1. Using Non-targeted Therapies in Targeted Lung Cancer Populations Nathan Pennell, M.D., Ph.D. September 6, 2014

2. Objectives Discuss the role of chemotherapy in molecularly defined populations Discuss the addition of chemo and/or bevacizumab (Avastin) to targeted therapy Do immune checkpoint inhibitors (anti-PD- 1/PDL-1) have a role in treatment of molecularly defined populations? 2

3. Why would anyone use chemotherapy in an EGFR mutant or ALK+ lung cancer patient? 3

4. Case 1 – 24M with ALK+ NSCLC Presented in 2011 with extensive adenopathy and malignant effusions Started crizotinib with CR 4 September 2011 January 2012

5. EML4-ALK Translocations in NSCLC EML4-ALK frequency: ~4% (64/1709) Primarily lung adenocarcinoma EML4-ALK frequency: ~4% (64/1709) Primarily lung adenocarcinoma Soda et al., Nature 448: 561-566, 2007

6. First line chemotherapy versus crizotinib in ALK+ NSCLC (Mok ASCO 2014)

7. Case 1 – 24M with ALK+ NSCLC Presented in 2011 with extensive adenopathy and malignant effusions Crizotinib with CR 8 months until progression Ceritinib (on trial as LDK378) CR 6 months until progression 7

8. What are the options? Third generation TKI? Clinical trial, i.e. HSP90? How about chemotherapy? 8

9. Chemotherapy vs. BSC: Meta-analysis summary ChemoHazard RatioMST (m)1-yr OS (%) Alkylating1.26- 6 Vinca/VP160.87+1+ 4 Cisplatin0.73+2+10 BMJ 311: 899, 1995

10. Platinum doublet chemotherapy in nonsquamous patients Scagliotti GV et al, JCO 2008;26(21):3543-51

11. Case 1 – 24M with ALK+ NSCLC Presented in 2011 with extensive adenopathy and malignant effusions Crizotinib with CR 8 months until progression Ceritinib (on trial as LDK378) CR 6 months until progression Started carboplatin, pemetrexed, and bevacizumab followed by pem/bev maintenance in late 2012… 11

12. Maintenance pemetrexed and bevacizumab December 2012March 2013

13. June 2014 – 18 months on chemo 13

14. Case 2 – 36 year old woman with hip pain August 2008 Scans showed destructive bone lesion in pelvis Biopsy showed lung adenocarcinoma Started on carboplatin, paclitaxel, bevacizumab in late 2008 Progressed in summer 2009, started pemetrexed 14

15. Case 2 – Now 42 year old woman without hip pain On intermittent pemetrexed until 2012 (2.5 years) when test showed she was ALK+ 4 treatment breaks ranging from 6-12 months No ALK directed therapy yet! June 2014

16. Pemetrexed may have significant benefit for ALK+ pts 65 ALK+ patients response to chemotherapy retrospectively analyzed 1 ORR to pem 34% (9% in unselected NSCLC pts 2 ) 16 1 Lee et al., Lung Cancer 2013, 79(1); 2 Hanna et al., JCO 2004

17. Pemetrexed may have significant benefit for ALK+ pts 17 Berge et al., Clin Lung Cancer. Nov 2013; 14(6): 636–643.

19. Erlotinib vs. CT in Advanced NSCLC Patients With EGFR Mutations: Interim Results of the European Erlotinib Versus CT (EURTAC) Phase III Randomized Trial PFS probability Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p<0.0001 Time (months) 03691215182124273033 Data cut-off: 26 Jan 2011 1.0 0.8 0.6 0.4 0.2 0 9.75.2 Slide courtesy of Tony Mok, ASCO discussant. Rosell R, et al. J Clin Oncol. 2011;29(suppl): abstr# 7503.

20. EGFR Mutation+ NSCLC and Erlotinib Day 0 4 months 25 months

21. Chemotherapy in unselected pts 21 Schiller et al., N Engl J Med 2002;346:92-8.)

22. Chemotherapy may be more effective in EGFR mutants than in wt patients StudyResponse Rate IPASS71% vs. 47% OPTIMAL83% vs. 36% NEJ 00274% vs. 31% WJTOG 340562% vs. 31% EURTAC58% vs. 15% 22 Chemo in BOLD

23. Pooled analysis of clinical outcome for EGFR TKI‐treated patients with EGFR mutation‐positive NSCLC Journal of Cellular and Molecular Medicine 6 AUG 2014 DOI: 10.1111/jcmm.12278 http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12278/full#jcmm12278-fig-0002 http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12278/full#jcmm12278-fig-0002

24. Conclusion: Chemo is effective in EGFR mutant and ALK+ NSCLC Chemotherapy is effective and should be considered in patients when TKIs fail 24 JJ (CHOP calendar) http://mbvshl.blogspot.com/2013/02/round-9-looking-good-billy-ray-feeling.html

25. Can we improve on the effectiveness of TKIs up front by adding non-targeted agents? Chemotherapy? Bevacizumab? (anti-VEGF) 25

26. EGFR TKIs + Chemotherapy = Not better than chemo alone? 4 large phase 3 trials with gefitinib (INTACT 1/2) and erlotinib (TRIBUTE/TALENT) All showed no evidence that chemo + TKI was better in unselected NSCLC patients But what about EGFR mutation+ patients? 26

27. FASTACT 2: Chemotherapy plus erlotinib versus chemotherapy 27 Wu et al., Lancet Oncol 2013; 14: 777–86 Median PFS 16.8 v 6.9 months

28. Chemotherapy plus TKI in EGFR mutation+ pts Promising signs but need randomized trial of chemo plus TKI versus TKI alone Chinese study ongoing of carboplatin + pemetrexed (CP), CP + gefitinib, and gefitinib (NCT02148380) 28

29. Does adding bevacizumab to TKIs improve efficacy? BeTa phase 3 trial of erlotinib +/- bev Not significant but promising trend towards better survival 29 Herbst et al., Lancet 2011 May 28;377(9780):1846-54

30. Study design Presented By Terufumi Kato at 2014 ASCO Annual Meeting - Phase 2 trial

31. Primary endpoint: PFS by independent review Presented By Terufumi Kato at 2014 ASCO Annual Meeting

32. PFS by EGFR mutation type Presented By Terufumi Kato at 2014 ASCO Annual Meeting

33. AEs (incidence >20%) Presented By Terufumi Kato at 2014 ASCO Annual Meeting

34. Conclusions: Adding to TKIs Chemotherapy plus EGFR TKI results in a promising PFS compared to chemo Bev plus erlotinib also results in a promising PFS compared to TKI alone Adding chemo or bev to the TKI adds a non- trivial amount of side effects and risk (and cost) Evidence for improved survival needed before it becomes SOC compared to TKI alone 34

35. Immunotherapy: i.e. Checkpoint inhibitors (anti-PD-1 and PDL-1)? 35

36. Checkpoint Inhibitors in Development in NSCLC Response rates consistently ~20%

37. Duration of Response and Overall Survival with Nivolumab in Pretreated Advanced NSCLC Presented By Scott Gettinger at 2014 ASCO Annual Meeting

38. Checkpoint Inhibitors in EGFR mutant population? In mouse models of EGFR mutant NSCLC PDL-1 was high and anti-PD1 was quite effective 1 In a cohort of 56 EGFR mutant NSCLCs, 71% were PDL-1 positive (compared to about 50% in unselected NSCLC) 2 38 Akbay et al., Can Disc 2013, 3, 1355; D’Incecco et al., ELCC 2914 PDL-1

39. Checkpoint Inhibitors in EGFR mutant population? In a small phase 2 trial, 20 pts with EGFR mutant NSCLC with AR were treated with nivolumab + erlotinib with ORR of 15% 2 39 Rizvi et al., ASCO Proc 2014, Abst,

40. Conclusions: Immunotherapy Too early to say whether checkpoint inhibitors will play a more significant role in EGFR mutant and ALK+ NSCLC treatment, BUT No reason to think they won’t be at least as effective as in unselected patients! 40

41. Take Home Points While TKIs are the most effective treatment for genetically defined NSCLC pts, chemotherapy can be an effective alternative Adding chemotherapy or bevacizumab to TKIs may make TKIs more effective, but the jury is still out Immunotherapy is enormously promising in all types of lung cancer! 41

42. Thank You!