11/21/2009. Early Stage. Stage III. From Mountain: Chest, 1997

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1 Combined odality egimens in Locally dvanced SCLC: Current Status and Future irections Primo. Lara, Jr, Professor of edicine University of California avis Cancer Center arly Stage Stage Five-Year Survival From Time of Surgery in SCLC Stage Clinical (%) Pathologic (%) (T1 0 0) B (T2 0 0) (T1 1 0) B (T2 1 0, T3 0 0) (T3 1 0, T ) B (T , T ) 3-7 From ountain: Chest, 1997 Clinically istinct Subsets Within Stage SCLC (ld Staging System) STG a T 3 1 Peripheral lesion with chest wall invasion or tumor < 2 cm distal to carina T Prognosis and therapy defined by status 2 (ipsilateral mediastinal nodes) * STG b T Prognosis and therapy largely defined by 3 disease (contralateral mediastinal, S.C. nodes) * T T Locally invasive primary tumor (T4) & no malignant pleural effusion; no contralateral or SC nodes* alignant pleural effusion (T 4 )** Clinically istinct Subsets Within Stage SCLC (ew Staging System) STG a T Peripheral lesion ( T T Peripheral lesion (<7 cm) with or without visceral pleural invasion, involvement of main bronchus >2 cm distal to carina, or obstructing pneumonitis extending to hilar region not involving entire lung Prognosis and therapy largely defined by 2 disease (ipsilateral mediastinal nodes) Tumor > 7 cm invading chest wall, phrenic nerve, mediastinal pleura, parietal pericardium, tumor < 2 cm from carina, or atelectasis or obstructing pneumonitis involving entire lung; or separate tumor nodules in the same lobe as primary. Prognosis and therapy largely defined by 2 disease (ipsilateral mediastinal nodes) Tumor of any size involving major mediastinal structures (e.g, heart, great vessels, etc) or separate tumor nodule(s) in a different lobe ipsilateral to primary STG b T Prognosis and therapy largely defined by T 4 2 Prognosis and therapy largely defined by 3 disease (contralateral mediastinal, S.C. nodes) Locally invasive primary tumor (T4);; no contralateral or SC nodes * Candidates for Combined odality Therapy **Treated as Stage V ll subsets amenable to combined modality therapy; malignant pleural effusion now 1a 1

2 Heterogeneity of Locally dvanced SCLC Locally dvanced (Unresectable) Stage SCLC: Brief History 1980s Sequential chemo-t improves survival vs T alone 1990s Concurrent chemo-t improves survival vs sequential chemo-t 2000s nvestigations begin with biologic ( targeted ) agents plus chemo-t usch et al. J Thorac ncol. 2007;2: Long-Term Survival Comparison % 5 yr S West Japan VP x 2 Cont T ay pts VP x 2/Split T ay pts 9% 19% Sequential Concurrent % 4 yr S TG 9410 Vinb/CisP x 2 Q T ay 50 Vinb/CisP x 2/Q T ay 1 CisP/to x 2/B T ay % 21% Sequential Concurrent CLGB 39801: Study esign = 366 Stage Surgically unresectable Vokes et al. Proc SC. 2004;616. bstract Concurrent (50 mg/m 2 ) + carboplatin (UC = 2) weekly XT 66 Gy nduction Concurrent 2 cycles PC (paclitaxel 200 mg/m 2 + carboplatin UC = 6) q 3 wk XT 66 Gy and weekly PC 2

3 CLGB 39801: esults Concurrent nduction Concurrent P Value, % edian S, mo y S, % y S, % edian FFS, mo G 3/4 neutropenia, % pts <.0001 G 3/4 esophagitis, % pts SWG 9504: ChemoT in Stage B SCLC Concurrent Chemoradiation P: Cisplatin 50 mg/m 2 V d 1, 8, 29, 36 toposide 50 mg/m 2 V d 1-5, T: 45 Gy (1.8 Gy/fraction) 16 Gy boost (2 Gy/fraction) Consolidation ocetaxel X 3 cycles edian Survival Time = 26 months Vokes et al. Proc SC. 2004;616. bstract Gandara et al JC 2003;21: HG LU HG LU 01-24: esults Unresectable, Stage -B SCLC; CG 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 (1.8 Gy/fr) C, P, or S; CG PS 0-2 andomize ocetaxel 75 mg/m 2 q 3 wk 3 bservation Hanna, JC 2008 ote: nly 147 patients were randomized Hanna, JC

4 Comparison of Patient and isease Characteristics Study Variable SWG 9504 HG o. Pts edian ge Female Pts. 27% 34% PS 0/1 94% 100% Stage B 100% 61% FV-1 > 2 *100% 47% *or FV-1 > 800 cc in contralateral lung ntegration of biologic agents with chemot in SCLC: Selected approaches aintenance only (eg: SWG gefitinib) Chemotherapy T aintenance X X Concurrent + aintenance (eg: CG thalidomide) Chemotherapy X X T Consolidation chemo +biologic X+B X+B aintenance biologic Concurrent Chemo + Biologic + T Systemic Therapy (eg: CLGB cetuximab) Concurrent Chemotherapy X+B X+B T Consolidation Chemotherapy B X X X Concurrent Chemo + Biologic + T Chemo+ Biologic (eg: SWG bevacizumab) Concurrent Chemotherapy X+B X+B T Consolidation Chemotherapy X +B X +B X +B B X = chemotherapy B = biologic agent T = radiation therapy Bevacizumab in Stage : S : Chemo/T +/- Thalidomide mended Schema Low isk disease defined by: 1. on squamous histology/cytology 2. primary tumor with no cavitation and not within 1 cm of a major vessel 3. o history of hemoptysis (bright red blood of > ½ teaspoon) within 28 days prior to registration. Patients who do not fulfill LL 3 are classified as High isk. T: The high-risk stratum permanently closed to accrual effective February 20, Stage, B SCLC 2 cycles Thalidomide 2 cycles Wkly carbo/paclitaxel T (60 Gy/6 weeks) Wkly carbo/paclitaxel T (60 Gy/6 weeks) + Thalidomide P, C, Stable mended 6/04/2003 after 288 patients had been registered Weekly concurrent carboplatin/paclitaxel added Thalidomide: total of 2 years Schiller, SC

5 Carbo/paclitaxel 3598: utcomes Carbo/paclitaxel + thalidomide P (H) PFS ntergroup Trial (S0023): Study esign esponse rate Survival edian (mo) 1 year 2 year TTP median (mo) 35% 39% mo ( ) 20.2) 57% (51-63%) 34% (29-41%) 7.4 mo ( ) 16.1 mo ( ) 18.5) 67% (62-73%) 33% (28-40%) 7.8 mo ( ) 0.84 (H= 0.98; ) 0.99 (H = 1.00; ) Higher rate of grade 3 + toxicities seen in thalidomide arm S Schiller, SC 2009 efinitive Treatment ( = 620) Cisplatin 50 mg/m 2 d 1, 8, 29, 36 + toposide 50 mg/m 2 d 1 5, T Kelly et al. JC 2008 Consolidation ( = 574) ocetaxel 75 mg/m 2 x 3 cycles aintenance ( = 263) Placebo Gefitinib 500 mg/d (then 250 mg/d*) * Patients were switched to lower dose due to lack of efficacy at higher dose esults of SWG 0023 verall Survival From andomization CLGB 30407: Stage SCLC Trial Kelly et al, JC 2008 rm rm B andomized Phase Trial UC 5 q3week x 4 cycles Pemetrexed 500/mg² q3week x 4 cycles XT 70 Gy over 7 weeks UC 5 q3week x 4 cycles Pemetrexed 500/mg² q3week x 4 cycles XT - 70 Gy over 7 weeks + 400mg/m² loading and 250mg/m² weekly o comparison between arm and arm B Primary endpoint: verall survival Further study if ST > 20.9 months Pemetrexed 500 mg/m 2 q 3 weekly x 4 Govindan, SC

6 Characteristic CLGB emographics Pemetrexed and n= 48 Pemetrexed, and = 51 ale 58% 65% edian ge in Years (ange) 62 (41-79) 65 (32-81) Proportion over 70 years 25% 20% Caucasians 77% 94% Histology denocarcinoma 46% 41% Squamous 33% 35% Poorly differentiated 19% 18% Stage Stage B 58% 40% 55% 45% Characteristic CLGB Treatment elivery (ll Planned Treatment) Percentage failed to complete LL planned systemic therapy Pemetrexed and (n- 48) Pemetrexed, and (n-51) 46% 51% dverse vents 19% 18% Patient efusal 13% 10% Progressive isease 8% 10% eath 2% 6% issing 4% 7% Characteristic CLGB on-hematological Toxicities (Grade and V) Pemetrexed and n- 48 (%) Pemetrexed, and n-51 (%) ysphagia Fatigue Pneumonitis 12 8 ash 2 21 ausea/vomiting 8 10 Probability CLGB 30407: verall Survival Survival Time (onths) CLGB verall Survival rm (=48) rm B (=51) p-value=0.779 edian verall Survival rm 21.2 months (95% C: 7.4-) rm B 22.4 months (95% C: 13-) 18 onth verall Survival rm 56% (95% C 43-74) rm B 51% (95% C 38-68) Hypersensitivity 2 8 eaths 4% 4% edian follow up: 23 months (as of ) H0: p 0.35 versus H1: p 0.55 p = survival probability at 18 months registration Govindan, SC

7 CLGB verall Survival by Histology CLGB Summary Probability CLGB 30407: verall Survival on-squamous (=65) Squamous (=34) p-value= Survival Time (onths) edian verall Survival SCC 18 months (95% C: ) on SCC 22 months (95% C: 17-) 18 onth verall Survival SCC 50% (95% C: 34-73) on SCC 56% (95% C: 44-69) dministration of pemetrexed, carboplatin and thoracic radiation with or without cetuximab produced a median survival of 22 months. Both regimens met the pre-defined threshold (median survival of 20.9 months) to be considered worthy for further development. Trends toward better outcomes observed with non- squamous SCLC in this study Toxicities related to concurrent chemoradiation are similar to previous studies Govindan, SC 2009 Govindan, SC 2009 on-squamous SCLC: PCL Trial - Schema TG Schema andomized Phase Trial andomized Phase Trial Cisplatin 75 mg/m² q3 week x 3 Pemetrexed 500 mg/m² q 3 week x 3 XT 66 Gy in 33 fractions rm rm B Cisplatin 50 mg/m² d1, 8 q4 week x 2 cycles toposide 50 mg/m² d1-5 q4week x 2 cycles XT 66 Gy in 33 fractions Primary objective : survival Superiority design Pemetrexed X 4 cycles Platinum based doublets x 2 cycles 80% Powered to detect Hazard atio=0.74- Sample Size 600 XT 60 Gy in 6 weeks XT 74 Gy in 7.5 weeks XT 60 Gy in 6 weeks XT 74 Gy in 7.5 7

8 G-3 as Phase study GT 3 as djuvant on-small Cell LunG Cance mmunotherapy Stage Trials 2009: Caveats G-3 SC o chemo andomization Powered for efficacy esected G-3 (+) SCLC Pathological stage B,, Placebo Powered for efficacy G-3 SC Chemo Up to 4 cycles of platinum-based chemo andomization Placebo o molecular profiling strategies o risk stratification based on tumor biology to aid in therapy selection Persistent use of targeted agents in an untargeted manner Conclusions: Unresectable Stage SCLC Stage SCLC is a heterogeneous disease Prognosis varies considerably as do treatment options Goals are local control (T ± chemo) and eradication of distant micrometastases (chemotherapy) Concurrent chemo-t is standard for good performance status patients Phase trials of full dose chemotherapy either as induction or consolidation have not yielded clear survival benefits ntegration of targeted agents now under investigation ny future progress will likely rely on molecular selection, similar to stage V disease 8