Integration Of Targeted Therapies With Radiation Lung Cancer

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  • 1. Integration of targeted therapies with radiation Lung Cancer Robert Pirker Medical University of Vienna ESMO/ESTRO/ESSO Joint Symposium 33rd ESMO Congress, Stockholm 2008
  • 2. NSCLC III Therapy • Stage III is heterogeneous • Prognosis dependent on lymph node involvement: N2 versus N3 minimal, clinical, „bulky“ • Local therapy and systemic chemotherapy • Optimal therapy for various subgroups unclear
  • 3. NSCLC stage III Therapeutic options CT RT CT-RT Induction CT CT-RT CT-RT Consolidation CT Inclusion of surgery (trimodality therapy) New radiotherapy techniques PCI Targeted therapy
  • 4. Integration of targeted therapies into the therapy of NSCLC stage III • Adjuvant therapy after complete tumor resection – Combined with adjuvant chemotherapy • Initial therapy in unresectable disease – Combined with chemoradiotherapy – Combined with radiotherapy – Combined with chemotherapy • Maintenance therapy • Monotherapy or in combination
  • 5. Targeted Therapies in advanced NSCLC • EGFR-directed therapies • Angiogenesis inhibitors • Dual & multikinase inhibitors • Others
  • 6. EGF-R as a target • EGFR expression in 40-80% of NSCLC • EGFR expression is associated with tumor proliferation, invasiveness, angiogenesis & shorter survival times • EGFR expression associated with radioresistance & preclinical models suggest radiosensitization following inhibition of EGFR signaling • Efficacy shown for – TKIs in pre-treated patients with advanced NSCLC – Cetuximab + chemotherapy in advanced NSCLC – Cetuximab + radiotherapy in head & neck cancer Bonner JA et al. NEJM 2006, 354, 567
  • 7. EGFR Inhibitors • Monoclonal antibodies – Cetuximab (ERBITUX®) – Matuzumab – Panitumumab • Tyrosine kinase inhibitors – Gefitinib – Erlotinib – Vandetanib (ZD6474; EGFR, VEGFR) – Lapatinib (GW572016; EGFR, ErbB2) – others
  • 8. NSCLC III Chemoradiotherapy (or RT) + Cetuximab • SCRATCH Hughes SR et al. ASCO 2007, abstract 18032 Radiotherapy + cetuximab: phase I trial • RTOG 0324 phase II trial Blumenschein GR et al. ASCO 2008, abstract 7516 Carboplatin/paclitaxel + radiotherapy + cetuximab • CAGLB 30407 randomized phase II trial Govindan R et al. ASCO 2008, abstract 7518 Carboplatin/pemetrexed + radiotherapy +/- cetuximab
  • 9. NSCLC III CRT + Cetuximab: RTOG 0324 phase II trial Blumenschein GR et al. ASCO 2008, abstract 7516 • Carboplatin AUC 2 weekly + paclitaxel 45 mg/m2 weekly (6x) plus cetuximab plus 63 Gy; Carboplatin AUC 6 + paclitaxel 200 mg/m2 + cetuximab (2x) • 93 (87) patients: 57% male, median 64 years, 47% PS 0, 46% IIIA • RR 62%, median OS 23 months, 2-yr OS 49% • Grade ¾ toxicity: hematotoxicity 20% esophagitis 8% pneumonitis 7% 5 treatment-related deaths
  • 10. NSCLC III Chemoradiotherapy + Cetuximab Blumenschein GR et al. ASCO 2008, abstract 7516 • Feasible and safe • Active with OS better than previously reported • Phase III trial
  • 11. NSCLC III Chemoradiotherapy + Cetuximab Olsen CC et al. ASCO 2008, abstract 7607 • RTOG 0324 phase II trial • 93 (87) patients • FISH analysis in 45 patients FISH + FISH - 2-year OS 62% 54% CR/PR 24% 8% • Conclusion: Tissue testing is feasible FISH-positive patients might have a better response
  • 12. NSCLC III CRT + Cetuximab: CALGB 30407 trial Govindan R et al. ASCO 2008, abstract 7518 • Carboplatin AUC 5 + pemetrexed 500 mg/m2, 4x with/without cetuximab (400, then weekly 250 mg/m2) plus 70 Gy; Carboplatin AUC 5 + pemetrexed 500 mg/m2, 4x • 106 patients: 61% male, median 64.5 years, 39% adeno Cetuximab Control Neutropenia 3/4 37% 36% Esophagitis 3/4 22% 35% Skin rash 23% 3%
  • 13. NSCLC III Chemoradiotherapy + Cetuximab • Based on – the results of these phase II trials, – the efficacy of cetuximab in combination with chemotherapy in advanced NSCLC, and – the positive results in head & neck cancer, a phase III trial is warranted: Inoperable stage III NSCLC Cisplatin-based doublet (e.g. cis/etoposide, cis/vinorelbine) + radiotherapy ± cetuximab Primary endpoint: overall survival
  • 14. NSCLC III EGFR-directed tyrosine kinase inhibitors • Chemoradiotherapy + TKIs – Gefitinib Rischin D et al. ASCO 2004, abstract 7077 Ready N et al. ASCO 2006, abstract 7046 – Erlotinib Hoffmann PC et al. ASCO 2005, abstract 7113 • TKI maintenance – Gefitinib Kelly K et al. ASCO 2007, abstract 7513 – Erlotinib Casal J et al. ASCO 2008, abstract 18501
  • 15. NSCLC III Chemoradiotherapy + Gefitinib CALGB 30106 Ready N et al. ASCO 2006, abstract 7046 Carbo AUC 6 + paclitaxel 200 mg/m2 + gefitinib 250 mg (2x) PS 0/1 PS 2 or poor risk carbo AUC 2 wkly gefitinib paclitaxel 50 mg/m2 wkly RT gefitinib RT OS 9 months 19 months
  • 16. NSCLC III Gefitinib maintenance • Survival disadvantage after chemoradiotherapy (SWOG 0023) Kelly K et al. ASCO 2007, abstract 7513 Concurrent chemoradiotherapy (575 pts.) Docetaxel consolidation Randomization (263 pts.): Gefitinib 250 mg or Placebo Gefitinib Placebo n 118 125 OS mo 23 35 p=0.01 Disease progression as primary cause of death
  • 17. NSCLC III Chemoradiotherapy + tyrosine kinase inhibitors • Combination of chemoradiotherapy with TKIs is feasible • Maintenance with gefitinib failed • TKIs did not improve outcome of chemotherapy in advanced NSCLC • Further trials ?
  • 18. NSCLC III Angiogenesis inhibitors • Increase antitumor activity of both cytotoxic drugs and radiotherapy • Several angiogenesis inhibitors – Bevacizumab – Thalidomide – Vandetanib (ZD6474) – others
  • 19. NSCLC III Chemoradiotherapy + Bevacizumab Socinski MA et al. ASCO 2008, abstract 7517 • Carboplatin AUC 6 + paclitaxel 225 mg/m2 + bevacizumab (15 mg/kg), 2x • Carboplatin AUC 2 weekly + paclitaxel 45 mg/m2 weekly (7x) plus 74 Gy (2 Gy per fraction) Cohorts Bevacizumab Erlotinib I 10 0 II 10 100 III 10 150
  • 20. NSCLC III Chemoradiotherapy + Bevacizumab Socinski MA et al. ASCO 2008, abstract 7517 • Conclusions – Incorporation of bevacizumab & erlotinib is feasible – Esophagitis more common than previous experience – Phase II continuing • However, limitations due to – Carboplatin-based protocol – Complex trial design (2 targeted therapies) – Interpretation will be difficult
  • 21. SCLC Bevacizumab • Irinotecan/carboplatin/bevacizumab in SCLC ED (phase II) Spigel DR et al. JCO 25, 18S, 2007 36 patients, 78% PR, no bleedings gr 3/4 • Tracheo-esophageal fistula Spigel DR et al. ASCO 2008, 7554 29 patients with irinotecan/carboplatin plus bevacizumab plus concurrent radiotherapy 2 events (1 fatal), another fatal event with suspected fistula
  • 22. Lung Cancer Chemoradiotherapy + angiogenesis inhibitors • Carboplatin-based protocols • Insufficient data • Tacheoesophageal fistula, other toxicities?
  • 23. BLP25 Liposome Vaccine in NSCLC Butts CA et al. JCO 23, 6674, 2005 • Randomized, open-label phase II • 171 pts. responding to 1st line chemotherapy: 65 pts with IIIB, 106 pts. with wet IIIB or IV • L-BLP25 (BLP25 Liposome Vaccine): 8 weekly subcutaneous vaccinations: • OS: all pts. 17.4 vs 13 months, p=0.11 IIIB pts. Not yet reached vs 13 months, p=0.07 2-year survival 60% versus 37% • Phase III trial ongoing (START)
  • 24. NSCLC III Targeted therapy plus chemoradiotherapy Summary • New treatment options • Integration is complex • Results from phase II trials with cetuximab warrant a phase III trial chemoradiotherapy ± cetuximab • Further studies on EGFR-directed tyrosine kinase inhibitors ? • Insufficient data on angiogenesis inhibitors but toxicity might become an issue • Phase III vaccination trial ongoing (START) • Simple but relevant trials required