integration of targeted therapies with radiation lung cancer
TRANSCRIPT
Integration of targeted therapies with radiationLung Cancer
Robert Pirker
Medical University of Vienna
ESMO/ESTRO/ESSO Joint Symposium
33rd ESMO Congress, Stockholm 2008
NSCLC IIITherapy
• Stage III is heterogeneous
• Prognosis dependent on lymph node involvement: N2 versus N3minimal, clinical, „bulky“
• Local therapy and systemic chemotherapy
• Optimal therapy for various subgroups unclear
CT RTCT-RT
Induction CT CT-RTCT-RT Consolidation CT
Inclusion of surgery (trimodality therapy)New radiotherapy techniques PCITargeted therapy
NSCLC stage IIITherapeutic options
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
Targeted Therapies in advanced NSCLC
• EGFR-directed therapies
• Angiogenesis inhibitors
• Dual & multikinase inhibitors
• Others
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
EGFR Inhibitors
• Monoclonal antibodies– Cetuximab (ERBITUX®)– Matuzumab – Panitumumab
• Tyrosine kinase inhibitors– Gefitinib– Erlotinib– Vandetanib (ZD6474; EGFR, VEGFR)– Lapatinib (GW572016; EGFR, ErbB2)– others
NSCLC III Chemoradiotherapy (or RT) + Cetuximab
• SCRATCH Hughes SR et al. ASCO 2007, abstract 18032 Radiotherapy + cetuximab: phase I trial
• RTOG 0324 phase II trialBlumenschein GR et al. ASCO 2008, abstract 7516 Carboplatin/paclitaxel + radiotherapy + cetuximab
• CAGLB 30407 randomized phase II trialGovindan R et al. ASCO 2008, abstract 7518Carboplatin/pemetrexed + radiotherapy +/- cetuximab
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
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
NSCLC III Chemoradiotherapy + CetuximabOlsen 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
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%
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 ± cetuximabPrimary endpoint: overall survival
NSCLC IIIEGFR-directed tyrosine kinase inhibitors
• Chemoradiotherapy + TKIs– Gefitinib
Rischin D et al. ASCO 2004, abstract 7077 Ready N et al. ASCO 2006, abstract 7046
– ErlotinibHoffmann 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
NSCLC IIIChemoradiotherapy + Gefitinib
CALGB 30106Ready 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 riskcarbo AUC 2 wkly gefitinibpaclitaxel 50 mg/m2 wkly RTgefitinib RT
OS 9 months 19 months
NSCLC III Gefitinib maintenance
• Survival disadvantage after chemoradiotherapy (SWOG 0023)Kelly K et al. ASCO 2007, abstract 7513
Concurrent chemoradiotherapy (575 pts.)Docetaxel consolidationRandomization (263 pts.): Gefitinib 250 mg or Placebo
Gefitinib Placebon 118 125OS mo 23 35 p=0.01
Disease progression as primary cause of death
NSCLC IIIChemoradiotherapy + 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 ?
NSCLC IIIAngiogenesis inhibitors
• Increase antitumor activity of both cytotoxic drugs and radiotherapy
• Several angiogenesis inhibitors
– Bevacizumab
– Thalidomide
– Vandetanib (ZD6474)
– others
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
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
SCLCBevacizumab
• Irinotecan/carboplatin/bevacizumab in SCLC ED (phase II)Spigel DR et al. JCO 25, 18S, 200736 patients, 78% PR, no bleedings gr 3/4
• Tracheo-esophageal fistulaSpigel DR et al. ASCO 2008, 755429 patients with irinotecan/carboplatin plus bevacizumab plus concurrent radiotherapy 2 events (1 fatal), another fatal event with suspected fistula
Lung CancerChemoradiotherapy + angiogenesis inhibitors
• Carboplatin-based protocols
• Insufficient data
• Tacheoesophageal fistula, other toxicities?
BLP25 Liposome Vaccine in NSCLCButts 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)
NSCLC IIITargeted 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