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 • Do immune checkpoint inhibitors (anti-PD1/PDL-1) have a role in treatment of molecularly defined populations? 2 Why would anyone use chemotherapy in an EGFR mutant or ALK+ lung cancer patient? 3 Case 1 – 24M with ALK+ NSCLC • Presented in 2011 with extensive adenopathy and malignant effusions • Started crizotinib with CR September 2011 January 2012 4 EML4-ALK Translocations in NSCLC EML4-ALK frequency: ~4% (64/1709) Primarily lung adenocarcinoma Soda et al., Nature 448: 561-566, 2007 First line chemotherapy versus crizotinib in ALK+ NSCLC (Mok ASCO 2014) 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 What are the options? • Third generation TKI? • Clinical trial, i.e. HSP90? • How about chemotherapy? 8 Chemotherapy vs. BSC: Meta-analysis summary Chemo Hazard Ratio MST (m) 1-yr OS (%) Alkylating 1.26 -1 -6 Vinca/VP16 0.87 +1 +4 Cisplatin 0.73 +2 +10 BMJ 311: 899, 1995 Platinum doublet chemotherapy in nonsquamous patients Scagliotti GV et al, JCO 2008;26(21):3543-51 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 Maintenance pemetrexed and bevacizumab December 2012 March 2013 June 2014 – 18 months on chemo 13 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 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 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 16 Pemetrexed may have significant benefit for ALK+ pts 17 Berge et al., Clin Lung Cancer. Nov 2013; 14(6): 636–643. 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 Erlotinib (n=86) Chemotherapy (n=87) PFS probability 0.8 HR=0.37 (0.25–0.54) 0.6 Log-rank p<0.0001 0.4 0.2 0 0 3 5.2 6 9 9.7 12 15 18 21 24 27 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. 30 33 EGFR Mutation+ NSCLC and Erlotinib Day 0 4 months 25 months Chemotherapy in unselected pts 21 Schiller et al., N Engl J Med 2002;346:92-8.) Chemotherapy may be more effective in EGFR mutants than in wt patients Study IPASS OPTIMAL NEJ 002 WJTOG 3405 EURTAC Response Rate 71% vs. 47% 83% vs. 36% 74% vs. 31% 62% vs. 31% 58% vs. 15% Chemo in BOLD 22 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 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 Oncol 2013; 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 Primary endpoint: PFS by independent review Presented By Terufumi Kato at 2014 ASCO Annual Meeting PFS by EGFR mutation type Presented By Terufumi Kato at 2014 ASCO Annual Meeting AEs (incidence >20%) Presented By Terufumi Kato at 2014 ASCO Annual Meeting 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 nontrivial 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 NSCLC Response rates consistently ~20% Duration of Response and Overall Survival with Nivolumab in Pretreated Advanced NSCLC Presented By Scott Gettinger at 2014 ASCO Annual Meeting 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 38 Akbay et al., Can Disc 2013, 3, 1355; D’Incecco et al., ELCC 2914 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!