GEFITINIB IN ESOPHAGEAL CANCER: JUST THE BEGINNING OF A SPICY STORY

1. GEFITINIB IN ESOPHAGEAL CANCER:JUST THE BEGINNING OF A SPICY STORY A. D. Roth MD CC Oncosurgery HUG Geneva

2. Overall Survival ESMO 29th Sept 2012

3. Boring! Another negative study in esophageal cancer!

4. Recrutement completed in 31 months,Congratulations! Recruitment from 51 UK sites from 30 Mar 2009 until 18 Nov 2011 ESMO 29th Sept 2012

5. Progression free survival Days on protocol therapy Placebo: median 35; IQR 27 to 62; range 0 to 372 Gefitinib: median 42; IQR 27 to 91; range 0 to 680 ESMO 29th Sept 2012

6. COG Response rates: There is something behind the stage Waterfall plots – Percentage change in longest diameter at 4 weeks from baseline, if measurable at both time points. • RECIST 1.0 response rates (all PR): 0.4% placebo, 3.1% gefitinib • Disease control rate at 8 weeks: 16% placebo, 26% gefitinib (p=0.014) ESMO 29th Sept 2012

7. Crizotinib Phase I-II clinical trial in NSCLC ≈ 1,500 patients screened => 82 (5.5%) enrolled! 2nd line treatment Response rate: 57%! Major screening effort. Neg patients lost for this study Kwak EL, NEJM 363:1693 2010

8. Conclusions • COG is the first RCT in the second line setting in esophageal cancer • The primary end point of OS was not met. • The dominant effect of PS on PFS and OS has been demonstrated for the first time. • The trial demonstrated positive secondary end point of PFS with HR 0.79, P = 0.017. • Significant relief of odynophagia (PRO data) in the gefitinib arm (p=0.004) • The disease control rate was 26% at 8 weeks (P = 0.014) on Gefitinib and durable responses were seen. • There were no new or worrying safety signals • The translational research project TRANSCOG will analyse predictive biomarkers in over 300/450 patients biopsies and give guidance to identification of the patients most likely to benefit from this treatment modality. Sponsored by: ESMO 29th Sept 2012

9. How to turn a negative trial into a nice story? Remember PETACC-3! Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer A. Roth et al JNCI 2012 (in press)

10. EGFR mutation causes conformational change and increased activation (at least in NSCLC) Wild Type EGFR Mutant EGFR Ligand Extracellular domain Trans-membrane domain Tyrosine kinase domain ATP Tyrosine phosphorylation Ras-Raf-MAPK Proliferation Pi3K-AKT Survival EGFR internalisation Degradation/recycling EGFR signals for longer at the cell membrane Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004

11. Common mutation sites in the EGFR gene in NSCLC ATP binding cleft Regulatory domain Transmembrane region Extracellular domain C-lobe N-lobe TK domain A-loop Chelix P-loop 21 20 19 18

12. “IPASS”: Comparison of progression-free survival by mutation status within treatment arms GEFITINIB EGFR M+ (n=132)GEFITINIB EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) Probabilityof PFS 1.0 GEFITINIB, HR=0.19, 95% CI 0.13, 0.26, p<0.0001No. events M+ = 97 (73.5%)No. events M- = 88 (96.7%) Carboplatin / paclitaxel, HR=0.78, 95% CI 0.57, 1.06, p=0.1103No. events M+ = 111 (86.0%)No. events M- = 70 (82.4%) 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Hazard ratio <1 implies a lower risk of progression in the M+ group than in the M- groupM+, mutation positive; M-, mutation negative Mok et al 2009, Fukuoka et al 2009

13. And what about esophageal cancer? • 50 -70% of esophageal cancers overexpress EGFR protein • EGFR exon 19 and 21 mutations are infrequent in esophageal cancer • No relation between gefitinib and erlotinib efficiency and EGFR status established in esophageal cancer so far

14. Why should esophageal cancer behave like NSCLC when treated by anti-EGFR TKIs? • CRC does not respond to cisplatin! • KRAS negative predictive value is restricted so far to CRC! • BRAFmutated melanoma and CRC do not respond the same way to vemurafenid! • …..etc.

15. We need to go deeper into the biology of esophageal cancer!

16. What should be looking for? • Mutations or other DNA abnomalities can be without any biological consequence • Biological consequences can be assessed by: • Genomic expression profiling (mRNA) • Proteomic studies (endproduct)

17. BRAFmut vs BRAF and KRAS wild type in CRC: Differentially expressed probesets with fold change > 2 and <1% FDR (53 probesets) Adjusted for MSI status and BRAF/MSI interactions S. Tejpar et al, ASCO 2010, V. Popovici JCO 30;1288, 2012

18. SAR according to BRAF mutation status Petacc3 – SAKK 60-00 (CRC) • Median survivals (95% CI): • BRAF mut: 7.49 m (4.8-11.2) • BRAF wt: 25.2 m (21.1-29.5) • (p = 1.9e-11) A. Roth ASCO 2010

19. BRAFmut-like signature in CRC • If average(Gene1) < average(Gene2) then predict 'BRAF-positive' S. Tejpar et al, ASCO 2010, V. Popovici JCO 30;1288, 2012

20. Survival after relapse (SAR) in CRC:BRAFmut-like patients behave like BRAF mutated! S. Tejpar et al, ASCO 2010, V. Popovici JCO 30;1288, 2012

21. Translational research in this study • Do not loose to much time at looking for discret mutations predicting response to gefitinib • Analyse the responding subpopulation by genomic profiling and examine if they correspond to a particular subtype • Validate findings in relatively small clinical studies

22. CONCLUSIONS • Gefitinib does not improve OS in second/third line treatment of esophageal cancer • A study of this size is a fantastic opportunity to learn more about esophageal cancer biology • Better knowledge in molecular biology in this disease might help to select patients who might benefit from anti-EGFR TKIs • Investigators should be encouraged in the conduct of this TR program