1. Do we know how to choose the best maintenance treatment? oliver.gautschi@onkologie.ch

2. Firstline therapy (metastatic disease) Continuation maintenance Switch maintenance Secondline therapy (at progression) 2 Definitions

3. Delay tumor progression Prolong survival Optimal tolerance No cumulative toxicity Maintain life quality 3 Aims and Expectations

4. Meta-analysis: PFS Soon JCO 2009

5. Meta-analysis: OS Soon JCO 2009

6. Continuation chemotherapy is not standard-of-careBelani ASCO 2010

7. Continuation of Bevacizumab ?Sandler NEJM 2006; Reck JCO 2009 E4599: cont. 53% AVAiL : cont. 41-42%

8. Switch to Pemetrexed: JMENCiuleanu ASCO 2008, Lancet Oncol 2010 Gem / Platin Pac / Platin Doc / Platin No PD PS 0,1

9. JMEN: HistologyBelani ASCO 2009, Ciuleanu Lancet 2009

10. JMEN : initial ResponseCiuleanu, Lancet 2009 OS for non-squamous: HR CR/PR 0.81 0.61 SD 1.2 1.0 0.8 0.6 0.4 Favours pemetrexed Favours placebo

11. JMEN : ToxicityCiuleanu, Lancet 2009 Relevant grade 2 toxicities Fatigue Nausea 20 % Anorexie

12. Switch to Erlotinib: SATURNCappuzzo ASCO 2009 / Lancet Oncol 2010

13. SATURN: OSCappuzzo, Lancet Oncol 2010

14. SATURN: SubgroupsCappuzzo, Lancet Oncol 2010

15. Response to Firstline TherapyCappuzzo, Lancet Oncol 2010

16. SATURN: EGFR MutationBrugger, ASCO 2009 EGFR mutation EGFR wild type HR=0.10 (0.04–0.25) HR=0.78 (0.63–0.96) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Log-rank p<0.0001 Log-rank p=0.0185 PFS probability 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Time (weeks)

18. What did we learn from these registration trials ? Maintainance therapy is an approved option Histology is predictive for pemetrexed EGFR mutations are predictive for erlotinib but it is still not proven if maintenance offers a true survival advantage over secondline therapy with the same drug given at the right time

19. Ongoing Phase III Trials

20. Large Cell Small Cell Squamous Adeno M. Gugger, Bern University

21. Predictive Markers for ChemotherapyGandara, Curr Opin Oncol 2010 Histology is a predictive factor for pemetrexed, gemcitabine and bevacizumab. Are molecular markers better ? Candidates: TTF1, ERCC1, TS, BRCA1, gene signatures

23. TS and Drug ResistanceOzasa, Cancer Sci 2010 23

24. SAKK19/09 (BIOPRO)Multicenter phase II trial

25. EGFR T790M Kobayashi, NEJM 2005 25

28. Case 1: EGFR mutation 15 MAR 2010 18 MAR 2011 Erlotinib 28

29. EGFR-TKI and Line of TherapyMok ESMO 2010, Rosell NEJM 2009

30. Case 2: ALK Translocation Crizotinib 19 FEB 2011 17 MAR 2011

31. ALK-FISHJ. Diebold, Pathology Luzern HE: Adenocarcinoma with signet ring cells ALK FISH (break apart probe): positive (patient) IHC: TTF1 + ALK FISH (break apart probe): negative control

32. ALK Inhibitor Crizotinib Kwak, NEJM 2010 pretreated = 94%

33. ETOP LUNGSCAPE

34. Sequential TestingHorn, JCO 2009

35. Parallel TestingKim AACR 2010+11

36. Circulating DNAJCO 2004/Cancer Lett 2007 mKRAS wtKRAS

37. Mok, IPASS 2010

38. Emerging markers: FGFR Weiss, Science Translat Med 2010

39. Perspectives Gandara 2010

40. Enroll patients in clinical trials If not possible, consider switch maintenance if SD, good PS or symptomatic Pemetrexed if non-SQ and not pretreated Erlotinib if SQ or previous pemetrexed or oral drug preferred Test for EGFR and ALK Recommendations

41. Disclosure Slide Chair of investigator-initiated clinical trials supported by Roche, Eli Lilly, AMGEN, Bayer Advisory role for AstraZeneca No stocks No employment