Best of ASCO 2014: Highlights in Metastatic Non-Small Cell Lung Cancer Howard (Jack) West, M JackWestM@gmail.com @JackWestM Swedish Cancer Institute Seattle, WA Best of ASCO 2014 Seattle, WA
Learning Objectives etermine 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 AZ9291 and CO1686 in treating acquired resistance to EGFR TKIs (*T790Mpositive)
Novel Agents in Broad (Molecularly Unselected) Advanced NSCLC Populations
SQUIRE: Chemotherapy +/- Necitumumab for First Line Adv Squamous NSCLC Necitumumab (Neci) (IMC-11F8) is a human IgG1 anti-egfr monoclonal antibody Adv squamous NSCLC Treatment-naïve N = 1093 Primary endpoint: OS R A N O M I Z E Cisplatin/Gemcitabine + Necitumumab up to 6 cycles Cisplatin/Gemcitabine up to 6 cycles 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 Maintenance neci until progression Thatcher, A#8008
SQUIRE: Efficacy of Necitumumab Chemo/Neci (N = 545) Chemo alone (N = 548) ORR (CR + PR) 31.2% 28.8% 0.400 CR (CR + PR +S) 81.8% 77.0% 0.043* P Progression-Free Survival (ITT) *Cochran-Mantel-Haenszel test (stratified) Overall Survival (ITT) Thatcher, A#8008
SQUIRE: Toxicity of Necitumumab Thatcher, A#8008
SQUIRE: FLEX Redux? (Re-FLEX?) SQUIRE FLEX Thatcher, A#8008 Pirker, Lancet 2009 Extremely similar agent; extremely similar results cetuximab has had negligible impact on NSCLC management Highlights distinction between statistical & clinical significance
REVEL: ocetaxel +/- Ramucirumab as Second Line Therapy for Adv NSCLC Ramucirumab (RAM) is a human IgG1 monoclonal antibody, specifically binding to the extracellular domain of VEGFR-2 Approved in previously treated gastric cancer Adv NSCLC (any histology) Prior platinumbased chemo Prior bev allowed N = 1253 Primary endpoint: OS R A N O M I Z E ocetaxel 75 mg/m2 + Ramucirumab 10 mg/kg IV Q21 days ocetaxel 75 mg/m2 + Placebo IV Q21 days Treat until P or prohibitive toxicity Perol, A#LBA-8006
REVEL: Efficacy of Ramucirumab RAM + OC (N = 628) PL + OC (N = 625) ORR (CR + PR) 22.9% 13.6% <0.001 CR (CR + PR +S) 64.0% 52.6% <0.001 P Progression-Free Survival (ITT) Overall Survival (ITT)
REVEL: Toxicity (Adverse Events in >20% of Patients or >5% Higher w/ram
Half Empty or Half Full? Optimistic oncologist perspective 1.4 mo increase in OS isn t much Cost: about $7K/treatment But options improving OS >2 nd line are very limited, especially for squamous NSCLC 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
(Not Very) Old and New Agents for ALK-Positive Advanced NSCLC
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 2 nd 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 1: 1 Crizotinib Cisplatin/Pemetrexed or Carboplatin/Pemetrexed Primary endpoint: PFS Mok, A#8002
First-Line Crizotinib vs. Chemo: Progression-Free Survival Mok, A#8002
Responses, Crizotinib vs. Chemo 74% 45% Mok, A#8002 Criz Chemo ORR 74% 45% Resp ur (wks) 49 23
Common AEs of Any Cause in 25% of Patients With 5% ifference Between Groups a Crizotinib (n=171), n (%) Higher frequency ( 5% absolute difference) in crizotinib arm Chemotherapy (n=169), n (%) b Any grade Grade 3/4 Any grade Grade 3/4 Vision disorder c 122 (71) 1 (1) 24 (14) 0 iarrhea 105 (61) 4 (2) 29 (17) 1 (1) Edema c 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 transaminases c 61 (36) 24 (14) 22 (13) 4 (2) Upper respiratory infection c 55 (32) 0 21 (12) 1 (1) Abdominal pain c 45 (26) 0 20 (12) 0 ysgeusia 45 (26) 0 11 (7) 0 Higher frequency ( 5% absolute difference) in chemotherapy arm Nausea 95 (56) 2 (1) 103 (61) 3 (2) ecreased appetite 51 (30) 4 (2) 59 (35) 1 (1) Fatigue 49 (29) 5 (3) 65 (38) 4 (2) Neutropenia c 36 (21) 19 (11) 51 (30) 26 (15) Asthenia 22 (13) 0 42 (25) 2 (1) Anemia c 15 (9) 0 54 (32) 15 (9) Permanent treatment discontinuations due to treatment-related AEs: 5% in crizotinib arm; 8% in chemotherapy arm b 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 a Not adjusted for differential treatment duration; b before crossover to crizotinib; c clustered term
Ceritinib: New Treatment Option for ALK-Positive NSCLC FA Approved April, 2014 Kim, A#8003 Cost: $13,500/mo
Change from baseline in sum of longest diameters (%) ose Expansion Cohort, 750 mg/day: Best Percentage Change from Baseline NSCLC with prior ALKi NSCLC ALKi naïve N=228* # # # ## # # # # # ## # # # # ## # # # # ## # # # ## # # ## # # # # # # # # # #### # # # # # # ## # # ### # # ## # # # ## # # # # PFS event # # # # # # # # # # # # # # # # # # ## ## # # # # # ## # ## # # ## # # # # # # # # # # # # # # *Patients with measurable disease at baseline and at least 1 post baseline assessment without unknown response for target lesion or overall response Kim, A#8003
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 x to Ceritinib 8.1 mo 21.2 mo isease Control, Brain Mets 70% 75% Modestly higher RR, longer responses in crizotinibnaïve patients Kim, A#8003
Toxicity Challenges with Ceritinib Greater than with crizotinib ose reduction 59% (!) Increased ALT/AST, nausea, diarrhea, vomiting iscontinuation due to adverse effects 10% Pneumonia, IL/pneumonitis, decreased appetite Oncologists need to know to dose-reduce early 750 mg daily may be more than needed Kim, A#8003
Timing of Ceritinib? Approval is for crizotinib-refractory and crizotinib-intolerant patients with ALK rearrangement Should it be used earlier? Trial in development ALK+ No Prior Rx N= 348 Primary endpoint: PFS R A N Ceritinib Cisplatin/Pemetrexed or Carboplatin/Pemetrexed Trial we need ALK+ No Prior Rx Primary endpoint: OS R A N Crizotinib Ceritinib Ceritinib Chemo or M choice Presented by: H. Jack West
Assessing Options for First Line Treatment of EGFR Mutation-Positive Advanced NSCLC
LUX Lung-3, LUX Lung-6 Trials LUX Lung-3 EGFR Mut n Pos Advanced NSCLC No Prior Rx N= 345 Global R A N 2:1 Sequist, JCO 2013 Afatinib 40 mg PO daily until progression Cisplatin/Pemetrexed Q21d up to 6 cycles Primary endpoint: PFS LUX Lung-6 EGFR Mut n Pos Advanced NSCLC No Prior Rx N= 364 Asia R A N 2:1 Wu, Lancet 2014 Afatinib 40 mg PO daily until progression Cisplatin d1, Gemcitabine d1,8 q21d up to 6 cycles Primary endpoint: PFS
Estimated OS probability OS Analysis: LUX-Lung 3, LUX-Lung 6 (el 19 and L858R only) Estimated OS probability 1.0 0.8 Median, months HR (95%CI), p-value LUX-Lung 3 Afatinib n=203 Pem/Cis n=104 31.57 28.16 0.78 (0.58 1.06), p=0.1090 1.0 0.8 Median, months HR (95%CI), p-value LUX-Lung 6 Afatinib n=216 Gem/Cis n=108 23.6 23.5 0.83 (0.62 1.09), p=0.1756 0.6 0.6 0.4 0.4 0.2 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (months) No of patients Afatinib 203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0 Pem/Cis 104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0 Time (months) No of patients Afatinib 216 214 202 190 172 158 141 118 104 93 80 51 19 9 1 0 Gem/Cis 108 101 93 87 81 70 61 55 49 36 30 17 8 3 0 0 Yang, A#8004
Combined OS Analysis: LUX-Lung 3, LUX-Lung 6 (el 19 and L858R only) Yang, A#8004
Combined OS Analysis: LUX-Lung 3, LUX-Lung 6 by Mutation Subtype Yang, A#8004
ifferences in Efficacy of Gefitinib/ Erlotinib: Exon 19 el vs. L858R Jackman, Clin Cancer Res, 2006 PFS OS Riely, Clin Cancer Res, 2006 OS
Treatment after Progression on First Line Therapy (el 19 and L858R only) LUX-Lung 3 LUX-Lung 6 Afatinib (n=203) Pem/Cis (n=104) Afatinib (n=216) Gem/Cis (n=108) iscontinued 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 (%) 81 (44) 78 (75) 50 (26) 61 (56) Erlotinib Gefitinib Afatinib AZ9291 acomitinib Icotinib EGFR TKI combinations 61 (33) 28 (15) 2 (1) 2 (1) 5 (3) 46 (42) 44 (42) 7 (7) 1 (1) 1 (1) 9 (9) 21 (11) 19 (10) 11 (6) 5 (3) 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
Treatment after Progression on First Line by Country s Reimbursement* Countries with universal reimbursement policies** Afatinib (n=144) Chemo (n=75) Countries without universal reimbursement policies*** Afatinib (n=275) Chemo (n=137) iscontinued 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) *etermined 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
Impact of subsequent EGFR TKIs on OS: exploratory analyses by category of EGFR TKI reimbursement policy in country of residence* Population Combined LL3/6 population (n=631) Countries with universal reimbursement policies** (n=219) Countries without universal reimbursement policies*** (n=412) Japan (n=77) % received TKI after 1 st line chemo HR (95% CI) Common mutations 66% 0.81 (0.66 0.99) 91% 0.71 (0.49 1.02) 52% 0.85 (0.66 1.08) 100% 0.57 (0.29 1.12) HR (95% CI) el19 0.59 (0.45 0.77) 0.50 (0.31 0.81) 0.59 (0.42 0.82) 0.34 (0.13 0.87) HR (95% CI) L858R 1.25 (0.92 1.71) 1.14 (0.64 2.03) 1.32 (0.91 1.92) 1.13 (0.40 3.21) *etermined 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
Med OS (mo) Is OS with Afatinib in LUX-Lung 3/6 Superior to That of Other EGFR TKIs? EGFR TKI Chemo NEJGSG 1 WJTOG 2 EURTAC 3 OPTIMAL 4 LUX- LUX- Lung 3 5 Lung 6 5 N=230 N=177 N=174 N=165 N=345 N=364 Terminated early, after Interim analysis? 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
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 el19 pts is robust, impressive
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? LUX-Lung 7 EGFR Mut+ N = 316 (Asia) Primary endpoint: OS R A N Gefitinib daily Afatinib daily Completed July, 2013 Toxicity assessment will also be critical
Or is optimal therapy now an EGFR TKI/bevacizumab combination?
Subsets emonstrate Benefit with Bev Added to 2 nd Line Erlotinib (BeTa) Herbst, Lancet 2011
Erlotinib +/- Bevacizumab as Maintenance Therapy (ATLAS): Clinical Subgroups Johnson, JCO 2013
VEGF (pg/300000 cell) EGFR Regulates VEGF in EGFR Mutant Cell Lines EGFR mutant NSCLC cell lines express higher levels of VEGF VEGF expression is reduced with EGFR inhibitors 2500 2000 1500 A549 (wt) HCC827 (mut) H3255 (mut) H1975 (mut) 1000 500 0 EGF(60ng/ml) - - + + - - + + - - + + - - + + Erlotinib(1mM) - + - + - + - + - + - + - + - + wild-type mutant Mutant + T790M Courtesy of Heymach et al.; manuscript in preparation
Erlotinib/Bevacizumab vs. Erlotinib for EGFR Mutation-Positive Adv NSCLC Adv NSCLC EGFR Mut n (exon 19/21) Treatment-naïve N = 154 Primary endpoint: PFS R A N Erlotinib 150 mg/day + bevacizumab 15 mg/kg IV Q21 days until progression or prohibitive toxicity Erlotinib 150 mg/days until progression or prohibitive toxicity EB E P ORR (CR/PR) 69% 64% ns CR (CR/PR/S) 99% 88% 0.018 Kato, A#8005
JO25587 PFS in Context of Other Trials in EGFR Mutation-Positive NSCLC Med PFS (mo) EURTAC 1 OPTIMAL 2 LUX- LUX- JO25587- Lung-3 3 Lung-6 4 Erlotinib 5 JO25587- Erloti/Bev 5 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
PFS probability PFS probability Erlotinib +/- Bevacizumab: PFS by EGFR mutation type Exon 19 deletion Exon 21 L858R EB group E group EB group E group Median (months) 18.0 10.3 Median (months) 13.9 7.1 1.0 HR 0.41 (95% CI: 0.24 0.72) 1.0 HR 0.67 (95% CI: 0.38 1.18) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 EB E 0.2 EB E 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Number at risk EB E 40 Time (months) 39 38 36 33 29 27 24 19 12 8 5 2 2 0 40 35 29 26 22 16 12 9 9 5 3 1 0 0 0 E Number at risk EB 35 37 Time (months) 33 31 28 27 24 22 14 11 8 5 3 2 2 0 31 28 18 17 13 12 12 9 7 7 4 2 1 0 Kato, A#8005
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 ifference? Greater toxicity in Japanese population? Greater toxicity in EGFR mutation-positive? Longer duration of therapy higher risk of ARs
Cost Considerations with Erlotinib/Bev Combination $16,700 Cost/ Month ($US) $6,300 Erlotinib Erlotinib/ Bevacizumab Addition of bevacizumab increases cost of first line treatment by ~$120,000 for 16 treatments (acquisition cost alone)
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? ACCRU Trial EGFR Mut+ N = 118 N Amer R A N Erlotinib daily Erlotinib daily & Bevacizumab q3wk Ongoing (slowly) PI T. Stinchcombe Primary endpoint: PFS
Breaking the Impasse for EGFR Mutation-Positive Patients with Acquired Resistance
Acquired Resistance: AZ9291 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 AZ9291 and CO1686 are mutant selective, irreversible inhibitors of EGFR with significant antitumor activity in preclinical tumor models with both EGFR TKI-sensitizing and T790M resistance mutations with greater wild-type sparing than first generation EGFR TKIs
AZ9291: Response rate* in overall population( T790M+ and T790M-) 40 20 ####### Best percentage change from baseline in target lesion: all evaluable patients, escalation and expansion (N=205) 0-20 -40-60 -80-100 Complete response Partial response* Non-response 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+S) = 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, S, or P), 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; P, progressive disease; PR, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; S, stable disease Jänne, A#8009
AZ9291: Response rate * in T790M+ (central test) 40 20 # # Best percentage change Best from percentage baseline in change target lesion: from baseline all evaluable in target T790M+ lesion: patients, Part B T790M+ evaluable patients, expansion cohorts only (N=107) 0-20 -40-60 -80 20 mg Q 40 mg Q 80 mg Q 160 mg Q 240 mg Q -100 ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC Overall disease control rate (CR+PR+S) = 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% *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, S, or P), N=107 (from 120 T790M+ patients; 13 patients with a current non-evaluable response are not included)., discontinued; Q, once daily Jänne, A#8009
AZ9291: Response rate * in T790M- (central test) 40 20 # # # # 0-20 -40-60 -80 20 mg Q 40 mg Q 80 mg Q 160 mg Q -100 ORR* = 22% (11/50; 95% Cl 12%, 36%) in patients with EGFR T790M- NSCLC Overall disease control rate (CR+PR+S) = 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, S, or P), N=50 (from 56 T790M- patients; six patients with a current non-evaluable response are not included) Jänne, A#8009
Response rate * according to T790M (central test) status: immediate prior EGFR-TKI, # yes vs no T790M+ T790M- 68/105 43/69 25/36 11/50 3/28 8/22 *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
Probability of progression-free survival AZ9291: Progression-free survival by T790M (central test) status 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- 0 T790M+ (95% CI) T790M- (95% CI) 0 6 12 18 24 30 36 42 Study week 115 55 96 33 78 21 ots 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) Jänne, A#8009 56 15 21 7 6 0 1 0
AZ9291: 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: iarrhea in 20% Rash in 27% Interstitial lung disease in 3% Hyperglycemia 1% Jänne, A#8009
CO-1686: Best Response in Phase I and Early Phase II Cohort Patients Sequist, A#8010
CO-1686: Progression-Free Survival Sequist, A#8010
Sequist, A#8010 CO-1686: Toxicity Profile
Current/Future evelopment of Third Generation EGFR TKIs AZ9291 AURA: Ph 2 expansion in T790M+ AURA 2: Confirmatory Ph 2 in T790M+ AURA 3: Ph 3 2 nd line vs. chemo in T790M+ CO-1686 TIGER X: expansion of 2 nd line or later in T790M+ TIGER 1: Ph 2/3 1 st 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+
Summary of Third Generation EGFR TKIs in Acquired Resistance BOTH agents have impressive efficacy and are granted breakthrough designation by FA Foot race to clinic Toxicity differences: AZ9291: rash & diarrhea (<erlotinib), IL 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
Closing Thoughts/ Summary
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 ifferent standard for adding bevacizumab? Conversely, is an intervention clinically significant if the trial needs >1000 patients to demonstrate statistical significance?
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 rug delivery to needy patients limits
Take Home Messages for Advanced NSCLC Management from ASCO 2014 Necitumumab: Re-FLEX?; not enough benefit vs. toxicity Ramicirumab for 2 nd 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 el 19; Unique to afatinib? Major differences between el 19 and L858R populations Bevacizumab significantly improved PFS w/erlotinib for EGFR mut n pos-nsclc AZ9291 and CO-1686 both very active in EGFR T790M+ acquired resistance after prior 1 st gen EGFR TKI