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Background: HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer., Methods: MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing., Findings: Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression., Interpretation: Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer., Funding: Seagen and Merck & Co., Competing Interests: Declaration of interests JHS reports support from Seagen for the present manuscript; grants paid to the institution by Amgen, Bayer, Erasca, Seagen, Daiichi-Sankyo, Gossamer Bio, AStar D3, Sanofi, Roche/Genentech, Curegenix, Nektar, AbbVie, and Silverback Therapeutics; receiving consulting fees from AbbVie, Takeda, AstraZeneca, Bayer, GlaxoSmithKline, Inivata, Mereo Biopharma, Pfizer, Roche/Genentech, Seagen, Silverback Therapeutics, and Viatris; receiving honoraria from Bayer, Natera, and Pfizer; receiving travel support from Seagen and Guardant Health; receiving other services from Guardant Health; and is a member of advisory boards for AbbVie and Pionyr Immunotherapeutics. AC reports grants paid to their institution by Seagen, GlaxoSmithKline, and Inspira (previously RGenix) and receiving advisory or consultancy fees from Bayer, Merck, Seagen, GlaxoSmithKline, Janssen, and G1 Therapeutics. SS is a member of advisory boards for Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, CheckmAb, Daiichi-Sankyo, Guardant Health, Menarini, Merck, Novartis, Pierre-Fabre, Roche-Genentech, and Seagen. TA reports attending advisory board meetings and receiving consulting fees from Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, GamaMabs Pharma Sa, GlaxoSmithKline, Gilead, Kaleido Oncology, Merck & Co, Pierre Fabre, Seagen, Servier Transgène, and Roche/Ventana; receiving support for attending meetings from Bristol Myers Squibb, Merck & Co, and Servier; and receiving honoraria for speaking, manuscript writing, or educational events from AstraZeneca, Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Merck & Co, Pierre Fabre, Seagen, Roche/Ventana, Sanofi, and Servier; and receiving travel support from Bristol Myers Squibb and Merck & Co. KN reports grants from Pharmavite, Revolution Medicines, Evergrande Group, and Janssen and receiving consultancy fees from Bayer, Seagen, X-Biotix Therapeutics, Array Biopharma, BiomX, Bicara Therapeutics, GlaxoSmithKline, Pfizer, and Redesign Health. EVC reports grants paid to the institution by Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier and receiving consulting fees from AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi, Halozyme, GlaxoSmithKline, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, and Zymeworks. CW reports grants paid to the institution by Boston Biomedical, Bristol Myers Squibb, Lycera, RAPT Therapeutics, Seagen, Symphogan, Vaccinex, INHBRX, and Pfizer; receiving honoraria from Array Biopharma, Signatera, Pfizer, Daiichi Sankyo; receiving travel support from Array Biopharma; and former employment at Winship Cancer Institute of Emory University, Atlanta, GA, USA (at the time of study conduct). ASP reports receiving support for the present from Seagen to provide medical writing assistance, institutional funding, study materials, processing charges; funding paid to the institution for clinical research trials from Ipsen, Bristol Myers Squibb, Exelixis, HutchMed, Seagen, Taiho, Lilly, AstraZeneca, Incyte, Deciphera, G1 Therapeutics, Zentalis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, and Bayer; receiving honoraria from Ideo Oncology and MJH Life Sciences (both educational event companies); participating in advisory boards for Amgen, Bristol Myers Squibb, Eisai, Ipsen, AAA, Exelixis, Pfizer, QED, Lilly, Mirati, HutchMed, Astellas, and Aadi; receiving travel support from Pfizer; owning stock or stock options from Aptose, Actinium, and Alexion; and receiving medical writing services from Bayer, Ipsen, HutchMed, Exelixis, and Seagen. JMH reports grants paid to the institution by Merck, Boston Biomedical, Senhwa Pharmaceuticals, Bayer, Incyte, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, G1 Therapeutics, Roche, and Treos Bio and participation on advisory boards with honoraria to the institution by Bayer, Merck, BeiGene, and Incyte. ALC reports grants from Nucana, Seagen, Abgenomics, Novocure, Actuate, Medimmune/AstraZeneca, PanCan, Amgen, and Nextrast. CF reports support for the present manuscript paid to the institution by Seattle Genetics (currently Seagen) and grants paid to their institution by the National Comprehensive Cancer Network Foundation, National Comprehensive Cancer Network Oncology Research Program, Taiho Oncology, National Cancer Institute (NCI), and Pfizer. AK reports no conflict of interest. PMK reports grants paid to the institution by Advanced Accelerator Applications, Tersera, and Boston Scientific; a consultancy and advisory board relationship with Elicio (scientific advisory board member/shares/stock ownership); receiving consulting fees from Natera, Foundation Medicine, Illumina, BostonGene, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, IPBA, QED Therapeutics, Boston Healthcare Associates, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, and Seattle Genetics; consulting fees paid to the institution by Taiho Pharmaceutical and Ipsen; receiving travel support from AstraZeneca; and former employment at University of Iowa Hospitals and Clinics, Iowa City, IA, USA (at the time of study conduct). H-JL reports grants from NCI (P30, U01, U2c, UG1, and UM1), US Department of Defense, Southwest Oncology Group; receiving consulting fees from Merck, Bayer, Merck KG, Roche, Fulgent, Oncocyte, G1 Therapeutics, Jazz Therapeutics, 3T bioscience, and Adagene; receiving honoraria from Bayer, Roche, and Pfizer; participating in unpaid leadership roles with Wunderglo Foundation, Debbie Dream Foundation, and Cancer Support Group; and owning stock options in Fulgent. KKC reports grants paid to the institution by Bristol Myers Squibb, Array, Incyte, Daiichi Sankyo, Nucana, Merck, Pfizer, Calithera, Genentech, and Seagen; participating on advisory boards and receiving consulting fees from Merck, Lilly/Loxo, Pfizer, Replimune, Personalis, Exelixis, and Array; receiving travel or hotel support for attending advisory board meeting from Array; and participating on the Board of Directors for Academic and Community Cancer Research United. EE reports grants, receiving consulting fees and payment for expert testimony, receiving honoraria, receiving travel support, and participating in advisory boards from Amgen, Bayer, Hoffmann-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD, Organon, Novartis, Servier and financial support for clinical trials or contracted research paid to the institution from Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmaceutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Developpement, Servier, Taiho Pharma USA. DLB reports a grant for trial support of the present study paid to the institution by Seagen; grants paid to the institution by Seagen, Rafael/Cornerstone, and Abbvie; receiving honoraria for speakers bureau from Natera; receiving salary support for participating on the local data safety monitoring board for University Hospitals; receiving no payment for participating on the advisory board for Rafael pharmaceuticals; and receiving study drug from Novartis and Epizyme. CC reports grants paid to the institution by Merck, Bayer, Servier, Amgen, and Roche; receiving honoraria from Roche, Amgen, Merck, MSD, Pierre Fabre, Servier, Bayer, and Nordic Pharma; receiving payment for expert testimony from Merck and Bayer; receiving travel support from Amgen; participating on advisory boards for Nordic Pharma, Amgen, MSD, Pierre Fabre, and Mirati. FS reports no conflict of interest. MS reports being employed by and owning stock in Seagen. WF reports being employed by and owning stock in Seagen. TSB-S reports research funding paid to the institution by Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and Bristol Myers Squibb; consulting fees paid to the institution by Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, and Merck; receiving consulting fees from Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina, and Foundation Medicine; participating on independent data monitoring committees or data safety monitoring boards for Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan, and 1Globe; participating on scientific advisory boards for Imugene, Immuneering, Xilis, Replimune Artiva, and Sun Biopharma; receiving royalties from Uptodate; and inventions or patents—WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF (licensed to Imugene) and WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA (licensed to Recursion)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements., Methods: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed., Findings: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related., Interpretation: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements., Funding: Incyte Corporation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)