Best of ASCO Metastatic Non-Small Cell Lung Cancer

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Dr. Jack West's presentation on highlights in advanced non-small cell lung cancer from ASCO 2014, focusing on new agents ramucirumab and necitumumab for broad NSCLC populations, crizotinib and ceritinib for ALK-positive NSCLC, EGFR inhibitor-options of afatinib and bevacizumab added to erlotinib for first line treatment of EGFR mutation-positive NSCLC, and AZD9291 or CO1686 for EGFR mutation-positive patients with acquired resistance.

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Best of ASCO Metastatic Non-Small Cell Lung Cancer

  1. 1. Best of ASCO 2014: Highlights in Metastatic Non-Small Cell Lung Cancer Howard (Jack) West, MD @JackWestMD Swedish Cancer Institute Seattle, WA Best of ASCO 2014 Seattle, WA
  2. 2. Learning Objectives • Determine whether evidence on necitumumab and ramucirumab for broad NSCLC populations are sufficient to modify current treatment standards • Evaluate treatment options of crizotinib and ceritinib for ALK-positive advanced NSCLC • Compare utility of various EGFR TKI-based options as first line treatment of advanced EGFR mutation-positive NSCLC • Recognize efficacy of both AZD9291 and CO1686 in treating acquired resistance to EGFR TKIs (*T790M- positive)
  3. 3. Novel Agents in Broad (Molecularly Unselected) Advanced NSCLC Populations
  4. 4. SQUIRE: Chemotherapy +/- Necitumumab for First Line Adv Squamous NSCLC Adv squamous NSCLC Treatment-naïve N = 1093 R A N D O M I Z E Cisplatin/Gemcitabine + Necitumumab up to 6 cycles Primary endpoint: OS • Necitumumab (Neci) (IMC-11F8) is a human IgG1 anti-EGFR monoclonal antibody Cisplatin/Gemcitabine up to 6 cycles Maintenance neci until progression Cisplatin 75 mg/m2 IV day 1 q21 days Gemcitabine 1250 mg/m2 IV days 1, 8 q21 days Necitumumab 800 mg/kg IV days 1, 8 q21 days Thatcher, A#8008
  5. 5. SQUIRE: Efficacy of Necitumumab Overall Survival (ITT)Progression-Free Survival (ITT) Thatcher, A#8008 Chemo/Neci (N = 545) Chemo alone (N = 548) P ORR (CR + PR) 31.2% 28.8% 0.400 DCR (CR + PR +SD) 81.8% 77.0% 0.043* *Cochran-Mantel-Haenszel test (stratified)
  6. 6. SQUIRE: Toxicity of Necitumumab Thatcher, A#8008
  7. 7. SQUIRE: FLEX Redux? (Re-FLEX?) SQUIRE FLEX • Extremely similar agent; extremely similar results – cetuximab has had negligible impact on NSCLC management • Highlights distinction between statistical & clinical significance Pirker, Lancet 2009Thatcher, A#8008
  8. 8. REVEL: Docetaxel +/- Ramucirumab as Second Line Therapy for Adv NSCLC Adv NSCLC (any histology) Prior platinum- based chemo Prior bev allowed N = 1253 R A N D O M I Z E Docetaxel 75 mg/m2 + Ramucirumab 10 mg/kg IV Q21 days Docetaxel 75 mg/m2 + Placebo IV Q21 days Primary endpoint: OS Treat until PD or prohibitive toxicity • Ramucirumab (RAM) is a human IgG1 monoclonal antibody, specifically binding to the extracellular domain of VEGFR-2 • Approved in previously treated gastric cancer Perol, A#LBA-8006
  9. 9. REVEL: Efficacy of Ramucirumab Overall Survival (ITT)Progression-Free Survival (ITT) RAM + DOC (N = 628) PL + DOC (N = 625) P ORR (CR + PR) 22.9% 13.6% <0.001 DCR (CR + PR +SD) 64.0% 52.6% <0.001
  10. 10. REVEL: Toxicity (Adverse Events in >20% of Patients or >5% Higher w/RAM
  11. 11. Half Empty or Half Full? • 1.4 mo increase in OS isn’t much • Cost: about $7K/treatment • But options improving OS >2nd line are very limited, especially for squamous NSCLC Optimistic oncologist perspective • Whether adding new agent with some increased toxicity and additional significant cost is “worth it” for 1.4 mo improvement in median OS is your judgment • Not a clear change in standard of care
  12. 12. (Not Very) Old and New Agents for ALK-Positive Advanced NSCLC
  13. 13. PROFILE 1014: First-Line Crizotinib vs. Chemo in ALK-Positive Adv NSCLC • Crizotinib has significant activity, RR 60-65%, in previously treated ALK+ NSCLC, & PFS 7.7 mo vs. 3.0 months compared with 2nd line chemo (Shaw, ESMO 2012, A#2862) • Though largely presumed to be superior to first line chemo in ALK-positive NSCLC, this hasn’t been prospectively demonstrated Advanced NSCLC ALK+ No Prior Rx N= 343 R A N D Crizotinib Cisplatin/Pemetrexed or Carboplatin/Pemetrexed Primary endpoint: PFS 1: 1 Mok, A#8002
  14. 14. First-Line Crizotinib vs. Chemo: Progression-Free Survival Mok, A#8002
  15. 15. Responses, Crizotinib vs. Chemo 74% 45% Mok, A#8002 Criz Chemo ORR 74% 45% Resp Dur (wks) 49 23
  16. 16. Common AEs of Any Cause in ≥25% of Patients With ≥5% Difference Between Groupsa Crizotinib (n=171), n (%) Chemotherapy (n=169), n (%)b Any grade Grade 3/4 Any grade Grade 3/4 Higher frequency (≥5% absolute difference) in crizotinib arm Vision disorderc 122 (71) 1 (1) 24 (14) 0 Diarrhea 105 (61) 4 (2) 29 (17) 1 (1) Edemac 83 (49) 1 (1) 22 (13) 1 (1) Vomiting 78 (46) 3 (2) 68 (40) 6 (4) Constipation 74 (43) 3 (2) 53 (31) 0 Elevated transaminasesc 61 (36) 24 (14) 22 (13) 4 (2) Upper respiratory infectionc 55 (32) 0 21 (12) 1 (1) Abdominal painc 45 (26) 0 20 (12) 0 Dysgeusia 45 (26) 0 11 (7) 0 Higher frequency (≥5% absolute difference) in chemotherapy arm Nausea 95 (56) 2 (1) 103 (61) 3 (2) Decreased appetite 51 (30) 4 (2) 59 (35) 1 (1) Fatigue 49 (29) 5 (3) 65 (38) 4 (2) Neutropeniac 36 (21) 19 (11) 51 (30) 26 (15) Asthenia 22 (13) 0 42 (25) 2 (1) Anemiac 15 (9) 0 54 (32) 15 (9) a Not adjusted for differential treatment duration; bbefore crossover to crizotinib; cclustered term ● Permanent treatment discontinuations due to treatment-related AEs: 5% in crizotinib arm; 8% in chemotherapy armb ● No grade 5 AEs reported to be related to treatment; 1 patient in chemotherapy arm had grade 5 pneumonitis after crossover to crizotinib, considered to be treatment-related
  17. 17. Ceritinib: New Treatment Option for ALK-Positive NSCLC Kim, A#8003 FDA Approved April, 2014 Cost: $13,500/mo
  18. 18. # ## Dose Expansion Cohort, 750 mg/day: Best Percentage Change from Baseline NSCLC with prior ALKi NSCLC ALKi naïve Changefrombaselineinsumoflongestdiameters(%) *Patients with measurable disease at baseline and at least 1 post baseline assessment without unknown response for target lesion or overall response N=228* # # # # # # # # # # # ## # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # ## #### # # # ## # # # # # # # # ### ## # # # # # ##### ## ## # # ## # ### ####### # # # ### # # # ### # # #PFS event Kim, A#8003
  19. 19. Activity of Ceritinib in ALK+ NSCLC Endpoint Criz-Naïve (N = 83) Criz-Refractory (N = 163) Response Rate 66% 55% 12-mo Prog-Free Survival 61% 28% Median Time from Dx to Ceritinib 8.1 mo 21.2 mo Disease Control, Brain Mets 70% 75% • Modestly higher RR, longer responses in crizotinib- naïve patients Kim, A#8003
  20. 20. Toxicity Challenges with Ceritinib • Greater than with crizotinib • Dose reduction – 59% (!) – Increased ALT/AST, nausea, diarrhea, vomiting • Discontinuation due to adverse effects – 10% – Pneumonia, ILD/pneumonitis, decreased appetite • Oncologists need to know to dose-reduce early – 750 mg daily may be more than needed Kim, A#8003
  21. 21. Timing of Ceritinib? Presented by: H. Jack West • Approval is for crizotinib-refractory and crizotinib-intolerant patients with ALK rearrangement • Should it be used earlier? ALK+ No Prior Rx N= 348 R A N D Ceritinib Cisplatin/Pemetrexed or Carboplatin/PemetrexedPrimary endpoint: PFS Trial in development ALK+ No Prior Rx R A N D Ceritinib Crizotinib Primary endpoint: OS Trial we need Ceritinib Chemo or MD choice
  22. 22. Assessing Options for First Line Treatment of EGFR Mutation-Positive Advanced NSCLC
  23. 23. LUX Lung-3, LUX Lung-6 Trials EGFR Mut’n Pos Advanced NSCLC No Prior Rx N= 345 Global R A N D Afatinib 40 mg PO daily until progression Cisplatin/Pemetrexed Q21d up to 6 cycles Primary endpoint: PFS Sequist, JCO 2013LUX Lung-3 R A N D Afatinib 40 mg PO daily until progression Cisplatin d1, Gemcitabine d1,8 q21d up to 6 cycles Wu, Lancet 2014 EGFR Mut’n Pos Advanced NSCLC No Prior Rx N= 364 Asia Primary endpoint: PFS LUX Lung-6 2:1 2:1
  24. 24. OS Analysis: LUX-Lung 3, LUX-Lung 6 (Del 19 and L858R only) Yang, A#8004 1.0 0.8 0.6 0.4 0.2 0 EstimatedOSprobability 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) 203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0 104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0 Afatinib Pem/Cis No of patients LUX-Lung 3 Afatinib n=203 Pem/Cis n=104 Median, months 31.57 28.16 HR (95%CI), p-value 0.78 (0.58–1.06), p=0.1090 LUX-Lung 6 Afatinib n=216 Gem/Cis n=108 Median, months 23.6 23.5 HR (95%CI), p-value 0.83 (0.62–1.09), p=0.1756 1.0 0.8 0.6 0.4 0.2 0 EstimatedOSprobability 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (months) 216 214 202 190 172 158 141 118 104 93 80 51 19 9 1 0 108 101 93 87 81 70 61 55 49 36 30 17 8 3 0 0 Afatinib Gem/Cis No of patients
  25. 25. Combined OS Analysis: LUX-Lung 3, LUX-Lung 6 (Del 19 and L858R only) Yang, A#8004
  26. 26. Combined OS Analysis: LUX-Lung 3, LUX-Lung 6 by Mutation Subtype Yang, A#8004
  27. 27. Differences in Efficacy of Gefitinib/ Erlotinib: Exon 19 Del vs. L858R OSPFS Jackman, Clin Cancer Res, 2006 Riely, Clin Cancer Res, 2006 OS
  28. 28. Treatment after Progression on First Line Therapy (Del 19 and L858R only) LUX-Lung 3 LUX-Lung 6 Afatinib (n=203) Pem/Cis (n=104) Afatinib (n=216) Gem/Cis (n=108) Discontinued treatment, n (%) 184 (100) 104 (100) 194 (100) 108 (100) Subsequent systemic therapy, n (%)† 144 (78) 88 (85) 123 (63) 70 (65) Chemotherapy, n (%) 131 (71) 49 (47) 114 (59) 29 (27) EGFR TKI therapy, n (%) Erlotinib Gefitinib Afatinib AZD9291 Dacomitinib Icotinib EGFR TKI combinations 81 (44) 61 (33) 28 (15) 2 (1) 2 (1) – – 5 (3) 78 (75) 46 (42) 44 (42) 7 (7) 1 (1) 1 (1) – 9 (9) 50 (26) 21 (11) 19 (10) – – – 11 (6) 5 (3) 61 (56) 22 (20) 39 (36) – – – 3 (3) 3 (3) Other systemic therapy±, n (%) 5 (3) 2 (2) 3 (2) 4 (4) Radiotherapy, n (%) 32 (17) 21 (20) 4 (2) 0 (0) †Collection of data on subsequent therapies still ongoing. ± include investigational agents, monoclonal antibodies, non-EGFR targeting protein kinase inhibitors etc Yang, A#8004
  29. 29. Treatment after Progression on First Line by Country’s Reimbursement* Countries with universal reimbursement policies** Countries without universal reimbursement policies*** Afatinib (n=144) Chemo (n=75) Afatinib (n=275) Chemo (n=137) Discontinued treatment, n (%) 127 (100) 75 (100) 251 (100) 137 (100) Subsequent systemic therapy, n (%) 112 (88) 69 (92) 158 (63) 89 (65) Chemotherapy, n (%) 103 (81) 35 (47) 142 (57) 43 (31) EGFR TKI, n (%) 76 (60) 68 (91) 55 (22) 71 (52) Other, n (%) 5 (4) 2 (3) 3 (1) 4 (3) Radiotherapy, n (%) 27 (22) 18 (24) 9 (4) 3 (2) *Determined by presence or absence of a national reimbursement policy in effect throughout the period of trial conduct: **Main countries contributing : Japan, Taiwan, Korea, Germany, France, Australia, UK, Belgium ***Main countries contributing : China, Thailand, Russia, the Philippines, Malaysia Yang, A#8004
  30. 30. Impact of subsequent EGFR TKIs on OS: exploratory analyses by category of EGFR TKI reimbursement policy in country of residence* Population % received TKI after 1st line chemo HR (95% CI) Common mutations HR (95% CI) Del19 HR (95% CI) L858R Combined LL3/6 population (n=631) 66% 0.81 (0.66–0.99) 0.59 (0.45–0.77) 1.25 (0.92–1.71) Countries with universal reimbursement policies** (n=219) 91% 0.71 (0.49–1.02) 0.50 (0.31–0.81) 1.14 (0.64–2.03) Countries without universal reimbursement policies*** (n=412) 52% 0.85 (0.66–1.08) 0.59 (0.42–0.82) 1.32 (0.91–1.92) Japan (n=77) 100% 0.57 (0.29–1.12) 0.34 (0.13–0.87) 1.13 (0.40–3.21) *Determined by presence or absence of a national reimbursement policy in effect throughout the period of trial conduct: **Main countries contributing : Japan, Taiwan, Korea, Germany, France, Australia, UK, Belgium, Ireland ***Main countries contributing : China, Thailand, Russia, the Philippines, Malaysia Yang, A#8004
  31. 31. Is OS with Afatinib in LUX-Lung 3/6 Superior to That of Other EGFR TKIs? Med OS(mo) WJTOG2 EURTAC3 OPTIMAL4 LUX- Lung 35 NEJGSG1 Gefitinib Erlotinib Afatinib 1) Maemondo et al. N Engl J Med. 2010;362:2380; 2) Mitsudomi et al. Lancet Oncol. 2010;11:121; 3) Rosell et al. Lancet Oncol. 2012;13:239; 4) Zhou et al. Lancet Oncol. 2011;12:735; 5) Yang et al. Proc ASCO 2014: A#8004 N=230 N=177 Terminated early, after Interim analysis? N=174 N=165 N=345 N=364 LUX- Lung 65 EGFR TKI Chemo
  32. 32. Multiple Shots on Goal • No survival difference for overall ITT population • No survival difference for LUX-Lung trials individually • Statistical significance is function of magnitude of difference & population size • Pooling two trials and eliminating rare mutations  statistical significance • Still, OS benefit for Del19 pts is robust, impressive
  33. 33. Relevant Comparison for Afatinib in 2014 is to Other EGFR TKIs • Is timing of EGFR TKI critical re: crossover? – L858R population showed PFS benefit but reversal w/OS – Sequence of therapy may be relevant • Would other EGFR TKIs show OS benefit if > 700 pts enrolled & results divided by mut’n subtype? EGFR Mut+ N = 316 (Asia) R A N D Afatinib daily Gefitinib daily Completed July, 2013Primary endpoint: OS LUX-Lung 7 • Toxicity assessment will also be critical
  34. 34. Or is optimal therapy now an EGFR TKI/bevacizumab combination?
  35. 35. Subsets Demonstrate Benefit with Bev Added to 2nd Line Erlotinib (BeTa) Herbst, Lancet 2011
  36. 36. Erlotinib +/- Bevacizumab as Maintenance Therapy (ATLAS): Clinical Subgroups Johnson, JCO 2013
  37. 37. EGFR Regulates VEGF in EGFR Mutant Cell Lines Courtesy of Heymach et al.; manuscript in preparation 0 500 1000 1500 2000 2500 VEGF(pg/300000cell) EGF(60ng/ml) - - + + - - + + - - + + - - + + Erlotinib(1mM) - + - + - + - + - + - + - + - + A549 (wt) HCC827 (mut) H3255 (mut) H1975 (mut) wild-type mutant Mutant + T790M • EGFR mutant NSCLC cell lines express higher levels of VEGF • VEGF expression is reduced with EGFR inhibitors
  38. 38. Erlotinib/Bevacizumab vs. Erlotinib for EGFR Mutation-Positive Adv NSCLC Adv NSCLC EGFR Mut’n (exon 19/21) Treatment-naïve N = 154 R A N D Erlotinib 150 mg/day + bevacizumab 15 mg/kg IV Q21 days until progression or prohibitive toxicity Primary endpoint: PFS Erlotinib 150 mg/days until progression or prohibitive toxicity EB E P ORR (CR/PR) 69% 64% ns DCR (CR/PR/SD) 99% 88% 0.018 Kato, A#8005
  39. 39. JO25587 PFS in Context of Other Trials in EGFR Mutation-Positive NSCLC 1. Rosell et al. Lancet Oncol. 2012;13:239; 11. Zhou et al. Lancet Oncol. 2011;12:735; 3. Sequist et al. J Clin Oncol. 2013;31:3327; 4. Wu et al. Lancet Oncol. 2014;15:213; 5. Kato, Proc ASCO 2014, A#8005 Med PFS (mo) EURTAC1 OPTIMAL2 JO25587- Erlotinib5 JO25587- Erloti/Bev5 LUX- Lung-33 LUX- Lung-64
  40. 40. Erlotinib +/- Bevacizumab: PFS by EGFR mutation type EB group E group Median (months) 18.0 10.3 HR 0.41 (95% CI: 0.24–0.72) EB E E EB Number at risk 0 1.0 0 40 40 E EB Number at risk EB E 1.0 0 0 35 37 Time (months) 4 8 122 6 10 14 18 22 2616 20 24 28 38 33 2739 36 29 24 12 5 219 8 2 0 29 22 1235 26 16 9 5 1 09 3 0 0 Time (months) 4 8 122 6 10 14 18 22 2616 20 24 28 31 27 2233 28 24 14 8 3 211 5 2 0 28 17 1231 18 13 12 7 4 19 7 2 0 0.2 0.4 0.6 0.8 PFSprobability PFSprobability 0.2 0.4 0.6 0.8 Exon 19 deletion Exon 21 L858R EB group E group Median (months) 13.9 7.1 HR 0.67 (95% CI: 0.38–1.18) Kato, A#8005
  41. 41. Toxicity Issues with Erlotinib/Bevacizumab on JO25587 • No unforeseen toxicities or Rx-related deaths • Grade >3 toxicity 91% vs. 53% (esp. HTN, proteinuria) • 41% discontinued bevacizumab for adverse effects – Primarily proteinuria (15%) or hemorrhagic (12%) • Bevacizumab discontinuation rate 10-15% in BeTa, ATLAS trials • Difference? – Greater toxicity in Japanese population? – Greater toxicity in EGFR mutation-positive? – Longer duration of therapy  higher risk of ADRs
  42. 42. Cost Considerations with Erlotinib/Bev Combination Cost/ Month ($USD) $6,300 $16,700 Erlotinib Erlotinib/ Bevacizumab Addition of bevacizumab increases cost of first line treatment by ~$120,000 for 16 treatments (acquisition cost alone)
  43. 43. Is Erlotinib/Bevacizumab the New Standard of Care for EGFR Mut+? • Kato: median PFS 16.0 vs. 9.7 mo, HR 0.54 (ECOG 4599: median PFS 6.2 vs. 4.5 mo, HR 0.66) • My preferred regimen moving forward • Threshold for clinical confidence ≠ threshold for coverage • Confirmatory trial needed? Outside of Japan? OS diff? • Will it be covered? EGFR Mut+ N = 118 N Amer R A N D Erlotinib daily Erlotinib daily & Bevacizumab q3wk Ongoing (slowly) Primary endpoint: PFS ACCRU Trial PI – T. Stinchcombe
  44. 44. Breaking the Impasse for EGFR Mutation-Positive Patients with Acquired Resistance
  45. 45. Acquired Resistance: AZD9291 and CO-1686 • The vast majority of patients with an activating EGFR mutation who respond well to initial EGFR TKI therapy demonstrate progression several months to years later • T790M mutation detected in approximately 60% of patients with acquired resistance • AZD9291 and CO1686 are mutant selective, irreversible inhibitors of EGFR with significant anti- tumor activity in preclinical tumor models with both EGFR TKI-sensitizing and T790M resistance mutations with greater wild-type sparing than first generation EGFR TKIs
  46. 46. Best percentage change from baseline in target lesion: all evaluable patients, escalation and expansion (N=205) Jänne, A#8009 AZD9291: Response rate* in overall population( T790M+ and T790M-) • First patient dosed Mar 6, 2013 • Longest response >9 months ongoing at time of data cutoff • ORR* = 53% (109/205; 95% CI 46%, 60%); no difference in ORR by race • Overall disease control rate (CR+PR+SD) = 83% (171/205; 95% CI 78%, 88%) 20 mg 40 mg 80 mg 160 mg 240 mg N (205) 20 57 61 55 12 ORR 55% 44% 54% 58% 67% *Includes confirmed responses and responses awaiting confirmation; #represents imputed values. Population: all dosed patients with a baseline RECIST assessment and an evaluable response (CR, PR, SD, or PD), N=205 (from 232 dosed patients, 27 patients with a current non-evaluable response are not included). CI, confidence interval; CR, confirmed complete response; ORR, overall response rate; PD, progressive disease; PR, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease 40 20 0 -20 -40 -60 -80 -100 Complete response ####### Partial response* Non-response
  47. 47. Jänne, A#8009 AZD9291: Response rate* in T790M+ (central test) • ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC • Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%) 20 mg 40 mg 80 mg 160 mg 240 mg N (107) 10 29 34 28 6 ORR 50% 62% 68% 64% 83% Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B *Includes confirmed responses and responses awaiting confirmation; #represents imputed values Population: all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD), N=107 (from 120 T790M+ patients; 13 patients with a current non-evaluable response are not included). D, discontinued; QD, once daily Best percentage change from baseline in target lesion: T790M+ evaluable patients, expansion cohorts only (N=107) 40 mg QD 80 mg QD 160 mg QD 240 mg QD 20 mg QD 40 20 -20 -40 -60 -80 -100 0 # # D D D D D D DD D D D D D D D D D D D D D D D
  48. 48. • ORR* = 22% (11/50; 95% Cl 12%, 36%) in patients with EGFR T790M- NSCLC • Overall disease control rate (CR+PR+SD) = 56% (28/50; 95% CI 41%, 70%) 20 mg 40 mg 80 mg 160 mg N (50) 3 17 17 13 ORR 67% 12% 24% 23% *Includes confirmed responses and responses awaiting confirmation; #represents imputed values Population: all dosed centrally confirmed T790M- patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD), N=50 (from 56 T790M- patients; six patients with a current non-evaluable response are not included) 40 mg QD 80 mg QD 160 mg QD 20 mg QD # # # # D D D D 40 20 -20 -40 -60 -80 -100 0 D D D D D D D D D D D D D D D D D D D D D D D D AZD9291: Response rate* in T790M- (central test) Jänne, A#8009
  49. 49. T790M+ T790M- 68/105 43/69 25/36 11/50 3/28 8/22 Response rate* according to T790M (central test) status: immediate prior EGFR-TKI,# yes vs no *Includes confirmed responses and responses awaiting confirmation; #TKI therapy is defined as being immediately prior if TKI was the last regimen taken prior to the study, with no subsequent therapy. Population: all dosed centrally confirmed T790M+ and T790M- patients with a baseline RECIST assessment and an evaluable response, T790M+ N=105 (from 107 T790M+ patients with response data; two patients not included as subgroup missing), T790M- N=50 Jänne, A#8009
  50. 50. AZD9291: Progression-free survival by T790M (central test) status 0 6 12 18 24 30 36 42 Study week Probabilityofprogression-freesurvival T790M+ (95% CI) T790M- (95% CI) Dots indicate censored observations, shaded area represents 95% CIs; progression events that do not occur within 14 weeks of the last evaluable assessment (or first dose) are censored. Population: all dosed centrally confirmed T790M+ and T790M- patients, N=170 (115 T790M+, 55 T790M-; six patients for whom start date is not yet known are not included) 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Patients at risk T790M+ T790M- 115 55 96 33 78 21 56 15 21 7 6 0 1 0 Jänne, A#8009
  51. 51. Jänne, A#8009 AZD9291: Toxicity Summary • No clear maximum-tolerated dose up to 240 mg/d – No clear correlation of toxicity with dose – 80 mg/d selected as optimal for therapeutic index • At 80 mg/d dose: – Diarrhea in 20% – Rash in 27% – Interstitial lung disease in 3% – Hyperglycemia 1%
  52. 52. CO-1686: Best Response in Phase I and Early Phase II Cohort Patients Sequist, A#8010
  53. 53. CO-1686: Progression-Free Survival Sequist, A#8010
  54. 54. Sequist, A#8010 CO-1686: Toxicity Profile
  55. 55. Current/Future Development of Third Generation EGFR TKIs • AZD9291 – AURA: Ph 2 expansion in T790M+ – AURA 2: Confirmatory Ph 2 in T790M+ – AURA 3: Ph 3 2nd line vs. chemo in T790M+ • CO-1686 – TIGER X: expansion of 2nd line or later in T790M+ – TIGER 1: Ph 2/3 1st line vs. erlotinib (no T790M+ requirement) – TIGER 2: Ph 2 after 1 prior EGFR TKI in T790M+ – TIGER 3: Ph 2 vs. chemo in T790M+
  56. 56. Summary of Third Generation EGFR TKIs in Acquired Resistance • BOTH agents have impressive efficacy and are granted breakthrough designation by FDA – Foot race to clinic • Toxicity differences: – AZD9291: rash & diarrhea (<erlotinib), ILD in minority – CO-1686: hyperglycemia, mild diarrhea, nausea, rare QTc prolongation • Though some potential toxicity concerns in both, anticipated benefit >> risk • For both agents, focus is on T790M+ patients
  57. 57. Closing Thoughts/ Summary
  58. 58. No absolute rule for the amount of evidence required to change practice • Big effects don’t require big trials • Crizotinib was justifiably approved based on phase I/II trial with >50% RR – Ceritinib similarly approved despite relatively small numbers, but large effect • EGFR TKI therapies became clear first line standard of care despite absence of OS benefit – Different standard for adding bevacizumab? • Conversely, is an intervention clinically significant if the trial needs >1000 patients to demonstrate statistical significance?
  59. 59. In 2014, Cost/Value of Therapy is a Factor in Cancer Care • Reality is that cost matters, especially as new drugs have eclipsed the prior $10,000/mo barrier • It is appropriate to expect a semblance of value and not merely p < 0.05 • We need to discuss value openly and not just have it bias our clinical judgment • Cost is limiting our ability to deliver best treatment Optimal Rx ($$$$) Cost/practical limits Drug delivery to needy patients
  60. 60. Take Home Messages for Advanced NSCLC Management from ASCO 2014 • Necitumumab: Re-FLEX?; not enough benefit vs. toxicity • Ramicirumab for 2nd line: Maybe; is 1.4 mo med OS diff worth cost?; improving OS is hard, esp in squam NSCLC • Crizotinib >> chemo first line (RR & PFS) in ALK+ • Ceritinib highly active for criz-naïve or criz-resistant ALK+(RR & PFS), & CNS activity, but toxicity challenging • Afatinib OS benefit specific to Del 19; Unique to afatinib? – Major differences between Del 19 and L858R populations • Bevacizumab significantly improved PFS w/erlotinib for EGFR mut’n pos-NSCLC • AZD9291 and CO-1686 both very active in EGFR T790M+ acquired resistance after prior 1st gen EGFR TKI

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