11lba phase i study of the selective brafv600 inhibitor encorafenib (lgx818) combined with cetuximab...

Plenary Session 8 Late Breaking Abstracts, Friday 20 November 2014 199

10LBA LATE BREAKING ABSTRACTInterim phase 2 results of study CO-1686-008: A phase 1/2 study

of the irreversible, mutant selective, EGFR inhibitor rociletinib

(CO-1686) in patients with advanced non small cell lung cancer

J. Soria1, L.V. Sequist2, J.W. Goldman3, H.A. Wakelee4, S.M. Gadgeel5,A. Varga1, H.A. Yu6, B.J. Solomon7, S.H. Ou8, V. Papadimitrakopoulou9,G.R. Oxnard10, L. Horn11, R. Dziadziuszko12, B. Chao13, A.I. Spira14,S. Liu15, T. Mekhail16, S. Matheny17, J. Litten17, R.D. Camidge18. 1InstitutGustave Roussy, Villejuif, France; 2Massachusetts General Hospital,Boston, USA; 3UCLA Santa Monica Hematology-Oncology, SantaMonica, USA; 4Stanford Cancer Institute, Stanford, USA; 5KarmanosCancer Institute Wayne State University, Detroit, USA; 6MemorialSloan-Kettering Cancer Center, New York, USA; 7 Peter MacCallumCancer Centre, Melbourne, Australia; 8University of California, Irvine,USA; 9The University of Texas MD Anderson Cancer Center, Houston,USA; 10Dana Farber Cancer Institute, Boston, USA; 11Vanderbilt-IngramCancer Center, Nashville, USA; 12Medical University of Gdansk,Department of Oncology and Radiotherapy, Gdansk, Poland; 13The OhioState University, Division of Medical Oncology, Columbus, USA; 14VirginiaCancer Specialists, Fairfax, USA; 15Georgetown University Hospital,Washington, USA; 16Florida Hospital, Orlando, USA; 17 Clovis Oncology,Boulder, USA; 18University of Colorado Cancer Center, Aurora, USA

Background: Rociletinib (CO-1686) is a potent, oral, irreversible inhibitor ofmutant EGFR, including the T790M resistance mutation. T790M accountsfor 60% of acquired resistance to first and second generation EGFRinhibitors. Early clinical data demonstrated encouraging preliminary activityin patients with T790M+ disease without the skin effects typical ofagents that do not spare wild type EGFR signaling. We now presentinterim phase 2 data from T790M+ patients in addition to data from aT790M negative cohort from the ongoing phase 1/2 study.Materials and Methods: Eligible patients have advanced EGFR mutantT790M+/− non small cell lung cancer (NSCLC), previous treatment withat least one EGFR inhibitor, ECOG PS 0−1, and adequate organ function.Stable brain metastases are allowed. Patients all received prior EGFR TKI,with separate phase 2 cohorts receiving EGFR TKI as the only priortreatment and others who had additional prior systemic therapies. Thedoses of rociletinib studied were 500mg bid, 625mg bid and 750mg bid.Results: As of August 31, 2014, 193 patients were enrolled at therapeuticdoses, with early efficacy data currently available for 99 (n = 81 T790M+,n = 18 T790M negative). Demographic characteristics reflect a Westernpopulation with advanced mutant EGFR NSCLC: median age 60 yrs,66% female, 68% white, 62% ECOG 1, median prior TKI lines 2, medianprior therapies 3. The only related �Grade 3 AE occurring in �5% patientswas hyperglycemia (21%) and no pt discontinued for this event.Related AEs (all grades) in �15% patients were: hyperglycemia (37%),nausea (23%), diarrhea (18%), and fatigue (17%). Related rash occurredin 3%, all grade 1. In the T790M+ group, the immature overall responserate (ORR) is currently 41/81 (51%). The T790M+ subset with maturedata shows ORR of 24/40 (60%) of which 20 are confirmed (1 respondercurrently not evaluable [NE] for confirmation). At the recommended phase 2dose (RP2D) of 625mg BID, ORR is currently 6/10 (60%) with duration ofresponse ranging from 85 to 184+ days. In the T790M negative group, theoverall response rate is 5/18 (28%) of which 4 are confirmed (1 respondercurrently NE for confirmation) and the duration of response ranges from1 to 205 days. All responding T790M negative patients progressed onEGFR TKI therapy immediately before starting rociletinib.Conclusion: Rociletinib is associated with durable clinical benefit inpatients with advanced EGFR mutant T790M+ NSCLC. The activity inthe T790M negative group may result from assay insensitivity, tumorheterogeneity or from concomitant inhibition by rociletinib of other tyrosinekinases involved in tumor growth. Comparison between local and centralEGFR testing, together with updated clinical data at the RP2D (N≈ 50)will be presented.

11LBA LATE BREAKING ABSTRACTPhase I study of the selective BRAFV600 inhibitor

encorafenib (LGX818) combined with cetuximab and with or without

the a-specific PI3K inhibitor alpelisib (BYL719) in patients with

advanced BRAF mutant colorectal cancer

J. Tabernero1, R. van Geel2, J.C. Bendell3, A. Spreafico4, M. Schuler5,T. Yoshino6, J.P. Delord7, Y. Yamada8, M.P. Lolkema9, J.E. Faris10,F.A.L.M. Eskens11, S. Sharma12, R. Yaeger13, H.J. Lenz14, Z. Wainberg15,E. Avsar16, A. Chatterjee16, S. Jaeger17, T. Demuth18, J.H.M. Schellens2.1Vall D’Hebron University Hospital, Medical Oncology Department,Barcelona, Spain; 2The Netherlands Cancer Institute, Department ofMedical Oncology, Amsterdam, Netherlands; 3Sarah Cannon ResearchInstitute, Department of Oncology, Nashville TN, USA; 4PrincessMargaret Cancer Centre, Department of Oncology, Toronto, Canada;5West German Cancer Center University Hospital Essen UniversityDuisburg-Essen, Department of Medical Oncology, Essen, Germany;6National Cancer Center Hospital East, Department of Gastroenterologyand Gastrointestinal Oncology, Chiba, Japan; 7 Institut Claudius Regaud,Departement Medecine, Toulouse, France; 8National Cancer CenterHospital, Division of Gastrointestinal Oncology, Tokyo, Japan; 9UniversityMedical Center Utrecht, Department of Medical Oncology, Utrecht,Netherlands; 10Massachusetts General Hospital, Department of Medicine,Boston MA, USA; 11Erasmus MC Cancer Institute, Department ofMedical Oncology, Rotterdam, Netherlands; 12Huntsman Cancer InstituteUniversity of Utah, Department of Internal Medicine, Salt Lake CityUT, USA; 13Memorial Sloan-Kettering Cancer Center, Department ofMedicine, New York NY, USA; 14Keck School of Medicine at the Universityof Southern California, Department of Medicine, Los Angeles CA, USA;15UCLA Medical Center, Department of Medicine, Santa Monica CA, USA;16Novartis Pharmaceutical Corporation, Oncology Translational Medicine,East Hanover NJ, USA; 17 Novartis Institutes for Biomedical Research,Oncology Translational Medicine, Cambridge MA, USA; 18NovartisPharma AG, Oncology Translational Medicine, Basel, Switzerland

Background: Unlike BRAFV600 mutated (BRAFm) advanced melanoma,BRAFm colorectal carcinoma (CRC) does not respond to BRAF inhibitors.In these tumors, BRAF inhibition is associated with strong feedbackactivation of the epidermal growth factor receptor (EGFR) and downstreamsignaling. Preclinical studies suggest strong synergistic activity with aBRAF and an EGFR inhibitor in combination with a PI3K inhibitor. Theaims of this study were to: (1) establish safety and preliminary activity ofcombination therapy with encorafenib (ENC), a highly selective BRAFV600inhibitor, the EGFR mAb cetuximab (CTX), ± the a-specific PI3K inhibitoralpelisib (ALP) in patients (pts) with BRAFm CRC; and (2) collect dataon predictive biomarkers by next generation sequencing (NGS) analysis oftumor samples.Methods: In this phase I study, safety, tolerability, and anti-tumor activityof ENC +CTX±ALP were evaluated in pts with advanced BRAFm/KRAS wild-type CRC. Cohorts of pts were treated with escalating dosesof oral ENC once daily (QD) in combination with the standard dosingof intravenous (IV) CTX (400mg/m2 loading dose, 250mg/m2 weekly) inthe dual arm, or with escalating doses of oral ENC and oral ALP QD incombination with IV CTX in the triple arm. Archival or fresh screening tumorsamples were analyzed by panel sequencing using NGS technology toevaluate alignment with response.Results: As of August 15, 2014, 54 pts were enrolled in the dose-escalation phase; 26 were in the dual arm (ENC+CTX) and 28 werein the triple arm (ENC+ALP+CTX). Recommended phase 2 dosing foreach treatment arm was established as 200mg ENC QD + CTX weekly(dual arm) and 200mg ENC QD + 300mg ALP QD + CTX weekly(triple arm). In the dual arm, the most common treatment-related adverseevents (AEs) were as follows: all grades [fatigue (46%), infusion-relatedreaction (35%)], and grade 3/4 [fatigue (8%), hypophosphatemia (15%)]. Inthe triple arm, the most common treatment-related AEs were as follows: allgrades [nausea, diarrhea (both 50%)], and grade 3/4 [hyperglycemia (11%),increased lipase (7%)]. Overall response rates (� partial response) were23% (dual arm, with 1 unconfirmed [u] PR and 1 uCR) and 25% (triplearm, with 4 uCR/PRs). Median PFS was 3.7 months (95%CI 12.0–46.1;dual arm) and 4.3 months (95%CI 18.1–39.6; triple arm). A total of 47 ptswere evaluated for baseline tumor mutation status; alignment with clinicalresponse by RECIST will be presented.Conclusions: These results indicate that combination treatment ofENC and CTX ± ALP is well tolerated with promising antitumor activityin pts with advanced BRAFm CRC who failed standard treatment. Thegenetics landscape will be presented alongside clinical efficacy data.