46MO - FRESCO-2: A global / multiregional phase III clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with metastatic colorectal cancer

Background

Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3 was approved in China in the 3L+ mCRC setting based on results from the FRESCO trial (NCT02314819). FRESCO-2 (NCT04322539) evaluated F in more heavily pretreated pts reflecting current global practices.

Methods

FRESCO-2 was a randomized, double-blind, placebo (P)-controlled, phase 3 MRCT conducted in the US, Europe, Japan & Australia comparing F + best supportive care (BSC) with P + BSC. F or P was given 5 mg PO, QD, 3 weeks on, 1 week off, in 28-day cycles. Key criteria: prior chemotherapy, anti-VEGF therapy, and, if RAS wild type (WT), anti-EGFR therapy; if BRAFV600E mutant (MT) or MSI-H, ≥1 targeted regimen; and prior exposure to trifluridine/tipiracil (T) and/or regorafenib (R). Pts were randomized 2:1 to F + BSC or P + BSC and stratified by: prior T, R, or both; RAS status (WT, MT); and duration of metastatic disease (≤18, >18 months [m]). The primary endpoint was overall survival (OS). Key secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Final OS analysis was after 480 OS events.

Results

From 02Sep2020 to 14Dec2021, 691 pts were randomized; F:461 vs P:230. Baseline characteristics were balanced. F significantly improved OS (median: 7.4 m vs 4.8 m P; HR=0.66 [95%CI: 0.55, 0.80]; p<0.001) & PFS (median: 3.7 m vs 1.8 m P; HR=0.32 [95% CI: 0.27, 0.39]; p<0.001). Median duration of follow-up was 11.3 m F vs 11.2 m P. Subsequent anti-cancer therapies were 29.4% F vs 34.3% P. DCR was 55.5% F vs 16.1% P & ORR was 1.5% F vs 0% P. Grade ≥3 treatment-emergent adverse events were 62.7% F vs 50.4% P; those occurring in ≥5% on F were hypertension (13.6% vs 0.9% P), asthenia (7.7% vs 3.9% P), & hand-foot syndrome (6.4% vs 0% P).

Conclusions

F had a significant and clinically meaningful improvement in OS in pts with refractory mCRC. F was well tolerated with a safety profile consistent with the established profile for F monotherapy. FRESCO-2 results are consistent with FRESCO and should support a new treatment option in refractory mCRC.

Clinical trial identification

NCT04322539.

Editorial acknowledgement

Editorial support in the preparation of this abstract was provided by Team 9 Science, a Vaniam Group agency, funded by HUTCHMED International.

Legal entity responsible for the study

Hutchison Medipharma Limited.

Funding

Hutchison Medipharma Limited.

Disclosure

T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Bayer, Ono, MSD; Financial Interests, Institutional, Invited Speaker: Ono, Sanofi, Daiichi Sankyo, Chugai, Pfizer; Financial Interests, Institutional, Research Grant: Taiho, MSD, Ono, Amgen, Genomedia, Sysmex, Daiichi Sankyo, Chugai, Boehringer Ingelheim. N.A. Dasari: Financial Interests, Institutional, Research Grant: HUTCHMED, Guardant Health, Natera Inc, AAA/Novartis, Eisai; Financial Interests, Personal, Advisory Board: HUTCHMED, Personalis Inc, Crinetics, Voluntis; Financial Interests, Personal, Research Grant: Crinetics. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Mirati; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GlaxoSmithKline, Roche; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech, MSD, Novartis, Pharma Mar, Pierre Fabre, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Personal, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Other, Personal, Other, Honoraria received by spouse for advisory board or invited speaker roles: AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, LILLY, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD; Financial Interests, Personal, Invited Speaker: Organon, Novartis; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd., Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune; Non-Financial Interests, Personal, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Personal, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Personal, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Personal, Other, Travel, accommodations, expenses.: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol Myers Squibb. A. Sobrero: Financial Interests, Personal, Advisory Board: servier, bms, msd, incyte; Financial Interests, Personal, Invited Speaker: bayer, pierre fabre, merck, amgen, sanofi; Financial Interests, Personal, Stocks/Shares: bayer. J.C. Yao: Financial Interests, Personal, Advisory Board: Ipsen, Chiasma Pharma, Amgen, Critics; Financial Interests, Personal, Other, Consultancy: Hutchison Medi Pharma; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Institutional, Invited Speaker: Advanced Accelerator Applications International, Novartis. P. García Alfonso: Financial Interests, Institutional, Research Grant: Roche, Lilly, Sanofi, Merck, Amgen, Servier, Piere Fabre; Financial Interests, Personal, Advisory Role, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Lilly, Sanofi, Merck, Amgen, Servier, Piere Fabre; Financial Interests, Personal, Other, Travel Support: Roche, Lilly, Sanofi, Merck, Amgen, Servier, Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche, Lilly, Sanofi, Merck, Amgen, Servier, Pierre Fabre. A. Sartore Bianchi: Financial Interests, Personal, Invited Speaker: Amgen, Bayer; Financial Interests, Personal, Advisory Board: Amgen, Bayer, Novartis, Servier. J. Tomasek: Financial Interests, Personal, Advisory Role: Servier, Bristol Myers Squibb, Amgen, Pierre Fabre, Merck; Financial Interests, Personal, Invited Speaker: Servier, Bristol Myers Squibb, Amgen, Pierre Fabre, Merck; Financial Interests, Personal, Other, Travel Support: Merck, Novartis. G. Chong: Financial Interests, Personal and Institutional, Research Grant: HUTCHMED, BMS, Isofol, Regeneron, Pharmacyclics, Incyte, Bayer, Merck Serono, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: BMS. Z. Yang: Financial Interests, Personal, Other, Employment: HUTCHMED. W. Schelman: Financial Interests, Personal, Other, Employment: HUTCHMED. M. Kania: Financial Interests, Personal, Other, Employment: HUTCHMED; Financial Interests, Personal, Stocks/Shares: HTUCHMED; Financial Interests, Personal, Leadership Role: HUTCHMED. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daichii Sankyo, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Other, Stocks: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Personal, Invited Speaker, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Personal, Invited Speaker, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Personal, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Personal, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Personal, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Personal, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Personal, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Personal, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Personal, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Personal, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Merck Healthcare KGAA, Menarini, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Personal, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Personal, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Personal, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. C. Eng: Financial Interests, Institutional, Research Grant: Pfizer, Elevar, Merck, Gritstone; Financial Interests, Personal, Advisory Role: Bayer, GSK, Halio Dx, Boston Scientific. T. Satoh: Financial Interests, Personal, Invited Speaker, invited speaker and advisory: Ono Pharmaceutical, Daiichi-Sankyo; Financial Interests, Personal, Invited Speaker, Invited speaer and adovisory: Bristol Myers; Financial Interests, Personal, Invited Speaker, Invited speaker and advisory: Elli-Lilly, Yakult-HOnsha; Financial Interests, Personal, Invited Speaker: Chugai Pharmazeutical, Merck-Biopharm, Takeda, Taiho; Financial Interests, Personal, Advisory Board: Takara-Bio; Financial Interests, Institutional, Invited Speaker: Merck-Biopharm, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Research Grant and Endosed Department: Ono Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Invited Speaker, Research Grant: Elli-Lilly, Daiichi-Sankyo, Parexell, Giliad, Taiho, Hutch-Med. All other authors have declared no conflicts of interest.