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In Search of the Long-Desired ‘Copernican Therapeutic Revolution’ in Small-Cell Lung Cancer

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Abstract

Small-cell lung cancer has defied our scientific community for decades. Chemotherapy has been the mainstay treatment for small-cell lung cancer (SCLC) and unlike its counterpart, non-small cell lung cancer, no significant therapeutic breakthroughs have been made since the 1970s. Among the reasons for this slow-paced therapeutic development, one that stands out is the distinctive and almost universal loss of function of the tumour suppressor genes TP53 and RB1 in this disease, for which pharmacological activation has yet to be achieved, despite having been highly sought after. Although no molecularly targeted approach has been approved for clinical practice thus far, several strategies are currently exploring the potential to drug the tumour’s “Achilles heel” that stems from essential pathways regulating DNA-damage response. Most recently, we have witnessed newfound reasons to hope, as the combination of immunotherapy and systemic chemotherapy has improved survival outcomes, representing the first landmark achievement in decades and a new standard of care for patients with extensive disease SCLC. However, continuous efforts are still needed towards a better understanding of the molecular pathways that singularise this tumour to eventually identify the predictive biomarkers that might result in the development of a more rational therapeutic approach, including the use of immunotherapy combinations. In this review we aim to uncover critical aspects of the immune microenvironment and biology of SCLC and provide an overview of the current and future landscape of promising therapeutic opportunities. The challenge still stands, but regardless, we are living in exciting times to finally check SCLC off the ”bucket list” of our scientific community.

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We thank Kyla M. Juett for improving the use of English in the manuscript.

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  1. Division of Medical Oncology, Medical Oncology Department, Hospital Clínic Barcelona, Villarroel 170, 08036, Barcelona, Spain

    Noemí Reguart, Elba Marin & Roxana Reyes

  2. Translational Genomics and Targeted Therapeutics in Solid Tumours, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Noemí Reguart, Elba Marin & Cristina Teixido

  3. Division of Medical Oncology, Centro Integral Oncología Clara Campal Bacelona, HM-Delfos, Barcelona, Spain

    Jordi Remon & Cristina Teixido

  4. Department of Pathology, Hospital Clínic, Barcelona, Spain

    Cristina Teixido

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Dr N. Reguart reports receiving honoraria from AstraZeneca, Novartis, Takeda, Eli Lilly, MSD, Boehringer Ingelheim and Pfizer for consulting, advisory role or speaker’s bureaus; travel and accommodation expenses from Roche, MSD; and research funding from Pfizer and Novartis. C. Teixido reports receiving honoraria from Bristol-Myers Squibb, Pfizer and MSD for advisory role or speaker’s bureaus; travel and accommodation expenses from Roche, MSD; and research funding from Novartis. Jordi Remon reports receiving honoraria from Boehringer Ingelheim, Pfizer, MSD, Bristol-Myers Squibb and AstraZeneca for consulting, advisory role or speaker’s bureaus; travel and accommodation expenses from Bristol-Myers Squibb, OSE-Immunotherapeutics, AstraZeneca and Roche. Elba Marin and Roxana Reyes declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Reguart, N., Marin, E., Remon, J. et al. In Search of the Long-Desired ‘Copernican Therapeutic Revolution’ in Small-Cell Lung Cancer. Drugs 80, 241–262 (2020). https://doi.org/10.1007/s40265-019-01240-8

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