RTOG Lung Cancer Committee 2012 Clinical Trial Update Wally Curran RTOG Group Chairman 1
RTOG Lung Committee: Active Trials Small Cell Lung Cancer Limited Stage (Intergroup Trial) Extensive Stage (RTOG 0937) Early Stage NSCLC In-operable (0813 and 0915) Operable (RTOG 1021 / ACOSOG Z4099) Locally advanced NSCLC Stage IIIA with minimal N2 disease (0839) Stage IIIA Individualized RT Rx with PET-adapted boost (1106) 2
Phase III Comparison of Thoracic Radiotherapy Regimens in Limitedstage Small Cell Lung Cancer CALGB 30610 RTOG 0538 Principal Investigator: Jeff Bogart, MD RTOG PI: Ritsuko Komaki, MD 3
CALGB 3060/RTOG 0538 R 45 Gy 1.5 Gy BID A N CDDP VP-16 CDDP VP-16 CDDP VP-16 CDDP VP-16 D O M I 61.2 Gy, 1.8 Gy QD FB Con bst CDDP VP-16 CDDP VP-16 CDDP VP-16 CDDP VP-16 PCI Z 70 Gy Gy, 2.0 Gy QD E CDDP VP-16 CDDP VP-16 CDDP VP-16 CDDP VP-16
100 Prophylactic cranial irradiation in extensive disease small cell lung cancer Overall survival 90 80 70 60 50 40 1 year: 27.1% VS. HR: 0.68 (0.52-0.88) p=0.003 13.3% 30 20 10 Control PCI 0 0 4 8 12 16 20 24 28 32 36 (months) Slotman et al. NEJM 2007
Phase II Study of PCI and consolidative Extra-Cranial Radiation for ED-SCLC RTOG 0937 Study Design RT to Chest and Other Sites Chemotherapy (4-6 cycles) Any response PCI 25 Gy in 10 fx Random Observation Stratify: PR vs CR 1 vs 2-3 mets PI: Elizabeth Gore, MD 6
RTOG 0937 Specifics Primary Objective: To compare 1-year median survival Eligibility: ES-SCLC, excluding brain metastases AND Only 1-3 metastatic sites prior to platinum-based chemotherapy AND Radiographic PR or CR Sample size = 154 Radiation therapy dosing PCI given in 2.5 Gy fractions to 25 Gy Metastases dosing is 3 Gy fractions to 45 Gy Acceptable alternative is 4 Gy fractions to 40 Gy 7
RTOG Lung Committee Small Cell Lung Cancer Limited Stage (Intergroup Trial) Extensive Stage (RTOG 0937) Early Stage NSCLC In-operable Operable (RTOG 1021 / ACOSOG Z4099) Locally advanced NSCLC Stage IIIA with minimal N2 disease (0839) Stage IIIA with PET-adapted boost (1106) 8
Physical Targeting with SBRT RTOG 0813 Phase I/II study of SBRT for early stage centrally located NSCLC in medically inoperable pts 9
RTOG 0813 - SBRT Dose Levels Level 5 10.0 Gy x 5 50.0. Gy Level 6 10.5 Gy x 5 52.5 Gy Level 7 11.0 Gy x 5 55.0 Gy Level 8 11.5 Gy x 5 57.5 Gy Level 9 12.0 Gy x 5 60.0 Gy 10
RTOG 0915-SBRT for early stage medically inoperable lung cancer R e g i s t e r R a n d o m i z e PI: Videtic 34 Gy X 1 Primary Endpoint > grade 3 rates of Toxicity Respiratory VS. 12 Gy x 4 12 Gy X 4 Soft tissue/chest wall Skin Secondary Endpoints LC/OS/DFS PET response PFTs Biomarkers 11
RTOG SBRT Plan Medically Inoperable Early Stage NSCLC SBRT (18 Gy X 3) Randomize III Altered Fx SBRT Randomize II RTOG 0915 SBRT 34 Gy X 1 SBRT 12Gy X4 12
ACOSOG Z4099/ RTOG 1021 H. Fernando, MD (ACOSOG); R. Timmerman, MD (RTOG) Histological confirmed Stage I NSCLC Registration and Randomization Activated June 2011 ARM 1: Sublobar Resection ± Brachytherapy (SR) ARM 2: Stereotactic Body Radiation Therapy (SBRT) 18 Gy X 3 = 54 Gy F O L L O W U P 13
ACOSOG Z4099/ RTOG 1021 400+ patient randomized trial Enrolled in 4-5 years (8 patient/month) Primary endpoint is 3 year overall survival Randomize prior to treatment Intent to treat +/- brachytherapy is optional in surgery arm CTC Version 4 toxicity assessment for both arms 14
RTOG Lung Cancer Strategy Small Cell Lung Cancer Limited Stage Extensive Stage Early Stage NSCLC In-operable Operable Locally advanced NSCLC Stage IIIA with minimal disease Stage IIIA with PET-adapted boost 15
RTOG 0229: Phase II Trial of Concurrent Chemo and Full Dose RT Followed by Surgical Resection and Consolidative Tx for LA NSCLC Induction Chemo-RT Paclitaxel and Carboplatin 1x/week for 6 weeks plus Concurrent RT to 61.2 Gy Reassessment of Mediastinum: 4 weeks post Induction Chemoradiation Resection Within 2 wks of Reassessment (Prophylactic Cranial Irradiation, if indicated) Not Resectable Consolidation Chemotherapy No later than 10 weeks post-surgery Pacilitaxel and Carboplatin q 21 days x 2 16
Tumor Characteristics (n=57) Histology Squamous Cell Carcinoma 11 (19.3%) Adenocarcinoma 29 (50.9%) Large cell undifferentiated 1 ( 1.8%) NSCLC, NOS 16 (28.1%) AJCC Stage IIIA 56 (98.2%) IIIB 1 ( 1.8%) T-Stage T1 18 (31.6%) T2 28 (49.1%) T3 11 (19.3%) N-Stage N2 56 (98.2%) N3 1 ( 1.8%) 17
Mediastinal Nodal Clearance (N=43*) Residual Mediastinal Disease Mediastinal nodal clearance Patients Eligible for Assessment of Primary Endpoint Surgery Performed Reasons for No Surgery Residual Mediastinal Nodes Primary Unresectable Medical contraindications MD refusal Died prior to Surgery Progressive disease Other 16 (37%) 27 (63%) 43 Pts 37 pts 20 pts 6 pts 2 pts 5 pts 1 pt 1 pt 1 pt 4 pts 18
Survival Overall Survival Progression-Free Survival Time (Months) % Alive (95% Cl) # at Risk %Alive (95% Cl) # at Risk 0 6 12 18 24 100% 57 87.7% (76.0, 93.9) 50 77.2% (64.0, 86.1) 43 66.4% (52.5, 77.1) 37 53.8% (40.0, 65.8) 29 100% 57 75.4% (62.1, 84.7) 43 50.8% (37.2, 62.9) 28 38.1% (25.6, 50.5) 21 32.7% (20.9, 45.0) 17 Fail/Total Median (95% Cl) 32/57 26.6 months (18.5, ) 45/57 12.9 months (8.0, 18.8) 19
Overall Survival by Mediastinal Nodal Clearance Status No Mediastinal Nodal Clearance Mediastinal Nodal Clearance Time (Months) % Alive (95% Cl) # at Risk % Alive (95% Cl) # at Risk 0 6 12 18 24 100 % 16 87.5% (58.6, 96.7) 14 81.3% (52.5, 93.5) 12 60.9% (32.7, 80.3) 9 54.2% (27.1, 75.0) 8 100% 27 100% 27 92.6% (73.5, 98.1) 25 81.5% (61.1, 91.8) 22 66.7% (45.7, 81.1) 17 Fail/Total Median Survival Time (95% Cl) 8/16 32.7 months (13.8, ) 12/27 Not Reached 20
NSCLC IIIA CBDCA AUC =2.0 Paclitaxel 50 mg/m 2 XRT 61.2 Gy (1.8 Gy/d) Tissue: MALDI-TOF Specimens for proteomic analysis & other correlative studies RTOG 0839 Panitumumab Y Resectable N Anatomic lobectomy or pneumonectomy Muscle flap for bronchial stump Resection: MALDI-TOF & other specimens CBDCA AUC=6 Paclitaxel 225 mg/m 2 x 2 cycles PI: Martin Edelman, MD 21
Thinking newer strategies Personalized medicine AM4/ALK and EGFR mutation trial Wild-type (non mutant) trial Adaptive XRT (RTOG 1106) Mid-treatment FDG-PET based target volumes adapted radiation therapy Isoeffect radiation dose prescriptions Why? PET tumor volumes shrink during XRT May incorporate all Stage III patients, not just those selected to get 74 Gy based on NTCP 22
RTOG 1210/ Alliance 31101 Submitted to NCI 7/12 A Randomized Phase II Trial Stage III NSCLC With either EGFR TK mutation or ALK Fusion Experimental EGFR Mutation + Erlotinib 3 months followed by ChemoRT* ALK Fusion Alk +: Fusion + Crizotinib Crizotinib 3 months months followed by ChemoRT* Control EGFR Mutation+/Alk Fusion+ ChemoRT* ONLY *Pemetrexed 500 mg/m 2 q 3 weekly x 4 Carboplatin AUC 5 (4 cycles) with Thoracic Radiation 64 Gy 23
PET-based Adaptive RT for Stage III NSCLC RTOG 1106: Just Activated!! PD Off Study D/C RT R E G I S T E R FDG-PET ChemoRT 44 Gy SD/Response FDG-PET R A N D O M I Z E RT to 64 Gy RT to 64 Gy + 10+ Gy boost based on FDG-PET 24
PET-MTV (%) Tumor Volume Reduced During-RT (UMCC 2003-76, UMCC 2006-040) PET-MTV (cc) CT-GTV (%) CT-GTV (cc) Change in PET-MTV Change in CT-GTV 400 360 320 280 240 200 160 120 80 40 0 Pre-RT During-RT Post-RT 500 450 400 350 300 250 200 150 100 50 0 Pre-RT During-RT Post-RT Change in PET-MTV based on Pre-RT Change in CT-GTV based on Pre-RT 200 180 160 140 120 100 80 60 40 20 0 Pre-RT During-RT Post-RT 250 225 200 175 150 125 100 75 50 25 0 Pre-RT During-RT Post-RT
Pre-RT Pre-RT PET-CT based plan: 17.2% lung NTCP~ 70 Gy 9.8% NTCP ~ 50 Gy During-RT During-RT PET-CT adapted composite plan: 17.2% lung NTCP~ 86 Gy to during-rt PET-PTV (102 ED2 lung, ~92 Gy ED2 tumor, ~120 Gy BED for a/b=10).
RTOG 0617 (CALGB, NCCTG) Phase III Trial of Standard-Dose (60 Gy) Versus High-Dose (74 Gy) Conformal RT w Concurrent & Consolidation Cb/P in Stage III NSCLC Stage IIIA/B PS 0-1 FEV 1 1.5L; V 20 <37% No Supraclav LNs PET recommended R A N D O M I Z E Concurrent ChemoRT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 60 Gy (2 Gy/d) + Cetuximab Concurrent ChemoRT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 Consolidation Paclitaxel 200mg/m 2 Carboplatin AUC 6 q3wks x2 cycles RT 74 Gy (2 Gy/d) + Cetuximab Primary Endpoint Survival (n=512)
Research RFP for RTOG 0617 RTOG 0617 512 Pts Enrolled Banked Specimens on 50% Formal RFP for Translational Proposals IALSC and ASTRO broadcast 25 Applicants External Peer Review Ongoing 28
RTOG Lung Committee Future NRG Oncology Will Have 7 Disease Site Committees Lung Cancer Committee will be One HQ in Philadelphia Lung Cancer Biobanking at UCSF Seeking Links with SPORES/P30/P01 s 29