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