1) The document discusses integrating targeted therapies such as EGFR inhibitors and angiogenesis inhibitors with chemoradiotherapy for the treatment of stage III non-small cell lung cancer (NSCLC). 2) Several phase II trials showed that combining chemoradiotherapy with the EGFR inhibitor cetuximab was feasible and resulted in promising survival outcomes. This warrants a phase III trial. 3) Combining chemoradiotherapy with tyrosine kinase inhibitors and angiogenesis inhibitors like bevacizumab is also being explored, but data is still limited and complex trial designs make results difficult to interpret. Further research is still needed.

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