Targeted therapies have improved outcomes for patients with lung cancer harboring specific mutations. Several studies showed first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improved response rates and progression-free survival over chemotherapy for patients with EGFR mutations. Resistance often emerges due to the T790M mutation. Irreversible EGFR TKIs like afatinib have shown activity against T790M resistance. Crizotinib demonstrated high response rates and prolonged progression-free survival in patients with anaplastic lymphoma kinase (ALK) rearrangements. New ALK inhibitors are in development. Selumetinib, a MEK inhibitor, showed clinical benefit in patients with KRAS mutations

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

4. Targeting EGFR
Ciardiello F, N Engl J Med 2008; 358: 1160-1174

5. EGFR Mutations
Sharma S, Nature Rev Cancer 2007;7:169-181.

6. Mok T, ESMO 2008.
IPASS: Study Design
Patients
• Chemonaive
• Age ≥8 years
• Adenocarcinoma histology
• Never or light
ex-smokers*
• Life expectancy ≥12 weeks
• PS 0-2
• Measurable stage IIIB/ IV
disease
Gefitinib
(250 mg / day)
Endpoints
Primary
• Progression-free survival (non-
inferiority)
Secondary
• Objective response rate
• Overall survival
• Quality of life
• Disease-related symptoms
• Safety and tolerability
Exploratory
• Biomarkers
– EGFR mutation
– EGFR-gene-copy number
– EGFR protein expression
• Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped ≥15 years ago and smoked ≤10 pack years
Carboplatin
(AUC 5 or 6) /
paclitaxel
(200 mg / m2)
3 weekly X 6
1:1 randomization

7. IPASS
Mok TS, N Engl J Med 2009; 361: 947-957
RR CP – 23.5%
Gef – 1.1%
RR CP – 47.3%
Gef – 71.2%

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

16. LUX-Lung 2
EGFR Exon 19 del Response
Yang JC, Lancet Oncol 2012; 13: 539-548

17. Role of Afatinib – LUX-7
Clinicaltrials.gov, NCT01466660

19. ALK Pathway
Shaw AT, Clin Cancer Res 2011; 17: 2081-2086

21. Crizotinib
 Phase II trial
 Approximately 1500 patients screened for ALK
rearrangements
 82 patients with advanced disease enrolled
 Crizotinib 250 mg twice daily
Kwak EL, N Engl J Med 2010; 363: 1693- 1703

22. Crizotinib
Kwak EL, N Engl J Med 2010; 363: 1693- 1703

23. Crizotinib
Kwak EL, N Engl J Med 2010; 363: 1693- 1703
Median PFS 9 months

26. New ALK Inhibitors

28. AP26113
Camidge DR, Proc Am Soc Clin Onc 2013 Abstr 8301

29. Targeting KRAS Mutation
Selumetinib (MEK inhibitor)
Jane PA, J Clin Oncol 2012; 30: Abstr 7503

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

31. New Mutations
Bergethon K, J Clin Oncol 2012; 30: 863-870
Kohno T, Nat Medicine 2012; 18: 375-377

32. ROS-1
Shaw AT, J Clin Oncol 2012; 30: Abstr 7508

34. BRAF Mutation
 2% of lung cancer (V600E, and non-V600E)
 Exon 11 & 15
 Poor prognostic marker

35. BRAF Inhibition
Dabrafenib
Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

36. Dabrafenib in Melanoma
Phase 3 Study BREAK-3
Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009
FDA approved on 5/29/13

37. BRF113928 Design
Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

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

39. Dabrafenib
Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

40. GPS testing is done at Wash U

41. Questions?