Presentation on theme: "Zeroing in on Non-Small Cell Lung Cancer: Integrating Targeted Therapies into Practice."— Presentation transcript:
Zeroing in on Non-Small Cell Lung Cancer: Integrating Targeted Therapies into Practice
Genomic Profiling of NSCLC for EGFR Inhibitors Fred R. Hirsch, MD, PhD Professor of Medicine and Pathology University of Colorado Denver Aurora, Colorado
Presentation Genetic profiling of lung tumors –EGFR mutations and overexpression –K-ras mutations Genomic profiles inform therapy and outcomes Implications of proteomic profiling
Selection of EGFR TKIs Clinical –Gender –Histology –Smoking status –Race Biologic –EGFR protein (IHC) –EGFR gene (FISH) –EGFR mutation –K-ras mutation
IPASS—Study Design Gefitinib (250 mg/day) Carboplatin (AUC 5 or 6)/ paclitaxel (200 mg/m 2 ) 3 weekly b 1:1 randomization Patients Chemonaive Chemonaive Age ≥18 years Age ≥18 years Adenocarcinoma histology Adenocarcinoma histology Never or light ex-smokers a Never or light ex-smokers a Life expectancy ≥12 weeks Life expectancy ≥12 weeks PS 0–2 PS 0–2 Measurable stage IIIB/IV disease Measurable stage IIIB/IV disease Endpoints Primary Primary –Progression-free survival (noninferiority) Secondary Secondary –Objective response rate –Overall survival –Quality of life –Disease-related symptoms –Safety and tolerability Exploratory Exploratory –Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression a Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked <10 pack years. b Limited to a maximum of 6 cycles. Carboplatin/paclitaxel was offered to gefitinib patients upon progression. Abbreviations: EGFR, epidermal growth factor receptor; PS, performance status.
PFS in EGFR Mutation Positive and Negative Patients Treatment by subgroup interaction test, P <.0001 ITT population. Cox analysis with covariates. HR (95% CI) = 2.85 (2.05, 3.98) P <.0001 No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) HR (95% CI) = 0.48 (0.36, 0.64) P <.0001 No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Abbreviations: C/P, carboplatin/paclitaxel; EGFR, epidermal growth factor receptor; PFS, progression-free survival. With permission from Mok T, et al. Ann Oncol. 2008;19(suppl 8):abstract LBA2.
OSI STUDY 402—Phase II Study Schema and Results C/P d1 x 4; erlotinib 150 mg/d, d2–15 N = 71 Primary endpoint = 6-month PFS rate (% of patients not progressing at 6 months). Abbreviations: C/P, carboplatin/paclitaxel; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PD, progressive disease; PFS, progression-free survival; NSCLC, non–small cell lung cancer. Erlotinib 150 mg/d N = 72 Erlotinib 150 mg/d PD Chemonaive advanced NSCLC EGFR IHC and/or FISH+ N = 143 RANDOMIZERANDOMIZE Hirsch FR, et al. J Thorac Oncol. 2008;3(suppl 2):s138-s Mo PFS Median PFS 31%2.7 mo 26%4.6 mo
Efficacy by EGFR Mutation CP + intercalated erlotinib (N = 6) Median: 4.90 mo 6-mo rate: 41.7% Erlotinib (N = 9) Median: mo 6-mo rate: 88.9% HR: % CI: (0.73, 12.65) P =.109 PFS-EGFR Activating Mutations Probability PFS-EGFR Activating Mutations (mo) PFS-EGFR WT Probability PFS-EGFR WT (mo) CP + intercalated erlotinib (N = 45) Median: 5.06 mo 6-mo rate: 30.4% Erlotinib (N = 45) Median: 2.10 mo 6-mo rate: 22.2% HR: % CI: (0.42, 1.03) P =.066 Kaplan-Meier Plots of PFS-EGFR Activating Mutations Kaplan-Meier Plots of PFS- EGFR WT Hirsch FR, et al. J Thorac Oncol. 2008;3(suppl 2):s138-s142. Erlotinib: 8 exon 19 del, 1 L858R; CP+E: 3 exon 19 del, 3 L858R
FISH Predicts Benefit of EGFR-TKIs Log-rank: P =.008 HR = 0.44 (0.23, 0.82) Log-rank: P =.59 HR = 0.85 (0.48, 1.51) ISEL FISH+BR21 FISH+ Cox: P =.07 HR = 0.61 (0.36, 1.04) BR21 FISH–ISEL FISH– Cox: P =.42 HR = 1.16 (0.81, 1.64) Hirsch FR, et al. J Clin Oncol. 2006;24: Tsao MS, et al. N Engl J Med. 2005;353:
INTEREST—Study Design Gefitinib 250 mg/day Docetaxel 75 mg/m 2 every 3 weeks 1:1 randomization 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 Endpoints Primary –Overall survival (co-primary analyses of noninferiority 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 Kim ES, et al. Lancet. 2008;372:
INTEREST—OS in EGFR FISH+ Patients (Co-primary Endpoint) (84.7%) (79.8%) n Events Cox analysis without covariates HR (95% CI) = 1.09 (0.78, 1.51), P =.6199 Median OS (mo) 1-y survival % % Conclude no statistical superiority in EGFR FISH+ patients GefitinibDocetaxel Months At risk : Gefitinib Docetaxel Probability of Survival Kim ES, et al. Lancet. 2008;372:
MARVEL—Predictive Marker Study Design PFS endpoint –Less influenced by treatment crossover –Will require synchronized treatment schedules, independent blinded imaging review Power –90% to detect 50% PFS improvement favoring erlotinib in FISH+ –90% to detect 30% PFS improvement favoring pemetrexed in FISH− –>90% to detect interaction 2nd-line NSCLC with specimen Initial Registration FISH testing EGFR FISH+ (~30%) EGFR FISH− (~70%) Erlotinib Pemetrexed Erlotinib Pemetrexed StrataRandomize Outcome 1° PFS 2° OS, ORR NCCTG, CALGB, ECOG, SWOG, NCIC Others: C-Path & industry partners, Pharma 957 patients 4 years accrual, 1196 patients 1–2 years minimum additional follow-up
Proteomic Predictive Marker (Veristrat ® ) Italian NSCLC patients treated with gefitinib (n = 67) 1. Generation and initial testing of predictive algorithm 2. Refinement of predictive algorithm and independent blinded validation 3. Determination of prognostic significance of algorithm in NSCLC patients not treated with EGFR TKIs NSCLC patients treated with second-line chemotherapy—no EGFR TKI (n = 32) Patients with advanced NSCLC—no EGFR TKI (n = 61) Italian NSCLC patients treated with gefitinib (n = 70) Japanese NSCLC patients treated with gefitinib (n = 69) Taguchi F, et al. J Natl Cancer Inst. 2007;99:
Blinded Validation in E3503—Patients Treated with Erlotinib n = 96 Patients with Available Plasma or Serum Taguchi F, et al. J Natl Cancer Inst. 2007;99:
Cetuximab in NSCLC
S0342—Phase II Selection Design Paclitaxelcarboplatincetuximab x 4 cycles RANDOMIZERANDOMIZE Cetuximab weekly x 1 year Paclitaxel: 225 mg/m 2 Cetuximab: 400 mg/m 2 then 250 mg/m 2 weekly Carboplatin: AUC = 6 Concurrent Paclitaxelcarboplatin x 4 cycles Cetuximab weekly x 1 year Sequential Hirsch FR, et al. J Clin Oncol. 2008;26:
S0342—Response Rate and Disease Control Rate by EGFR FISH EGFR FISH Status # PatientsOR (CR/PR) DCR (CR/PR/SD) FISH–3126%55% FISH+4545%81% (P =.02) Hirsch FR, et al. J Clin Oncol. 2008;26:
S0342 Unselected Versus Selected PFS OS FISH + With permission from Hirsch FR, et al. J Clin Oncol. 2008;26:
BMS 099 Treatment Schema Advanced NSCLC Chemonaive R 1:1 Paclitaxel 225 mg/m 2 d1 a or Docetaxel 75 mg/m 2 d1 a + Carboplatin AUC = 6 d1 q3wk for a maximum of 6 cycles + Cetuximab 400 mg/m 2 d1 wk1; 250 mg/m 2 weekly Paclitaxel 225 mg/m 2 d1 a or Docetaxel 75 mg/m 2 d1 a + Carboplatin AUC = 6 d1 q3wk for a maximum of 6 cycles Stratification Site ECOG PS Taxane a Choice of taxane per individual patient, by investigator.
Is There Difference in Biomarker Expression—Early-Stage vs Late-Stage NSCLC?
Are There Differences in EGFR Biology Between Early and Late Stages of NSCLC? RADIANTBR21 N% PositiveN IHC FISH EGFR mutations* K-ras mutations *Exon 19 del or Exon 21 L858R Zhu C, et al. J Clin Oncol. 2008;26: Tsao M, et al. N Engl J Med. 2005;325:
Biomarker Expression— The Role of Race?
Race/Ethnicity in Lung Cancer Are there racial and ethnic variations that influence EGFR tumor biology and response to EGFR inhibitors? No. of Patients EGFR Mutations Japan (33%) Taiwan9332 (34%) China4110 (24%) Korea15330 (20%) Other Asian areas (30%) United States39548 (12%) Italy86039 (5%) Australia836 (7%) Other areas15813 (8%) Sekine I, et al. Br J Cancer. 2008;99:
EGFR Pathway in African-American Patients with NSCLC Tissue Assay African Americans White Italians Univariate Analysis EGFR mutationn = 53n = 89 Positive2% (1)19% (17) P =.003* Negative98% (52)81% (72) FISH for EGFRn = 53n = 102 Positive51% (27)32% (33) P =.024* Negative49% (26)68% (69) K-ras mutationn = 53n = 79 Positive23% (12)20% (16) P =.742 Negative77% (41)80% (63) *Remained significant in the multivariate analysis EGFR mutation P =.016 FISH P =.033 Hamdan A, et al. J Thorac Oncol. 2008;3(suppl 4):abstract 15.
Cetuximab + Cisplatin + Vinorelbine n = 550 Stage IIIB or IV EGFR POSITIVE Eligibility Criteria: EGFR-expressing, advanced stage NSCLC; No prior CT Eligibility Criteria: EGFR-expressing, advanced stage NSCLC; No prior CT Primary Endpoint: Median overall survival Primary Endpoint: Median overall survival Secondary Endpoints: Survival rate (1 and 2 y), PFS rate (6 and 12 mo), response rate, safety, QoL Secondary Endpoints: Survival rate (1 and 2 y), PFS rate (6 and 12 mo), response rate, safety, QoL Sample Size: 1100 in 170 centers in EU, Latin America, Asia Sample Size: 1100 in 170 centers in EU, Latin America, Asia Cisplatin + Vinorelbine n = 550 Cisplatin + Vinorelbine n = 550 Survival R FLEX Pirker R, et al. Lancet. 2009;373:
FLEX STUDY: BIOMARKERS KRAS mutation analysis: OS FISH analysis: OS 1st-cycle rash and OS Cl, confidence interval; CT, chemotherapy; HR, hazard ratio; OS overall survival K-ras wild type CT + Cetuximab(N = 49) CT(N = 53) K-ras mutant CT + Cetuximab(N = 82) CT(N = 95) Any grade:CT + Cetuximab (N = 290) Grade ):CT + Cetuximab (N = 228) FISH+ CT + Cetuximab(N = 49) CT(N = 53) FISH- CT + Cetuximab(N = 82) CT(N = 95) With permission from O’Byrne KJ, et al. J Clin Oncol. 2009;27:15s. Abstract 8007.
Sensitivity ( + ) Sensitivity (–) Responders Survival benefit Nonresponders Toxicity without survival benefit Delay of effective treatment Anticancer agent Today—One Size Fits All
The Future—Tailored Therapy Sensitivity ( + ) Sensitivity (–) Responders Survival benefit Nonresponders Toxicity without survival benefit Delay of effective treatment Molecular profiling 1 Right therapy for right patient 2
Current and Emerging Therapies in NSCLC George R. Blumenschein, Jr., MD Associate Professor of Medicine Department of Thoracic/Head & Neck Medical Oncology The University of Texas, M. D. Anderson Cancer Center Houston, Texas
Upstream Block Downstream Block Both Angiogenesis Downstream Block
Epidermal Growth Factor Receptor Inhibitors in NSCLC (Gefitinib, Erlotinib) Signal Transduction Blocked TKI Ligand KK TKI Signal Transduction Blocked MoAb KK Cetuximab Abbreviations: MoAb, monoclonal antibody; TKI, tyrosine kinase inhibitor.
BR.21 SCHEMA Stratified by: Center PS (0/1 vs 2/3) Response prior Rx (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (yes vs no) Erlotinib 150 mg daily Placebo “150 mg” daily * 2:1 Randomization Shepherd FA, et al. N Engl J Med. 2005;353: RANDOMIZE*RANDOMIZE*
Overall Survival All Patients * HR and P-value adjusted for stratification factors at randomization + EGFR status. With permission from Shepherd FA, et al. N Engl J Med. 2005;353: HR* = 0.70, P <.001
FLEX—Pivotal Trial Cetuximab + Chemotherapy in 1st-Line Advanced NSCLC Chemotherapy- naive advanced NSCLC Stratified by IIIB or IV ECOG PS 0,1, or 2 Vinorelbine 25 mg/m 2 d1, 8 + cisplatin 80 mg/m 2 d1, q3wk Primary endpoint: overall survival Secondary endpoints: PFS, ORR, DCR, QOL, safety, PK n = 557 n = 568 Cetuximab 400 mg/m 2 d1 wk1, then 250 mg/m 2, qwk + vinorelbine 25 mg/m 2 d1, 8 + cisplatin 80 mg/m 2 d1, q3wk RANDOMIZERANDOMIZE Up to 6 cycles of chemotherapy; patients not progressing continue on cetuximab maintenance All histologic subtypes included ECOG PS 0–2 No known brain metastases EGFR expression by IHC (≥1 positive tumor cells) Pirker R, et al ASCO; May 31-June 3, Oral presentation and abstract 3.
FLEX — Results CV + CetuximabCVP-value RR36%29%.012 PFS4.8 mo NS TTF4.2 mo3.7 mo.015 Abbreviations: CV, cisplatin/vinorelbine; NS, not significant; OS, overall survival; PFS, progression-free survival; RR, response rate; TTF, time to treatment failure. Median OS 1-Y OS CV + Cetuximab 11.3 mo 47% CV 10.1 mo 42% HR: 0.871; P =.044 With permission from Pirker R, et al. J Clin Oncol. 2008;26:3 (abstract). Overall Survival (%) Months
Phase III Trial of Bevacizumab in Nonsquamous NSCLC ECOG 4599 (PC) Paclitaxel 200 mg/m 2 Carboplatin AUC = 6 (q3wk) x 6 cycles (PCB) PC x 6 cycles + bevacizumab (15 mg/kg q3wk) to PD Eligibility Non-squamous NSCLC No Hx of hemoptysis No CNS metastases No crossover to bevacizumab permitted Stratification Variables RT vs no RT Stage IIIB or IV vs recurrent Wt loss <5% vs ≥5% Measurable vs nonmeasurable Sandler A, et al. N Engl J Med. 2006;355:
Overall Survival by Treatment 12 mo 24 mo RR 44% 15% 15% 51% 23% 35% Probability PC PCB P = Months Medians: 10.3, 12.3 HR: 0.79 (0.67, 0.92) With permission from Sandler A, et al. N Engl J Med. 2006;355:
Tumors Are Organs and it Makes Sense to Target Multiple Compartments 2. Anti-EGFR: at the tumor cell Inhibits cell proliferation Decreases invasion Promotes apoptosis Inhibits metastasis Decreases VEGF production 1. Anti-VEGFR: at the tumor endothelial cell Inhibits angiogenesis by decreasing endothelial cell proliferation and migration Inhibits angiogenesis by decreasing endothelial cell proliferation and migration Inhibits VEGF-dependent endothelial cell survival Decreases vascular permeability
Examples of Recent Drug Development Strategies 2-drug clinical combinations –Bevacizumab + EGFR inhibitors Multikinase inhibitors –Sorafenib –Sunitinib –Vandetanib
Sunitinib (SU11248)—Multitargeted Tyrosine Kinase (TK) Inhibitor Oxindole TK inhibitor Orally bioavailable small molecule Selective multitargeted Inhibition of –PDGFR –VEGFR –KIT –FLT3 Antitumor and anti-angiogenic activity Long plasma half-life ≈ 40 hours Active metabolite N H O N H F H3CH3C CH 3 N H O N
Tumor cell Blood vessel cell Sorafenib inhibits tumor cell proliferation/survival by targeting the RAF/MEK/ERK pathway at the level of RAF kinase Sorafenib exerts an antiangiogenic effect by targeting the receptor tyrosine kinases VEGFR-2 and PDGFR- and their associated signaling cascades BAY : Sorafenib Sorafenib
Vandetanib A once-daily oral agent that targets VEGFR and EGFR signaling Preclinical data suggest vandetanib has potential to inhibit VEGFR and EGFR signaling in the clinic at doses of 100 mg/day Vandetanib EGFR inhibition RET inhibition Tumor cell growth Tumor angiogenesis VEGFR inhibition KinaseIC 50 (µM) VEGFR-2 (KDR)0.04 VEGFR-3 (Flt-4)0.11 RET0.13 EGFR0.50 Wedge SR, et al. Cancer Res. 2002;62: Herbst RS, et al. J Clin Oncol. 2009;27:18s. Abstract CRA Herbst RS, et al. Expert Opin Invest Drugs. 2007;16:
2nd- and 3rd-Line NSCLC Targeted Monotherapies Prior TherapyResponse Sunitinib 1 1–2 prior chemotherapeutic regimens (N = 63) 39.7% disease control rate (DCR) (SD + PR); median PFS 12 wk; median OS of 23.4 wk Erlotinib 2 1–2 prior chemotherapeutic regimens (N = 731) 45% DCR; median PFS 9.4 wk; median OS 29.1 wk Sorafenib 3 Vandetanib 4 1–2 prior treatments (N = 51) 1–2 prior chemotherapeutic regimens (N = 83) 59% DCR; PFS 11.9 wk; median OS of 29.3 wk 45% DCR; PFS 11 wk; median OS of 26.4 wk 1. Socinski MA, et al. J Clin Oncol. 2008;26: Shepherd FA, et al. N Engl J Med. 2005;353: Gatzemeier U, et al. J Clin Oncol. 2006;24:abstract Natale RB, et al. J Clin Oncol. 2006;24:abstract 7000.
Combinations with Targeted Therapies
Phase II 2 nd and 3 rd -Line NSCLC Trial Erlotinib +/- Sorafenib N = 168 1–2 prior chemotherapies ECOG PS 0–2 Prior antiangiogenic therapy limited to bevacizumab only Squamous cell histology allowed IIIB/IV NSCLC R A N D O M I Z E 2:1 Erlotinib 150 mg QD + sorafenib 400 mg BID Erlotinib 150 mg QD + placebo BID Randomized (2:1) double-blind placebo-controlled study Primary endpoint: progression-free survival, response rate Secondary endpoints: overall survival, safety, duration response, biomarkers PI: David Spigel (SCRI LUN160) Cycle = 4 wk Restage q2 cycles until PD, then off-study
Phase II Study of Erlotinib with or Without Sunitinib A Randomized, Double-Blind, Multicenter Study RANDOMIZERANDOMIZE Erlotinib daily + Sunitinib daily Erlotinib daily + Placebo daily Run-in phase Erlotinib 150 mg daily + Sunitinib 37.5 mg daily Eligibility NSCLC 1–2 prior therapies No CNS metastases
ZODIAC—Vandetanib + Docetaxel vs Docetaxel in 2nd-Line NSCLC A Randomized, Double-Blind, Parallel-Group, Multicenter Study Primary endpoint of progression-free survival (PFS) >90% power to detect 25% prolongation of PFS (hazard ratio <0.80) Efficacy and safety in females assessed as coprimary analysis population All histologies of NSCLC eligible Treated CNS metastases and previous use of bevacizumab permitted Placebo + docetaxel 75 mg/m 2 (Max six 21-d cycles) n = 697 Vandetanib 100 mg/day + docetaxel 75 mg/m 2 (Max six 21-d cycles) n = 694 Recurrent (stage IIIB/IV) NSCLC after failure of 1st-line chemotherapy Total recruitment = 1391 patients 1:1 randomization Herbst RS, et al. J Clin Oncol. 2009;27:18s. Abstract CRA 8003.
Primary Endpoint—Progression-Free Survival All Patients (n = 1391) Females Only (n = 421) Hazard ratio % CI0.70, , sided P-value< Estimated median PFS Vandetanib 100 mg + docetaxel Placebo + docetaxel 4.0 mo 3.2 mo 4.6 mo 4.2 mo % progression-free at 6 mo Vandetanib 100 mg + docetaxel Placebo + docetaxel 28.0% 22.2% 33.9% 29.6% The treatment effect observed in Japan and China was consistent with that seen outside each country. Herbst RS, et al. J Clin Oncol. 2009;27:18s. Abstract CRA 8003.
Phase III Trial of Erlotinib +/- Bevacizumab in Nonsquamous NSCLC (BETA Lung) 1 o Endpoint: OS; 2 o endpoints: PFS, ORR, DOR E dosing was at 150 mg daily. B/P dosing was 15mg/kg intravenous every 3 weeks. Responses were assessed every 6 weeks until week 24 and every 12 weeks thereafter. Recurrent NSCLC 1 prior regimen Bevacizumab-appropriate ECOG PS 0–2 (n=636) Arm 1 erlotinib[E] + placebo [P] (n=317) Arm 2 erlotinib[E] +bevacizumab[B] (n=319) 1:1 randomization stratified by ECOG PS, smoking history, sex, and study site FPI: June 2005, LPI: April Follow Up: Median 19mos(0.2-34) Treatment continued until disease progression or unacceptable toxicity Hainsworth, J. et al. J Thorac Oncol. 2008;3(suppl 4):S302.
Results in ITT Population (BETA Lung) The OS and PFS results for patients in the biomarker defined subgroups was consistent with the overall results of the trial. Erlotinib alone (n = 317)Bevacizumab + Erlotinib (n = 319) PFS Median, mo Overall survival Median, mo Response rate, % CR/PR612 OS PFS Hainsworth, J. et al. J Thorac Oncol. 2008;3(suppl 4):S302.
SWOG 0536—Phase II Trial of Carboplatin, Paclitaxel, Cetuximab, and Bevacizumab, Followed by Cetuximab and Bevacizumab in Advanced NSCLC Paclitaxel 200 mg/m 2 Carboplatin AUC = 6 (q3wk) x 6 cycles + Bevacizumab 15 mg/kg (q3wk) + Cetuximab 250 mg/m 2 weekly Eligibility Nonsquamous NSCLC No Hx of hemoptysis No CNS metastases Bevacizumab + Cetuximab until progression N = 110 Endpoints Primary: feasibility defined by the frequency/severity of grade ≥4 hemorrhagic toxicities Secondary: response rate, progression-free survival, overall survival, and toxicity Gandara D, et al. J Clin Oncol. 2009;27:15s. Abstract 8015.
SWOG 0536—Results Gandara D, et al. J Clin Oncol. 2009;27:15s. Abstract N = 110 (95 evaluable)Efficacy/Toxicity Partial response54% Stable disease23% Median progression-free survival7 mo Median overall survival Pulmonary hemorrhage rate (severe) 14 mo 2%
S0819—SWOG Phase III Study Paclitaxel Carboplatin a Bevacizumab RANDOMIZERANDOMIZE Paclitaxel Carboplatin Cetuximab a Bevacizumab Cetuximab a Bevacizumab PC: paclitaxel: 200 mg/m 2 & carboplatin: AUC = 6 cetuximab: 400 mg/m 2, then 250 mg/m 2 weekly Correlative Science: Tumor: EGFR/HER pathways; K-ras Genomic DNA: EGFR polymorphisms Plasma: Proteomic predictor NSCLC Adv Stage Tumor Tissue Available Co-Primary Endpoints: 1545 patients (618 FISH +) Primary Endpoints: OS (entire study), PFS (EGFR FISH) a In bevacizumab eligible: 15 mg/kg q3wk (piloted in S0536)
Iressa Pan Asian Study (IPASS) Phase III Trial— Gefitinib vs Carboplatin/Paclitaxel in Selected Patients With Advanced NSCLC Never or light ex-smoker* with adenocarcinoma histology PS 0–2 Stage IIIB or IV chemotherapy-naive NSCLC N=1217 RANDOMIZERANDOMIZE Gefitinib (250 mg/day) Offered carboplatin/paclitaxel on progression Carboplatin (AUC 5 or 6) + Paclitaxel (200 mg/m 2 ) 3 times weekly up to 6 cycles Primary endpoint: progression-free survival (noninferiority) Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and tolerability Exploratory: biomarkers – EGFR mutation, gene copy number, and protein expression Mok T, et al. Ann Oncol. 2008;19:abstract LBA2. *Never smoker = smoked <100 cigarettes in lifetime; light ex-smoker = stopped ≥15 years ago and smoked ≤10 pack-years.
IPASS—Results in ITT Population Probability of PFS Progression-Free Survival Gefitinib Carboplatin/paclitaxel Months Probability of Survival 24 Gefitinib Overall Survival Months GC/P N Events453 (74.4%)497 (81.7%) Median PFS 5.7 mos5.8 mos HR = 0.741; P < Mo PFS25%7% Carboplatin/paclitaxel GC/P Events223 (36.6%)227 (37.3%) ORR43.0%32.2% Median OS a 18.6 mos17.3 mos HR = 0.91; P = NR 12-Mo OS68%64% a Follow-up ongoing. Abbreviations: C/P, carboplatin/paclitaxel; G, gefitinib; NR, not reported. Mok T, et al. Ann Oncol. 2008;19:abstract LBA2.
Progression-Free Survival (PFS) in EGFR Mutation Positive and Negative Patients EGFR mutation positiveEGFR mutation negative Treatment by subgroup interaction test, P <.0001 HR (95% CI) =.48 (.36,.64) P <.0001 No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129) ITT population – mutation rate ~60%. Cox analysis with covariates. HR (95% CI) = 2.85 (2.05, 3.98) P <.0001 No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) Gefitinib C/P Probability of PFS At risk : Probability of PFS Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85) Months With permission from Mok T, et al. Ann Oncol. 2008;19:abstract LBA2.
Biomarker-Integrated Targeted Therapy for Lung Cancer Elimination
Hypotheses of the BATTLE Program Multiple hubs of dysregulated signaling pathways associated with lung cancer Specific altered dominant signaling pathways –EGFR axis –VEGF axis –Retinoid axis –Cyclin D1 axis –Ras/Raf axis –PI3 K/AKT-mTOR axis Altered biomarkers representing aberrant pathways of lung cancer can be detected Molecularly targeted agent(s) matched dysregulated pathways lead to improved clinical response or disease control
Endpoints Primary endpoint –Anticancer activity (progression-free survival rate at 2 months) in patients with stage IV NSCLC Secondary endpoints –Response rate –Overall survival –Time to progression Biologic endpoint inclusive of a tissue biopsy –Receptor modulation, endothelial cell apoptosis –To explore the effects of therapy on surrogate markers in serum
Summary New targeted therapies may improve treatment outcomes either in combination with chemotherapy or as part of a biologic therapy cocktail Patient selection may be critical, and toward this end further molecular studies are needed Correlative scientific enquiries with tissue analysis and blood based biomarkers to match predictive markers with clinical outcome should become a component of future trials
Targeted Therapy and Multimodality Treatment in NSCLC Walter J. Curran, Jr., MD Lawrence Davis Professor and Chair Department of Radiation Oncology Emory University Atlanta, Georgia
Nonoperative Care of Good PS Patients with Stage III NSCLC What Do We Know? Chemotherapy-radiotherapy (CT-RT) results in better survival than RT alone –CALGB , RTOG , EORTC 3, CEBI 4 Concurrent is better than sequential CT-RT –West Japan Trial 5, RTOG , GLOT 7, Czech Trial 8 1. Dillman RO, et al. J Natl Cancer Inst. 1996;88: Sause W, et al. Chest. 2000;117: Uitterhoeve AL, et al. Radiat Oncol. 2007;2: Le Chevalier T, et al. J Natl Cancer Inst. 1991;83: Wada H, et al. J Clin Oncol. 1996;14: Curran WJ, et al. Proc Am Soc Clin Oncol. 2002;19:484a. 7. Fournel P, et al. J Clin Oncol. 2005;23: Zatloukal P, et al. Lung Cancer. 2004;46:87-98.
Meta-Analysis of Concurrent vs Sequential CT-RT—Overall Survival Median follow-up: 6 years RT + conc CT effect: P =.004 CALGB /4639/ (0.73;1.72) Trial No. Deaths/No. Entered RT + conc CTRT + seq CT Hazard Ratio HR (95% CI) RT + conc CT better | RT + seq CT better WJLCG131/156142/ (0.61;0.99) RTOG /204189/ (0.65;0.98) GMMA Ankara 9515/ (0.41;1.82) GLOT-GFPC NPC87/10296/ (0.60;1.07) EORTC /8066/ (0.69;1.39) Total521/603547/602 Test for heterogeneity: P =.66 I 2 = 0 % 0.84 (0.74;0.95) Auperin A, et al. J Thorac Oncol. 2007;2:S310.
Overall Survival—Meta-Analysis Absolute benefit in OS with concomitant CT: At 2 years: At 3 years: At 5 years: 5.3% 5.7% 4.5% HR = 0.84 (0.74;0.95), P =.004 RT + conc CT RT + seq CT Survival (%) Time from Randomization (Years) 01234>5> Auperin A, et al. J Thorac Oncol. 2007;2:S310.
Good PS Stage III NSCLC— What Don’t We Know? Does radiotherapy dose/volume matter? Role of adjuvant chemotherapy (SWOG/HOG)? Optimal chemotherapy doublet with radiotherapy? Any role for targeted therapy?
Good PS Stage III NSCLC— What Don’t We Know? Does radiotherapy dose/volume matter? Role of adjuvant chemotherapy (SWOG/HOG)? Optimal chemotherapy doublet with radiotherapy? Any role for targeted therapy?
Role of Targeted Therapy in Stage III NSCLC
EGFR Targeted Therapies in Stage III NSCLC
RTOG 0324—Cetuximab/CT-RT Study Rationale EGFR and NSCLC –EGFR is over-expressed in NSCLC –Associated with aggressive behavior and poor outcomes –EGFR inhibition → radiosensitization in preclinical systems Cetuximab enhances antitumor efficacy of RT –RT in head and neck cancer 1 Prior randomized studies indicate that the addition of cetuximab to CT may improve efficacy in advanced NSCLC The addition of cetuximab to CT-RT had not been evaluated in NSCLC 1. Bonner JA, et al. N Engl J Med. 2006;354:
RTOG 0324—Treatment Schema Cetuximab Paclitaxel Carboplatin Cetuximab CRT 400 mg/m 2 day 1 Paclitaxel Carboplatin Cetuximab Paclitaxel (45 mg/m 2 /wk) Carboplatin (AUC = 2/wk ) Cetuximab (250 mg/m 2 /wk) CRT (63 Gy/7 wk/35 daily fx) Paclitaxel (200 mg/m 2 q3wk x 2) Carboplatin (AUC = 6 q3wk x 2) Cetuximab (250 mg/m 2 /wk) Cetuximab 250 mg/m 2 /wk x 3 Weeks 2–8 Week 1Weeks 9–11Weeks 12–17 Follow-Up Time to Date Median, 21.6 months Range, 1.4–39.3 months Komaki R, et al. Int J Rad Oncol Biol Phys. 2007;69:S57-S58.
RTOG 0324—Conclusions The addition of cetuximab to CT-RT → CT is feasible and safe –RT was delivered per protocol for 86% of patients –Cetuximab and the cetuximab/CT combination were delivered per protocol in the majority of patients Loading dose, 96% CT-RT, 80% Consolidation, 68% –Grade ≥3 nonhematologic adverse event rate was similar to historical control RTOG 0324, 67% BMS/ACR 427, 60% –There were 5 grade 5 events on this trial. Three of these are felt to have been related to excessive V20 and unrelated to cetuximab Median survival, 22.7 months 24-month survival is 49.3%! Komaki R, et al. Int J Rad Oncol Biol Phys. 2007;69:S57-S58.
Long-Term Outcome in RTOG LA-NSCLC Trials TrialRadiotherapyChemotherapySequenceMST5-y OS Gy (SDFx)Pac-CarboCon-Consol22.7 mN/A Gy (BID Fx)Pac-Carbo/AmifInd-Con17.317% Gy (BID Fx)Pac-CarboInd-Con17.916% Gy (SDFx)VBL-DDPCon17.016% Gy (SDFx)VBL-DDPInd14.610% Gy (BID Fx)VP-16/DDPCon15.113% Potential explanations True superiority (C225 enhances the efficacy of chemoradiation) Will Rogers phenomenon (routine PET scans stage migration) Improved RT technique and supportive care Patient selection Luck
CALGB 30407—Concurrent Carboplatin + Pemetrexed/RT Followed by Carboplatin + Pemetrexed + Cetuximab for Stage III NSCLC RANDOMIZERANDOMIZE Arm A Arm B Carboplatin AUC 6 q3wk x 4 Pemetrexed 500/mg² q3wk x 8 XRT – 70 Gy over 7 wk Carboplatin AUC 6 q3wk x 4 Pemetrexed 500/mg² q3wk x 8 XRT – 70 Gy over 7 wk + Cetuximab 400mg/m² loading and 250 mg/m² weekly during RT A Randomized Phase II Trial Govindan R, et al. J Clin Oncol. 2008;26:Abstract 7518.
CALGB Grades 3–4 Toxicities Arm A (n = 54) No Cetuximab Arm B (n = 52) Cetuximab Neutropenia3637 Feb/neutropenia57 ↓ Platelets3034 Anemia1416 Esophagitis3522 Fatigue2218 Skin rash322 Govindan R, et al. J Clin Oncol. 2008;26:Abstract 7518.
CALGB Efficacy Data—ASCO 2009 Arm A (n = 54) No Cetuximab Arm B (n = 52) Cetuximab Adenocarcinoma46%41% Partial/complete response 73%71% Median failure- free survival 12.9 mo10.3 mo 18-mo survival57%47% Median survival time 22.3 mo18.7 mo Govindan R, et al. J Clin Oncol. 2009;27:Abstract 7505.
RTOG 0617 Phase III Trial of Standard-Dose (60 Gy) vs High-Dose (74 Gy) Conformal RT with Concurrent and Consolidation CT and +/- Cetuximab in Stage III NSCLC Primary endpoint: survival (n = 512) (2 X 2 design evaluating dose and cetuximab independently) Stratified by stage (A vs B), type of RT (3-D vs IMRT), and PS (0 vs 1) Stage IIIA/B PS 0–1 FEV 1 ≥1.5 L; V 20 <37% No Supraclav LNs PET recommended R A N D O MI Z E Concurrent CT/RT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 60 Gy (2 Gy/d) Concurrent CT/RT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 74 Gy (2 Gy/d) Consolidation Paclitaxel 200 mg/m 2 Carboplatin AUC 6 q3wk x2 cycles
RTOG 0617: Revised! Phase III Trial of Standard-Dose (60 Gy) vs High-Dose (74 Gy) Conformal RT with Concurrent and Consolidation CT and +/- Cetuximab in Stage III NSCLC Primary endpoint: survival (n = 512) (2 X 2 design evaluating dose and cetuximab independently) Stratified by stage (A vs B), type of RT (3-D vs IMRT), and PS (0 vs 1) Stage IIIA/B PS 0–1 FEV 1 ≥1.5 L; V 20 <37% No Supraclav LNs PET recommended R A N D O MI Z E Concurrent CT/RT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 60 Gy (2 Gy/d) + Cetuximab Concurrent CT/RT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 74 Gy (2 Gy/d) + Cetuximab Consolidation Paclitaxel 200 mg/m 2 Carboplatin AUC 6 q3wk x2 cycles
SWOG 0023—Schema CDDP/VP-16 XRT 1.8–2 Gy/d 61 Gy Docetaxel 75 mg/m 2 x 3 cycles 1 o Endpoint: overall survival; 2 o Endpoint: PFS, toxicity, and correlative science Maintenance therapy could continue for a maximum of 5 years. Stratification factors: IIIA vs IIIB; measurable vs nonmeasurable disease; squamous vs nonsquamous. PLACEBO Gefitinib 500 mg/d 250 mg/d (5-1-03) Definitive TX Consolidation Maintenance RANDOMIZERANDOMIZE Kelly K, et al. J Clin Oncol. 2008;26:
SWOG 0023—Overall Survival from Randomization Median 0% 20% 40% 60% 80% 100% Months After Randomization Gefitinib Placebo N Events (mo) P =.01 2-sided stratified Log-rank With permission from Kelly K, et al. J Clin Oncol. 2008;26:
EGFR-Directed Therapy in Stage III NSCLC RTOG 0324 encouraging for cetuximab/carboplatin/paclitaxel/RT regimen CALGB not encouraging for adding cetuximab to a pemetrexed-based regimen Cetuximab incorporated into the current RTOG/CALGB/NCCTG phase III trial Data with EGFR TKIs (gefitinib, erlotinib) not encouraging
Vascular-Targeted Therapies in Stage III NSCLC
NSCLC Trials Selected Bevacizumab/CT-RT Regimens SITEREGIMENSTATUS Ca Consortium (IIIB/IV) RT → CP/bevClosed; 1 gr 5 hemorrhage Northwestern (IIIB/IV) RT → CP/bevNever opened Dana FarberCP wkly + bev q3wk + RT → CP/bev q3wk → bev x 1 y Closed; 4 patients – 1 gr 5 hemorrhage, 1 PE NCI 7213 (Vokes) CP/bev/RTClosed; 1 patient accrued Sarah Cannon (Spigel) Carbo/pem/bev/RT → Carbo/pem/bev → bev Closed; 5 patients – 2 TE fistulas UNC (Socinski)CP/bev → CP/bev/RT → Bev/erlotinib Active; 21 patients – 1 gr 5 and 1 gr 3 hemorrhage
Bevacizumab Phase I/II Stage III Unresectable NSCLC—LCCC 0511 Primary endpoint: progression-free survival at 1 year PET P –225 mg/m 2 D1D22 Socinski MA, et al. J Clin Oncol. 2009;27:Abstract Concurrent CT/RTx Platform TCRT – 74 Gy (2 Gy/d) C – AUC 2 P – 45 mg/m 2 D43 q wk x 7 D92 Bv – 10 mg/kg q2wk x 4 Bv – 10 mg/kg q2wk x 4 Er – 100 mg/d Tues–Fri during TCRT Bv – 10 mg/kg q2wk x 4 Er – 150 mg/d Tues–Fri during TCRT Consolidation Therapy Bv – 15 mg/kg q3wk x 6 Er – 150 mg/d for the 6 cycles D101 – 122
LCCC 0511—Summary of Concurrent Therapy 25/26 patients completed therapy to 74 Gy Grade 3 neutropenia–30% Grade 3 esophagitis–19% Grade 3 pneumonitis–<10% Median days of RT delay–0 (0–8) One grade 3 and one grade 5 pulmonary hemorrhage in 2 squamous cell patients 1-yr survival: 79% Encouraging preliminary data Socinski MA, et al. J Clin Oncol. 2009;27:Abstract 7528.
SWOG 0533 Concurrent Chemoradiation PE:Cisplatin 50 mg/m 2 IV d 1, 8, 29, 36 Etoposide 50 mg/m 2 IV d 1–5, 29–33 RT:1.8 Gy X 36 fractions COHORT 1: No Bevacizumab (35 patients/risk group) COHORT 2: Bevacizumab d 15, 36, 57 (28 patients/risk group) COHORT 3: Bevacizumab d 1, 22, 43 (28 patients/risk group) Consolidation (4–8 wk) Docetaxel 75 mg/m 2 IV q21d x 3 All cohorts: bevacizumab q21d x 3 Parallel studies: low-risk and high-risk patients
Unresectable stage III nonsquamous NSCLC No cavitation and no tumor close to a major vessel No hemoptysis ( ½ tsp within 28 days of registration) Unresectable stage III squamous cell cancer OR Tumor of any histology with cavitation or close to a major vessel OR History of hemoptysis Stratum 2 closed to accrual in 2009 due to toxicity Stratum 1 Low Risk Stratum 2 High Risk
Stage III NSCLC Conclusions Combined chemotherapy-radiotherapy represents the standard of care; no universal agreement as to specific optimal strategy Novel approaches targeting loco-regional as well as systemic compartments are needed Clinical trial enrollment paramount to making progress