Combined Chemotherapy and Radiation Therapy for Locally Advanced NSCLC

Transcription

1 Combined Chemotherapy and Radiation Therapy for Locally Advanced 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 12 th International Lung Cancer Congress 2011 Carlsbad CA 8/11/2011

2 Optimizing Therapy for Locally Advanced NSCLC Not a surgical candidate Carefully selected stage II/III patients No pleural effusions Good performance status Minimal weight loss Good FEV1

3 Options for Locally Advanced NSCLC Chemotherapy Radiation ChemoRT Chemotherapy RT Chemotherapy ChemoRT ChemoRT Chemotherapy Chemotherapy ChemoRT Chemotherapy

4 Chemotherapy Dose Chemotherapy Schedule Radiation dose/type Issues Low Dose (radiosensitizing) Higher Dose (cytotoxic) Cyclic (full dose) Weekly or twice weekly Daily (low dose) Prolonged Continuous Infusion High Dose Proton Sequence with Radiation: Sequential: CT RT Concurrent: CT/RT Combination: CT CT/RT CT/RT CT

5 RTOG 9410: Sequential vs Concurrent Chemoradiation in Stage III NSCLC Unresectable Stage III NSCLC N = 595 R A N D O M I Z E VP x 2 63 Gy, QD VP x 2 + Concurrent 63 Gy, QD PE (po) + Concurrent 69.2 Gy, BID Curran et al, ASCO 2003

6 RTOG 9410: Sequential vs Concurrent Chemoradiotherapy in Stage III NSCLC Sequential Concurrent Conc BID Median survival (mos) 3 yr survival 5 yr survival % 10% 17.1 * 25% 14.6% % NA Non-hem toxicity (Gr 3-5) Pneumonitis (Gr 3-5) Rx-related death 30% 13% 5% 48% 11% 4% 62%** 13% 5% Local Failure 38% 33% 25%** Curran et al, ASCO, 2003 *p = **p < 0.05

7 5-year OS (%) 4-year OS (%) Efficacy Results: Sequential vs. Concurrent Chemoradiotherapy, Two Major Trials West Japan RTOG 9410 MVP RT x 2 56 Gy St III NSCLC N = R A N D 9% Seq MVP x 2 Concurrent RT 56 Gy (split course) 19% Conc St III NSCLC N = R A N D 12% VP x 2 PE (po) x 2 conc BID RT RT 63 Gy VP x 2 conc RT 63 Gy 21% 17% Seq Conc HyperFx Furuse et al, JCO 1999 Curran et al, PASCO 2003

8 Survival Comparison between Sequential and Concurrent Chemoradiation Therapy (n=709) WJLCG GLOT (n=716) CZECH LAMP RTOG 9410 BROCAT 10 Sequential Concurrent Choy et al, ASCO 2003 P < 0.05 (Kruskal-Wallis Test)

9 Early Toxicity Comparison between Sequential and Concurrent CT/RT % WJLCG GLOT % CZECH LAMP RTOG 9410 BROCAT 0 Sequential Concurrent

10 CALGB 9431: Randomized Phase II Trial of Newer Chemoradiotherapy N=181 Unresectable stage III NSCLC INDUCTION CHEMO CONCURRENT CT/RT Vokes et al. JCO. 2002; (20) :

11 CALGB 9431: Randomized Phase II Trial of Newer Chemoradiotherapy VnP GemP PacP RR % MST, mo yr surv, % Grades 3/4, % PLT WBC Esoph Vokes et al, JCO 2002

12 CALGB 39801: Role of induction chemotherapy Stage III NSCLC R A N D N = 184 N = 182 Carboplatin AUC 6 Paclitaxel 200 mg/m 2 Q3wk x 2 63 Gy XRT QD + Carboplatin AUC 2 Paclitaxel 45 mg/m 2 weekly x 7 63 Gy XRT QD + Carboplatin AUC 2 Paclitaxel 45 mg/m 2 weekly x 7 Arm Med OS (mo) 2-yr OS (%) 3-yr OS (%) Med PFS (mo) 2-yr PFS (%) 3-yr PFS (%) CT/RT CT CT/RT Vokes et al, ASCO 2004

13 Consolidation Chemotherapy SWOG Phase II Trials S9019, n= 50 S9504, n=83 pstage IIIB pstage IIIB Cisplatin/VP-16 XRT Cisplatin/VP-16 XRT Cisplatin/VP-16 Docetaxel

14 SWOG 9504 Design Cisplatin/VP-16 X X RT Docetaxel X X X Cisplatin 50mg/m 2 d 1, 8, 29, 36 Etoposide 50mg/m 2 d1-5, RT: 61 Gy: 45Gy(1.8Gy/fx), 16Gy boost(2gy/fx) Docetaxel: 75mg/m 2 x 3 cycles Gandara et al. JCO. 2003; 21: Gandera et al. ASCO 2005

15 Survival in Sequential ChemoRT SWOG Trials Stage IIIB NSCLC Study Median (months) 2 year 3 year 4 year 5 year S9504 (PE/RT Docetaxel) 26 (18-35)* 54% (43-65)* 37% (24-55)* 29% (19-29)* 29% (19-29)* S9019 (PE/RT PE 15 (10-22)* 34% (21-47)* 17% (7-27)* 17% (6-28)* 15% (6-28)* PE: Cisplatin/Etoposide; RT: Radiotherapy (61 Gy) *95% CI

16 HOG LUN Unresectable, Stage IIIA-IIIB NSCLC; ECOG PS 0-1; <5% Weight Loss in Prior 3 mo ChemoRT Induction Cisplatin 50 mg/m 2 d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & Concurrent RT 59.4 Gy N=230;203 accrued CR, PR, or SD; ECOG PS 0-2 Primary endpoint: Overall Survival Docetaxel 75 mg/m 2 q 3 wk 3 Randomize Observation Hanna et al, JCO 2008; 26:

17 #7512 HOG Trial: Overall Survival (ITT) Randomized Patients (n=147) Percent of patients surviving 100% 75% 50% 25% Observation: Median: 24.1 ms ( ) 3 year survival rate: 27.6% Docetaxel: Median: 21.5 ms ( ) 3 year survival rate: 27.2% P-value: % Observation Docetaxel Consolidation Hanna et al, JCO 2008; 26: Months since registration

18 Some Current New Approaches EGFR inhibitors New Cytotoxics (pemetrexed) PARP Inhibitors New Radiation schedules Protons

19 RTOG Treatment Schema Week 1 Weeks 2-8 Weeks 9-11 Weeks Cetuximab 400 mg/m 2 day 1 Paclitaxel Carboplatin Cetuximab CRT Cetuximab 250 mg/m 2 /wk x 3 Paclitaxel Carboplatin Cetuximab Paclitaxel (45 mg/m 2 /wk) Carboplatin (AUC = 2/ wk ) Cetuximab (250 mg/m 2 /wk) CRT ( 63 Gy/7weeks/35 daily fx) Paclitaxel (200 mg/m 2 Q 3 wk x 2) Carboplatin (AUC = 6 Q 3 wk x 2) Cetuximab (250 mg/m 2 /wk) Primary endpoint: Compliance and Safety Blumenschein et al JCO 2011

20 RTOG Eligibility Criteria Histologically or cytologically confirmed IIIA/B NSCLC No prior therapy Uni-dimensionally measurable disease Zubrod PS 1 Wt loss 5% past 3 months No grade 1 neuropathy Pleural effusion - cytologically neg, non-bloody, transudate Adequate hepatic, renal, hematologic function Patient has not had prior surgery for the present cancer

21 RTOG Overall Survival Median survival 22.7 months 2yr survival 49.3% Blumenschein, et al JCO 2011

22 Longterm Outcome in RTOG Stage III NSCLC Trials Trial RT Chemo Sequence MST 5 yr OS Gy (SDFx) Pac-Carbo Con-Consol 22.7 m N/A LAMP 63 Gy (SD Fx) Pac-Carbo Con-Consol 16.3 NA LAMP 63 Gy (SD Fx) Pac-Carbo Ind-Con 12.7 NA LAMP 63 Gy (SD Fx) Pac-Carbo Ind-RT 13 NA Gy (BID Fx) Pac-Carbo/Amif Ind-Con % Gy (BID Fx) Pac-Carbo Ind-Con % Gy (SDFx) VBL-DDP Con % Gy (SDFx) VBL-DDP Ind % Gy (BID Fx) VP-16DDP Con %

23 RTOG 0617: Conventional vs High Dose RT (3d Conformal) R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin RT: 74 Gy Paclitaxel Carboplatin Paclitaxel Carboplatin x 2

24 RTOG 0617: Conventional vs High Dose RT (3d Conformal) +/- C225 R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin +/- Cetuximab RT: 74 Gy Paclitaxel Carboplatin +/- Cetuximab Primary endpoint: Survival Paclitaxel Carboplatin x 2 N=500

25 RTOG 0617 Update Accrual about 17 pts/month ( approximately 450 as of 7/11) HD RT arms closed 2 nd futility 6/11 Continued accrual to 60 Gy arms

26 CALGB 30605/RTOG 0972 POOR RISK STAGE III NSCLC (60+/76 Enrolled) -IIIA/B - PS 2 - PS 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 TRT (66Gy) CALGB PIs: R. Lilenbaum; P Janne; M. Samuels RTOG PI: Spring Kong

27 CALGB Treatment Schema R A N D O M I Z E LA NSCLC Pemetrexed: 500 mg/m 2 I.V. x 4 cycles Carbopltin: AUC 5 I.V. x 4 cycles RT: 70 Gy x 7 weeks Pemetrexed: 500 mg/m 2 I.V. x 4 cycles Carboplatin: AUC 5 I.V. x 4 cycles Cetuximab: 400 mg/m 2 loading dose followed by 250 mg/m 2 weekly x 6 weeks RT: 70 Gy x 7 weeks Pemetrexed: 500 mg/m 2 I.V. x 4 cycles Primary endpoint : survival Govindan et al, JCO 2011

28 CALGB Eligibility: Tx-naive stage III NSCLC, PS 0-1, adequate organ indices; no significant weight loss Primary endpoint: 18 mo survival % (target > 55%) Secondary endpoints; failure free survival; response rates; toxicity Results: 99 eligible pts (48 in arm A and 51 arm B) Enrolled from 09/05 to 12/07: male 61%, median age 64.5 years (range 32-81). Most common histological type: adenocarcinoma (45%). Govindan et al, JCO 2011

29 CALGB Response rate Median PFS (months) Median OS (months) 18 month OS Arm A (CbPem /RT) 77% % (44-75) Arm B (CbPem + C225) 72% % (27-68) Govindan et al, JCO 2011

30 PROCLAIM Treatment Schema R A N D O M I Z E Pemetrexed: 500 mg/m 2 q 3 weeks. x 3 cycles Cisplatin: 75 mg/m 2 q 3 weeks x 3 cycles RT: 66 Gy in 33 fractions Etoposide: 50 mg/m 2 d1-5 q 4 weeks x 2 cycles Cisplatin: 50 mg/m 2 d1, 8 q4 weeks x 2 cycles RT: 66 Gy in 33 fractions Pemetrexed: x 4 cycles Etoposide/CDDP: x 2 cycles LA Non-SCC NSCLC Primary endpoint : survival N=600 Govindan et al, ASCO 2009

31 PROCLAIM Update Accrual about 15 pts/month (350 in 8/11) DMC meetings q 4 months Continued Acrual Central XRT review

32 NCI 8811: Phase I/II Trial of RT, carboplatin, paclitaxel, and ABT-888 for Stage III NSCLC David Gandara, California Phase II Consortium

33 PARP: (poly[adp-ribose] polymerase PARP-1 is the founding member of a family of enzymes that catalyze the addition of ADPribose units to proteins that mediate DNA repair pathways Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation. Albert et al, CCR 2007

34 ABT-888 plus chemort for stage III NSCLC CCCP (PHII-107/NCI 8811); PI: Argiris Stage IIIA/B NSCLC TREATMENT SCHEMA RUN-IN PHASE I Unresectable ECOG PS 0/1 No prior chemotherapy No prior RT to chest Adequate organ function Stratification: PS (0 vs 1) Weight loss (<=5% vs >5% in previous 3 months) Age (<=65 vs >65) R E G I S T E R Primary endpoint : DLT and MTD Chest RT (63 Gy) weeks 1 7 Paclitaxel 45 mg/m 2 Qw, weeks 1-7 Carboplatin AUC2 Qw, weeks 1-7 ABT-888 twice daily po, weeks 1-7 Dose Escalation Schedule Dose Level ABT-888 Dose mg 1 40 mg 2 80 mg 3* 120 mg 4* 200 mg * dose levels 3 and 4 will be considered, dependent on available toxicity data from previous levels. 4 6 wks Carboplatin AUC 6 day 1 Paclitaxel 200 mg/m 2 day 1 ABT mg BID po days 1-7 ** Q 3 weeks x 2 cycles ** Based on the results of ongoing phase I study

35 ABT-888 plus chemort for stage III NSCLC CCCP (PHII-107/NCI 8811); PI: Argiris TREATMENT SCHEMA RANDOMIZED PHASE II PART Stage IIIA/B NSCLC Unresectable ECOG PS 0/1 No prior chemotherapy No prior RT to chest Adequate organ function Stratification: PS (0 vs 1) Weight loss (<=5% vs >5% in previous 3 months) Age (<=65 vs >65) R A N D O M I Z E Primary endpoint : PFS Chest RT (63 Gy) weeks 1 7 Paclitaxel 45 mg/m 2 Qw, weeks 1-7 Carboplatin AUC2 Qw, weeks 1-7 ABT-888 twice daily po, weeks 1-7 Chest RT (63 Gy) weeks 1 7 Paclitaxel 45 mg/m 2 Qw, weeks 1-7 Carboplatin AUC2 Qw, weeks 1-7 Placebo twice daily po, weeks 1-7 N=104 (52 per arm) 4 6 wks 4 6 wks Carboplatin AUC 6 day 1 Paclitaxel 200 mg/m 2 day 1 ABT-888 BID po days 1-7 * Q 3 weeks x 2 cycles Carboplatin AUC 6 day 1 Paclitaxel 200 mg/m 2 day 1 Placebo BID po days 1-7 Q 3 weeks x 2 cycles * Based on the results of ongoing phase I study

36 Hypofractionation: SOCCAR Trial Design pathologically confirmed N=130 NSCLC stage III, PS 0-1, CT± mediastinoscopy, PET-CT CONCURRENT ARM unsuitable for surgery SEQUENTIAL ARM 55Gy/20f/4weeks cisplatinum 80mg/m 2 weeks 1,4 vinorelbine 15mgs/m 2 weekly 4 weeks cisplatinum 80mg/m 2 day 1 vinorelbine 25mg/m 2 day 1, 8 4 cycles 4 weeks cisplatinum 80mg/m 2 day 1 vinorelbine 25mg/m 2 d 1, d 8 2 cycles 55Gy/20f/4weeks

37 SOCCAR NSCLC Stage III PS 0-1 CON SEQ n median 27.4 m 18.6 m 1 year 73.1% 83.1% 2 year 54% 42% 3 year 38% 27% 5 year 33.6% NR Local PD 10% 22% Con Seq Months

38 Conclusions 55Gy/20f/26-28d with concurrent cisplatinum and vinorelbine is a feasible, safe and effective treatment for stage III NSCLC, PS year survival in concurrent group > 50% outstanding local control rates this trial confirms the potential value of an accelerated hypofractionated radiotherapy schedule as a therapeutic approach in NSCLC

39 RTOG 1013 Randomized Phase II Trial of Standard vs. Hypofractionated RT PS 2 or wt loss > 5% or PS 0/1 and wt loss < 5% but medically unfit unresectable stage IIIA/B Erlotinib- Standard Radiation Therapy Erlotinib 150mg po daily for duration of radiotherapy RT 2 Gy daily, 5 days/week, total 60 Gy Stratify Histology Sq vs non-sq % weight loss performance status Comorbity scale Erlotinib- HypoFractionated Radiation Therapy Erlotinib 150mg po daily for duration of radiotherapy RT 3 Gy daily, 5 days/week, total 45 Gy LOI submitted to CTEP

40 Protons Compared To Photons Treatment for Patients with LA NSCLC ESTRO Anniversary 8-12 May 2011 London Ritsuko Komaki, MD, FACR, FASTRO Professor of Radiation Oncology GLT Distinguished Endowed Prof. In Lung Cancer Research

41 Trial of Adaptive IMRT and PBT NCI Program grant CA (P01 CA ) MDACC and MGH Randomized phase II trial: Stage II/III NSCLC 74 Gy with concurrent Carb/Taxol in both proton and IMRT Grade 3 pneumonitis and local control Patients randomized:107 /168

42 Current Treatment Paradigms in Unresectable Stage III NSCLC ChemoRT superior to either alone Concurrent therapy has a modest survival benefit over sequential; not suitable for all patients Optimal chemo strategy undefined (agent, dose, sequence) Improved systemic control will need to be an essential component of more effective therapies Optimal RT dose (conventional vs. HD ) undefined Preliminary results from the addition of agents targeting EGFR to CRT are promising and warrant further study.

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