ESMO 2019 Update Axel Grothey Director, GI Oncology Research West Cancer Center Research Institute Encorafenib plus Cetuximab With or Without Binimetinib for BRAF V600E–Mutant Metastatic Colorectal Cancer: Expanded Results from a Randomized, 3-Arm, Phase 3 Study vs. the Choice of Either Irinotecan or FOLFIRI plus Cetuximab (BEACON CRC) Josep Tabernero, Axel Grothey, Eric Van Cutsem, Rona Yaeger, Harpreet Wasan, Takayuki Yoshino, Jayesh Desai, Fortunato Ciardiello, Fotios Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod Kyrre Guren, Hendrik-Tobias Arkenau, Pilar Garcia-Alfonso, Ashwin Gollerkeri, Michael Pickard, Kati Maharry, Janna Christy-Bittel, Lisa Anderson, and Scott Kopetz BEACON CRC: Binimetinib, Encorafenib, And Cetuximab COmbiNed to Treat BRAF-mutant ColoRectal Cancer 2 Study Design Patients with BRAFV600E mCRC with disease progression after 1 or 2 prior regimens; ECOG PS of 0 or 1; and no prior treatment with any RAF inhibitor, MEK inhibitor, or EGFR inhibitor Phase 3 Primary Endpoints: Safety Lead-in ENCORAFENIB + Triplet therapy BINIMETINIB + ENCORAFENIB + BINIMETINIB + CETUXIMAB Triplet vs Control n = 205 CETUXIMAB N = 30 OS R Doublet therapy (All randomized Pts) Encorafenib 300 mg PO daily 1:1:1 ENCORAFENIB + CETUXIMAB Binimetinib 45 mg PO bid n = 205 Cetuximab standard weekly ORR – dosing Blinded Central Control arm Review FOLFIRI + CETUXIMAB, or (1st 331 randomized Pts) irinotecan + CETUXIMAB n = 205 Randomization was stratified by ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. no), and cetuximab source (US-licensed vs. EU-approved) Secondary Endpoints: Doublet vs Control and Triplet vs Doublet - OS & ORR, PFS, Safety QOL Assessments: EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer, EuroQol 5D5L, and Patient Global Impression of Change). Overall Survival and Objective Response Rate Triplet vs Control Doublet vs Control HR (95% CI): 0.52 (0.39-0.70) Triplet HR (95% CI): 0.60 (0.45-0.79) 2-sided P<0.0001 Doublet 2-sided P=0.0003 Median OS in months (95% CI) Median OS in months (95% CI) Triplet Control Doublet Control 9.0 (8.0-11.4) 5.4 (4.8-6.6) 8.4 (7.5-11.0) 5.4 (4.8-6.6) Control Control Objective Response Rate (First 331 Randomized Patients) Triplet Doublet Control Confirmed Response by BICR N=111 N=113 N=107 Objective Response Rate 26% 20% 2% 95% (CI) (18, 35) (13, 29) (<1, 7) p-value vs. Control <0.0001 <0.0001 Kopetz et al. Ann Oncol 2019;30 (Supplement 4): iv137–iv151 (LBA-006). Overall Survival: Triplet vs Doublet (All Randomized Patients) Study not powered to formally compare the results of the triplet combination to the doublet combination HR (95% CI): 0.79 (0.59-1.06) Median OS in months (95% CI) Triplet Triplet Doublet 9.0 (8.0-11.4) 8.4 (7.5-11.0) Median Follow up: 7.8 Months* 33% of patients alive with less than 6 months FU Doublet 5 *all randomized patients. Overall Survival: Triplet vs Doublet (First 331 Randomized Patients*) Study not powered to formally compare the results of the triplet combination to the doublet combination HR (95% CI): 0.74 (0.53-1.04) Median OS in months (95% CI) Triplet Triplet Doublet 9.5 (8.1-12.0) 8.3 (6.2-10.7) Median Follow up: 12.5 Months 1% of patients alive with less than 6 months FU Doublet 6 *Post-hoc descriptive analysis. Waterfall Plots of Best Change in Sum of Diameters (based on central review) Triplet Control N=87 DoubletDoublet N=73 N=98 *Patients whose SoD was contraindicated by assessment of PD. SoD=sum of longest diameter. Includes patients with measurable disease with a baseline and at least one post-baseline scan. 7 Combined Waterfall Plots: Triplet and Doublet Triplet (N=87) Doublet (N=98) WilcoxonDoublet Rank Sum P-Value: 0.033 *Patients whose Sum of longest diameter was contraindicated by assessment of PD. 2-sided p-value is descriptive only for this analysis. Comparison of the two waterfall plots is suggestive of a shift towards greater tumor reduction from baseline in the Triplet. 8 Grade ≥3 Adverse Events and Laboratory Abnormalities* Triplet Doublet Control Event N=222 N=216 N=193 Grade ≥3 Grade ≥3 Grade ≥3 Diarrhea 10% 2% 10% Abdominal pain 6% 2% 5% Nausea 5% <1% 1% Vomiting 4% 1% 3% Pulmonary embolism 4% 1% 4% Intestinal obstruction 3% 4% 3% Asthenia 3% 3% 5% Acute kidney injury 3% 2% <1% Fatigue 2% 4% 4% Dermatitis acneiform 2% <1% 3% Ileus 2% 1% 2% Urinary tract infection 1% 2% 1% Cancer pain <1% 2% <1% Laboratory Abnormality Grade ≥3 Grade ≥3 Grade ≥3 Hemoglobin (g/L), hypo 11% 4% 4% Creatinine (umol/L), hyper 5% 2% 1% Creatine Kinase (IU/L), hyper 3% 0 0 Bilirubin (umol/L), hyper 2% 2% 3% 9 *Occurring in at least 2% of patients in either triplet or doublet arms. Other CRC Highlights • FOxTROT: • Neoadjuvant FOLFOX (x3) in locally advanced colon cancer decreases R1 resection rate • Decreased surgical morbidity • 20% of patients overstaged (unnecessary chemo) • No tumor regression in MSI-H cancer • MOUNTAINEER: • HER-2 pos CRC: Tucatinib + Trastuzumab generate 55% RR (in 22 pts) • IDEA high-risk stage II: • Same regimen-effect as seen in stage III (CAPOX vs FOLFOX) • IDEA France: • ctDNA in stage III is prognostic (we knew that), but intensified chemo can improve outcome (that’s new) ctDNA in IDEA France • First documentation that “intensification” of adjuvant chemotherapy (6 vs 3 months) can improve outcome in ctDNA pos stage III colon cancer Taieb, ESMO 2019 KEYNOTE-062 Study Design (NCT02494583) Key Eligibility Criteria N = 256 • Locally advanced, Pembrolizumab 200 mg Q3W unresectable or for up to 35 cyclesb metastatic gastric or gastroesophageal adenocarcinoma N = 763 Until unacceptable Pembrolizumab 200 mg Q3W toxicity, disease • HER2/neu negative, R N = 257 (to 35 cycles) progression, or PD-L1-positive disease (1:1:1) + patient/physician (CPS ≥1) Chemotherapyc • ECOG PS 0 or 1 withdrawal decision Stratification Factors N = 250 Placebo • Regiona + Chemotherapy • Locally advanced or metastatic disease • 5-FU or Capecitabine Primary endpoints: OS and PFS Secondary endpoints: ORR, Safety aEU/North America/Australia, Asia (South Korea, Hong Kong, Taiwan, Japan), Rest of World (including South America). Tabernero ASCO 2019 bAdministration of pembrolizumab monotherapy was not blinded. cChemotherapy: Cisplatin 80 mg/m2 Q3W + 5-FU 800 mg/m2/d for 5 days Q3W or capecitabine BID d1-14 Q3W (Cisplatin may be capped at 6 cycles as per country guidelines). Overall Survival: P vs C (CPS ≥1) 100 Events HR (99.2% CI) NIa 90 Pembro 79% 0.91 1.2 Chemo 86% (0.69-1.18) 80 70 12-mo rate 47% 24-mo rate 60 46% 27% 19% b 50 Median (95% CI) 10.6 mo (7.7-13.8) OS,% 40 11.1 mo (9.2-12.8) 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 No. at Risk Time, months 256 201 162 139 120 107 94 83 59 38 23 12 4 0 0 250 230 192 144 114 94 75 49 38 21 15 6 2 2 0 aNI, non-inferiority margin; bHR (95% CI) = 0.91 (0.74-1.10), P = 0.162 for superiority of P vs C; Data cutoff: March 26, 2019. Tabernero ASCO 2019 Shitara ESMO 2019 Genetic Landscape of Biliary Cancers ICC ECC FGFR1-3 fusions, mutations ERBB2/3 amplification & amplifications (11-45%) (11-17%) IDH1/2 mutation (5-36%) IDH1/2 mutation (0-7%) RNF43 mutation (9%) PIK3CA mutation (7%) PIK3CA mutations (3-9%) MET mutation (4%) BRAF mutations (3-7%) BRAF mutations (3%) ERBB3 amplification (7%) MET amplification (1%) MET amplification (2-7%) ERBB3 mutation (7%) GBCA MET mutation (5%) ERBB2/3 amplification EGFR mutation (1-2%) (10-19%) PIK3CA mutation (6- 13%) BRAF mutation (1-6%) RNF43 mutation (4%) MAP2K4 mutation (4%) EGFR mutation (4%) FGFR1-3 fusions, mutations & amplifications (3%) IDH1/2 mutation (2%) Frequencies of Actionable Mutations in BTCs 30% 25% 20% 15% 10% ICC ECC 5% GBCA 0% Goyal et al., ESMO GI 2017 Phase II: BGJ398 in FGFR altered Cholangiocarcinomas RR: 14.8% SD: 60.7% 2/3 patients with more than 2 lines of prior therapy Javle et al, JCO 2018 Pemigatinib – Study Cohorts Pemigatinib RR (Cohort A – FGRF Fusions) Pemigatinib – Overall Survival ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib vs placebo in patients with advanced cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) mutation Ghassan K. Abou-Alfa,1,2 Teresa Maraculla,3 Milind Javle,4 R. Kate Kelley,5 Sam Lubner,6 Jorge Adeva,7 James M. Cleary,8 Daniel V. Catenacci,9 Mitesh J. Borad,10 John Bridgewater,11 William P. Harris,12 Adrian G. Murphy,13 Do-Youn Oh,14 Jonathan Whisenant,15 Bin Wu,16 Liewen Jiang,16 Camelia Gliser,16 Shuchi S. Pandya,16 Juan W. Valle,17 Andrew X. Zhu18 1Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Weill Medical College at Cornell University, New York, NY, USA; 3Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4MD Anderson Cancer Center, Houston, TX, USA; 5University of California San Francisco, San Francisco, CA, USA; 6University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 7Hospital Universitario 12 de Octubre, Madrid, Spain; 8Dana-Faber Cancer Institute, Boston, MA, USA; 9University of Chicago Medical Center, Chicago, IL, USA; 10Mayo Clinic Cancer Center, Phoenix, AZ, USA; 11UCL Cancer Institute, London, UK; 12University of Washington, Seattle, WA, USA; 13Johns Hopkins University, Baltimore, MD, USA; 14Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; 15Utah Cancer Specialists, Salt Lake City, UT, USA; 16Agios Pharmaceuticals, Inc., Cambridge, MA, USA; 17University of Manchester, The Christie NHS Foundation Trust, Manchester, UK; 18Massachusetts General Hospital Cancer Center, Harvard Medical