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Using Non-targeted Therapies in Targeted Lung Cancer Populations

Using Non-targeted Therapies in Targeted Lung Cancer Populations. Nathan Pennell, M.D., Ph.D. September 6, 2014. Objectives. Discuss the role of chemotherapy in molecularly defined populations Discuss the addition of chemo and/or bevacizumab (Avastin) to targeted therapy

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Using Non-targeted Therapies in Targeted Lung Cancer Populations

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  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?

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

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

  5. EML4-ALK Translocations in NSCLC 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

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

  9. Chemotherapy vs. BSC: Meta-analysis summary 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…

  12. Maintenance pemetrexed and bevacizumab December 2012 March 2013

  13. June 2014 – 18 months on chemo

  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

  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 analyzed1 • ORR to pem 34% (9% in unselected NSCLC pts2) 1Lee et al., Lung Cancer 2013, 79(1); 2Hanna et al., JCO 2004

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

  18. Erlotinib vs. CT in Advanced NSCLC Patients With EGFR Mutations: Interim Results of the European Erlotinib Versus CT (EURTAC) Phase III Randomized Trial 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p<0.0001 PFS probability 0 3 6 9 12 15 18 21 24 27 30 33 5.2 9.7 Time (months) Data cut-off: 26 Jan 2011 Slide courtesy of Tony Mok, ASCO discussant. Rosell R, et al. J Clin Oncol. 2011;29(suppl): abstr# 7503.

  19. EGFRMutation+ NSCLC and Erlotinib Day 0 4months 25 months

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

  21. Chemotherapy may be more effective in EGFR mutants than in wt patients Chemo in BOLD

  22. Pooled analysis of clinical outcome for EGFR TKI‐treated patients with EGFR mutation‐positive NSCLC Journal of Cellular and Molecular Medicine6 AUG 2014 DOI: 10.1111/jcmm.12278http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12278/full#jcmm12278-fig-0002

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

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

  25. 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. FASTACT 2: Chemotherapy plus erlotinib versus chemotherapy Median PFS 16.8 v 6.9 months Wu et al., Lancet Oncol2013; 14: 777–86

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

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

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

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

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

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

  35. Checkpoint Inhibitors in Development in NSCLCResponse rates consistently ~20%

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

  37. Checkpoint Inhibitors in EGFR mutant population? • In mouse models of EGFR mutant NSCLC PDL-1 was high and anti-PD1 was quite effective1 • In a cohort of 56 EGFR mutant NSCLCs, 71% were PDL-1 positive (compared to about 50% in unselected NSCLC)2 PDL-1 Akbay et al., Can Disc 2013, 3, 1355; D’Incecco et al., ELCC 2914

  38. 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 Rizvi et al., ASCO Proc 2014, Abst,

  39. 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. 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. Thank You!

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