Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

doi:10.1016/j.lanepe.2024.100838

Review

. 2024 Mar 1:38:100838.

doi: 10.1016/j.lanepe.2024.100838. eCollection 2024 Mar.

Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

Vincent D de Jager¹, Wim Timens¹, Arnaud Bayle², Johan Botling³, Luka Brcic⁴, Reinhard Büttner⁵, Maria Gabriela O Fernandes⁶, Libor Havel⁷, Maximilian J Hochmair^{8

9}, Paul Hofman¹⁰, Annelies Janssens¹¹, Mikael Johansson¹², Léon van Kempen¹³, Izidor Kern¹⁴, Fernando Lopez-Rios¹⁵, Margreet Lüchtenborg^{16

17}, José Carlos Machado^{18

19}, Katja Mohorcic²⁰, Luis Paz-Ares²¹, Sanjay Popat²², Aleš Ryška²³, Phillipe Taniere²⁴, Jürgen Wolf²⁵, Ed Schuuring¹, Anthonie J van der Wekken²⁶

Affiliations

¹ Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
² Oncostat U1018, Inserm, Paris-Saclay University, Gustave Roussy, Villejuif, France.
³ Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden.
⁴ Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
⁵ Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
⁶ Pulmonology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.
⁷ Charles University and Thomayer Hospital, Prague, Czech Republic.
⁸ Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria.
⁹ Department of Respiratory and Critical Care Medicine, Klinik Floridsdorf, Vienna Healthcare Group, Vienna, Austria.
¹⁰ IHU RespirERA, FHU OncoAge, Nice University Hospital, Côte d'Azur University, Nice, France.
¹¹ Department of Oncology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
¹² Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
¹³ Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
¹⁴ Laboratory for Cytology and Pathology, University Clinic Golnik, Golnik, Slovenia.
¹⁵ Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Research Institute Hospital 12 de Octubre (i+12), Ciberonc, Madrid, Spain.
¹⁶ National Disease Registration Service, NHS England, London, United Kingdom.
¹⁷ Centre for Cancer, Society & Public Health, King's College London, London, United Kingdom.
¹⁸ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
¹⁹ Faculty of Medicine of the University of Porto, Institute for Research and Innovation in Health (i3S), Porto, Portugal.
²⁰ University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
²¹ Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, H12O-CNIO Lung Cancer Clinical Research Unit, Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Ciberonc, Madrid, Spain.
²² Lung Unit, Royal Marsden NHS Trust, London, United Kingdom.
²³ The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital, Czech Republic.
²⁴ Department of Histopathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
²⁵ Lung Cancer Group Cologne, Department I for Internal Medicine and Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany.
²⁶ Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

PMID: 38476742
PMCID: PMC10928289
DOI: 10.1016/j.lanepe.2024.100838

Review

Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

Vincent D de Jager et al. Lancet Reg Health Eur. 2024.

. 2024 Mar 1:38:100838.

doi: 10.1016/j.lanepe.2024.100838. eCollection 2024 Mar.

Authors

Affiliations

¹ Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
² Oncostat U1018, Inserm, Paris-Saclay University, Gustave Roussy, Villejuif, France.
³ Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden.
⁴ Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
⁵ Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
⁶ Pulmonology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.
⁷ Charles University and Thomayer Hospital, Prague, Czech Republic.
⁸ Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria.
⁹ Department of Respiratory and Critical Care Medicine, Klinik Floridsdorf, Vienna Healthcare Group, Vienna, Austria.
¹⁰ IHU RespirERA, FHU OncoAge, Nice University Hospital, Côte d'Azur University, Nice, France.
¹¹ Department of Oncology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
¹² Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
¹³ Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
¹⁴ Laboratory for Cytology and Pathology, University Clinic Golnik, Golnik, Slovenia.
¹⁵ Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Research Institute Hospital 12 de Octubre (i+12), Ciberonc, Madrid, Spain.
¹⁶ National Disease Registration Service, NHS England, London, United Kingdom.
¹⁷ Centre for Cancer, Society & Public Health, King's College London, London, United Kingdom.
¹⁸ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
¹⁹ Faculty of Medicine of the University of Porto, Institute for Research and Innovation in Health (i3S), Porto, Portugal.
²⁰ University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
²¹ Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, H12O-CNIO Lung Cancer Clinical Research Unit, Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Ciberonc, Madrid, Spain.
²² Lung Unit, Royal Marsden NHS Trust, London, United Kingdom.
²³ The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital, Czech Republic.
²⁴ Department of Histopathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
²⁵ Lung Cancer Group Cologne, Department I for Internal Medicine and Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany.
²⁶ Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

PMID: 38476742
PMCID: PMC10928289
DOI: 10.1016/j.lanepe.2024.100838

Abstract

In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control.

Keywords: Europe; Non-small cell lung cancer; Predictive biomarker testing; Targeted therapy.

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Conflict of interest statement

WT has received consulting fees from Merck Sharp and Dohme, Bristol-Myers Squibb, and Altana (fees to institution), is board member of Dutch Society of Pathology and member of Council for Research and Innovation of the Federation of Medical Specialists (FMS); AB has received consulting fees from Sanofi (OncoCollective advisory board), payments or honoraria from Roche (oral presentation), support for attending ASCO 2023 from Pfizer; JB has received research grants from Amgen and Bristol-Myers Squibb, lecture honoraria from AstraZeneca, Merck Sharp and Dohme, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, GSK, Eli Lilly, Amgen, and Sanofi, and support for attending meetings and/or travel from Amgen; LB has received grants or contract from Takeda, Roche, AstraZeneca, and Bristol-Myers Squibb, payments or honoraria from Invitae, Eli Lilly, AstraZeneca, Roche, Merck Sharp and Dohme, Merck, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, and Janssen, has participated in data safety monitoring boards or advisory boards for Invitae, Eli Lilly, AstraZeneca, Roche, Merck Sharp and Dohme, Merck, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, and Janssen, is Int. Secretary of the Austrian Society of Pathology, PPS Membership and Awards Committee, and is Member of the Mesothelioma Committee of IASLC; RB has received payments or honoraria for lectures and advisory boards for Abbvie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Illumina, Janssen, Lilly, Merck-Serono, Merck Sharp and Dohme, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc., has received payments for expert testimony from Merck Sharp and Dohme, is co-founder and co-owner of Gnothis Inc. (SE), Timer Therapeutics Inc. (GE); GF has received fees for advisory boards participation, meetings, or as invited speaker, from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Janssen, Merck Sharp and Dohme, Pfizer, Roche Farmacêutica Química Lda, and Takeda; MH has received payments or honoraria from Merck Sharp and Dohme, Roche, Lilly, AstraZeneca, and Takeda; PH has received consulting fees from AstraZeneca, Roche, Abbvie, Qiagen, and Pfizer, has received payments or honoraria from Thermofisher Scientist, Novartis, Janssen, AstraZeneca, and Biocartis, has received support for attending meetings and/or travel from Thermofisher Scientist, Novartis, Janssen, AstraZeneca, and Biocartis, has participated on a Data Safety Monitoring Board or Advisory Board for Thermofisher Scientist, Novartis, Janssen, AstraZeneca, Biocartis, Bristol-Myers Squibb, Sanofi, Roche, and Abbvie; LvK has received institutional grants or contract from Amgen, AstraZeneca, Bayer, Janssen-Cilag, Merck, Roche, and Servier, has received institutional payments or honoraria from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, and Roche, has received institutional support for attending meeting and/or travel from Roche, has participated on a Data Safety Monitoring Board or Advisory Board from Janssen-Cilag, Merck, and Roche, has a leadership or fiduciary role in the Commission Personalized Medicine—Belgium (unpaid), has stock or stock options in Cyclomics (institutional/personal); JCM has received payments or honoraria from Lilly Portugal, Novartis Portugal, Roche Portugal, Fresco Produções, Janssen-Cilag Portugal, Pierre Fabre Portugal, and Servier Portugal; has participated on a Data Safety Monitoring Board or Advisory Board of Roche Portugal; KM has received payments or honoraria from Takeda, Janssen, Pfizer, Merck Sharp and Dohme, Bristol-Myers Squibb, Roche, Amgen, Novartis, and Eli Lilly, has participated on a Data Safety Monitoring Board or Advisory Board of BMS, Takeda, AstraZeneca, Amgen, Roche, Boehringer Ingelheim, and Janssen; SP has received consulting fees (personal fees) from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, Merck Sharp and Dohme, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx, has received payments or honoraria (personal fees) from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda, has received payments for expert testimony (personal fees) from Roche, and Merck Serono, has received reimbursement of travel expenses from Janssen, and Roche, has participated on a Data Safety Monitoring Board or Advisory Board as per consulting fees, has a leadership role or fiduciary role (all unpaid) in the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board; AR has received consulting fees for participation on advisory boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Amgen, Merck Sharp and Dohme, Gilead, and Sanofi, has received honoraria for lectures and presentations from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Amgen, Merck Sharp and Dohme, Gilead, Roche, Merck-Serono, has received support for attendings meetings and travel from Sanofi, Gilead, Roche, and Bristol-Myers Squibb; JW has received payments or honoraria, has received support for attendings meetings and travel, and has participated in a Data Safety Monitoring Board or Advisory Board, from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda, and Turning Point; ES has received unrestricted grants (all paid to UMCG institution) from Abbott, Biocartis, AstraZeneca, Invitae/Archer, Bayer, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics, MSD/MERCK, and Boehringer Ingelheim, has received consulting fees (all paid to UMCG institution) from MSD/Merck, AstraZeneca, Roche, Novartis, Bayer, BMS, Lilly, Amgen, Illumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson & Johnson), Astellas Pharma, GSK, Sinnovisionlab, and Sysmex, has received payments or honoraria (all paid to UMCG institution) from Bio-Rad, Seracare, Roche, Biocartis, Lilly, Agena Bioscience, and Illumina, has received support for attending meetings and/or travel from BioRad, Biocartis, Ageno Sciences, and Illumina, is a board member for the Dutch Society of Pathology (unpaid), European Society of Pathology (unpaid), European Liquid Biopsy Society (unpaid), is a secretary/member of the advisory committee for assessment of molecular diagnostics (cieBOD) (honoraria paid to UMCG institution), is committee member of national guideline advisory (honoraria paid to UMCG institution); AvdW, has received grants or contracts from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, and Takeda, has received consulting fees from AstraZeneca, Janssen, Lilly, Roche, and Takeda, has received payments or honoraria from AstraZeneca, BMS, Lilly, Pfizer, and Roche, has a leadership or fiduciary role in the oncology section NVALT, guideline committee NSCLC and CUP, dure geneesmiddelen committee NVALT and FMS. All other authors declare no competing interests.

Figures

**Fig. 1**
Timeline of EMA-approved targeted therapies and the ESMO-recommendations for predictive biomarker testing associated with these targeted drugs for patients with advanced stage NSCLC (as of July 2023).

**Fig. 2**
Availability of targeted therapies for patients with metastatic NSCLC across eleven European countries. For each country, the displayed information was provided by a detailed questionnaire (Supplementary File 1) that was completed by a (molecular) pathologist, clinical scientist in molecular pathology and/or (pulmonary) oncologist with expertise in the field of NSCLC. ∗Presented availability concerns crizotinib (FDA-approved), due to its better availability compared to tepotinib and capmatinib (EMA-approved) (see also Table 2).

See this image and copyright information in PMC

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References

1. Sung H., Ferlay J., Siegel R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. - PubMed
1. Malvezzi M., Santucci C., Boffetta P., et al. European cancer mortality predictions for the year 2023 with focus on lung cancer. Ann Oncol. 2023;34(4):410–419. - PubMed
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[1] Sung H., Ferlay J., Siegel R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. - PubMed

[2] Sung H., Ferlay J., Siegel R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. - PubMed

[3] Malvezzi M., Santucci C., Boffetta P., et al. European cancer mortality predictions for the year 2023 with focus on lung cancer. Ann Oncol. 2023;34(4):410–419. - PubMed

[4] Malvezzi M., Santucci C., Boffetta P., et al. European cancer mortality predictions for the year 2023 with focus on lung cancer. Ann Oncol. 2023;34(4):410–419. - PubMed

[5] Gregor A., Inage T., Hwangbo B., Yasufuku K. Lung cancer staging: state of the art in the era of ablative therapies and surgical segmentectomy. Respirology. 2020;25(9):924–932. - PubMed

[6] Gregor A., Inage T., Hwangbo B., Yasufuku K. Lung cancer staging: state of the art in the era of ablative therapies and surgical segmentectomy. Respirology. 2020;25(9):924–932. - PubMed

[7] Howlader N., Forjaz G., Mooradian M.J., et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640–649. - PMC - PubMed

[8] Howlader N., Forjaz G., Mooradian M.J., et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640–649. - PMC - PubMed

[9] Hendriks L.E., Kerr K.M., Menis J., et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):339–357. - PubMed

[10] Hendriks L.E., Kerr K.M., Menis J., et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):339–357. - PubMed

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Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

Affiliations

Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

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Abstract

Conflict of interest statement

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