Combined Modality Therapy State of the Art Everett E. Vokes The University of Chicago
What we Know Some patients are cured (20%) Induction and concurrent chemoradiotherapy are each superior to radiotherapy alone Concurrent beats Induction No apparent role for adding induction or consolidation to concurrent chemoradiotherapy (incl maintenance EGFR inhibition)
Induction versus Concomitant Therapy Meta-analysis Hazard ratio (HR) plots: (A) survival, (B) PFS Auperin, A. et al. J Clin Oncol; 28:2181-2190 2010
Induction followed by Concurrent CT/XRT CALGB 39801 Design R E G I S T E R A (Standard CT/X) B (Ind CT/X) Paclitaxel 50 mg/m 2 IV/1h/week Carboplatin AUC 2 IV/30 min/wk XRT 6600 cgy (total) Paclitaxel 200 mg/m 2 IV/3h Carboplatin AUC 6 IV/30 min q 21 days for a total of 2 cycles Paclitaxel 50 mg/m 2 IV/1h/week Carboplatin AUC 2 IV/30 min/wk XRT 6600 cgy (total) (d 43)
Intent-to-Treat Survival Vokes et al JCO, 2007
Consolidation HOG LUN 01-24/USO 02-033 ChemoRT Cisplatin 50 mg/m 2 IV d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & 29-33 Concurrent RT 59.4 Gy (1.8 Gy/fr) 203 Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-cr Randomize 147 73 74 Docetaxel 75 mg/m 2 q 3 wk 3 Observation Hanna et al JCO 26: 5755-5760 2008
Overall Survival (ITT) Docetaxel : Median: 21.5 months (17.-34.8) 3 year survival rate: 27.2% Observation: Median: 24.1 months (18.0-34.2) 3 year survival rate: 27.6% P-value: 0.940 Hanna et al JCO 26: 5755-5760 2008
GILT CT-RT Design (1) Radiotherapy - starting day 1 of chemotherapy - 2 Gy/day on weekdays for 6.5 weeks - at least 66 Gy Arm A: Consolidation Chemotherapy + Best Supportive Care -21 0/1 8 15 22 29 36 43 50 57 Randomisation* CR, PR, SD Cisplatin 80 mg/m 2 D1 D22 Oral Vinorelbine 60 mg/m 2 D1 D8 Oral Vinorelbine 80 mg/m 2 D22 D29 Cisplatin 20 mg/m 2 Screening Oral Vinorelbine 50 mg/m 2 4-6 weeks Arm B: Best Supportive Care *stratified according to stage
GILT CT-RT Patient Distribution REGISTERED PATIENTS N = 288 Recruitment period: 07/05-05/09 Patients treated with CT-RT (2 cycles) N = 279 (96.9%) N evaluable = 242 (86.7%) Randomised patients N = 201 N evaluable 165 (82.1%) Arm A : CT + BSC (2 cycles) N = 96 N evaluable = 76 Arm B : BSC N = 105 N evaluable = 89
GILT CT-RT Drug Delivery and Dose Intensity CT-RT Phase N=279 Consolidation Phase N=188 CT+BSC N=86 BSC N=102 Number of patients by cycle of chemotherapy, N (%) First cycle of phase Second cycle of phase 279 (100%) 255 (91.4%) 86 (100%) 78 (90.7%) 102 (100%) 97 (95.1%) Median number of cycles during phase, N 2 2 2 Number of patients with RT alone at cycle 2, N 16 Number of patients with at least 1 delayed dose 37 (13.3%) 26 (30.2%) Number of patients with at least 1 cancelled dose 75 (26.9%) 6 (7.0%) Number of patients with at least 1 dose reduction 8 (2.9%) 22 (25.6%) Median relative dose intensity of NVBo, % (range) Median relative dose intensity of CDDP, % (range) 94.1% (14.7-118.4) 98.5% (37.9-115.5) 93.3% (48.2-117.7) 96.5% (37.3-106.1)
GILT CT-RT Progression Free and Overall Survival (ITT) Progression-Free Survival Overall Survival ARM A= CT+BSC ------ ARM B= BSC ARM A= CT+BSC ------ ARM B= BSC A: CT+BSC B: BSC 6.4 (5.0-8.7) 5.5 (3.8-7.4) 83 90 13 15 Median (95% CI) Number of events Number censored A: CT+BSC B: BSC 20.8 (13.5-25.3) 18.5 (13.6-24.7) 66 76 30 29
GILT Conclusions Patient numbers are small (96 vs 105) Oral NVB is not a standard There is a positive trend for DCR Subsets of SCCA and stage IIIB of interest What is impact of break times between modalities All other stages of NSCLC are treated with more than 2 cycles
Meta-analysis Literature search Yamamoto et al, PASCO 2012 Systematic search using key words (n=1,209) Potentially relevant references identified and screened for retrieval (n=506) Not English-language (n=144), Not phase II or phase III (n=559) Not clinical trials (n=98). Non NSCLC (n=40). Not concurrent chemoradiotherapy (n=26). Not phase II or phase III (n=102). Including Surgery or induction chemotherapy (n=105). No survival endpoint (n=15). Not platinum doublet chemotherapy (n=44). Small study size (n=14). Potentially appropriate trials to be included (n=62) OS did not reach to median (n=3). Including patients with Stage I/II/IV (n=5). Limiting to poor PS, poor risk, or elderly patients (n=8). Excluding patients with progressive diseases after chemoradiotherapy (n=3). Reanalyzed studies which are already included (n=2). 41 studies (7 PIII studies and 34 PII studies) with 45 arms. Without CCT (CCT-): 20 arms (No. of patients: 1,740) With CCT (CCT+): 25 arms (CCCT: 21 arms, SCCT: 4 arms) (No. of patients: 1,707)
Factors influencing Survival Median OS (month) Study characteristics Total No. mean SD p Clinical trial 0.980 Phase II 34 19.36 5.91 Phase III 11 19.31 4.27 Chemo regimen 0.480 CDDP 29 18.93 5.77 CBDCA 16 20.11 5.08 Period 0.022 1995-2000 12 16.40 3.80 2001-2005 14 19.08 4.87 2006-2011 19 21.41 6.15 Region 0.035 Asian 22 21.12 5.97 Non-Asian 23 17.65 4.53 No significant difference was found in the distribution of clinical trial, chemo regimen, period, and region between CCT- and CCT+ (p 0.182).
Individual and pooled median OS 10 20 30 40 50 60 month CCT- CCT+ 18.1 (95%CI: 16.5-20.2) 18.5 (95%CI: 16.7-20.5) HR= 0.98 (95%CI: 0.84-1.13) p= 0.757 *Adjusted HR= 0.95 (95%CI: 0.75-1.21) p= 0.515 * Adjusted for period and region. I 2 values for assessing heterogeneity were 15.3% in all studies.
Subgroup analysis of hazard ratio (Comparison between CCT+ and CCT-) Period 1995-2000 2001-2005 2006-2011 Region Asian Non-Asian Hazard ratio (95%CI) 1.15 (0.82-1.60) 0.96 (0.72-1.29) 0.91 (0.68-1.22) 0.84 (0.68-1.04) 1.01 (0.83-1.24) p 0.428 0.791 0.543 0.105 0.891 Clinical Trial Phase II Phase III Total 1.03 (0.84-1.26) 0.94 (0.77-1.16) 0.98 (0.84-1.13) 0.802 0.566 0.757 0.5 Favors CCT+ 1 2 Favors CCT-
Yamamoto analysis in Perspective Specific trials (20+25) included in final analysis not specified Quality of individual trials unclear Inclusion of both phase-ii and phase-iii populations Specific patient numbers would be of interest (eg. number of patients in phase-iii trials) Conclusions supported by the larger trials we know: There is no significant effect of consolidation chemotherapy
Chemotherapy Matters Dominance of Systemic Failure in CALGB 39801 (n = 213) Patients progressed 213 (Vokes et al JCO, 2007) Local Local and distant Distant only Missing data 38 93 77 5 Distant relapses 170 Brain and other 30 Brain only 31 Distant, but not brain 109
Wang, L et al. Lung Cancer, 77(1): 89-96, 2012 IS there an Optimal Regimen? Carbo-tax-XRT v Cis-etopo-XRT
Overall survival and the progression-free survival curves Wang, L et al. Lung Cancer, 77(1): 89-96, 2012
CALGB 9431, 9534 Survival Months from Randomization Arm 1: Gemcitabine/Cisplatin(9431) Arm 2: Paclitaxel/Cisplatin(9431) Arm 3: Vinorelbine/Cisplatin(9431) Arm 4: Paclitaxel/Carboplatin(9534)
Pemetrexed-Cisplatin-XRT Phase I Trial Pemetrexed 500 mg/m 2 and carboplatin AUC 5 or 6 can be administered with concurrent chest radiotherapy No major enhancement of in-field toxicity Pemetrexed/carboplatin based CRT allows administration of systemically active doses Examination in a larger Phase II trial is warranted: CALGB 30407 Seiwert et al, Clin Cancer Res 2007, 13: 515
Optimal chemoradiotherapy platform Cis or carbo with Pemetrexed CALGB 30407 (PI: R. Govindan) Carboplatin AUC 5 q3wk Pemetrexed 500/mg² q3wk x 4 XRT 70 Gy Carboplatin AUC 5 q3wk Pemetrexed 500/mg² q3 wk x 4 XRT 70 Gy Cetuximab 400mg/m² loading and 250mg/m² weekly Pemetrexed 500/mg² q3week x 4
Probability 0.0 0.2 0.4 0.6 0.8 1.0 CALGB 30407 Overall Survival CALGB 30407: Overall Survival Arm A (N=48) Arm B (N=51) p-value=0.779 Median Overall Survival Arm A Arm B 21.2 months (95% CI: 7.4-NA) 22.4 months (95% CI: 13-NA) 18 Month Overall Survival Arm A 56% (95% CI 43-74) Arm B 51% (95% CI 38-68) 0 10 20 30 40 Survival Time (Months) Median follow up: 23 months (as of 7 23 09) H0: p 0.35 versus H1: p 0.55 p = survival probability at 18 months registration
Phase II Study Design Cisplatin 75 mg/m 2 q 3 weeks for 3 cycles with Pemetrexed 500 mg/m 2 q 3 weeks XRT 66 Gy Consolidation with docetaxel N=28 MST: 34 months Gadgeel et al: JTO, 2011
Phase I Dose escalation schema Dose level Pemetrexed Cisplatin Concurrent chemotherapy/radiotherapy phase 1 300 mg/m2 Days 1 and 22 25 mg/m2 Days 1 3 and Days 22 24 2 400 mg/m2 Days 1 and 22 25 mg/m2 days 1 3 and Days 22 24 3 500 mg/m2 Days 1 and 22 25 mg/m2 Days 1 3 and Days 22 24 4 500 mg/m2 Days 1 and 22 20 mg/m2 Days 1 5 and Days 22 26 Consolidation chemotherapy phase 1 4 500 mg/m2 Day 1, every 21 days 2 cycles 75 mg/m2 Day 1, every 21 days 2 cycles Brade A, et al. Int J Radiat Oncol Biol Phys, June 2, 2010
Study Design Choy, Schwartzberg et al, PASCO 2012 Original Key Eligibility Criteria: Stage IIIA/IIIB NSCLC Measurable disease ECOG PS 0-1 No prior chemotherapy No prior surgery All histologies* Randomization Arm A Concurrent Radiation Therapy Total dose: 64-68 Gy (2 Gy per day, 5 days/week, Days 1~45) Pemetrexed 500 mg/m 2 IV q 21 days 3 Carboplatin AUC 5 IV q 21 days 3 Arm B Concurrent Radiation Therapy Total dose: 64-68 Gy (2 Gy per day, 5 days/week, Days 1~45) Pemetrexed 500 mg/m 2 IV q 21 days 3 Cisplatin 75 mg/m 2 IV q 21 days 3 Consolidation Chemotherapy Pemetrexed 500 mg/m 2 IV q 21 days 3 Begin 3 weeks after completion of chemoradiation Follow-up * Protocol was amended in October 2008 to exclude squamous histology Abbreviations: AUC=area under the curve; IV=intravenous; q=every.
Overall Survival CI = confidence interval; NA = not assessable/estimable; PC=pemetrexed-/cisplatin; PCb=pemetrexed/carboplatin;
Time to Disease Progression
Future Directions Non-squamous NSCLC PROCLAIM- Schema A Randomized Phase III Trial R A N D O M I Z E Arm A Arm B Cisplatin 75 mg/m² q3 week x 3 Pemetrexed 500 mg/m² q 3 week x 3 XRT 66 Gy in 33 fractions Cisplatin 50 mg/m² d1, 8 q4 week x 2 cycles Etoposide 50 mg/m² d1-5 q4week x 2 cycles XRT 66 Gy in 33 fractions Primary objective : survival Superiority design 80% Powered to detect Hazard Ratio=0.74- Sample Size 600 Pemetrexed X 4 cycles Platinum based doublets x 2 cycles
PROCLAIM Update Accrual over 15 pts/month (578 of 600 pts) DMC meetings q 4 months Continued Accrual Central XRT QA review
Targeted Therapies with Combined Modality Therapy NOT STATE OF THE ART (YET)
CALGB 30605/RTOG 0972 POOR RISK STAGE III NSCLC (n=76 fully accrued) -IIIA/B - PS 2 - PS 0-1 + Wt loss 10% R E G I S T E R Carboplatin AUC 5 D1 Albumin-bound paclitaxel 100/m 2 D1 and 8 every 21 days x 2 cycles Erlotinib 150 mg/day (no maintenance) concomitant with XRT (66Gy) CALGB PIs: R. Lilenbaum; P Janne; M. Samuels RTOG PI: Spring Kong
RTOG 0617- Schema A Randomized Phase III Trial R A N D O M I Z E Carboplatin Paclitaxel XRT 60 Gy in 6 weeks Carboplatin Paclitaxel XRT 74 Gy in 7.5 weeks Carboplatin Paclitaxel Cetuximab XRT 60 Gy in 6 weeks Carboplatin Paclitaxel Cetuximab XRT 74 Gy in 7.5 Carboplatin Paclitaxel Carboplatin Paclitaxel Cetuximab
Biomarker Approach Stage III NSCLC For initial exploration avoid concurrent or adjuvant setting (SWOG 0023, BR19; awaiting RADIANT) Explore single agent Induction in selected patients followed by standard chemoradiotherapy Molecular testing done as standard of care (EGFR, ALK)
ALLIANCE-RTOG Proposal
Hypofractionation Administration of large fractions to carefully defined field Highly cytotoxic but associated with toxicity with conventional radiation Feasible with modern targeting Increases dose intensity and saves time Utilized in early stage setting May allow for better integration with chemotherapy
CALGB 31102 Schema Phase I: Dose Level 1: 60 Gy; Dose Level 2: 60 Gy; Dose Level 3: 60 Gy; Dose Level 4: 60 Gy 2.22 Gy/fx * 27 fractions 2.50 Gy/fx * 24 fractions 2.73 Gy/fx * 22 fractions 3.00 Gy/fx * 20 fractions Chemotherapy: Concurrent: carboplatin/taxol (AUC=2)/paclitaxel 45 mg/m 2 given weekly on days 1,8,15,22 Consolidation: carboplatin (AUC=6) and paclitaxel 200 mg/m 2 every three weeks * 2 cycles. Phase II Based on Phase I Dose above with same chemotherapy
Conclusions Several promising new radiation and systemic approaches are under investigation Improved systemic control will need to be an essential component of more effective therapies Randomized approaches and molecular tumor characterization needed due to stage migration and increased understanding of molecular foundation of NSCLC