ASCO Annual Meeting 2015 │ May 29–June 2 │ Chicago, IL TIGER 1: A randomized, open-label, phaseXXX 2/3 study of rociletinib (CO-1686) or erlotinib as first-line treatment for EGFR-mutant non-small cell lung cancer Poster # TPS8108 Board # 430a D. Ross Camidge,1 Jürgen Wolf,2 Jason Litten,3 Jeffrey Isaacson,3 and Tony Mok4 of Colorado, Denver, CO; 2Universitätsklinikum Köln, Köln, Germany; 3Clovis Oncology, Inc., San Francisco, CA; 4Chinese University of Hong Kong, Hong Kong, China BACKGROUND PATIENT CHARACTERISTICS • Activating epidermal growth factor receptor (EGFR) mutations including the exon 21 L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.1 • Patients with these activating EGFR mutations typically have good initial responses to therapy with firstgeneration EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib and also with the secondgeneration inhibitor afatinib.2-4 • However, after 9–14 months of EGFR TKI therapy, disease progression invariably ensues,5 driven by a secondary T790M “gatekeeper” mutation in exon 20 of EGFR, in 50%–60% of patients.6-8 • Furthermore, approximately 2%–3% of patients with EGFR-mutant NSCLC will exhibit T790M mutations in tumors at baseline; these patients have no approved therapies and very poor outcomes on currently available TKIs.9,10 Key inclusion criteria 1500 Screening Period Treatment Period 35 days Erlotinib-resistant tumors collected from 3 mice Erlotinib 1000 0 0 20 40 60 80 100 120 Days of study Vehicle Erlotinib (50 mg/kg QD) Rociletinib (150 mg/kg BID) Crossover to rociletinib for T790M+ patients in PHASE 2 only 28 ± 7 days End of treatment assessment Q3 monthly follow-up for survival and subsequent treatment Crossover 7 mice to rociletinib treatment 500 Follow-up Period Rociletinib Disease progression by RECIST 1.1 Tumor volume mean ± SEM (mm3) Figure 1. Long-term activity of rociletinib and erlotinib in PC-9 (EGFR del19) front-line mouse model • Exon 20 insertion activating mutation in the EGFR gene. • Prior chemotherapy in the metastatic setting. • Central nervous system disease. Randomize • Rociletinib (CO-1686) is a novel, oral, irreversible TKI for the treatment of patients with mutant EGFR NSCLC. Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M; Figure 1), while sparing wild-type (WT) EGFR.11 • Given that T790M EGFR-mutated subclones commonly emerge during tumor evolution, early targeting of T790M along with initial activating mutations is a rational approach to impeding progression. Key exclusion criteria Figure 2. TIGER-1 study design Informed consent FIRST-LINE ROCELITINIB IN NSCLC • Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced recurrent NSCLC. • Documentation of ≥1 activating EGFR mutation. • Undergone a biopsy or surgical resection of either primary or metastatic tumor tissue within 60 days. Treatment discontinuation 1University • The same patient eligibility criteria will be used for the phase 2 and phase 3 portions of TIGER-1. • The phase 2 portion is currently enrolling and will transition to the phase 3 portion upon enrolment of the 201st patient. For more information: Contact Clovis Oncology Medical Information at [email protected] OBJECTIVES CONCLUSIONS Primary • Preclinical models and preliminary clinical data provide compelling evidence that rociletinib inhibits mutEGFR targets, and the lack of cutaneous toxicities seen in the phase 1/2 TIGER-X trial support sparing of WT EGFR. • Preclinical data further suggest that first-line use of rociletinib may improve the durability of tumor responses. • TIGER-1 is an active comparator trial evaluating rociletinib vs erlotinib in the first-line setting of mutEGFR NSCLC. • PFS by investigator assessment is the primary study endpoint, which will be complemented by additional response-based endpoints, patient-reported outcomes, and diagnostic/biomarker evaluation. • To evaluate whether rociletinib can improve progression-free survival (PFS) in the first-line setting versus erlotinib according to Response Criteria in Solid Tumors (RECIST) version 1.1 as determined by investigator review. Secondary • To compare the overall response rate, duration of response, disease control rate, and overall survival in the rociletinib and erlotinib arms. • To assess PFS in patients with baseline T790M mutations detected in tumor using local screening EGFR mutation assay. • Change from baseline in patient-reported outcomes using the Dermatology Life Quality Index. • Safety and tolerability. • Rociletinib population pharmacokinetics and assessment of pharmacokinetic:pharmacodynamic interrelationships. Exploratory Endpoints • Tumor growth kinetics. • Improvement or deterioration in the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC QLQ Lung Cancer module (EORTC QLQ-LC13). • PFS and response rate and duration between treatment arms in patients with baseline T790M-positive disease, detected using a high-sensitivity research assay. • The safety and efficacy of rociletinib in patients after radiographic progression on erlotinib who are T790M positive at progression and crossover to receive rociletinib. • Concordance of mutant EGFR detection between tissue and plasma and assessment of rociletinib- or erlotinib-mediated alterations in mutant EGFR levels over time using circulating tumor DNA. • Evaluation of predictive biomarkers and mechanisms of resistance in plasma. REFERENCES ACKNOWLEDGMENTS 1. Herbst R et al. N Engl J Med. 2008;359:13;1367-1380. The authors would like to acknowledge all patients and their families and caregivers who are participating in the TIGER-1 study, along with all TIGER-1 investigators. The authors also thank Infusion Communications for providing editorial assistance, which was funded by Clovis Oncology, Inc. (Boulder, CO). 2. Mok TS et al. N Engl J Med. 2009;361:947-957. 3. Rosell R et al. N Engl J Med. 2009;361:958-967. 4. Sequist LV et al. J Clin Oncol. 2013;31:3327-3334. 5. Jiang T, Zhou C. Transl Lung Cancer Res. 2014;3:370-372. 6. Pao W et al. PLoS Med. 2005;2:e73. 7. Sharma SV et al. Nat Rev Cancer. 2007;7:169-181. 8. Yu HA et al. Clin Cancer Res. 2013;19:2240-2247. 9. Riely GJ et al. J Clin Oncol. 2013;31(suppl; abstr 8018). 10. Oxnard GR et al. J Thorac Oncol. 2012;7:1049-1052. 11. Walter AO et al. Cancer Discov. 2013;3:1404-1415. 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