Best of ASCO 2014 Lung

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1 Best of ASCO 214 Lung Heather Wakelee, MD Associate Professor of Medicine, Oncology Stanford Cancer Institute Stanford, California USA Outline ALK: 82: 1st line crizotinib Profile : ASCEND ceritinib EGFR: 84: Lux lung 3+6 OS analysis 8: onartuzumab- Met lung 85: Bevacizumab + erlotinib 89: AZD9291 : 81: CO : RADIANT OTHER ANTIBODIES: 86: ramucirumab-revel 87: PD-L1 MK : Necitumumab-Squire SCLC: 752: SCLC Thoracic XRT 753: SCLC PCI 1

2 Outline ALK: 82: 1st line crizotinib Profile : ASCEND ceritinib EGFR: 84: Lux lung 3+6 OS analysis 8: onartuzumab- Met lung 85: Bevacizumab + erlotinib 89: AZD9291 : 81: CO : RADIANT OTHER ANTIBODIES: 86: ramucirumab-revel 87: PD-L1 MK : Necitumumab-Squire SCLC: 752: SCLC Thoracic XRT 753: SCLC PCI Results: Patient and Disease Characteristics Demographic characteristics Patients N=273 Age at NSCLC diagnosis (years), mean ± SD 65.1 ± 12.2 Male, N (%) 142 (52%) Race, N (%) White 162 (59%) Black or African American 49 (18%) Asian 36 (13%) Hispanic or Latino 22 (8%) American Indian or Alaska Native 3 (1%) Native Hawaiian or Other Pacific Islander 1 (%) Smoking history, N (%) Never smoker 9 (33%) Light smoker 91 (33%) Heavy smoker 89 (33%) Unknown 3 (1%) Comorbidities and Disease Characteristics Patients N=273 Comorbidity index 2, N (%) CI (73%) CI (24%) CI >5 1 (4%) Disease characteristics Cancer histology, N (%) Adenocarcinoma 222 (81%) Large cell carcinoma 13 (5%) Squamous cell carcinoma 8 (3%) Mixed 3 3 (11%) Wakelee PASCO 214, Abstr 862 2

3 PROFILE 114 Study Design Mok abstr 82 Key entry criteria ALK-positive by central FISH testing a Locally advanced, R recurrent, or A metastatic nonsquamous NSCLC D N O No prior systemic M treatment for I advanced disease Z ECOG PS 2 b E Measurable disease Stable treated brain N=343 metastases allowed Crizotinib 25 mg BID PO, continuous dosing (n=172) Pemetrexed 5 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC 5 6 q3w for 6 cycles (n=171) CROSSOVER TO CRIZOTINIB PERMITTED AFTER PROGRESSION c a ALK status determined using standard ALK break-apart FISH assay b Stratification factors: ECOG PS (/1 vs. 2), Asian vs. non-asian race, and brain metastases (present vs. absent) c Assessed by IRR Endpoints Primary PFS (RECIST 1.1, independent radiologic review [IRR]) Secondary ORR OS Safety Patient-reported outcomes (EORTC QLQ- C3, LC13) PROFILE 114: NCT Primary Endpoint Met: Crizotinib Superior to Pemetrexed-based Chemotherapy in Prolonging PFS a PFS probability (%) Crizotinib (N=172) Chemotherapy (N=172) Events, n (%) 1 (58) 137 (8) Median, months HR (95% CI).45 (.35.6) P b <.1 ORR 74% vs 45% No. at risk Crizotinib Chemotherapy Time (months) Data cutoff: November 3, 213 a Assessed by IRR b 1-sided stratified log-rank test Mok abstr 82 3

4 Waterfall Plot: Best Percent Change from Baseline in Target Lesion Size Change from baseline (%) Crizotinib (n=152) a Best overall response (RECIST v1.1) Complete response Partial response Stable disease Progressive disease Change from baseline (%) Chemotherapy (n=147) a b b a Patients with early death, indeterminate response, or non-measurable disease not shown b Per RECIST v1.1, a complete response can occur with <1% change from baseline when lymph nodes are included as target lesion ASCEND-1 Study Design- Kim abstr 83 NCT Global pivotal phase 1 trial including 2 centers across 11 countries 1 Expansion Phase Evaluate 75 mg RD N=255 patients with ALK+ tumors N=246 patients with ALK+ NSCLC tumors ALK inhibitor treated N=163 ALK inhibitor naïve N=83 Key Objectives: to determine anti-tumor efficacy and safety of ceritinib Dose escalation phase (n=59) closed May 212 with RD of 75 mg/day 1 Shaw A et al. NEJM 214;37(13): ALKi: ALK inhibitor; RD: recommended dose Recruitment closed July October 213 data cut-off used for current analysis Study ongoing 9 ALK+ patients had cancers other than NSCLC All received crizotinib and 5 also received alectinib Presented by: Dong-Wan Kim 4

5 Best Percentage Change from Baseline (NSCLC) Best % change in sum of longest diameters PFS event ALK inhibitor treated ALK inhibitor naïve N=228 Patients with measurable disease at baseline and at least 1 post baseline assessment without unknown response for target lesion or overall response Presented by: Dong-Wan Kim Progression-Free Survival in Patients with ALK+ NSCLC Probability (%) Time (Months) Number of patients still at risk Time (Months) NSCLC with prior ALKi NSCLC ALKi naïve All NSCLC ALK inhibitor treated (N=163) ALK inhibitor naïve (N=83) All (N=246) Median: non-estimable (95% CI 8.31, non-estimable) PFS rate at 12 months: 61.3% Median: 8.21 months (95% CI 6.7, 1.12) PFS rate at 12 months: 39.1% Median: 6.9 months (95% CI 5.39, 8.41) PFS rate at 12 months: 28.4% 18 Presented by: Dong-Wan Kim 5

6 Outline ALK: 82: 1st line crizotinib Profile : ASCEND ceritinib EGFR: 84: Lux lung 3+6 OS analysis 8: onartuzumab- Met lung 85: Bevacizumab + erlotinib 89: AZD : CO : RADIANT OTHER ANTIBODIES: 86: ramucirumab-revel 87: PD-L1 MK : Necitumumab-Squire SCLC: 752: SCLC Thoracic XRT 753: SCLC PCI Treatment Naïve EGFR mut Patients EGFR TKIs vs Chemotherapy Study Treatment N Median PFS, months Median OS, months Maemondo Gefitinib vs Carboplatin / Paclitaxel vs 5.4 (P <.1) 3.5 vs 23.6 (P =.31) Mitsudomi Gefitinib vs Cisplatin / Docetaxel vs 6.3 (P <.1) 36 vs 39 (HR: 1.19) OPTIMAL Erlotinib vs Carboplatin / Gemcitabine vs 4.6 (P <.1) HR: 1.65 (P =.65) EURTAC Erlotinib vs plat-based chemotherapy vs 5.2 (P <.1) 19.3 vs 19.5 (P =.87) LUX-Lung 3 Afatinib vs Cisplatin/pemetrexed vs 6.9 (P =.1) ASCO 214 Maemondo MN Engl J Med. 21;362: ; Mitsudomi TLancet Oncol. 21;11: ; Mitsudomi T, et al. ASCO 212. Abstract 7521; Zhou C, Lancet Oncol. 211;12: ; Zhang C, et al. ASCO 212. Abstract 752; Rosell R, et al. Lancet Oncol. 212;13: ; Sequist LV, et al. J Clin Oncol

7 LUX 3+6: Combined OS analysis: common mutations (n=631) - Neither trial alone reach significance Estimated OS probability Afatinib n=419 Chemo n=212 Median, months HR (95%CI), p-value.81 (.66.99), p= Time (months) No of patients Afatinib Chemo Presented by: James Chih-Hsin Yang, abstr 84 Combined OS analysis: mutation categories Estimated OS probability Median, months HR (95%CI), p-value Del19 Afatinib n=236 Chemo n= (.45.77), p=.1 Estimated OS probability Median, months HR (95%CI), p-value L858R Afatinib n=183 Chemo n= ( ), p= Time (months) No of patients Afatinib Chemo Time (months) No of patients Afatinib Chemo Presented by: James Chih-Hsin Yang, abstr 84 7

8 Resistance Despite impressive results in first line trials RESISTANCE almost always develops Strategies looking at addition of drugs to delay resistance Promise with chemotherapy or bevacizumab, but limited with other agents Strategies to overcome resistance once it has developed Exciting data with afatinib/cetuximab, CO-1686, AZD9291 Global Phase 3 Trial (METLung) of Onartuzumab plus Erlotinib in NSCLC: Trial Design Patients with stage IIIB/ IV 2L/3L NSCLC (N=49) 1:1 Erlotinib + onartuzumab Treatments: Erlotinib 15mg PO QD Onartuzumab/placebo 15mg/kg i.v. q3w Erlotinib + placebo PD PD Survival follow-up No crossover tx Survival follow-up Stratification criteria EGFR mut vs wt MET 2+ vs 3+ Number of prior treatments Histology Primary endpoint OS Secondary endpoints PFS ORR QoL Safety PK METLung (OAM4971g, NCT ) Presented by: David R. Spigel, M.D., PASCO

9 OAM4971g: Overall Survival Results EGFR mutation placebo N=29 Med OS:NE Onartuzumab N=28, Med OS 12.6 mo HR 4.68: ( ) Probability of overall survival Number of patients at risk: Placebo + erlotinib Onartuzumab + erlotinib HR 1.27 (95% CI: ) p= Time (months) Placebo + erlotinib (n=249) Onartuzumab + erlotinib (n=25) Censored Presented by: David R. Spigel, M.D abstr 8. Median 9.1 months (95% CI ) Median 6.8 months (95% CI ) Erlotinib+Bevacizumab Study design Chemotherapy-naïve Non-squamous NSCLC Activating EGFR mutations Exon 19 deletion Exon 21 L858R No brain metastasis T79M excluded R 1:1 EB combination Erlotinib 15mg qd + bevacizumab 15mg/kg q3w (n = 75) E monotherapy Erlotinib 15mg qd (n = 75) Primary endpoint: PFS (RECIST v1.1, independent review) Secondary endpoints: OS, tumor response, QoL, safety PD PD Terufumi Kato, ABSTR 85, ASCO 214 9

10 Primary endpoint: PFS by independent review PFS probability Median (months) HR P value EB E.54 (95% CI:.36.79) Number at risk Time (months) EB E Terufumi Kato, ABSTR 85, ASCO 214 EB E log-rank test, two-sided EGFR-TKIs: Secondary Resistance 37 patients rebiopsied at the time of progression 6/18 patients with T79M had other molecular abnormalities 5 patients had SCLC phenotype Red slice represents patient with both SCLC transformation and PIK3CA. Sequist L et al. Sci Transl Med. 211;3:75ra26.. 1

11 Two Trials to Compare Ongoing EGFR TKI for Acquired Resistance PI: Tony Mok & Jean-Charles Soria 1 R A N Activating EGFR TKI D Response to EGFR TKI > 4 mo O M No prior chemotherapy I N = 25 Z E D Primary endpoint: progression-free survival Cisplatin/Pemetrexed Cisplatin/Pemetrexed + ongoing gefitinib PI: Leora Horn (Vanderbilt) 2 Advanced NSCLC Activating EGFR TKI Response to EGFR TKI > 4 mo No prior chemotherapy PS /1 N = 12 R A N D O M I Z E D Cis /Carbo + Pemetrexed + ongoing erlotinib Cis/Carbo +Pemetrexed Primary endpoint: progression-free survival Erlotinib re-treatment 1. Clinicaltrials.gov/show/NCT Accessed May 14, Clinicaltrials.gov/ct2/show/record/NCT Accessed May 14, 214. Afatinib + Cetuximab at MTD: Responses by T79M Mutation Maximum percentage decrease from baseline (%) T79M+ T79M- EGFR wt Uninformative T79M Patient index sorted by maximum % decrease Janjigian YY, et al. ESMO 212. Abstract 1227O, Cancer Discovery

12 CO1686: Best response in Ph1 + early Phase 2 expansion cohort patients 1 Centrally confirmed T79M+ patients within therapeutic dose range (N=4) Change from Baseline (%) Sequist, ASCO 214 ORR to date: 58% Ongoing 2 3 CO-1686 Adverse events Treatment-related adverse events occurring in >1% of CO-1686 patients (N=72) treated at efficacious doses, n (%) Preferred term Grade 1 Grade 2 Grade 3 Grade 4 Nausea 14 (19) 1 (14) 1 (1) Hyperglycemia 14 (19) 8 (11) 16 (22) Diarrhea 14 (19) 3 (4) Vomiting 9 (13) 1 (1) 2 (3) Decreased appetite 7 (1) 7 (1) 1 (1) Myalgia 7 (1) 1 (1) QTc prolonged 3 (4) 3 (4) 5 (7) excluding malignancy-related adverse events (eg, disease progression) 3 (4%) patients with any form of rash, all Grade 1 12

13 AZD9291: ORR in overall population 4 2 Best percentage change from baseline in target lesion: all evaluable patients, escalation and expansion (N=25) Complete response Partial response Non-response -8-1 First patient dosed Mar 6, 213 Longest response >9 months ongoing at time of data cutoff ORR = 53% (19/25; 95% CI 46%, 6%);: ORR 64% in T79M+ Overall disease control rate (CR+PR+SD) = 83% (171/25; 95% CI 78%, 88%) 2 mg 4 mg 8 mg 16 mg 24 mg Presented by: Pasi A. Jänne, ASCO 214 N (25) 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=25 (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; PR, confirmed partial response; PD, progressive disease; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease AZD9291 Adverse events Patients with an AE, % 2 mg (N=21) 4 mg (N=57) 8 mg (N=74) 16 mg (N=6) 24 mg (N=2) Any Gr Gr 3 Any Gr Gr 3 Any Gr Gr 3 Any Gr Gr 3 Any Gr Gr 3 AE by preferred term, occurring in at least 1% of patients overall Diarrhea Rash (grouped terms) Nausea Dry skin Pruritus Decreased appetite Fatigue Constipation Paronychia Cough Select AEs of interest Hyperglycemia 1 3 QT prolongation 1 5 ILD-like event All seven patients responded well to treatment with no fatal events. Review of these events is ongoing Population: all dosed patients, N=232; does not include first-line or tablet cohorts Presented by: Pasi A. Jänne 13

14 Preliminary Comparison RR T79M + RR T79M - PFS Afatanib/Cetux 32% 28% 4.66 HM % 12% 4.34 CO % Inc.! AZD % 22%! Lynch Discussion ASCO 214 RADIANT Adjuvant NSCLC +/-Erlotinib ELIGIBLE: Resected I-IIIA Lobectomy Required IHC/FISH for EGFR Chemo optional R A N D O M I Z E Erlotinib 15 mg po qd X 2 yrs Placebo x 2 yrs 2:1 DFS as primary endpoint Kelly PASCO 214, Abstr

15 RADIANT OS KM Plot FAS 1. E rlo tin ib P la c e b o.9 O verall Survival Probability P laceb o (95 events ) M edian: not reached E rlotinib (182 events ) M edian: not reached L og-rank test: p = H R : (9 5 % C I:.8 8 1, ) O v e ra ll S u rv iv a l (M o n th s ) N u m b e r a t R is k P la c e b o 3 5 E rlo tin ib Median follow-up duration = 47 months. Kelly PASCO 214, Abstr 751 RADIANT DFS EGFR M+ Disease-free Survival Probability Placebo (32 events) Median: 28.5 m Erlotinib (39 events) Median: 46.4 m Erlotinib Number at Risk Placebo Erlotinib Disease-free Survival (Months) Placebo Log-rank test: p=.391 (not sta's'cally significant due to hierarchical tes'ng) HR:.61 (95% CI:.384,.981) 43 8 Kelly PASCO 214, Abstr

16 RADIANT OS EGFR M+ Overall Survival Probability Placebo (13 events) Median: not reached Erlotinib (22 events) Median: not reached Log-rank test: p=.8153 HR: 1.9 (95% CI:.545, 2.161) Number at Risk Placebo Erlotinib Kelly PASCO 214, Abstr Overall Survival (Months) Erlotinib Placebo 5 7 US ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial Stage I-III NSCLC <6 mo post-op N=6-8 For ~3-4 EGFR mut (Sequencing) ALK+ (FISH) Erlotinib x 2 yrs Placebo x 2 yrs Crizotinib x 2 yrs Placebo x 2 yrs 16

17 Outline ALK: 82: 1st line crizotinib Profile : ASCEND ceritinib EGFR: 84: Lux lung 3+6 OS analysis 8: onartuzumab- Met lung 85: Bevacizumab + erlotinib 89: AZD9291 : 81: CO : RADIANT OTHER ANTIBODIES: 86: ramucirumab-revel 87: PD-L1 MK : Necitumumab-Squire SCLC: 752: SCLC Thoracic XRT 753: SCLC PCI REVEL: Study Design Perol abstr 86 1:1 - Stage IV NSCLC after one platinumbased chemo +/- maintenance - Prior Bev allowed - All histologies - PS or 1 R A N D O M I Z E Ramucirumab 1 mg/kg + Docetaxel 75 mg/m 2 q3wks N=628 Placebo + Docetaxel 75 mg/m 2 q3wks N=625 Treatment until disease progression or unacceptable toxicity Stratification factors: ECOG PS vs 1 Gender Prior maintenance East-Asia vs. ROW Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes Abbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; PFS=progression-free survival; ROW=rest of the world; q3wks=every 3 weeks. 17

18 REVEL Progression-Free Survival = ITT Population, Investigator Assessment Progression-Free Survival (%) RAM+DOC PL+DOC Censored RAM+DOC PL+DOC Median (95% CI) Censoring Rate 4.5 ( ) 11.1% 3. ( ) 6.7% RAM+DOC vs PL+DOC: Stratified HR (95% CI) =.762 ( ) Stratified log-rank P <.1 No diff by histology or prior therapy Number at risk RAM+DOC PL+DOC Survival Time (months) REVEL: Overall Survival ITT Population Overall Survival (%) RAM+DOC PL+DOC Censored Median (95% CI) Censoring Rate RAM+DOC 1.5 ( ) 31.8% PL+DOC 9.1 (8.4-1.) 27.% RAM+DOC vs PL+DOC: Stratified HR (95% CI) =.857 ( ) Stratified log-rank P =.235 Number at risk RAM+DOC 628 PL+DOC Survival Time (months)

19 Clinical Development of PD-1 Immune Checkpoint Inhibitors Target Antibody Molecule Development stage PD-1 PD-L1 Nivolumab- BMS Pidilizumab CT-11 Pembrolizumab MK-3475 BMS (no longer in development in NSCLC) MedI-4736 MPDL-328A Fully human IgG4 Humanized IgG1 Humanized IgG4 Fully human IgG4 Engineered human IgG1 Engineered human IgG1 Phase III Phase II multiple tumors Phase III Phase I Phase I Phase III MSB1718C Human IgG1 Phase I Slide courtesy Julie Brahmer, ASCO discussant KEYNOTE-1: PD-L1 Expression in Previously Untreated NSCLC Previously Untreated Patients With Advanced NSCLC Screened for PD-L1 N = 84 Tumor Biopsy Evaluable for PD-L1 n = 73 PD-L1 + Tumors (Proportion Score 1) n = 57 78% PD-L1 + Analysis cut-off date: March 3, 214. Patients Eligible for Treatment with Evaluable Imaging at Baseline by irrc n = 45 Patients with Evaluable Imaging at Baseline by RECIST 1.1 n = 42 62% PD-L1 + in 2L+ Presented by: Naiyer A. Rizvi, abstr 87 19

20 Antitumor Activity by MK-3475 Dose RECIST v1.1, Central Review a irrc, Investigator Review MK-3475 Dose 2 mg/kg Q 3W 1 mg/kg Q 3W 1 mg/kg Q 2W ORR b DCR b ORR b DCR b n n (% ) [95% CI] 6 2 (33) [4-78] 2 4 (2) [6-44] 16 5 (31) [11-59] Total (26) [14-42] Presented by: Naiyer A. Rizvi abstr 87 n (%) [95% CI] 3 (5%) [12%, 88%] 14 (7%) [46%, 88%] 1 (63) [35-85] 27 (64) [48 78] n n (%) [95% CI] 6 4 (67) [22-96] 22 1 (46) [24-68] 17 7 (41) [18-67] (47) [32-62] Interim median PFS c : 27. weeks (95% CI, ) by RECIST v1.1 per central review 37. weeks (95% CI, 27.-NR) by irrc per investigator review n (%) [95% CI] 5 (83) [36-1] 18 (82) [6-95] 12 (71) [44-9] 35 (78) [63-89] Analysis cut-off date: March 3, 214. DCR = Disease Control Rate (complete response + partial response + stable disease) a 3 patients did not have measurable disease by RECIST v1.1 per indepdendent central review at baseline and were not evaluated for response by RECIST v1.1/ b Includes confirmed and unconfirmed responses. c From product-limit (Kaplan-Meier) method for censored data. Study Design Screening Entry criteria: Stage IV squamous NSCLC 1,2 ECOG PS -2 R 1 1 Gem-Cis + Neci q3w (N = 545) Necitumumab (8 mg D1, D8) Gemcitabine (125 mg/m², D1, D8) Cisplatin (75 mg/m², D1) Maximum of 6 cycles Gem-Cis q3w (N = 548) Gemcitabine (125 mg/m², D1, D8) Cisplatin (75 mg/m², D1) PR CR SD PD Neci q3w (8 mg D1, D8) PD PD Randomization (R) stratified by: ECOG PS (-1 vs. 2) and geographic region (North America, Europe and Australia; vs. South America, South Africa and India; vs. Eastern Asia) Radiographic tumor assessment (investigator read): at baseline and every 6 weeks until PD Mandatory tissue collection 3 1 AJCC TNM Classification, 7th edition, 29; 2 UICC TNM Classification of Malignant Tumors, 7 th edition, 29 3 Minimum 4 slides archived paraffin-embedded tumor tissue Presented by: Nick Thatcher, abstr 88 2

21 OVERALL SURVIVAL: SQUIRE vs FLEX H score NS in Squire Median OS, mo: Chemo + cetux: 11.3 Chemo: 1.1 HR:.871; p=.4 ORR Chemo + Ab 31.2% 5.7mo Chemo 28.8% p=.4 Median PFS 5.5 mo (HR.85 p=.2) Thatcher Abstr 88, Pirker R et al Lancet 29; slide courtesy Julie Brahmer ORR Chemo + Ab 36% 4.8 mo Chemo 29% (p=.1) Median PFS 4.8 mo p=.39 Outline ALK: 82: 1st line crizotinib Profile : ASCEND ceritinib EGFR: 84: Lux lung 3+6 OS analysis 8: onartuzumab- Met lung 85: Bevacizumab + erlotinib 89: AZD9291 : 81: CO : RADIANT OTHER ANTIBODIES: 86: ramucirumab-revel 87: PD-L1 MK : Necitumumab-Squire SCLC: 752: SCLC Thoracic XRT 753: SCLC PCI 21

22 CREST Trial Design ES-SCLC, WHO platinum-based chemotherapy TRT (1 x 3Gy) Start 2-7 wks post chemo PCI RANDOMIZE PCI Any response No brain mets No pleural mets Primary Endpoint: Overall Survival Presented by: Ben Slotman ABSTR 752 CREST results N= 498, Median age 63, 55% male, 76% distant mets Randomized to thoracic radiotherapy (3 Gy in 1 fx) Minimal Toxicity Noted OS HR =.84 (95%CI ), p= month OS +/- TRT (95% CI) 13% vs 3% PFS HR =.73 (95%CI ), p=.1 Thoracic radiotherapy could be offered in addition to PCI to patients responding to initial chemotherapy ongoing RTOG study Presented by: Ben Slotman,ABSTR

23 Prophylactic cranial irradiation in Extensive stage SCLC : OS year: 27.1% vs. 13.3% HR:.68 ( ) p= Control PCI (months) Slotman NEJM 27 Months from moment of randomization Design of current PCI study 1 st line chemo Platinumbased doublet No response Any response No Brain mets by MRI R PCI: 25 Gy 1 fractions no PCI Follow-up by MRI imaging Primary endpoint: Overall Survival N= 163; median age 69; >8% men Seto PASCO 214,

24 Time to Brain Metastasis 1 9 Arm A: PCI n=84 Arm B: no PCI n=79 BM at 12 months 32.4% 58.% Gray s test: P <.1 (2-sided) Arm A: PCI Arm B: No PCI Seto PASCO 214, 752 months Overall Survival Arm A: PCI n=84 Arm B: no PCI n=79 No. of OS Events 61 5 Hazard ratio (95%CI) 1.38 ( ) Median OS (95%CI), mo 1.1 ( ) 15.1 ( ) 6 5 PFS HR 1.12, NS Stratified log-rank test: P=.91 (2-sided) Bayesian predictive probability: <.1% Arm A: PCI Arm B: No PCI Slightly more 2 nd, 3 rd line chemo in No PCI arm Seto PASCO 214, 752 month 24

25 Conclusions ALK: 82: 1st line crizotinib Profile st line crizotinib now SOC 83: ASCEND ceritinib Ceritinib now approved after crizotinib failure EGFR: 84: Lux lung 3+6 OS analysis OS benefit in combined analysis, Del19 different 8: onartuzumab- Met lung - Negative 85: Bevacizumab + erlotinib Could consider as 1 st line in EGFRmut NSCLC 89: AZD9291 : 81: CO-1686 Both very promising with ongoing trials 751: RADIANT Negative trial, No OS benefit even in EGFRmut, ongoing studies OTHER ANTIBODIES: 86: ramucirumab-revel positive, but unclear how much impact 87: PD-L1 MK3475 positive, PD-1 and PD-L1 coming soon 88: Necitumumab - Squire positive, but unclear how much impact SCLC: 752: SCLC Thoracic XRT positive, could consider 753: SCLC PCI negative, PCI not for everyone 25