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Corey J. Langer, MD, FACP Medical Director, Thoracic Oncology Fox Chase Cancer Center

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  1. Challenging Cases in Cancer:Integration of Findings from ASCO 2007 into Clinical Practice Lung Cancer Corey J. Langer, MD, FACP Medical Director, Thoracic Oncology Fox Chase Cancer Center Philadelphia, PA

  2. Extensive Stage Small Cell Lung Cancer

  3. Case 1Extensive Stage SCLC • 72-year-old WM former smoker (50 pack-years) presents with cough, DOE and hoarseness over a 6-week course • CXR suggests a (L) para-hilar infiltrate • He initially receives antibiotics, but symptoms worsen • PE is notable for a (L) SCN measuring 2 cm, with focal wheezing in the (L) mid-lung field • Liver edge extends 3 cm below the RCM with focal tenderness

  4. Case 1Extensive Stage SCLC • Follow-up CXR demonstrates worsening infiltrate • CT shows a dense, coalescent mass in the (L) hilar area measuring 9 x 8 cm with prominent hilar and mediastinal adenopathy; multiple, bilateral pulmonary nodules; and hepatic masses ranging between 2-3 cm in size and occupying 15% of the hepatic volume • FNA of an anterior hepatic mass demonstrates classical SCLC • PS is 1 • CBC and chemistries are WNL

  5. Case 1Extensive Stage SCLC Which of the following is appropriate therapy for this patient? • Irinotecan + cisplatin • Etoposide + cisplatin • Irinotecan + carboplatin • Etoposide + carboplatin • All of the above

  6. Case 1Extensive Stage SCLC Which of the following is appropriate therapy for this patient? • Irinotecan + cisplatin • Etoposide + cisplatin • Irinotecan + carboplatin • Etoposide + carboplatin • All of the above Recommended Approach: • All of the options above are appropriate for this patient.

  7. Case 1Extensive Stage SCLC Bevacizumab has been proven in phase III trials to enhance therapeutic outcome in patients receiving cisplatin in combination with either irinotecan or etoposide • True • False

  8. Case 1Extensive Stage SCLC Bevacizumab has been proven in phase III trials to enhance therapeutic outcome in patients receiving cisplatin in combination with either irinotecan or etoposide • True • False Answer: • False, bevacizumab has not been proven in phase III trials to enhance outcomes.

  9. 5-Year Survival (%) • LTD SCLC 15-25 • EXT SCLC < 1 • ST IA 70-85 • ST IB 60-70 • ST IIA 35-45 • ST IIB 25-35 • ST IIIA 5-20 • ST IIIB 3-7 • ST IV NSCLC < 1 Goal 25-30 2-5 85-95 70-85 45-60 35-45 20-30 10-20 2-5 2006-2007 > 175,000 NSCLC 139,000 SCLC 36,000 STAGE I-III 78,500 STAGE IV 60,500 EXT 24,000 LTD 12,000 STAGE I/II 39,250 STAGE III 39,250 Lung Cancer Incidence and 5-Year Survival in the U.S.

  10. Biologic Behavior High cellular proliferation Short cell cycle time Rapid doubling time Central presentation Early metastases Chemo-Radiation Sensitivity Molecular Profile 3p (del) p53 mutations: 80% Rb abnormalities: 100% High Expression of myc High Expression of c-Kit Small Cell Lung Cancer Epidemiology & Biology • 170,000 new cases of lung cancer/year in USA • Decreasing proportion of SCLC: 30%  15% • Nearly all cases of SCLC associated with smoking • Distinct molecular profile & biologic behavior

  11. Limited Stage EP – 4-cycles Concurrent chest XRT PCI for CR Clinical trials: consolidation or maintenance for CR Extensive Stage EP (IP) or EP/CAV x 4-6 cycles CNS mets: chemo or XRT XRT: bone metastasis or obstructive lesions Window of opportunity for clinical trials Small Cell Lung CancerStandard Therapy

  12. E: 300 mg/m2 days 1 to 3 P: 50 mg/m2 days 1 and 2 q3 weeks x 6 E: 300 mg/m2 days 1 to 3 Carb: 300 mg/m2 day 1 q3 weeks x 6 PCI and TRT in third cycle RANDOMIZATION N = 143 Responding patients EP vs. ECarb in Extensive Disease SCLCHellenic Co-operative Oncology Group • Treatment was with EP or ECarb in ED or LD SCLC • No difference in response or survival was seen between treatments • EP was more toxic, with a higher incidence of leukopenia (P = 0.09), infection (P = 0.05), nausea and vomiting (P = 0.0001), neurotoxicity (P = 0.0002), and hyperergic reactions (P = 0.001) in this treatment arm EP = etoposide, cisplatin; ED = extensive-disease; LD = limited-disease; PCI = prophylactic cranial irradiation; TRT = thoracic radiotherapy. Skarlos DV et al. Ann Oncol. 1994;5:601-607.

  13. R A N D O M I Z E CPT-11 60 mg/m2 d1,8,15 Cisplatin 60 mg/m2 d1 Q4wk x 4 Stratify PS (0, 1, 2) Etoposide 100 mg/m2 d1-3 Cisplatin 80 mg/m2 d1 Q3wk x 4 Phase III Extensive Disease SCLC TrialDesign • First-line extensive disease SCLC • Primary endpoint: survival • Secondary endpoints: response, response duration, mode of recurrence, TTP, toxicity, QOL Noda et al. Proc Am Soc Clin Oncol. 2000;19. Abstract 1887; NEJM 1/2002; 346: 85-91.

  14. Irinotecan/Cisplatin (PI) vs. Etoposide/Cisplatin (PE) in Extensive SCLC (JCOG 9511) Noda et al., NEJM 1/2002; 346: 85-91.

  15. SWOG Arm 1 q 4w Arm 2 q 3w CPT-11 Cisplatin 65 mg/m2 60 mg/m2 d 1, 8, 15 d 1 + + Cisplatin VP-16 60 mg/m2 100 mg/m2 d1 d 1-3 Irinotecan/Cisplatin vs. Etoposide/CisplatinU.S. Randomized Trials PFIZER Arm 1 q 3w Arm 2 q 3w CPT-11 Cisplatin 65 mg/m2 60 mg/m2 d 1, 8 d 1 + + Cisplatin VP-16 30 mg/m2 120 mg/m2 d1, 8 d 1-3 N = 331 N = 670 (03/07)

  16. IP EP Intent-to-Treat Population (N = 221) (N = 110) (ITT) % % Complete response 3.6 2.7 Partial response 44.3 40.9 Overall response 48.0 43.6 Stable disease 4.1 7.3 Progressive disease 20.0 20.0 Not evaluable 28.1 29.1 Irinotecan/Cisplatin vs. Etoposide/Cisplatin Tumor Response Rate Hermes et al., ASCO 2005, Abstract 7004.

  17. IP (N = 219) EP (N = 109) IP: median 4.1 mo (0.1-31.1) P = 0.2522 EP: median 4.6 mo (0.3-18.4) Irinotecan/Cisplatin vs. Etoposide/Cisplatin Time to Disease Progression (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 0 27 30 24 0 12 15 18 21 3 6 9 Months Hermes et al., ASCO 2005, Abstract 7004.

  18. IP (N = 221) 1.0 EP (N = 110) 0.9 IP: median 9.3 mos. (0.1-32.6) 1-yr 35.4%, 2-yr 8.0% 0.8 EP: median 10.2 mos. (0.3-44.6) 1-yr 36.7%, 2-yr 7.9% 0.7 0.6 P = 0.6226 0.5 Probability 0.4 0.3 0.2 0.1 0 0 10 20 30 40 Months Irinotecan/Cisplatin vs. Etoposide/Cisplatin Overall Survival (ITT) Hermes et al., ASCO 2005, Abstract 7004.

  19. IP EP Grade 3 or 4 Toxicity (N = 210) (N = 104)P-value % % Neutropenia 36.2 86.5 < 0.0001 Anemia 4.8 11.5 < 0.0268 Thrombocytopenia 4.3 19.2 < 0.0001 Irinotecan/Cisplatin vs. Etoposide/Cisplatin Hematological Toxicities Hermes et al., ASCO 2005, Abstract 7004.

  20. Irinotecan/Cisplatin vs. Etoposide/Cisplatin Non-Hematological Toxicities IP EP Grade 3 or 4 Toxicity (N = 216) (N = 106) P-value % % Febrile Neutropenia 3.7 10.4 0.0577 Dehydration 13.0 2.8 0.015 Vomiting 12.5 3.8 0.0445 Diarrhea 21.3 0 0.0001 Alopecia* 6.9 32.1 0.0001 Infection 7.4 11.3 0.5027 Nausea 13.0 5.7 0.1343 Fatigue 11.6 6.6 0.3748 Asthenia 6.0 5.7 0.9918 Dyspnea 5.1 5.7 0.9773 Anorexia 5.6 1.9 0.3164 *Grade 2 Hermes et al., ASCO 2005, Abstract 7004.

  21. Irinotecan/Cisplatin vs. Etoposide/Cisplatin Conclusions • Treatment with this regimen of IP results in similar efficacy outcomes when compared with EP • Response Rates • Time to Progression • Overall Survival • IP results in statistically significant lower rates of • Neutropenia and neutropenic fever • Anemia and thrombocytopenia • IP results in statistically significant higher rates of • Diarrhea, vomiting and dehydration Hermes et al., ASCO 2005, Abstract 7004.

  22. Irinotecan/Cisplatin vs. Etoposide/Cisplatin Conclusions (cont.) • The dose intensity of Irinotecan delivered on this trial was higher compared to the JCOG trial • The explanation(s) for the differences in outcomes between this effort and the JCOG trial remain speculative; they may be accounted for by: • Pharmacogenomic disparities • Platinum dose and schedule changes • Patient characteristic differences in the study populations Hermes et al., ASCO 2005, Abstract 7004.

  23. SWOG Arm 1 q 4w Arm 2 q 3w CPT-11 Cisplatin 65 mg/m2 60 mg/m2 d 1, 8, 15 d 1 + + Cisplatin VP-16 60 mg/m2 100 mg/m2 d1 d 1-3 Irinotecan/Cisplatin vs. Etoposide/CisplatinU.S. Randomized Trials PFIZER Arm 1 q 3w Arm 2 q 3w CPT-11 Cisplatin 65 mg/m2 60 mg/m2 d 1, 8 d 1 + + Cisplatin VP-16 30 mg/m2 120 mg/m2 d1, 8 d 1-3 Negative N = 331 N = 670 (07/06)

  24. R A N D O M I Z E • Eligibility: • Ext SCLC • PS 0-4 • No upper age limit • Stratifications: • PS: 0-1, 2, 3-4 • Age: < 70 vs. ≥ 70 • Center Irinotecan 175 mg/m2 q 3 wk Carboplatin AUC 4 (Chatelut) Etoposide 120 mg/m2 po q d X 5 Carboplatin AUC 4 (Chatelut) Resuscitating Irinotecan? Hermes et al., ASCO 2007, Abstract 7523.

  25. 220 patients randomized, 210 eligible PS 0: 20; PS 1: 91; PS 2: 61; PS 3: 29, PS 4: 8 Significant benefit for IC No significant difference with respect to QoL, grade 3 and 4 toxicities Resuscitating Irinotecan? Hermes et al., ASCO 2007, Abstract 7523.

  26. Irinotecan 65 mg/m2 d 1, 8 q 3wk Cisplatin 30 mg/m2 d 1, 8 q 3wk Bevacizumab 15 mg/kg q 3wk Continues for 1-yr or PD • Extensive Stage SCLC • Treatment-naïve • PS 0-2 CALGB 30306: Phase II Trial of Cisplatin/Irinotecan and Bevacizumab in Extensive Stage SCLC • Targeted 72 patients for enrollment • Activated 12/04; Completed accrual 4/16/06 • Data presented at ASCO 2007 Ready et al., ASCO 2007, Abstract 7563.

  27. Rationale: SCLC is a highly vascularized tumor which metastasizes quickly Objectives: Improvement in PFS from 16% to 33% at 6 months Number of patients: 66 Laboratory Endpoints: VEGF levels Passed interim analysis; re-opened 12/05 66 patients entered through summer ‘06 No bleeding thus far Cis/etoposide x 4 + Bev 15 mg/kg q 3 wk Bevacizumab q 3 wks Continues for 1-yr or PD E3501: Phase II Trial in Extensive SCLC Cisplatin/Etoposide and Bevacizumab Sandler et al., ASCO 2007, Abstract 7564.

  28. Ready, CALGB 30306, Abs#7563 Integrating Bevacizumab into First-Line ED-SCLC: Phase II Trials Sandler, ECOG 3501, Abs#7564 Cisplatin 30 mg/m2 IV d1,8 Irinotecan 65 mg/m2 IV d1,8 Bevacizumab 15 mg/kg d1 q 21 days x 6 cycles No Maintenance Bev Cisplatin 60 mg/m2 IV d1 Etoposide 120 mg/m2 IV d1-3 Bevacizumab 15 mg/kg d1 q 21 days x 4 cycles then Bevacizumab until PD • No brain metastases; no recent hemoptysis Ready et al., ASCO 2007, Abstract 7563. Sandler et al., ASCO 2007, Abstract 7564.

  29. Integrating Bevacizumab into First-Line ED-SCLC: Phase II TrialsToxicity Results • Ready et al., CALGB 30306 • No grade 3-5 hemoptysis • One patient died w/thromboembolic CVA, secondary bleeding • Other treatment-related mortality due to FN, sepsis or PNA • Sandler et al., ECOG 3501 • No serious hemoptysis reported • Two treatment related deaths • Mutli-organ failure • Infection with grade 3/4 neutropenia • Grade 5 toxicities seen at similar or higher rate with chemo alone as well (e.g., Noda, NEJM 2002 & Hanna JCO 2006) • Central location does not appear to be correlated with bleeding risk on bevacizumab in Tx of SCLC (vs. squamous histology) Ready et al., ASCO 2007, Abstract 7563. Sandler et al., ASCO 2007, Abstract 7564.

  30. Chemotherapy with Bevacizumab in First-Line ED-SCLCEfficacy Results *28% non-evaluable **29% non-evaluable

  31. Chemo with Bevacizumab in ED-SCLC Conclusions • Neither trial reached the median survival of 12.8 months for cisplatin-irinotecan in Noda, NEJM 2002 • Results of SWOG 0124 still pending • Both regimens are feasible, with few treatment-related deaths and no evidence of serious hemoptysis • Encouraging results with bevacizumab vs. US-based historical controls, but phase II trials typically exceed broader experience • Phase III study of chemo ± bevacizumab is an appropriate consideration

  32. Case 1 Extensive Stage SCLC • Patient receives 4 cycles of systemic therapy with etoposide 100 mg/m2 days 1, 2, and 3 along with carboplatin (AUC 5) every three weeks • Enters a near CR with complete resolution of the hepatic and pulmonary metastases and SCN • 80% regression of the primary lung mass and mediastinal adenopathy • You elect to radiate the remaining volume of tumor in the chest

  33. Case 1Extensive Stage SCLC Is there a role for PCI in this patient? • Yes • No

  34. Case 1Extensive Stage SCLC Is there a role for PCI in this patient? • Yes • No Recommended Approach: • Yes, this patient should be treated with PCI to improve outcomes.

  35. Prophylactic Cranial Irradiation (PCI) • Decreases brain relapse • Dose related • Survival advantage of 5%* • Does not appear dose related • Neurotoxicity < 10 % • Found pre-Rx; ± PCI in 50% ! • Timing and dose less certain *Auperin et al. NEJM(1999) 341: 476-84.

  36. PCI Survival Auperin et al. NEJM(1999) 341: 476-84.

  37. R A N D O M I Z E PCI 20-30 Gy in 5-12 fractions No response Chemotherapy (4-6 cycles) Any response No PCI < 5 weeks 4-6 weeks • Stratify: • Institution • PS PCI in ED-SCLCEORTC 08993-22993 Slotman et al., ASCO 2007, Abstract 4

  38. PCI in ED-SCLCEfficacy Slotman et al., ASCO 2007, Abstract 4

  39. Late Radiation Reactions With PCI Slotman et al., ASCO 2007, Abstract 4.

  40. Case 1Extensive Stage SCLC • Patient receives PCI and does well • After 9 months, he ultimately relapses in the chest and liver

  41. Case 1Extensive Stage SCLC Which of the following agents is FDA-approved for chemo-sensitive relapse of SCLC? • Oral topotecan • Intravenous topotecan • Oral etoposide • Intravenous etoposide • Paclitaxel

  42. Case 1Extensive Stage SCLC Which of the following agents is FDA-approved for chemo-sensitive relapse of SCLC? • Oral topotecan • Intravenous topotecan • Oral etoposide • Intravenous etoposide • Paclitaxel Answer: • Intravenous topotecan is the only FDA-approved agent for second-line SCLC.

  43. Salvage Therapy for SCLC • Topotecan: de facto standard • Not very popular (in US) • Other options • Taxanes • Gemcitabine • Oral etoposide • Phase I approaches

  44. SCLC: Outcome Contingent on Status at Time of Relapse Time to relapse Response (%) Med Survival (mos.) > 2 years 60-80 8-10 > 10 wks 20-40 5-6 < 10 wks 10-15 < 4

  45. Topotecan (T) vs. CAVChemosensitive Relapse T CAV P-value N 107 104 OR (%) 24.3* 18.3 NSS TTP (wk) 13.3 12.3 0.552 MS (wk) 25 24.2 0.795 1-yr Surv. (%) 14.2 14.4 0.955 *statistically significant  LCSS Schiller et al., J Clin Onc 17: 2, 1999.

  46. PO IV N 153 151 ≥ 65 yrs 43 42 PS 2 13 12 Med # cyc 4 4 Range 1-14 1-19 RDI (%) 97.6 92.4 PO IV OR (%) 18 22 TTP (wks) 11.9 14.6 MS ( wk) 33 35 1-Yr OS 33% 29% Toxicity (Gr ≥ 3) ANC 47 64 Plts 29 18 H/H 23 31 Diarrhea (AE) 36 20 Oral vs. IV TopotecanStudy Results QoL, TOI, Sx Scores:No difference between PO and IV Conclusion: Oral topotecan offers activity and tolerability comparable to IV topotecan, more convenient alternative

  47. RANDOM I ZE • Stratification • Gender • PS (0/1 or 2) • Presence of liver metastases at baseline • TTP from end of prior chemo (≤ 60 or >60 days) Topotecan 2.3 mg/m2/day PO days 1–5 + BSC • BSC alone Cycles repeated q 21 d Oral Topotecan vs. BSCStudy Design Open-Label, Randomized, Multicenter Phase III Trial O`Brien et al J Clin Oncol 2006;24:5441-5447.

  48. 1.0 0.9 Cumulative Proportion Alive Topo + BSC 0.8 BSC alone 0.7 0.6 0.5 HR = 0.64 (0.45, 0.90) Log-rank P = .0104 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 72 84 108 120 132 96 60 Time (weeks) Oral Topotecan vs. BSCOverall Survival (ITT) O`Brien et al J Clin Oncol 2006;24:5441-5447.

  49. Relapsed SCLCRandomized Trial BSC vs. BSC + Oral Topotecan N = 141 pts BSC Oral Topotecan OR 7% MS wks 14 26 P = 0.01 6 mos. (%) 26 49 Sepsis 4% QOL Faster  O`Brien et al J Clin Oncol 2006;24:5441-5447.

  50. ASCO 2007 – SCLC Commentary