Zie ook literatuurlijst niet-toxische middelen en weinig invasieve behandelingen specifiek bij borstkanker zoals opgesteld door arts-bioloog drs. Engelbert Valstar

19 december 2022: Bron: JAMA Oncol. Published online December 1, 2022

Uit de resultaten van de HER2CLIMB studie blijkt dat de Tyrase Kinase Remmer (TKR)  Tucatinib (Tukysa) in combinatie met herceptin - trastuzumab en capecitabine (Xeloda) de mediane overall overleving verbeterde met maar liefst 9,1 maanden bij borstkankerpatiënten type HER2 positief. Zelfs patiënten met hersenmetastasen profiteerden in gelijke mate van deze aanpak. Ook verminderde deze behandeling het risico op het ontwikkelen van nieuwe hersenuitzaaiingen en verminderde het risico op overlijden met 45,1% bij alle deelnemende patiënten in vergelijking met een placebo ipv tucatinib.

De HER2CLIMB studie is een gerandomiseerde, internationale, multicenter studie bij patiënten met progressieve inoperabele lokaal gevorderde of gemetastaseerde HER2+ borstkanker (621 patienten) die eerder zijn behandeld met trastuzumab, pertuzumab en T-DM1.
Deze studie bestaat uit twee fasen: de dubbelblinde fase en de niet-geblindeerde fase. In de dubbelblinde fase werden de deelnemers gerandomiseerd in een verhouding van 2:1 om tucatinib of placebo te krijgen in combinatie met capecitabine en trastuzumab. In de niet-geblindeerde fase kunnen patiënten op placebo overstappen en tucatinib krijgen.

Patiënten werden 2:1 gerandomiseerd naar tucatinib (300 mg oraal tweemaal daags) of placebo (oraal tweemaal daags), beide in combinatie met trastuzumab (6 mg/kg intraveneus of subcutaan elke 3 weken met een initiële oplaaddosis van 8 mg/kg ) en capecitabine (1000 mg/m2 oraal tweemaal daags op dag 1-14 van elke cyclus van 3 weken).

Resultaten vertaalt uit het abstract:

Bij aanvang hadden 291 van de 612 patiënten (47,5%) hersenuitzaaiingen (BM's). De mediane leeftijd was 52 jaar (variërend van 22-75 jaar) en 289 (99,3%) waren vrouw. Bij een mediane follow-up van 29,6 maanden (spreiding 0,1-52,9 maanden) was de mediane OS 9,1 maanden langer in de tucatinib-combinatiegroep (21,6 maanden; 95% BI, 18,1-28,5) versus de placebo-combinatiegroep (12,5 maanden). 95% BI, 11,2-16,9).

De combinatiegroep met tucatinib vertoonde een groter klinisch voordeel in CNS-PFS en ORR-IC in vergelijking met de combinatiegroep met placebo. De DOR-IC was 8,6 maanden (95% BI, 5,5-10,3 maanden) in de tucatinib-combinatiegroep en 3,0 maanden (95% BI, 3,0-10,3 maanden) in de placebo-combinatiegroep. Het risico op het ontwikkelen van nieuwe hersenlaesies als plaats van eerste progressie of overlijden was verminderd met 45,1% in de tucatinib-combinatiegroep versus de placebo-combinatiegroep (hazard ratio, 0,55 [95% CI, 0,36-0,85]).

Conclusie:

Uit deze subgroepanalyse bleek dat tucatinib in combinatie met trastuzumab en capecitabine de overall overleving (OS) verbeterde terwijl het risico op het ontwikkelen van nieuwe hersenmetastases werd verminderd, wat het belang van deze behandelingsoptie voor patiënten met ERBB2-positieve MBC, inclusief die met hersenuitzaaiingen (BM's), verder ondersteunt.

Het volledige studierapport is gratis in te zien of te downloaden, klik daarvoor op de titel van het abstract:

Key Points

Question  Can tucatinib, trastuzumab, and capecitabine provide systemic and intracranial benefit for patients with ERBB2 (HER2)-positive metastatic breast cancer and brain metastases?

Findings  In this exploratory subgroup analysis of a randomized clinical trial of 612 patients with ERBB2-positive breast cancer, overall survival, intracranial efficacy, and new brain lesion–free survival were evaluated. Tucatinib in combination with trastuzumab and capecitabine prolonged median overall survival by 9.1 months in patients with brain metastases and reduced the risk of developing new brain lesions as sites of first progression or death by 45.1% in all patients.

Meaning  Findings suggest tucatinib in combination with trastuzumab and capecitabine provides survival benefits and delays development of new brain lesions, representing an important treatment option for patients with ERBB2-positive metastatic breast cancer, including those with brain metastases.

Abstract

Importance  It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs.

Objective  To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up.

Design, Setting, and Participants  HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed.

Interventions  Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle).

Main Outcomes and Measures  Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion–free survival in all patients. Only OS was prespecified before the primary database lock.

Results  At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]).

Conclusions and Relevance  This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs.

Trial Registration  ClinicalTrials.gov Identifier: NCT02614794

Article Information

Accepted for Publication: August 17, 2022.

Published Online: December 1, 2022. doi:10.1001/jamaoncol.2022.5610

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Lin NU et al. JAMA Oncology.

Corresponding Author: Nancy U. Lin, MD, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 (nancy_lin@dfci.harvard.edu).

Author Contributions: Dr Ramos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lin, Anders, Borges, Cameron, Curigliano, Krop, Loibl, Mueller, Pegram, Slamon, Ramos, Feng, Winer.

Acquisition, analysis, or interpretation of data: Lin, Murthy, Abramson, Anders, Bachelot, Bedard, Borges, Cameron, Carey, Chien, Curigliano, DiGiovanna, Gelmon, Hortobagyi, Hurvitz, Loi, Loibl, Mueller, Oliveira, Paplomata, Pegram, Zelnak, Ramos, Feng.

Drafting of the manuscript: Lin, Borges, Curigliano, Loi, Paplomata, Ramos, Feng.

Critical revision of the manuscript for important intellectual content: Lin, Murthy, Abramson, Anders, Bachelot, Bedard, Borges, Cameron, Carey, Chien, Curigliano, DiGiovanna, Gelmon, Hortobagyi, Hurvitz, Krop, Loi, Loibl, Mueller, Oliveira, Pegram, Slamon, Zelnak, Ramos, Feng, Winer.

Statistical analysis: Curigliano, Slamon, Ramos, Feng.

Administrative, technical, or material support: Bachelot, Gelmon.

Supervision: Borges, Chien, Curigliano, Hortobagyi, Krop, Oliveira, Zelnak.

Conflict of Interest Disclosures: Dr Lin reported receiving nonfinancial support from Seagen for manuscript preparation during the conduct of the study; grants from Genentech, Merck, AstraZeneca, Zion Pharmaceuticals, Seagen, Olema Pharmaceuticals, and Pfizer outside the submitted work; personal fees from Pfizer, Puma, Seagen, Daiichi Sankyo, Prelude Therapeutics, Denali Therapeutics, Olema Pharmaceuticals, AstraZeneca, Aleta BioPharma, Affinia Therapeutics, and Voyager Therapeutics outside the submitted work; consulting fees from Affinia Therapeutics, Aleta BioTherapeutics, AstraZeneca, Daiichi Sankyo, Denali Therapeutics, Olema Oncology, Pfizer, Prelude Therapeutics, Seagen, Voyager Therapeutics, and Artera Inc; and royalties from UpToDate outside the submitted work. Dr Murthy reported receiving grants from Seagen, Oncothyreon, and Cascadian Therapeutics during the conduct of the study; consulting fees and nonfinancial support for manuscript writing and travel from Seagen during the conduct of the study; grants from Genentech/Roche, Pfizer, Daiichi Sankyo, AstraZeneca, and EMD Serono outside the submitted work; and consulting fees from Novartis, AstraZeneca, Pfizer, Genentech/Roche, Puma, and Sanofi outside the submitted work. Dr Abramson reported serving on the advisory boards of Eisai, Seagen, and Daiichi Sankyo outside the submitted work; receiving consulting fees from AstraZeneca and Daiichi Sankyo; and receiving research funding from Genentech and Lilly. Dr Anders reported receiving grants from Seagen during the conduct of the study; consulting fees from Genentech, Eisai, Ipsen, Seagen Inc, AstraZeneca, Novartis, Immunomedics, Elucida Oncology, and Athenex outside the submitted work; grants from PUMA, Lilly, Merck, Nektar, Tesaro, G1 Therapeutics, Zion Pharma, Novartis, Pfizer, AstraZeneca, and Elucida outside the submitted work; and royalties from Jones and Bartlett and UptoDate.com outside the submitted work; and participating in an education program with Eisai. Dr Bachelot reported receiving consulting fees from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche, and Seagen; grants from AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, and Seagen; and nonfinancial support from Pfizer outside the submitted work. Dr Bedard reported receiving grants from Seagen during the conduct of the study; grants from Amgen, Bicara, Bristol Myers Squibb, AstraZeneca, GlaxoSmithKline, Genentech/Roche, Novartis, Merck, Lilly, Seagen, Zymeworks, Pfizer, Medicenna, Nektar Therapeutics, Immunomedics, and Sanofi outside the submitted work; nonfinancial consulting relationship with Seagen, Lilly, Amgen, Merck, Gilead Sciences, Bristol Myers Squibb, and Pfizer; and serving in an uncompensated advisory capacity for Amgen, Lilly, Seagen, Zymeworks, Gilead, and Merck. Dr Borges reported receiving consulting fees and grants from Seagen during the conduct of the study; personal fees from AstraZeneca outside the submitted work; and grants from AstraZeneca, Olema Oncology, and Oncosec Medical; and having equity ownership in PERLATX. Dr Cameron reported receiving consulting fees from Novartis, Roche, and Seagen; receiving grants from AstraZeneca, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Roche, and Seagen; and serving on the Independent Data Monitoring Committee for Synthon outside the submitted work. Dr Carey reported receiving research funding from Syndax Pharmaceuticals, Novartis, NanoString Technologies, AbbVie, Seagen, and Veracyte; having uncompensated relationships with Eisai, Sanofi-Aventis, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/Daiichi Sankyo, Aptitude Health, and Exact Sciences; and having an immediate family member with a royalty-sharing agreement and investorship interest in licensed intellectual property to Falcon Therapeutics. Dr Chien reported receiving grants from Seagen during the conduct of the study; grants from Amgen, Merck, Puma Biotechnology, and Seagen; and grants from Merck, Amgen, and Puma paid to her institution outside the submitted work. Dr Curigliano reported serving on the advisory boards of Roche, Daiichi Sankyo, AstraZeneca, Lilly, Novartis, Pfizer, Celcuity, Exact Sciences, Ellipsis, Bristol Myers Squibb, Seagen, Merck, Menarini, and Gilead; receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Foundation Medicine, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seagen; receiving honoraria from Ellipses Pharma; receiving reimbursement for travel expenses from Pfizer and Roche/Genentech; serving on a speakers bureau for Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seagen; and receiving grants from Daiichi Sankyo and Merck outside the submitted work. Dr DiGiovanna reported receiving royalties from Dako and NeoMarkers; and grants from Cascadian Therapeutics, Genentech, and Seagen to conduct clinical research at Yale University. Dr Gelmon reported receiving consulting fees from AstraZeneca, Ayala Pharmaceuticals, Lilly, Merck, Mylan, Novartis, Pfizer, Roche, and Seagen outside the submitted work; serving on an advisory board for Gilead Sciences; and serving on a speakers bureau for AstraZeneca and Novartis. Dr Hortobagyi reported receiving grants from Seagen during the conduct of the study, consulting fees from Novartis outside the submitted work, and grants from Novartis. Dr Hurvitz reported having equity ownership in NKMax; receiving grants from Seagen during the conduct of the study; receiving grants from Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, CytomX, Daiichi Sankyo, Dantari, Digitana, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Immunomedics, Lilly, MacroGenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs Ltd, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Samumed, Sanofi, Seagen, and Zymeworks; and receiving reimbursement for travel expenses from Lilly outside the submitted work. Dr Krop reported receiving consulting fees from Bristol Myers Squibb, Context Therapeutics, Daiichi Sankyo, Genentech/Roche, Ionis Pharmaceuticals, MacroGenics, Merck, Novartis, Seagen, and Taiho Pharmaceuticals; receiving grants from Seagen paid to his institution during the conduct of the study; receiving honoraria from AstraZeneca and Genentech/Roche; receiving grants from Pfizer, MacroGenics, and Genentech/Roche; receiving personal fees from AstraZeneca, Daiichi Sankyo, MacroGenics, Genentech/Roche, Seagen, Merck, and Novartis outside the submitted work; and being an employee and equity owner of Freeline Therapeutics and PureTech Health. Dr Loi reported receiving research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seagen. She has acted as consultant (not compensated) to Seagen, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seagen, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Meyers Squibb. Dr Loi is supported by National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. Dr Loibl reported receiving assistance from Seagen with manuscript preparation during the conduct of the study; receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, GlaxoSmithKline, Gilead Sciences, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Seagen, Sanofi, and Roche; receiving honoraria from AbbVie, Amgen, AZ, Celgene/Bristol Meyers Squibb, DSI, Immunomedics/Gilead, Novartis, Pfizer, Roche, EirGenix, GlaxoSmithKline, Lilly, Mercl kGA, Pierre Fabre, Seagen, and Sanofi outside the submitted work; receiving research funding from AbbVie, AstraZeneca, Celgene, Daiichi Sankyo, Gilead, Novartis, Pfizer, and Roche; holding a patent for VM Scope GmbH with royalties paid to her institution; holding pending patents (EP14153692.0, EP21152186.9, EP15702464.7, and EP19808852.8); and being an employee of GBG Forschungs GmbH. Dr Mueller reported receiving personal fees from Seagen during the conduct of the study; receiving honoraria from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre, and Medscape; receiving consulting fees from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, and Pierre Fabre; receiving grants from Novartis, Roche, Seagen, and Genentech; receiving grants from Roche, Pfizer, Daiichi Sankyo, and Gilead outside the submitted work; and serving on speakers bureaus for Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GlaxoSmithKline, MSD, Novartis, Pfizer, Roche, Seagen Inc, Gilead, and Onkowissen.de. Dr Oliveira reported receiving grants from Seagen during the conduct of the study; receiving consulting fees from Roche, GlaxoSmithKline, Gilead, Puma Biotechnology, AstraZeneca, iTeos Therapeutics, Pierre Fabre, and MSD; receiving research funding from AstraZeneca, Genentech, Roche, Novartis, Immunomedics, Seagen, GlaxoSmithKline, Boehringer Ingelheim, Puma Biotechnology, and Zenith Epigenetics; receiving honoraria from Roche, Seagen, Novartis, AstraZeneca, and Eisai; receiving travel grants from Roche, Pierre Fabre, Novartis, and Eisai outside the submitted work; and being a member of the SOLTI executive board and scientific committee. Dr Paplomata reported receiving grants from Seagen during the conduct of the study; receiving personal fees from ICON Plc and OncLive; receiving consulting fees from Mylan, Novartis, Pfizer, Puma Biotechnology, R-pharm, and Biotheranostics; receiving honoraria from Mylan, Novartis, Pfizer, Puma, and R-pharm; receiving research funding from AbbVie, Cascadian Therapeutics, Corcept Therapeutics, Genentech, Hoosier Cancer Research Network, ImmunoGen, Merck, Novartis, Seagen Inc, and Immunogenicity; receiving reimbursement for travel expenses from Amgen, Genentech, Merck, Novartis, and Tesaro; receiving nonfinancial support from Tesaro; receiving nonfinancial support from Amgen outside the submitted work; and serving on a speakers bureau for OncLive Clinical Congress Consultants. Dr Pegram reported serving on the steering committee for Seagen during the conduct of the study and receiving consulting fees from Seagen and Roche/Genentech outside the submitted work. Dr Slamon reported receiving consulting fees from Lilly, Novartis, Pfizer, and Seagen; having equity ownership in Amgen, BioMarin Pharmaceutical, MSD, Pfizer, Seagen, 1200 Pharma, TORL BioTherapeutics, and Vertex Pharmaceuticals; receiving honoraria from Novartis; receiving research funding from Novartis, Pfizer, and Seagen; receiving reimbursement for travel expenses from BioMarin Pharmaceutical, Novartis, and Pfizer; serving on the advisory board for BioMarin Pharmaceutical; serving on the speakers bureau for Novartis; and founding 1200 Pharma and TORL BioTherapeutics outside the submitted work. Dr Zelnak reported receiving personal fees from Seagen during the conduct of the study; consulting fees from AstraZeneca, Gilead Sciences, Immunomedics, Novartis, Pfizer, and Puma Biotechnology; and personal fees from Gilead, AstraZeneca, Novartis, and Puma Biotechnology outside the submitted work. Dr Ramos reported being an employee of Seagen and receiving equity. Dr Feng reported being an employee of Seagen and receiving equity. Dr Winer reported receiving consulting fees from Carrick Therapeutics, Genentech/Roche, GlaxoSmithKline, and Jounce Therapeutics; honoraria from Carrick Therapeutics, Genentech/Roche, Genomic Health, GlaxoSmithKline, Jounce Therapeutics, and Leap Therapeutics; and research funding from Genentech/Roche outside the submitted work. No other disclosures were reported.

Funding/Support: This study was sponsored by Seagen Inc, Bothell, Washington, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey.

Role of the Funder/Sponsor: The study sponsors supported the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Presented at the 2021 San Antonio Breast Cancer Symposium; December 8, 2021; San Antonio, Texas.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank the patients who participated in this trial and their families, the investigators and research staff at all HER2CLIMB clinical sites, and the members of the independent data and safety monitoring committee. Irene Park, PhD (Seagen Inc, Bothell, Washington), provided medical writing and editorial support in accordance with Good Publication Practice (GPP3) guidelines. She did not receive any additional compensation beyond usual salary.

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