1. SCLC: Future Directions Michael Perry, MD, FACP

2. Small Cell Lung Cancer: What’s New in 2003 Bristol Myers Squibb/ImClone Systems Lung Cancer Summit Michael C. Perry, MD, FACP University of Missouri/Ellis Fischel Cancer Center

3. Small Cell Lung Cancer Demographics: –15-25% of 177,000 lung cancer cases or 26,550-44,250 cases/year –Major risk factor: smoking Characteristics: –Typically an endobronchial lesion with hilar adenopathy –Considered metastatic at diagnosis

4. Small Cell Lung Cancer Biologic behavior –Rapid doubling time –High growth fraction –Early metastases –Acquired drug resistance –Paraneoplastic syndromes (SIADH, Cushing’s, Eaton-Lambert, Anti-Hu, etc.)

5. Small Cell Lung Cancer Molecular characteristics –Deletion of 3p (90%) –Loss of retinoblastoma gene at 13q14 (90%) –Mutations of p53 (75-100%) –Amplification of myc-dominant oncogenes (30%) –Bcl-2 Expression (95%) –VEGF expression (>100 fold variation)

6. Small Cell Lung Cancer: Staging Limited disease: disease confined to one hemi-thorax, including ipsilateral mediastinal, hilar, or supraclavicular nodes (originally the amount of disease that could be incorporated into a “tolerable” radiation port). Now ~33% of SCLC. Extensive disease: any disease beyond the above. Now ~ 67% of SCLC.

7. SCLC: Prognostic Factors Good prognosis –Limited stage disease –Female gender –Performance status of 0,1 Poor prognosis –CNS or liver involvement –Performance status of 2 or greater

8. SCLC Current Standards: PDQ Limited stage: –Combination chemotherapy Etoposide/cisplatin –Thoracic radiation therapy 4,000-4,500 cGy –Prophylactic cranial irradiation (PCI) For Complete Response (CR) or Very Good Partial Response (VGPR)

9. SCLC Current Standards: NCCN Limited stage: –Combination chemotherapy: Etoposide/cisplatin or Etoposide/carboplatin for 4-6 cycles –Concurrent RT: either 1.5 Gy bid or 1.8 Gy/day to at least 54 Gy, starting with cycle 1 or 2. –PCI: 24 Gy in 8 FX to 36 Gy in 18 FX

10. SCLC Current Standards: MCP Limited stage: Clinical trial or etoposide/cisplatin (or carboplatin) with thoracic RT starting with cycle 3 for a total of 5 cycles

11. Limited Stage SCLC: Results Overall response rates of 65-90% Complete response rates of 45-75% Median survival of 18-24 months 40-50% 2 year survival 20-25% 5 year survival

12. SCLC Current Standards: PDQ Extensive stage: –Combination chemotherapy CAV (cyclophosphamide/doxorubicin/vincristine) CAE (cyclophosphamide/doxorubicin/etoposide) Etoposide/cisplatin or etoposide/carboplatin ICE (Ifosfamide/carboplatin/etoposide) –Prophylactic cranial irradiation (PCI) For CR or VGPR

13. SCLC Current Standards: NCCN Extensive Stage: –Chemotherapy with etoposide/cisplatin or etoposide/carboplatin (+/- ifosfamide) for 4-6 cycles.

14. SCLC Current Standards: MCP Extensive stage: Clinical trial or etoposide/cisplatin (carboplatin)

15. Extensive Stage SCLC: Results Overall response rates of 70-85% Complete response rates of 20-30% Median survival of 6-12 months 2 year survival uncommon

16. SCLC Current Standards: PDQ Progressive disease: –Clinical trial –Palliative symptom management, including localized RT or clinical trial or second-line chemotherapy (PS 0-2) Relapse: –“Salvage radiation therapy” –Second line chemotherapy (topotecan or CAV) or Best Supportive Care

17. SCLC Current Standards: NCCN Relapse: –Second line chemotherapy or Best Supportive Care Progressive disease: –Palliative symptom management localized RT or clinical trial or second-line chemotherapy (PS 0-2)

18. SCLC Current Standards: MCP Recurrent disease: Clinical trial or topotecan

19. SCLC Problems Drug resistance Radio-resistance Minimal residual disease detection Toxicity of therapy Second primaries

20. Special Problems/Issues Surgery The elderly High dose chemotherapy BID RT Brain metastases

21. SCLC: Surgery Not helpful for established diagnosis May be done for solitary pulmonary nodules where histologic diagnosis not yet obtained. In this setting, CT and RT are usually given

22. SCLC: The Elderly* Single agent therapy or low dose therapy is less effective than conventional IV therapy at standard doses –*(Or poor performance score or co-existing illnesses)

23. SCLC: Radiotherapy The ECOG study of BID RT resulted in improved survival, but at the cost of increased esophagitis. It has not taken the world by storm due to scheduling Intensity modulated RT (IMRT) is the latest best thing. Is it more likely to reduce toxicity than improve local control? Radiosensitizers?

24. SCLC: Brain metastases 40% of brain metastases Standard therapy is whole brain radiation In NSCLC there are promising results with temozolomide and motexafin with RT

25. SCLC: Brain metastases ASTRO 2002:Greek study of 129 patients, (80%) lung cancer WBRT with or without concurrent and sequential Temozolomide Improved radiographic responses, time to neurologic progression and medial survival with combined modality Rx

26. SCLC: Brain metastases ASTRO 2002: Mehta et al, U Wisconsin –Phase III trial of 400 patients (66% lung cancer) randomized to WBRT +/-motexafin –Median survival: WBRT 5.2 ms, WBRT+M 4.0 ms –Time to progression: WBRT 4.3ms Vs 3.8 ms –Median time to progression M+RT> RT

27. SCLC: Chemotherapy No improvement in survival with: –High dose chemotherapy –Increased dose intensity –Addition of a third agent

28. SCLC: Chemotherapy CPT-11 –Topoisomerase I inhibitor –Activity in preclinical models –May be synergistic with other agents (Cisplatin) –Radiosensitizer?

29. Japan Clinical Oncology Group Trial

30. CPT-11/CDDP for ES-SCLC Phase III Schema RANDOMIZATIONRANDOMIZATION CPT-11 60 mg/m 2 d1, 8, 15 CDDP 60 mg/m 2 d1 VP-16 100 mg/m 2 d1-3 CDDP 80 mg/m 2 mg/m 2 d1 Stratification PS (0, 1, 2) Noda et al NEJM 346:85-91, 2002 q4wk q3wk

31. 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0200400600800100012001400 Days after Randomization Survival Proportion CP EP P=0.0021 (unadjusted one-sided log rank test) Overall Survival CPEP (95% C.I.)(95% C.I.) MST (mo)12.89.5 % 1-yr. survival58.4(47.4-69.4)37.7(26.8-48.5) % 2 yr. survival19.5(10.0-27.8)5.5(1.0-12.0)

32. Summary of JCOG Phase III Trial Study terminated early at 2 nd interim analysis with 154 patients CPT-11/CDDP yielded remarkably better survival than standard EP –Treatment compliance identical in the two arms –Toxicity profiles differed CPT-11/CDDP - New Japanese standard CPT-11/CDDP- New US Option

33. SCLC: CPT-11 Carboplatin can replace cisplatin Can be combined with etoposide, giving inhibition of topoisomerase I and II Other possible chemotherapy combinations: ifosfamide, paclitaxel, or docetaxel, navelbine, or gemcitabine Novel combinations: cyclosporine, MTA, or phenobarbital

34. SCLC: ASCO 2002 Three drugs versus two for Extensive stage: –CALGB 9732 Phase III 587 pts:Paclitaxel plus etoposide/cisplatin= increased toxicity without survival advantage (Abstract 1169) –SWOG Phase II 82 pts: Paclitaxel plus carboplatin /topotecan=median survival of 12 mos, 1-year 50% (33% gr4, 7% deaths), (Abstract 1184)

35. SCLC: ASCO 2002 Three drugs versus two for Extensive stage: –Italian group: Cisplatin/gemcitabine versus etoposide/cisplatin/gemcitabine. More toxicity and more benefit with three drugs? (abstract 1219) –Conclusion? It is doubtful that three drugs will be significantly better than two, and at the risk of increased toxicity

36. SCLC: ASCO 2002 –Phase II Study of STI 571 (Gleevec) in SCLC-no objective responses in 19 pts, although only 4/14 were + for CD117 (abstract 1171) –Increased initial dose of cyclophosphamide did not increase survival in limited stage disease (abstract 1172) –Phase I trial of monoclonal Ab conjugate, BB-10901 (abstract 1232).

37. CALGB-ECOG-RTOG Phase I Trial Cisplatin 60 mg/M2 with irinotecan 40- 6-Mg/M2 days 1 and 8, every 21 days for 4 cycles Thoracic radiotherapy as either 4,500 cGy (twice daily) or 7,000 cGy (once daily)

38. SCLC: New Initiatives CPT-11 in extensive disease-confirmatory studies CPT-11 with RT in limited disease Other new agents: paclitaxel, docetaxel, vinorelbine, gemcitabine Higher doses of RT New targets: VEGFR, VEGF, COX-2, Bcl-2, Gastrin CALGB strategy: DDP/CPT-11 +MTT

39. SCLC: Conclusions Increments of 5% in survival will not be sufficient for cure. Improvements in conventional CT and/or RT will be small. New therapies for brain mets, PCI? New approaches are needed-targeted agents, radiopharmaceuticals, vaccines, etc.

40. SCLC: Future Directions Michael Perry, MD, FACP