Certinib in ALK-Rearranged Non- Small-Cell Lung Cancer Alice T. Shaw, M.D., Ph.D., Dong-Wan Kim, M.D., Ph.D., Ranee Mehra, M.D., Daniel S.W. Tan, M.B., B.S., Enriqueta Felip, M.D., Ph.D., Laura Q.M. Chow, M.D., D. Ross Camidge, M.D., Ph.D., Johan Vansteenkiste, M.D., Ph.D., Sunil Sharma, M.D., Tommaso De Pas, M.D., Gregory J. Riely, M.D., Ph.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Juergen Wolf, M.D., Ph.D., Michael Thomas, M.D., Martin Schuler, M.D., Geoffrey Liu, M.D., Armando Santoro, M.D., Yvonne Y. Lau, Ph.D., Meredith Goldwasser, Sc.D., Anthony L. Boral, M.D., Ph.D., and Jeffrey A. Engelman, M.D., Ph.D N Engl J Med 370;13 R4 변자민 / Prof 김시영

INTRODUCTION ANAPLASTIC LYMPHOMA KINASE GENE ALK

NSCLC ALK rearrangement in 5% Crizotinib  response rates of 60%  median progression-free survival of 8 to 10 months mutation

–Inhibit the insulin-like growth factor 1 –Enzymatic assays: 20 times as potent as crizotinib –Xenograft models (NSCLC): antitumor activity against crizotinib- sensitive and crizotinib-resistant tumors

OBJECTIVE: Phase 1 study of ceritinib to determine the safety, maximum tolerated dose, pharmacokinetic properties, and antitumor activity of this drug in patients with advanced, ALK-rearranged NSCLC and other cancers harboring ALK alterations INTRODUCTION

Locally advanced or metastatic cancer with genetic alterations in ALK ALK - FISH – at least 15% Inclusion criteria –18 years or older –ECOG performance status 0,1,2 –Adequate end organ function METHODS -PATIENTS

Study Design –Primary object: determine the MTD of ceritinib –Secondary objective: safety, side effect profile, pharmacokinetic profile, anti-tumor activity Study Assessments –Tumor imaging: at baseline → restaging at 6- week intervals –RECIST version 1.0 Statistics METHODS -STUDY DESIGN,ASSESSMENTS dose-escalation phaseexpansion phase

RESULTS -PATIENTS

RESULTS -ADVERSE EVENTS MTD All dose-limiting toxic events resolved on discontinuation of treatment

RESULTS -PHARMACOKINETICS 3-day pharmacokinetic evaluation –Cmax: 6 hours after administration –Mean terminal half-life: approximately 40 hours –Steady-state levels of ceritinib achieved by approximately day 15

RESULTS -EFFICACY Figure 1. Response to Ceritinib in ALK-Rearranged NSCLC Crizotinib treatedCrizotinib naiveTotal Ceritinib 400~750m g ORR 56% (95% CI, ) ORR 62% (95% CI, ) ORR 58% (95% CI, 48-67) Ceritinib 750mg ORR 56% (95% CI, ) ORR 59% (95% CI, 47-70) 52% tumor burden reduction 30% reduction Received ceritinib at doses of 400 to 750 mg daily

Figure 2. Progression-free Survival 7 months 10.4 months 6.9 months Received ceritinib at doses of 400 to 750 mg daily

Figure 3. Correlation of Response to Ceritinib with ALK Gene Alteration among Patients with Crizotinib Resistance A total of 19 patients with NSCLC who had had disease progression during crizotinib treatment underwent repeat tumor biopsy Tumor regression was in all the patients, regardless of molecular status Activity of ceritinib in patients with crizotinib resistance is independent of the underlying mechanism of acquired resistance All 19 samples (+) ALK rearrangement by FISH 1)2: ALK gene amplification 2)5: secondary resistance mutations in the ALK tyrosine kinase domain 3)12: no genetic alteration of ALK other than the original rearrangement

Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK CONCLUSION