Disclosures None 1 Objectives Identify options after 1 st line - PDF document

Winship Cancer Institute of Emory University Standard Dose Chemotherapy for Patients Failing First ‐ Line Chemotherapy in Metastatic Germ Cell Tumors Bradley Carthon, MD, PhD Assistant Professor, Genitourinary Medical Oncology Winship Cancer Institute, Emory University Atlanta, GA 30322 Disclosures • None 1

Objectives • Identify options after 1 st line chemotherapy in advanced germ cell cancer • Review data regarding high dose chemotherapy and conventional dosed chemotherapy as salvage therapy in advanced germ cell tumors Germ Cell Tumors (GCT) Epidemiology  8820 new cases/year (US, 2014)  380 deaths/year (US)  15 ‐ 34 year age group  Most common tumor  10% of all cancer deaths  Caucasians 5 : 1 African American  Rising incidence over past 4 decades  Cure rates are increasing over last 2 decades 2

Management of Advanced NSGCT  Includes patients requiring full doses of systemic chemotherapy: >Stage II or S1 Stratified by IGCCCG risk categories at presentation   Good Risk: EP x 4 or BEP x 3 Intermediate Poor Risk: BEP x 4 (VIP)   Strong role for surgical resection of any residual mass after chemotherapy Half Lives HCG = 1-3 days AFP = 5-7 days LDH = 1 day NSGCT International Germ Cell Consensus Classification 16 Curr Oncol Rep (2013) 15:232 ‐ 238; IGCCC 1997, JCO 3

Salvage Options for Relapsed Testicular Cell Carcinoma • 20 to 30% of advanced GCT patients require salvage therapy • 40 to 50% of poor risk IGCCCG patients • Potential Cure Exists • Options, per NCCN Guidelines Include: 1. Conventional Dose Chemotherapy +/ ‐ Surgery: Testicular primary, Prior Complete Response, Low tumor markers, Low Disease burden 2. High Dose Chemotherapy + Autologous Stem Cell Transplant +/ ‐ Surgery: Incomplete response, High Tumor Markers, Extratesticular Primary 3. Clinical Trials Should ALL patients receive HDCT and ASCT? Variance in Practices Around the World Presented By Darren Feldman at 2014 ASCO Annual Meeting CDCT = conventional dose chemotherapy 4

Prognostic Models for High Dose Chemotherapy in NSGCT Beyer, J. et al. J Clin Oncol. 1996; 14:2638 ‐ 45. Vaena et al. J Clin Oncol. 2004;21:4100 ‐ 4. Nieto, Y. Curr Oncol Rep (2013) 15:232 ‐ 238. Slide 22 Presented By Darren Feldman at 2014 ASCO Annual Meeting 5

Slide 23 Presented By Darren Feldman at 2014 ASCO Annual Meeting Prognostic Factors From High Dose Chemotherapy Regimen Trials TI ‐ CE Regimen Indiana University Regimen • 107 patients that had progressed on 1st line • 184 patents that progressed on cisplatin therapy. • Carboplatin 700mg/m2 + 750mg/m2 Etoposide • Extragonadal, incomplete response or relapse x 3 days + ASCT on ifosfamide based salvage. Paclitaxel • 38.6% pts were initial Low risk, 21% 200mg/m2 + Ifosfamide 2000mg/m2 for intermediate, 41% high risk mobilization + Carboplatin AUC 8 + 400mg/m2 • 8.2% of patients had Beyer Score 3 ‐ 4 Etoposide x 3 days + ASCT x 3 • No Mediastinal primaries in this study • 33% were extragonadal and 25% were on 3 rd line of therapy or higher • 2 or more prior lines of therapy, site of primary, Tumor burden, ICCCCG high risk, Platinum refractory Feldman D R et al. JCO 2010;28:1706-1713. Einhorn LH et al. N Engl J Med 2007;357:340-348. 6

Standard Dose Chemotherapy for Initial Salvage: VIP or VeIP Pizarro ‐ Poor /Int Risk Included 28/36. VIP not effective in those with primary refractory, progressors or mediastinal primary. Farhat – Poor risk included. 17% non ‐ testicular primary. 39% of CDCT for Initial Salvage: VIP/VeIP patients with advanced dx. McCaffrey –Poor risk included, extragonadal primaries. Loehrer ‐ Poor risk included. 32/135 extragonadal NSGCT. Excluded primary progressors. Adapted from: Feldman, D., 2014 ASCO Annual Meeting TIP Chemotherapy Salvage at MSKCC Patients: Gonadal Primary AND achieved a CR or PR lasting > 6 months with 1 st line therapy N = 46. Median F/U = 69 Months Outcomes Overall Survival Outcome N % CR 32 70 Chemotherapy 29 63 Chemo + Surgery 3 7 IR (PR ‐ marker neg) 14(2) 30(4) Relapsed 3 7 Sustained NED 29 63 2 yr OS 36 78 Kondagunta G V et al. JCO 2005; 23: 6549-6555 7

CDCT vs. HDCT Overall Survival Rates In IPFSG Database Retrospective Review Very Low Low ntermediate High All Pts N 5 YR (N=1594) OS CDCT 773 41% HR = 0.65 Very HDCT 821 53% p< High 0.001 Lorch A et al. JCO 2011;29:2178-2184 CDCT vs. HDCT Overall Survival Rates by Retrospective Review of UK and German Databases • Pts between 1981 and 95. 4 or 5 factor • N =193. matched pairs • UK MRC and German Center patients • Matched base on: primary tumor location, response, duration, and tumor markers. Multivariate analysis. • 5/5 matches for 38 pairs. 4/5 matches for 17 pairs. 4 factor matched • Suggest OS improvement of 9 ‐ pairs 11% with HDCT Beyer et. Al. Ann Oncol (2002) 13 (4): 599 ‐ 605. 8

CDCT vs. HDCT OS Retrospective Review of German GTCSCG Database N= 143 Patients • • 73% Gonadal Primary • 31% with LBB mets • 59% had CR response to initial therapy 34% 48/143 had CDCT • Salvage (>3) • 66% 95/143 had HDCX Salvage (3) Berger et al. J Cancer Res Clin Oncol (2014) 140: 1211 ‐ 1220 No OS Benefit: IT ‐ 94 Randomized Control Trial of CDCT vs. HDCT for Salvage Treament in Advanced GCT No Difference in OS • The sole RCT completed • No Difference in OS • Between 2/94 and 09/01 • 280 patients from 43 institutions and 11 countries • Randomized to VeIP x 4 or VeIP x 3 + High Dose P=0.16 Chemo • Median F/U 45 Months • 7% treatment related mortality in HDCX arm • Only includes 1 dose HDCX Pico J et al. Ann Oncol 2005;16:1152-1159 9

Points to Consider from These HDCT Trials in 1 st Line Setting • Only retrospective reviews and case matches with OS benefit due to HDCT + ASCT • Subject to bias, small numbers, and patient heterogeneity • Newer retrospective analysis shows no OS benefit with high dose chemotherapy. Improved care? • Newer studies with TIP conventionally dosed chemotherapy show 2 year OS up to 78% • Randomized Controlled trial on of CDCT vs. HDCT and Transplant showed no overall survival benefit • NO RANDOMIZED CONTROLLED DATA to suggest benefits for all patients across the board. • Heterogeneity exists & randomized controlled trial Needed Considerations with High Dose Chemotherapy with ASCT for Advanced Germ Cell Tumors • Potential for Cure, especially in poor risk patients • Notable Toxicities and Adverse Events • Highly Specialized and expensive • 1 ‐ 7% Mortality in Past Studies • Not Universally Available to All Patients • Notable retrospective data, but limited prospective data 10

Alliance 031102 / EORTC 1407 (TIGER) Presented By Darren Feldman at 2014 ASCO Annual Meeting Conclusions • Various patterns of practice exist for patients failing 1 st line chemotherapy in advanced germ cell • Options include conventional dose chemotherapy and high dose chemotherapy with ASCT with varying practice patterns • Prognostic models have been validated and help risk stratify • Data in small heterogenous populations, vary, but does suggest benefit, particularly in some POOR risk patients • Increased effectiveness with conventional dosed chemotherapy • Randomized Clinical trial of HDCT + ASCT vs. CDCT planned • Currently, high dose chemotherapy for ALL patients remains controversial and may be an overtreatment for some 11