Lessons learned from gefitinib and crizotinib clinical trials in NSCLC Shun Lu Shanghai Lung Cancer Center Shanghai Chest Hospital affiliated to Jiao Tong University
New Era of Cancer Care: Genomic Era * Change the Paradym Cancer Care: Old Paradigm It is time to change the paradigm, and begin Organ Oriented: lung, breast thinking directing therapy at a molecular Histologic classification eg: Squamous, Adeno target rather than developing organ-specific Genomic era may profoundly alter the landscapes of cancer care, clinical research, and scientific investigation treatments. George Sledge
Gefitinib and Crizotinib: 9 year and 4 year Gefitinib Any line Gefitinib in EGFR M+ (EMEA) Phase I trial 2/3L IDEAL EGFR M+ 2/3L ISEL Gefitinib vs placebo IPASS 2L INTEREST Gefitinib vs Texotere 1L Gefitinib 1L vs CP in Gefitinib vs EGFR DP in EGFR MUT+ MUT+ 1L IPASS Gefitinib vs CP in EGFR MUT+ 1LM INFORM 2000 2002 Crizotinib 2004 2006 2007 EML4 ALK transgenic mice developed lung cancer 2008 2009 All objective responders were ALK+ cancer patients 2010 Phase III trials about ALK+ NSCLC 2011 NEJM: the clinical data of Crizotinib to treat ALK+ NSCLC 2011 Aug 26 Crizotinib approved for ALK+ NSCLC by FDA 1.Fokuoka 2002; Kris 2002. 2. Thatcher Lancet 2005; 3. Kim 2007; 4 Mok, et al. NEJM 2008; 5. Mitsdomi 2009; 6. NEJ002 2009 ; 7. Zhou, et al.2010; 8.Bang ASCO 2010
2011: A new treatment era is just beginning
Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Kris et al ASCO 2011 Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%)
Driver genes Mutations for Adeno: East vs. West LCMC China Japan EGFR 17% 40% 50% KRAS 22% 7% 15% ELM4-ALK 7% 7% 5% BRAF 2% 2% 1% HER2 1% NA 3% PIK3CA 1% 4% NA PTEN NA 6% NA MET Amp 1% 5% 4% Nil 46% 29% 22%
ISEL A double-blind Phase III survival study comparing IRESSA (250mg) plus BSC vs placebo plus BSC in patients with advanced NSCLC who have received 1 2 prior chemotherapy regimens and are refractory or intolerant to their most recent regimen 2:1 Randomisation IRESSA 250mg daily + BSC Placebo + BSC Primary endpoint Overall survival Secondary endpoints TTF, OR, QoL, Safety 1692 patients in 210 centres across 28 countries 342 patients of Asian origin no Japanese / US sites BSC = best supportive care TTF = time to treatment failure OR = objective response QoL = quality of life
ISEL: Overall survival, time-to-treatment failure and objective response rate OS: TTF HR=0.89 (0.77, 1.02) HR=0.82 (0.73, 0.93) n=1692, deaths=976 n=1316, progressions=1137 Median survival: IRESSA 5.6m, Placebo 5.1m Median TTF: IRESSA 3.0m, Placebo 2.6m Proportion surviving 1.0 0.8 0.6 0.4 0.2 Stratified log rank test, p=0.0871 Cox analysis, p=0.0299 IRESSA Placebo Proportion without treatment failure 1.0 0.8 0.6 0.4 0.2 Stratified log rank test, p=0.0018 Cox analysis p=0.0006 Objective Response Rate 8.0% vs 1.3%, p<0.0001 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Months Months HR <1 implies a lower risk of event on IRESSA
ISEL: Overall survival in Asians and never-smokers Asians: HR=0.66 (0.48, 0.91), p=0.010 n=342, events=173 Never Smokers: HR=0.67 (0.49, 0.92), p=0.0121 n=375, events=170 1.0 1.0 Proportion surviving 0.8 0.6 0.4 0.2 IRESSA Placebo Proportion surviving 0.8 0.6 0.4 0.2 IRESSA Placebo 0.0 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 Months HR <1 implies a lower risk of event on IRESSA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Months
IDEAL 1 & 2: Design scheme Patients Received 1 or 2 (IDEAL 1) or 2 (IDEAL 2) previous chemotherapy regimens Randomisation ZD1839 250 mg once daily ZD1839 500 mg once daily Primary endpoints Response rate (both trials) Safety profile (IDEAL 1) Symptom relief (IDEAL 2) Continue ZD1839 until disease progression or unacceptable toxicity
IDEAL 1: overall survival Proportion event free 1.0 ZD1839 (mg/day) Patients (n) Deaths (n) Median (months) 0.8 250 500 103 106 62 64 7.6 7.9 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Months from randomisation
IDEAL 2: overall survival Proportion event free 1.0 ZD1839 (mg/day) 250 Patients (n) 102 Deaths (n) 75 Median (months) 6.5 0.8 500 114 89 5.9 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 Months from randomisation
INTEREST Patients Age 18 years Life expectancy 8 weeks Progressive or recurrent disease following CT Considered candidates for further CT with docetaxel 1 or 2 CT regimens ( 1 platinum) PS 0-2 IRESSA 250 mg/day 1:1 randomization Docetaxel 75 mg/m 2 every 3 weeks Endpoints Primary Overall survival (co-primary analyses a of non-inferiority in all patients and superiority in patients with high EGFR gene copy number) Secondary Progression-free survival Objective response rate Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers A Modified Hochberg procedure applied to control for multiple testing CT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor
Overall survival in overall PP population Probability of survival 1.0 0.8 0.6 0.4 N Events 723 593 (82.0%) 710 576 (81.1%) Primary Cox analysis without covariates HR (96% CI) = 1.020 (0.905, 1.150) Median OS (months) 1-year survival IRESSA Conclude non-inferiority in the overall PP population 7.6 32% Docetaxel 8.0 34% 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 At risk : IRESSA 723 518 336 225 131 83 50 31 14 0 0 Docetaxel 710 503 339 228 139 89 46 24 7 0 0 Pre-specified NI limit in HR terms (translates to 50% effect retention [Rothmann 2003]) = 1.154 96% of historical docetaxel advantage over BSC from TAX-317 retained by IRESSA (96% CI: 52%, 129%) Indirect comparison of IRESSA with BSC: HR (96% CI) = 0.63 (0.42, 0.92), p=0.0137 PP, per-protocol; NI, non-inferiority; HR, hazard ratio; CI, confidence interval; OS, overall survival; BSC, best supportive care Months Douillard et al 2007
Overall survival by racial origin 1.0 Asian origin 1.0 Non-Asian origin Probability of survival 0.8 0.6 0.4 0.2 IRESSA Docetaxel Probability of survival 0.8 0.6 0.4 0.2 IRESSA Docetaxel 0.0 0.0 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 At risk: Months Months IRESSA Docetaxel 154 160 127 133 96 110 62 77 39 45 26 27 18 16 13 7 5 1 0 0 0 0 569 550 391 370 240 229 163 151 92 94 57 62 32 30 18 17 9 6 0 0 0 0 IRESSA Docetaxel IRESSA Docetaxel N 154 160 N 569 550 Events 112 117 Events 481 459 HR (95% CI) = 1.04 (0.80, 1.35) p = 0.7711 HR (95% CI) = 1.01 (0.89, 1.14) p = 0.9259 Median (mo) 10.4 12.2 Median (mo) 6.9 6.9 Racial origin by treatment interaction, p = 0.9566
Overall survival by biomarkers (ITT population) Overall EGFR FISH + EGFR FISH - EGFR expression + EGFR expression - EGFR mutation + EGFR mutation - K-RAS mutation + K-RAS mutation - N=1466 N=174 N=200 N=284 N=96 N=44 N=253 N=49 N=226 Cox analysis without covariates 0 0.5 1.0 1.5 2.0 HR (IRESSA vs. docetaxel) and 95% CI Favors IRESSA Favors docetaxel Douillard et al 2007
IPASS Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light exsmokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB / IV disease Gefitinib (250 mg / day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # Endpoints Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles ; Carboplatin / paclitaxel was offered to gefitinib patients upon progression ; PS, performance status; EGFR, epidermal growth factor receptor Mok et al NEJM 361:947 2009
IPASS: EGFR Mutation and Progression-free survival EGFR mutation positive EGFR mutation negative Probability of progression-free survival 1.0 0.8 0.6 0.4 0.2 Gefitinib (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) Probability of progression-free survival 1.0 0.8 0.6 0.4 0.2 Gefitinib (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 At risk : Gefitinib C / P 132 108 71 31 11 3 0 129 103 37 7 2 1 0 ITT population Cox analysis with covariates Months Treatment by subgroup interaction test, p<0.0001 Months 91 21 4 2 1 0 0 85 58 14 1 0 0 0 Mok et al NEJM 361:947 2009
IPASS: 2010 OS by EGFR mutation status (ITT) Gefitinib (n=132) Carboplatin/paclitaxel (n=129) Gefitinib (n=91) Carboplatin/paclitaxel (n=85) Probability of survival 1.0 0.8 0.6 0.4 0.2 HR (95% CI) 1.00 (0.76, 1.33); p=0.990 No. events G 104 (79%) C / P 95 (74%) Median OS G 21.6 months C / P 21.9 months Probability of survival 1.0 0.8 0.6 0.4 0.2 HR (95% CI) 1.18 (0.86, 1.63); p=0.309 No. events G 82 (90%) C / P 74 (87%) Median OS G 11.2 months C / P 12.7 months 0.0 Patients at risk: Gefitinib 132 C / P 129 0 4 8 12 16 20 24 28 32 36 40 44 48 Time from randomisation (months) 126 123 121 112 103 95 88 80 70 68 58 55 46 48 38 40 24 26 11 15 6 7 3 0 52 0 0 EGFR Mutation + 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time from randomisation (months) 91 85 69 76 52 57 40 44 29 33 26 25 19 19 16 16 11 11 8 3 5 1 1 1 EGFR Mutation - 0 1 52 0 0 Treatment by subgroup interaction test p=0.480
Phase III studies comparing 1st line gefitinib to standard chemotherapy for advanced NSCLC with EGFR mutations NEJ002 EGFR mutated chemo-naïve NSCLC, PS0-1 Carboplatin + Paclitaxel Gefitinib Primary Endpoint: PFS Sample size: 320 (stopped at 230) Maemondo, N Engl J Med 2010
Progression-free survival in NEJ002 Gefitinib CBDCA/TXL ORR 74% 31% Median PFS 10.8 m 5.4 m HR (95%CI) 0.30 (0.22-0.41) P value** <0.001 Maemondo, N Engl J Med 2010 Inoue, ASCO2011
Toxicity Common adverse events in NEJ002 Gefitinib (n = 114) Grade >3 CBDCA+TXL (n = 114) Grade >3 Grade 1 2 3 4 % 1 2 3 4 % P value Diarrhea 32 6 1 0 0.9 7 0 0 0 0 <0.001 Appetite loss 7 4 6 0 5.3 39 18 7 0 6.2 <0.001 Fatigue 8 1 3 0 2.6 19 11 1 0 0.9 0.002 Rash 38 37 6 0 5.3 8 14 3 0 2.7 <0.001 Neuropathy 0 1 0 0 0 28 27 7 0 6.2 <0.001 Arthralgia 1 2 1 0 0.9 25 21 8 0 7.1 <0.001 Pneumonitis 3 0 2 1* 2.6 0 0 0 0 0 0.02 AST/ALT 20 13 29 1 26.3 31 5 0 1 0.9 <0.001 Nuetropenia 5 1 0 1 0.9 4 9 37 37 65.5 <0.001 Anemia 19 2 0 0 0 35 32 6 0 5,3 <0.001 Platelet 8 0 0 0 0 25 3 3 1 3.5 <0.001 Any 17 44 43 4* 41.2 4 25 41 40 71.7 <0.001 Generally, gefitinib is less toxic than chemotherapy
Good QOL was maintained longer in gefitinib arm For pain and dyspnea (in physical category) For daily functioning (in life-wellbeing category) Yoshizawa, ESMO2010 (paper in submission)
WJTOG3405:PFS EGFR mutated chemo-naïve NSCLC, PS0-1 Cisplatin + Docetaxel Gefitinib Primary Endpoint: PFS Sample size: 200 (stopped at 177) Mitsudomi T et al. Lancet, December 21, 2009
Clinical trials about EGFR mutation positive NSCLC first line therapy Author Study N (EGFR mut +) RR Median PFS OS Mok et al IPASS (Gefitinib) 261 71.2% vs 47.3 9.8 vs 6.4 months 18.8 vs 17.4 months Lee et al First-SIGNAL (Gefitinib) 42 84.6% vs 37.5% 8.4 vs 6.7 months 21.3 vs 23.3 months Mitsudomi et al WJTOG 3405 (Geftinib) 174 62.1% vs 32.2% 9.2 vs 6.3 months 30.9 vs not reached Maemondo et al NEJGSG002 (Gefitinib) 230 73.7% vs 30.7% 10.8 vs 5.4 months 30.5 vs 23.6 months Zhou et al OPTIMAL (Erlotinib) 154 83% vs 36% 13.1 vs 4.6 months ND Rosell et al EURTAC (Erlotinib) 175 83% vs 36% 13.1 vs 4.6 months Mok et al NEJM 2009, Lee et al WCLC 2009, Mitsudomi et al Lancet Oncology 2010, Maemondo NEJM 2010
Western guidelines already been revised ASCO guideline ESMO guideline
2007 2011: The history of Crizotinib Crizotinib; cmet and ALK inhibitor Crizotinib: Phase I trial Indentified EML4 ALK fusion gene in NSCLC Phase I trial Modified: AKL+ NSCLC were enrolled ALK+ NSCLC: phase III trial Crizotinib approved by the FDA for treatment of ALK+NSCLC 2005 2006 2007 2008 2009 Antitumor activity of crizotinib for ALK + cells EML4 ALK transgenic mice developed lung cancer All objective responders were ALK+ Response rate of Crizotinib for ALK+ NSCLC >50% 2010 2011 NEJM: Clinical data of Crizotinibto treat ALK+ NSCLC
A8081001 A8081001: Phase I Trial of Crizotinib (Year 2006) Cohort 4 200 mg BID Cohort 5 300 mg BID MDZ sub-study Cohort 6 250 mg BID MTD/RP2D Cohort 1 50 mg QD Cohort 2 100 mg QD MDZ sub-study Cohort 3 200 mg QD 37 patients were enrolled 3 patients: PR MTD = Maximum tolerated dose; RP2D = Recommended phase 2 dose MDZ = Midazolam (in-vitro data indicated that PF-02341066 is a major substrate and inhibitor of CYP3A activity) Kwak EL, et al. ESMO/ECCO 2009 (Abstract G6 and oral presentation)
First Description of EML4-ALK Translocation in NSCLC (Year 2007)
Evidence for EML4-ALK as a Lung Cancer Oncogene Insertion of EML4-ALK into NIH 3T3 fibroblasts was tumorigenic when implanted subcutaneously into nude mice. Engineered the specific expression of EML4-ALK fusion gene in lung progenitor cells using a surfactant protein C gene promoter. 100% of EML4-ALK transgenic mice developed lung adenocarcinoma that were + for ALK by IHC. No other primary cancers were observed. Following IV injection of EML4-ALK/3T3 cells into nude mice, all developed lung cancer. Ten animals were treated with an ALK-specific TKI and 10 were observed:
A8081001 A8081001: phase I clinical trial Of the 3 objective responders, all had ALK translocations: Inflammatory myofibroblastic sarcoma: NPM-ALK translocation NSCLC (2): EML4-ALK translocation Key Collaboration: Pfizer and Massachusetts General Hospital Protocol modified,alk+ NSCLC were enrolled: 82 patients were evaluated for response rate Kwak EL, et al. ESMO/ECCO 2009 (Abstract G6 and oral presentation)
Clinical and Demographic Features of Patients with ALK-positive NSCLC Young Non-smoker Adeno N=82 Mean (range) age, years 51 (25 78) Gender, male/female 43/39 0 24 (29) Performance status,* n (%) Race, n (%) Smoking history, n (%) Histology, n (%) Prior treatment regimens, n (%) 1 44 (54) 2 13 (16) 3 1 (1) Caucasian 46 (56) Asian 29 (35) Never smoker 62 (76) Former smoker 19 (23) Current smoker 1 (1) Adenocarcinoma 79 (96) Squamous 1 (1) Other 2 (2) 0 5 (6) 1 27 (33) 2 15 (18) 3 34 (41) Not reported 1 (1) Y Bang et al: ASCO 2010
A8081001 肿 瘤 直 径 的 最 大 变 化 比 例 (%) Tumor Responses Rate (57%) to Crizotinib for 82 Patients with ALK-positive NSCLC 60 40 20 0 20 40 60 80 30% Objective RR = 57% (95% CI: 46-68%) DCR (CR+PR+SD): 87% (95% CI: 77-93%) Progressive disease Stable disease Confirmed partial response Confirmed complete response 100 * Partial response patients with 100% change have non-target disease present Kwak et al. NEJM 2010;363:1693 703 Bang et al. JCO 2010;28:18S abstract 3 *
A8081001 & A8081005 The response rates of ALK+ NSCLC patients who received Crizotinib were 61% and 51% 2 1. Camidge R et al. 2011 ASCO; Abstract 2501 2. Riely GJ et al. WCLC, 2011; Abstract 1618
A8081001 & A8081005 Crizotinib for ALK+ patients Response rate Age Patients A8081001 1 <65 岁 65 岁 N=116 % (n/n) 60 (60/100) 69 (11/16) A8081005 2 N=133 % (n/n) 50 (58/115) 56 (10/18) Sesx Male Female 61 (36/59) 61 (35/57) 44 (28/64) 58 (40/69) ECOG PS 0 1 2 Therapy before Crizotinib 0 1 2 3 4 54 (21/39) 63 (39/62) 79 (11/15) 80 (12/15) 57 (16/28) 62 (13/21) 59 (13/22) 57 (17/30) 56 (20/36) 53 (38/72) 40 (10/25) NA 44 (7/16) 58 (23/40) 55 (21/38) 44 (17/39) Race Asia Non-asia 82 (28/34) 52 (43/82) 62 (26/42) 46 (42/91) Y Bang et al: ASCO 2010
A8081001 & A8081005 The results of these 2 trials A8081001 1 N=116 A8081005 2 N=133 Best overall response Complete response 2 1 Partial response 69 67 Stable disease 31 45 Progressive disease 6 10 Other 8 10 Objective response (CR+PR) rate 61% (95% CI: 52%, 70%) 51% (95% CI: 42%, 60%) Duration of response 48 weeks (median) 7-42 weeks (range) Duration of treatment, median 32 weeks 22 weeks Median PFS 10.0 months (95% CI: 8.2, 14.7) Not mature Study 1001 - Independent Radiology Review ORR (n=105) 52% (95% CI: 42%, 62%), as assessed by RECIST version 1.0 Study 1005 from 60-day clinical data update - Independent Radiology Review ORR (n=105) 41.9% (95% CI: 32.3%, 51.9%), as assessed by RECIST version 1.1 Including indeterminate and early death 1. Camidge R et al. Presented at 2011 ASCO; Abstract 2501 2. Riely GJ et al. To be presented at WCLC on July 6, 2011; Abstract 1618
A8081001 & A8081005 The safety of Crizotinib A8081001 1 (N=119) A8081005 2 (N=136) Adverse event All grades, n (%) All grades, n (%) Visual effects 74 (62) 80 (59) Nausea 58 (49) 78 (57) Diarrhea 51 (43) 58 (43) Vomiting 42 (35) 59 (43) Edema 33 (28) 39 (29) Constipation 32 (27) 37 (27) Decreased appetite 20 (17) 30 (22) Fatigue 17 (14) 37 (27) AE occurring in 20% of patients in one arm of the study 1. Camidge R et al. Presented at 2011 ASCO; Abstract 2501 2. Riely GJ et al. To be presented at WCLC on July 6, 2011; Abstract 1618
A8081001 & A8081005 Grade 3/4 treatment related AE A8081001 1 (N=119) A8081005 2 (N=136) Adverse event Grade 3/4, n (%) Grade 3/4, n (%) Increased ALT 5 (4) 9 (7) Increased AST 4 (3) 1 (1) Neutropenia 4 (3) 8 (6) Fatigue 2 (2) 2 (2) Neuropathy 1 (1) 0 (0) Lymphopenia 2 (2) 3 (2) Pneumonitis 2 (2) 1 (1) Constipation 1 (1) 0 (0) Leukopenia 0 (0) 1 (1) Electrocardiogram QT prolonged 0 (0) 2 (2) Renal Cyst 0 (0) 1 (1) 1. Camidge R et al. Presented at 2011 ASCO; Abstract 2501 2. Riely GJ et al. To be presented at WCLC on July 6, 2011; Abstract 1618
The trial of 1027and 1029 approved by SFDA: ALK+ is the key point Study A8081027 Design: Single Arm, Open Label Endpoints: 1º: ORR, Safety 2º: PFS, DR, 1 YR PFS, OS Advanced NSCLC Non- Squamous ALK translocation positive 1 platinum-based prior therapy ECOG PS 0-2 N=50 Countries: 40 China, 10 Hong Kong and Taiwan Crizotinib 250 mg BID Continuous dosing schedule (cycle = 21 days)
The trial of 1027and 1029 approved by SFDA: ALK+ is the key point Study A8081029 Trial Design Multi-center, randomized, open-label Interim analysis safety and efficacy: sequential filing at 75% events Endpoints 1º:PFS 2º: OS, ORR, DR, DCR, Safety, biomarkers Stratification: PS status (0,1 vs. 2) Key Entry Criteria: Positive for ALK gene translocation No prior chemo for metastatic disease Non-squamous histology N=200 R A N D O M I Z E 1:1 Countries: 150 patients China and 50 from 2-3 other Asian countries Crizotinib: 250mg BID continuous dosing schedule Cisplatin/Pemetrexed or Carboplatin/Pemetrexed Study Sites: China Singapore Thailand Hong Kong Taiwan
Key entry criteria; N=318 ALK-positive advanced or metastatic stage IIB/IV NSCLC ECOG 0-2 Phase III (A8081007) - Second line therapy for NSCLC 1 prior platinum-based chemotherapy R A N D O M I Z E N=159 N=159 Crizotinib 250 mg BID continuous dosing schedule Pemetrexed 500 mg/m 2 OR Docetaxel 75 mg/m 2 (Day 1/21) Trial design Endpoints Stratification Worldwide Multicenter Open-label Randomized Primary: PFS* Secondary: OS; ORR, DCR, DR, safety, QoL, PK *Based on RECIST v 1.1 and confirmed by independent radiology review www.clinicaltrials.gov (NCT00932893) ECOG PS (0/1 vs 2) Previous anti-egfr TKI Brain metastases
Phase III (A8081005) - Third line therapy for NSCLC Key entry criteria; N=250 ALK-positive NSCLC with prior chemotherapy Not eligible for Phase 3 (A8081007) RECIST-defined PD in chemo arm of study A8081007 or >1 prior chemotherapy Brain metastases allowed Crizotinib 250 mg BID continuous dosing schedule (21-day cycles) Trial design World-wide Multicenter Single-arm Open-label Endpoints Primary: ORR, safety Secondary: OS, DR, DCR, PFS, EML4-ALK fusion variant ALK protein expression biomarker expression in tumor samples www.clinicaltrials.gov (NCT00932451)
Phase III (A8081014) - First line therapy for NSCLC Key entry criteria; N=334 ALK-positive locally adv/metastatic nonsquamous NSCLC No prior treatment for advanced disease R A N D O M I Z E N=167 N=167 Crizotinib 250 mg BID continuous dosing schedule Crossover on PD Pemetrexed/ cisplatin or pemetrexed/ carboplatin (Day 1/21) Trial design Endpoints Stratification World-wide Multicenter Randomized Open-label Focused screening Primary: PFS* Secondary: OS, ORR*, DR, safety, QoL, Lung cancer-specific symptoms ECOG PS (0/1 vs. 2) Ethnicity (Asian vs. non- Asian) Brain metastases *Based on RECIST v 1.1 and confirmed by independent radiology review www.clinicaltrials.gov (NCT01154140)
2012NCCN guideline for Crizotinib and ALK
2012 NCCN guideline: EML4-ALK,EGFR and KRAS as a molecular diagnostic marker
Many key targets still await drugs Cancer Mutant target Small-molecule drug Bladder FGFR3 TBA Acute leukemia Flt3 TBA Papillary renal cell c-met TBA Endocrine neoplasia c-ret TBA Lung/CRC K-Ras TBA Breast PIK3CA TBA Disease Wild-type target Large-molecule drug Breast cancer HER3 IGF-1 TBA
MODELS FOR MOLECULAR SELECTION Scenario I: Test a Single Biomarker During the Screening Phase of the Phase II Clinical Trial Scenario II: Assess a Limited Number of Relevant Molecular Alterations Outside Phase II Clinical Trials Scenario III: Perform a Molecular Screening Based on High-Throughput Technologies Scenario IV: Use Clinical Surrogates for Molecular Testing
Informed consent signed for molecular test and biology-driven phase II trial Progressive disease under Previous regimen Phase of molecular testing : Diagnosis of the molecular alteration targeted by the drug Molecular alteration present 10% A Inclusion in the biology-driven trial Molecular alteration not present Screen failure not eligible for the biology-driven trial Implication: No time for a new molecular screening for other trial means patient will not be treated based on biology
Target A Informed consent signed for clinical trial B Target B Trial A Informed consent signed for Molecular testing done at any time Target C IF progressive disease Target B Trial B Trial C
Molecular screening using high-throughput technologies (gene expression array and/or CGH plus sequenome) Informed consent signed for clinical trial C Trial A Informed consent signed for molecular screening done at any time IF progressive disease Target B Trial B Trial C Trial X,Y, Z
Informed consent signed for clinical trial D Patients presenting a clinical feature correlated with molecular alteration (men, nonsmoker for EML4-ALK) Clinical trial with Targeted agent Molecular alteration present Efficacy of drug when the target is present Molecular alteration not present 100% treatment failure experienced by patients who did not present the target
Table 1. Strengths and Weaknesses of Each Molecular Selection Model Model Strength Weaknesses Test single biomarker during the screening phase of the biologydriven phase II trial (common model) Test a limited number of biomarkers outside the screening phase of biology-driven trials (Best-Rx model) Test molecular screening using high-throughput technologies outside the screening phase of the biology-driven trials (SAFIR01 model) Select patients based on clinical characteristics that correlate with the genomic alteration Uses FDA-approvable bioassay Uses same technology for each patient Decreases the rate of screen failure by performing several tests outside the screening phase of the phase II trials Uses FDA-approvable tests Identifies a large number of patients who are eligible for biology-driven trials, which minimizes the risk of screen failure Detects rare genomic events Avoids implementing a bioassay for each target Has no need for molecular tests Rate of screen failure for the trial is high because of single biomarker and because the test is performed during the screening phase of the trial Misses high number of relevant molecular alterations Needs to implement bioassay for target under investigation Technology is not available in each center Exposes some patients to a drug that is not expected to work (lack of targets)
Take home message Strategy From single biomarker to multi-biomarker 3M:Multi-way detection, multi-biomarker and multi-center Prospective confirm of biomarker Technical methods IHC, qrt-pcr, mutation test, FISH, microarray Optimal criterion and management of standardization Biology problem Second mutation Re-biopsy
Crizotinib和ALK的3篇文献 + 1篇述评 2010.10.28新英格兰医学杂志发表