New Developments in Targeted Therapy in

Lung Cancer Andrea Wang-Gillam MD, PhD

Division of OncologyWashington University School of Medicine in

St. Louis

Jemal, A. et al. CA Cancer J Clin 2010;60:277-300

Incidence of Mutations in Lung Cancer

Mutation found in 54% (280/516) oftumors completely tested (95% CI 50-59%)

Kris MG, J Clin Oncol 2011; 29: Abstr CRA 7506

Targeting EGFR

Ciardiello F, N Engl J Med 2008; 358: 1160-1174

EGFR Mutations

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

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

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%

Randomized Studies on First Line EGFR TKI in Patients with EGFR

MutationAuthor 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 2010Maemondo M N Engl J Med 2010Zhou C, Lancet Oncol 2011Rosell R, Lancet Oncol 2012

First-line EGFR TKI improves ORR and PFS compared to chemotherapy

Prevalence of Mechanisms ofResistance to EGFR TKIs

Nguyen KSH, Clin Lung Cancer 2009; 10: 281-289

Mechanisms of Resistance to EGFR TKIs Repeated Biopsy Study

Sequist LV, Sci Translat Med 2011, 3: 75ra26

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.

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

LUX-1: PFS by Independent Review

Miller VA, Lancet Oncol 2012; 13: 428-538

LUX-Lung 2Afatinib in EGFR

Mutants Phase II study 129 patients

1st line 61 patients2nd line 68 patients

Afatinib 40 mg or 50 mg daily

LUX-Lung 2 – PFS and OS

Yang JC, Lancet Oncol 2012; 13: 539-548

LUX-Lung 2 EGFR Exon 19 del Response

Yang JC, Lancet Oncol 2012; 13: 539-548

Role of Afatinib – LUX-7

Clinicaltrials.gov, NCT01466660

ALK Pathway

Shaw AT, Clin Cancer Res 2011; 17: 2081-2086

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

Crizotinib

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

Crizotinib

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

Median PFS 9 months

New ALK Inhibitors

AP26113

Camidge DR, Proc Am Soc Clin Onc 2013 Abstr 8301

Targeting KRAS MutationSelumetinib (MEK inhibitor)

Jane PA, J Clin Oncol 2012; 30: Abstr 7503

Targeting KRAS MutationSelumetinib (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

New Mutations

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

ROS-1

Shaw AT, J Clin Oncol 2012; 30: Abstr 7508

BRAF Mutation

2% of lung cancer (V600E, and non-V600E)

Exon 11 & 15 Poor prognostic marker

BRAF InhibitionDabrafenib

Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

Dabrafenib in MelanomaPhase 3 Study BREAK-3

Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

FDA approved on 5/29/13

BRF113928 Design

Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

Dabrafenib in NSCLCMaximum Reduction in

Stage 1PR 40%SD 20%PD 30%NA 10% - SAE prior to assessment

First 20 patients

Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

Dabrafenib

Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009

GPS testing is done at Wash U

Questions?