Slide 1 ___________________________________ Systemic Therapy for - PDF document

Slide 1 ___________________________________ Systemic Therapy for Small Cell Lung Cancer Paul A. Bunn, Jr, MD, Dudley Professor, Univ. of Colorado Cancer Center, ___________________________________ Aurora, CO, USA ___________________________________ ___________________________________ Consultant: Amgen, Allos, AstraZeneca, Abraxis, Bayer, Biodesix, Boehringer- Ingelheim, Bristol-Myers Squibb, Daiichi- Sankyo, Eli Lilly, GlaxoSmithKline, Merck, Novartis, OSI/Genentech/Roche, Poniard, Sanofi Aventis ___________________________________ ___________________________________ ___________________________________ Slide 2 ___________________________________ SCLC Epidemiology and Etiology ___________________________________ Epidemiology – ~26,000 cases in US annually – Worldwide • 10-20% of lung ca in males • 10-30% in women ___________________________________ – Causes 35,000-40,000 of 160,000 lung cancer deaths annually Etiology ___________________________________ – TOBACCO 90% – Other respiratory carcinogens, underlying lung disease, familial clusters ___________________________________ ___________________________________ ___________________________________ Slide 3 ___________________________________ US SCLC Age-Adjusted Incidence Rates: 1973 – 1997 ___________________________________ ___________________________________ ___________________________________ SEER = Surveillance, Epidemiology, and End Results. Data from Ries et al, eds. SEER Cancer Statistics Review, 1973-1997. National Cancer Institute; 2000. ___________________________________ ___________________________________ ___________________________________

Slide 4 ___________________________________ SCLC Biology • Tumor suppressor loss/silencing ___________________________________ – 3p loss in 90% of tumors • FHIT, VHL, RAR,RassF1 – Other genes: p53, RB in 80-90% ___________________________________ – Aberrant methylation: RASSF1 • Expression of activating genes – MYC, BCL-2 ___________________________________ • Cellular pathways – GRP,IGF, c-KIT,TGF-b, PKC, PI3K ___________________________________ ___________________________________ ___________________________________ Slide 5 ___________________________________ Survival by IASLC proposed TNM stage 100% Median Deaths / N in Months ___________________________________ IA 17 / 25 31 IB 14 / 19 35 80% IIA 8 / 15 68 IIB 84 / 101 17 IIIA 332 / 384 13 60% IIIB 424 / 481 12 IV 1400 / 1439 8 ___________________________________ 40% 20% ___________________________________ 0% 0 5 10 15 Years After Enrollm ent ___________________________________ ___________________________________ ___________________________________ Slide 6 ___________________________________ Phase III Trials in Extensive SCLC: Prior to 2000 ___________________________________ Regimen Ref MST (mo) CAV vs CAV/PE Evans *8.0 vs 9.6 CAV vs PE vs CAV/PE Fukuoka 9.9vs9.9v11.8 ___________________________________ CAV vs PE vs CAV/PE Roth 8.3vs8.6vs8.1 VIP vs VP Loehrer *9.1 vs 7.3 ___________________________________ *p<0.05 ___________________________________ ___________________________________ ___________________________________

Slide 7 ___________________________________ Any New Treatment Options? Chemotherapy • Picoplatin • Topo I Inhibitors • Amrubicin ___________________________________ – Irinotecan Targeted Agents – Topotecan • Antiangiogenics • Dose intensification ___________________________________ • HDAC inhibitors • Pemetrexed • BCL2 inhibitors • Radiation • Maintenance ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 8 ___________________________________ Irinotecan vs Etoposide & Cisplatin:ED SCLC Noda et al 2002 Lara et al. 2009 ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 9 Meta analysis EP vs IP ___________________________________ Jiang et al. J. Thor. Oncol. 5,867,2010 ___________________________________ ___________________________________ ___________________________________ Journal of Thoracic Oncology. 5(12):1986-1993,2010. ___________________________________ ___________________________________ ___________________________________

Slide 10 ___________________________________ Topotecan PO vs. BSC for Relapsed SCLC • RR 7%, SD 44% Overall Survival ___________________________________ Arm Med 6-mo Surv. Surv ___________________________________ BSC 13.9 26% wk Topo 25.9 49% wk ___________________________________ O’ Brien et al, JCO 2006 ___________________________________ ___________________________________ ___________________________________ Slide 11 ___________________________________ Any New Treatment Options? Chemotherapy • Picoplatin • Topo I Inhibitors • Amrubicin ___________________________________ – Irinotecan Targeted Agents – Topotecan • Antiangiogenics • Dose intensification ___________________________________ • HDAC inhibitors • Pemetrexed • BCL2 inhibitors • Radiation • Maintenance ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 12 ___________________________________ Intensified Chemotherapy ___________________________________ ___________________________________ ___________________________________ Jiang et al. Lung Cancer 65,214,2009 ___________________________________ ___________________________________ ___________________________________

Slide 13 ___________________________________ Randomized Trial of TEP vs EP in Extensive SCLC ___________________________________ No. %GR Febrile Rx Pts. OR CR MS 1YS ¾ PMN PMN EP 74 48% 4% 11.5 46% 39% 13% ___________________________________ TEP+G 62 50% 3% 10.5 46% 44% 24% ___________________________________ Proc. ASCO. 2000;19:484a. ___________________________________ ___________________________________ ___________________________________ Slide 14 ___________________________________ Phase III Pemetrexed/CB vs Etop/CB Eligibility Pem 500 mg/m 2 , d 1 R  ES-SCLC Cb AUC 5, d 1  A every 21 days x 6 cycles PS 0-2  No prior chemo N Prophylactic folic acid, B 12 , dexamethasone Stratification factors D ___________________________________  Center O  PS M  LDH  Gender I  Age Z E 100 mg/m 2 , d 1, 2, 3  No. metastatic sites Cb AUC 5, d 1 every 21 days E  History of brain metastases x 6 cycles ___________________________________ Median (95% CI) Probability Without Pem-Cb: 3.68 (3.38, 4.2) E-Cb: 5.32 (5.03, 5.85) Socinski, ASCO 2008 Log rank p<.0001 Event PFS HR = 1.79 (90% CI: 1.49, 2.15) ___________________________________ Socinski, ASCO 2008 ___________________________________ ___________________________________ ___________________________________ Slide 15 ___________________________________ PCI in ED SCLC: Time to Symptomatic brain mets & Survival ___________________________________ Time to Sx. Br. Mets Overall Survival 100 100 90 90 80 1 year: 14.6% vs. 40.4% 80 1 year: 27.1% vs. 13.3% 70 HR: 0.27 (0.16-0.44) 70 HR: 0.68 (0.52-0.88) p=0.003 ___________________________________ 60 p<0.001 60 50 50 40 Control 40 30 30 PCI 20 20 PCI Control 10 10 ___________________________________ 0 (mo) 0 0 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36 Months from moment of randomization Months from moment of randomization ___________________________________ ___________________________________ ___________________________________

Slide 16 ___________________________________ More extensive RT for ED SCLC? Ongoing trials ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 17 ___________________________________ Maintenance Therapy for SCLC:Hanna Trial Hanna, Ann Oncol 13: 95, 2002 Etoposide 50 mg PO CR/PR/SD ___________________________________ 21 of 28 days x 3 R SCLC-ED Cis/Etop/Ifos A N = 233 x4 cycles N D Observation N = 144 ___________________________________ Endpoint Maintenance Observation Progression-Free Surv (mo) 8.2 6.5 Median Survival (mo) 12.2 11.2 1-year Survival (%) 51.4 40.3 ___________________________________ 3-year Survival (%) 8.8 1.8 • An appropriate place for minimally toxic targeted therapies? ___________________________________ ___________________________________ ___________________________________ Slide 18 ___________________________________ Results of Maintenance Chemo in SCLC Topotecan vs Placebo: ECOG • Progression-free survival ___________________________________ significantly better with maintenance topotecan (3.7 vs. 2.3 mo) • Overall survival was no ___________________________________ different (9.3 vs. 8.9 mo) • Grade 4 neutropenia 60%, thrombocytopenia 13% ___________________________________ • Grade 4/5 infection 1.8% ___________________________________ ___________________________________ ___________________________________