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New developments of targeted therapy in nsclc
1. New Developments in
Targeted Therapy in Lung
Cancer
Andrea Wang-Gillam MD, PhD
Division of Oncology
Washington University School of Medicine in St. Louis
2. Jemal, A. et al. CA Cancer J Clin 2010;60:277-300
3. Incidence of Mutations in Lung Cancer
Mutation found in 54% (280/516) of
tumors completely tested (95% CI 50-59%)
Kris MG, J Clin Oncol 2011; 29: Abstr CRA 7506
8. Randomized Studies on First Line EGFR TKI
in Patients with EGFR Mutation
Author Study N (EGFR mutation) RR (TKI vs
chemotherapy)
Median PFS
(months)
Mok IPASS 261 71.2% vs 47.3 9.8 vs 6.4
Mitsudomi WJTOG 3405 177 62.1% vs 32.2% 9.2 vs 6.3
Maemondo NEJGSG002 228 73.7% vs 30.7% 10.8 vs 5.4
Zhou OPTIMAL 154 82% vs 36% 13.1 vs 4.6
Rosell EURTAC 174 58% vs 15% 9.7 vs 5.2
Mok TS, New Engl J Med 2009
Mitsudomi T, Lancet Oncology 2010
Maemondo M N Engl J Med 2010
Zhou C, Lancet Oncol 2011
Rosell R, Lancet Oncol 2012
First-line EGFR TKI improves ORR and PFS compared to chemotherapy
9. Prevalence of Mechanisms of
Resistance to EGFR TKIs
Nguyen KSH, Clin Lung Cancer 2009; 10: 281-289
10. Mechanisms of Resistance to EGFR TKIs
Repeated Biopsy Study
Sequist LV, Sci Translat Med 2011, 3: 75ra26
11. Irreversible TKIs
Reversible TKIs such as erlotinib, gefitinib and icotinib are
competitive inhibitors of ATP, blocking its binding to the TK
domain of the EGFR.
The presence of T790M mutations increase the ATP affinity by
approximately 5 fold compared to the initial EGFR mutation
alone, decreasing the TKI efficacy.
Irreversible TKI inhibitors bind covalently with the Cys 797 at
the ATP-binding cleft of mutant EGFR, providing a prolonged
EGFR inhibition.
Preclinical studies have shown activity for irreversible TKIs in
cell lines resistant to gefitinib.
12. LUX-Lung 1
Randomization 2:1
(Double Blind)
Oral afatinib 50 mg once daily
plus BSC
Oral placebo once daily
plus BSC
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter
• Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab)
Serum EGFR mutational analysis (all patients)
Patients with:
• Adenocarcinoma of the lung
• Stage IIIB/IV
• Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen)
and ≥12 weeks of treatment with erlotinib or gefitinib
• ECOG 0–2
N=585
13. LUX-1: PFS by Independent Review
Miller VA, Lancet Oncol 2012; 13: 428-538
14. LUX-Lung 2
Afatinib in EGFR Mutants
Phase II study
129 patients
1st line 61 patients
2nd line 68 patients
Afatinib 40 mg or 50 mg daily
15. LUX-Lung 2 – PFS and OS
Yang JC, Lancet Oncol 2012; 13: 539-548
30. Targeting KRAS Mutation
Selumetinib (MEK inhibitor)
Jane PA, J Clin Oncol 2012; 30: Abstr 7503
First prospective trial to demonstrate a clinical benefit from targeted
therapy in patients with KRAS mutation
38. Dabrafenib in NSCLC
Maximum Reduction in Stage 1
PR 40%
SD 20%
PD 30%
NA 10% - SAE prior to assessment
First 20 patients
Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009