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