842 patients with 792 events corresponds to detecting a HR of 0.82

  9. Baseline Characteristics

  10. Overall Survival

  11. Progression-free Survival

  12. Toxicity

  13. Conclusion/Comments Pravastatin Ineffective Sub-group analyses / Translational studies? A lot of patients/money wasted!

  14. A Randomized Phase 2 Study of Ganitumab or Rilotumumab with Platinum-Based Chemotherapy as First-Line Treatment for Extensive-Stage SCLC • B. Glisson, et al

  15. Rationale IGF1-R Inhibition sensitizes cell lines to etoposide and carboplatin High levels correlate with short survival MET Expressed and functional in SCLC Mutant in a subset of SCLC cell lines and tumor samples Ganitumab and rilotumumab Fully human mAbs targeting IGF1-R and hepatocyte growth factor (HGF)/scatter factor

  16. Rilotumumab Ganitumab Previously untreated ES SCLC, PS 0-1 No thrombosis No diabetes (n=185) Platinum/Etoposide plus placebo Platinum/Etoposide plus Ganitumumab Platinum/Etoposide plus Rilotumumab Placebo R Study Design Until PD 1:1:1 Primary endpoint: OS

  17. Patients’ Charactheristics

  18. Overall Response Rate

  19. Overall Survival Progression Free Survival

  20. Adverse Events

  21. Biomarker analysis Only available for IGF axis (Serum) Low IGFBP-2 levels associated with increased response (but no OS) on ganitumab arm Tumor biomarkers pending

  22. Conclusion/Comments No improvement in ORR, PFS, or OS No pre-clinical data for activity in SCLC Experimental agents only active in a targeted population?

  23. MLN8237 (ALISERTIB), An Investigational Selective Aurora A Kinase (AAK) Inhibitor, In patients With Relapsed/Refractory SCLC: PHASE 2 RESULTS Havel et al

  24. Rationale Key mitotic regulator AAK is amplified or overexpressed in a variety of solid tumors Inhibition of AAK results in: Chromosome misalignment and instability Abnormal spindle formation Reduction in astral microtubule length/stability Small molecule inhibitor of AAK with single-agent antitumor activity Preclinical data support combination with taxanes, rituximab and other agents untreated Control treated treated treated α−tubulin, DNA, Centrosomes

  25. Gastric N=45 SCLC N=45 H&N N=45 Breast N=45 NSCLC N=45 RP2D: MLN8237 50 mg BID for 7 days (21-day cycles) Study Design ES SCLC ECOG PS 0–1 ≤2 prior lines No symptomatic brain mets RP2D determined duringphase 1 portion of study Treatment for 24 months, or until PD or unacceptable toxicity Primary endpoint: ORR

  26. Demographics *Based on safety population (n=60) Data as of April 2013

  27. Previous Treatment Data as of April 2013

  28. Efficacy and Safety Data as of September 2013

  29. Biomarker analysis 53 tumor tissues available (6 responders, 2 SCLC) Candidate biomarkers: amplification of Myc family genes and Aurora A, Ki-67) Whole exome sequencing

  30. Patient Patient Whole exome sequencing: Preliminary analysis Mutational landscape of SCLC Highly mutated NR R Gene Mutated genes found in responders Among 527 frequently mutated genes reported in SCLC, 122 genes found to be mutated in at least 1/6 patients Fisher’s exact test identified 8 mutated genes associated with responders NR R Gene

  31. Conclusion/Comments Manageable safety profile Activity similar to active agents in patients with relapsed SCLC RPh2 study: Paclitaxel +/-MLN8237 to start soon

  32. Take Home message No practice changing data Need better understanding of molecular biology Need tissue and possibly serum/plasma to be mandatory in trials

More Related