Slide 1 Combined Chemotherapy and Radiation Therapy for Locally Advanced NSCLC. Slide 2. Slide 3 Options for Locally Advanced NSCLC

Transcription

1 Slide 1 Combined Chemotherapy and adiation Therapy for Locally dvanced SCLC George. Blumenschein, Jr., M ssociate Professor of Medicine epartment of Thoracic/Head & eck Medical Oncology The University of Texas, M.. nderson Cancer Center Houston, Texas 12 th nternational Lung Cancer Congress 2011 Carlsbad C 8/11/2011 Slide 2 Optimizing Therapy for Locally dvanced SCLC ot a surgical candidate Carefully selected stage / patients o pleural effusions Good performance status Minimal weight loss Good FV1 Slide 3 Options for Locally dvanced SCLC Chemotherapy adiation ChemoT Chemotherapy T Chemotherapy ChemoT ChemoT Chemotherapy Chemotherapy ChemoT Chemotherapy

2 Slide 4 Chemotherapy ose Chemotherapy Schedule adiation dose/type ssues Low ose (radiosensitizing) Higher ose (cytotoxic) Cyclic (full dose) Weekly or twice weekly aily (low dose) Prolonged Continuous nfusion High ose Proton Sequence with adiation: Sequential: CT T Concurrent: CT/T Combination: CT CT/T CT/T CT Slide 5 Unresectable Stage SCLC = 595 TOG 9410: Sequential vs Concurrent Chemoradiation in Stage SCLC O M Z VP x 2 63 Gy, Q VP x 2 + Concurrent 63 Gy, Q P (po) + Concurrent 69.2 Gy, B Curran et al, SCO 2003 Slide 6 TOG 9410: Sequential vs Concurrent Chemoradiotherapy in Stage SCLC Sequential Concurrent Conc B Median survival (mos) 3 yr survival 5 yr survival on-hem toxicity (Gr 3-5) Pneumonitis (Gr 3-5) x-related death Local Failure % 10% 30% 13% 5% 38% 17.1 * 25% 14.6% 48% 11% 4% 33% % 62%** 13% 5% 25%** Curran et al, SCO, 2003 *p = **p < 0.05

3 5-year OS (%) 4-year OS (%) Slide 7 St SCLC = 314 fficacy esults: Sequential vs. Concurrent Chemoradiotherapy, Two Major Trials West Japan TOG 9410 MVP x 2 T 56 Gy % Seq MVP x 2 Concurrent T 56 Gy (split course) 19% Conc St SCLC = % VP x 2 T 63 Gy VP x 2 conc T 63 Gy P (po) x 2 conc B T 21% 17% Seq Conc HyperFx Furuse et al, JCO 1999 Curran et al, PSCO 2003 Slide 8 Survival Comparison between Sequential and Concurrent Chemoradiation Therapy (n=709) WJLCG GLOT (n=716) CZCH LMP TOG 9410 BOCT Sequential Concurrent Choy et al, SCO 2003 P < 0.05 (Kruskal-Wallis Test) Slide 9 arly Toxicity Comparison between Sequential and Concurrent CT/T 30 23% WJLCG 25 GLOT CZCH LMP % TOG 9410 BOCT 0 Sequential Concurrent

4 Slide 10 CLGB 9431: andomized Phase Trial of ewer Chemoradiotherapy =181 Unresectable stage SCLC UCTO CHMO COCUT CT/T Vokes et al. JCO. 2002; (20) : Slide 11 CLGB 9431: andomized Phase Trial of ewer Chemoradiotherapy VnP GemP PacP % MST, mo yr surv, % Grades 3/4, % PLT WBC soph Vokes et al, JCO 2002 Slide 12 CLGB 39801: ole of induction chemotherapy Stage SCLC = 184 = 182 Carboplatin UC mg/m 2 Q3wk x 2 63 Gy XT Q + Carboplatin UC 2 45 mg/m 2 weekly x 7 63 Gy XT Q + Carboplatin UC 2 45 mg/m 2 weekly x 7 rm Med OS (mo) 2-yr OS (%) 3-yr OS (%) Med PFS (mo) 2-yr PFS (%) 3-yr PFS (%) CT/T CT CT/T Vokes et al, SCO 2004

5 Slide 13 Consolidation Chemotherapy SWOG Phase Trials S9019, n= 50 S9504, n=83 pstage B pstage B Cisplatin/VP-16 XT Cisplatin/VP-16 Cisplatin/VP-16 XT ocetaxel Slide 14 SWOG 9504 esign Cisplatin/VP-16 X X T ocetaxel X X X Cisplatin 50mg/m 2 d 1, 8, 29, 36 toposide 50mg/m 2 d1-5, T: 61 Gy: 45Gy(1.8Gy/fx), 16Gy boost(2gy/fx) ocetaxel: 75mg/m 2 x 3 cycles Gandara et al. JCO. 2003; 21: Gandera et al. SCO 2005 Slide 15 Survival in Sequential ChemoT SWOG Trials Stage B SCLC Study Median (months) 2 year 3 year 4 year 5 year S9504 (P/T ocetaxel) 26 (18-35)* 54% (43-65)* 37% (24-55)* 29% (19-29)* 29% (19-29)* S9019 (P/T P 15 (10-22)* 34% (21-47)* 17% (7-27)* 17% (6-28)* 15% (6-28)* P: Cisplatin/toposide; T: adiotherapy (61 Gy) *95% C

6 Slide 16 HOG LU Unresectable, Stage -B SCLC; COG PS 0-1; <5% Weight Loss in Prior 3 mo ChemoT nduction Cisplatin 50 mg/m 2 d 1,8,29,36 toposide 50 mg/m 2 V d 1-5 & Concurrent T 59.4 Gy =230;203 accrued ocetaxel 75 mg/m 2 q 3 wk 3 Hanna et al, JCO 2008; 26: C, P, or S; COG PS 0-2 andomize Primary endpoint: Overall Survival Observation Slide 17 Percent of patients surviving #7512 HOG Trial: Overall Survival (TT) andomized Patients (n=147) 100% 75% 50% 25% 0% Observation ocetaxel Consolidation Observation: Median: 24.1 ms ( ) 3 year survival rate: 27.6% ocetaxel: Median: 21.5 ms ( ) 3 year survival rate: 27.2% P-value: Hanna et al, JCO 2008; 26: Months since registration Slide 18 Some Current ew pproaches GF inhibitors ew Cytotoxics (pemetrexed) PP nhibitors ew adiation schedules Protons

7 Slide 19 Cetuximab 400 mg/m 2 day 1 TOG Treatment Schema Week 1 Weeks 2-8 Weeks 9-11 Weeks Carboplatin Cetuximab CT (45 mg/m 2 /wk) Carboplatin (UC = 2/ wk ) Cetuximab (250 mg/m 2 /wk) CT ( 63 Gy/7weeks/35 daily fx) Primary endpoint: Compliance and Safety Cetuximab 250 mg/m 2 /wk x 3 Carboplatin Cetuximab (200 mg/m 2 Q 3 wk x 2) Carboplatin (UC = 6 Q 3 wk x 2) Cetuximab (250 mg/m 2 /wk) Blumenschein et al JCO 2011 Slide 20 TOG ligibility Criteria Histologically or cytologically confirmed /B SCLC o prior therapy Uni-dimensionally measurable disease Zubrod PS 1 Wt loss 5% past 3 months o grade 1 neuropathy Pleural effusion - cytologically neg, non-bloody, transudate dequate hepatic, renal, hematologic function Patient has not had prior surgery for the present cancer Slide 21 TOG Overall Survival Median survival 22.7 months 2yr survival 49.3% Blumenschein, et al JCO 2011

8 Slide 22 Longterm Outcome in TOG Stage SCLC Trials Trial T Chemo Sequence MST 5 yr OS Gy (SFx) Pac-Carbo Con-Consol 22.7 m / LMP 63 Gy (S Fx) Pac-Carbo Con-Consol 16.3 LMP 63 Gy (S Fx) Pac-Carbo nd-con 12.7 LMP 63 Gy (S Fx) Pac-Carbo nd-t Gy (B Fx) Pac-Carbo/mif nd-con % Gy (B Fx) Pac-Carbo nd-con % Gy (SFx) VBL-P Con % Gy (SFx) VBL-P nd % Gy (B Fx) VP-16P Con % Slide 23 TOG 0617: Conventional vs High ose T (3d Conformal) O M Z T: 60 Gy Carboplatin T: 74 Gy Carboplatin Carboplatin x 2 Slide 24 TOG 0617: Conventional vs High ose T (3d Conformal) +/- C225 O M Z T: 60 Gy Carboplatin +/- Cetuximab T: 74 Gy Carboplatin +/- Cetuximab Primary endpoint: Survival Carboplatin x 2 =500

9 Slide 25 TOG 0617 Update ccrual about 17 pts/month ( approximately 450 as of 7/11) H T arms closed 2 nd futility 6/11 Continued accrual to 60 Gy arms Slide 26 CLGB 30605/TOG 0972 POO SK STG SCLC (60+/76 nrolled) -/B - PS 2 - PS Wt loss 10% G S T CLGB Ps:. Lilenbaum; P Janne; M. Samuels TOG P: Spring Kong Carboplatin UC 5 1 lbumin-bound paclitaxel 100/m 2 1 and 8 every 21 days x 2 cycles rlotinib 150 mg/day (no maintenance) concomitant with TT (66Gy) Slide 27 CLGB Treatment Schema O M Z L SCLC Primary endpoint : survival Pemetrexed: 500 mg/m 2.V. x 4 cycles Carbopltin: UC 5.V. x 4 cycles T: 70 Gy x 7 weeks Pemetrexed: 500 mg/m 2.V. x 4 cycles Carboplatin: UC 5.V. x 4 cycles Cetuximab: 400 mg/m 2 loading dose followed by 250 mg/m 2 weekly x 6 weeks T: 70 Gy x 7 weeks Pemetrexed: 500 mg/m 2.V. x 4 cycles Govindan et al, JCO 2011

10 Slide 28 CLGB ligibility: Tx-naive stage SCLC, 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 esults: 99 eligible pts (48 in arm and 51 arm B) nrolled 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 Slide 29 CLGB esponse rate Median PFS (months) Median OS (months) 18 month OS rm (CbPem /T) 77% % (44-75) rm B (CbPem + C225) 72% % (27-68) Govindan et al, JCO 2011 Slide 30 POCLM Treatment Schema O M Z L on-scc SCLC Primary endpoint : survival Pemetrexed: 500 mg/m 2 q 3 weeks. x 3 cycles Cisplatin: 75 mg/m 2 q 3 weeks x 3 cycles T: 66 Gy in 33 fractions toposide: 50 mg/m 2 d1-5 q 4 weeks x 2 cycles Cisplatin: 50 mg/m 2 d1, 8 q4 weeks x 2 cycles T: 66 Gy in 33 fractions =600 Pemetrexed: x 4 cycles toposide/cp: x 2 cycles Govindan et al, SCO 2009

11 Slide 31 POCLM Update ccrual about 15 pts/month (350 in 8/11) MC meetings q 4 months Continued crual Central XT review Slide 32 C 8811: Phase / Trial of T, carboplatin, paclitaxel, and BT-888 for Stage SCLC avid Gandara, California Phase Consortium Slide 33 PP: (poly[p-ribose] polymerase PP-1 is the founding member of a family of enzymes that catalyze the addition of Pribose units to proteins that mediate repair pathways onizing radiation induces strand breaks, suggesting that PP-1 inhibition may sensitize tumor cells to radiation. lbert et al, CC 2007

12 Slide 34 BT-888 plus chemot for stage SCLC CCCP (PH-107/C 8811); P: rgiris Stage /B SCLC Unresectable COG PS 0/1 o prior chemotherapy o prior T to chest dequate organ function Stratification: PS (0 vs 1) Weight loss (<=5% vs >5% in previous 3 months) ge (<=65 vs >65) G S T Primary endpoint : LT and MT TTMT SCHM U- PHS Chest T (63 Gy) weeks mg/m 2 Qw, weeks 1-7 Carboplatin UC2 Qw, weeks 1-7 BT-888 twice daily po, weeks 1-7 ose scalation Schedule ose Level BT-888 ose 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 UC 6 day mg/m 2 day 1 BT mg B po days 1-7 ** Q 3 weeks x 2 cycles ** Based on the results of ongoing phase study Slide 35 BT-888 plus chemot for stage SCLC CCCP (PH-107/C 8811); P: rgiris TTMT SCHM OMZ PHS PT Stage /B SCLC Unresectable COG PS 0/1 o prior chemotherapy o prior T to chest dequate organ function Stratification: PS (0 vs 1) Weight loss (<=5% vs >5% in previous 3 months) ge (<=65 vs >65) O M Z Primary endpoint : PFS Chest T (63 Gy) weeks mg/m 2 Qw, weeks 1-7 Carboplatin UC2 Qw, weeks 1-7 BT-888 twice daily po, weeks 1-7 Chest T (63 Gy) weeks mg/m 2 Qw, weeks 1-7 Carboplatin UC2 Qw, weeks 1-7 Placebo twice daily po, weeks 1-7 =104 (52 per arm) 4 6 wks 4 6 wks Carboplatin UC 6 day mg/m 2 day 1 BT-888 B po days 1-7 * Q 3 weeks x 2 cycles Carboplatin UC 6 day mg/m 2 day 1 Placebo B po days 1-7 Q 3 weeks x 2 cycles * Based on the results of ongoing phase study Slide 36 Hypofractionation: SOCC Trial esign =130 pathologically confirmed SCLC stage, PS 0-1, CT± mediastinoscopy, PT-CT unsuitable for surgery COCUT M 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 d 1, d 8 2 cycles SQUTL M cisplatinum 80mg/m 2 day 1 vinorelbine 25mg/m 2 day 1, 8 4 cycles 4 weeks 55Gy/20f/4weeks

13 Slide 37 SOCC SCLC Stage PS 0-1 CO SQ 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% Local P 10% 22% Con Seq Months Slide 38 Conclusions 55Gy/20f/26-28d with concurrent cisplatinum and vinorelbine is a feasible, safe and effective treatment for stage SCLC, 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 SCLC Slide 39 TOG 1013 andomized Phase Trial of Standard vs. Hypofractionated T PS 2 or wt loss > 5% or PS 0/1 and wt loss < 5% but medically unfit unresectable stage /B rlotinib- Standard adiation Therapy rlotinib 150mg po daily for duration of radiotherapy T 2 Gy daily, 5 days/week, total 60 Gy Stratify Histology Sq vs non-sq % weight loss performance status Comorbity scale rlotinib- HypoFractionated adiation Therapy rlotinib 150mg po daily for duration of radiotherapy T 3 Gy daily, 5 days/week, total 45 Gy LO submitted to CTP

14 Slide 40 Protons Compared To Photons Treatment for Patients with L SCLC STO nniversary 8-12 May 2011 London itsuko Komaki, M, FC, FSTO Professor of adiation Oncology GLT istinguished ndowed Prof. n Lung Cancer esearch Slide 41 Trial of daptive MT and PBT C Program grant C (P01 C ) MCC and MGH andomized phase trial: Stage / SCLC 74 Gy with concurrent Carb/Taxol in both proton and MT Grade 3 pneumonitis and local control Patients randomized:107 /168 Slide 42 Current Treatment Paradigms in Unresectable Stage SCLC ChemoT 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) mproved systemic control will need to be an essential component of more effective therapies Optimal T dose (conventional vs. H ) undefined Preliminary results from the addition of agents targeting GF to CT are promising and warrant further study.

15 Slide 43