Lung cancer articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Lung cancer is a disease typically associated with tobacco smoking; however, lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths globally. Moreover, smoking rates are declining around the world and therefore LCINS is likely to increase as a proportion of all lung cancers over time. Thus, understanding the aetiology and features of LCINS is increasingly important. Herein, the authors review the emerging data on the epidemiology, clinical characteristics and molecular features of LCINS as well as the genetic and environmental risk factors for this disease. They also summarize the unique diagnostic and management paradigms of LCINS.

    • Jaclyn LoPiccolo
    • , Alexander Gusev
    •  & Pasi A. Jänne

  • Review Article |

    Despite improved outcomes owing to advances in systemic targeted therapies, patients with brain metastases from oncogene-driven non-small-cell lung cancer continue to have a poor prognosis. This situation largely reflects the limited central nervous system (CNS) penetrance of most targeted therapies, a limitation that is beginning to be addressed with the development of later-generation agents. In this Review, the authors describe the CNS activity of targeted therapies for patients with oncogene-driven non-small-cell lung cancers, including discussions of novel agents with improved CNS penetrance and the potential of intrathecal administration for patients with leptomeningeal disease.

    • Kelsey Pan
    • , Kyle Concannon
    •  & Xiuning Le

  • Review Article |

    Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

    • Giannis Mountzios
    • , Jordi Remon
    •  & Solange Peters

  • Review Article |

    Lung cancer is the commonest cancer globally. Reflecting patterns of smoking and other risk factor exposures, both the incidence of and mortality from lung cancer are highest in economically developed countries. Nonetheless, developing and less economically developed countries are likely to have the biggest increases in lung cancer in the coming years. In this Review, the authors describe the global epidemiology of lung cancer, and how changes in exposures, socioeconomic status, public health interventions and better treatment strategies are influencing both the incidence of and mortality from lung cancer.

    • Amanda Leiter
    • , Rajwanth R. Veluswamy
    •  & Juan P. Wisnivesky

  • Comment |

    Recent FDA reviews of cemiplimab and sintilimab combined with chemotherapy for patients with advanced-stage non-small-cell lung cancer reached discordant outcomes, as cemiplimab was approved and sintilimab was rejected. The applications share many serious faults, including neither serving an unmet need nor enrolling any patients from the USA. We argue that the FDA criteria should be more transparent and consistent; moreover, the historical policy of the FDA to abstain from consideration of the cost of a drug perpetuates a crisis in oncology care and should be re-examined.

    • Aakash Desai
    • , Caleb J. Smith
    •  & Howard Jack West

  • Review Article |

    Lung cancers harbouring ‘rare’ alterations (defined as those with a prevalence of <5% of oncogene-driven lung cancers) can be detected in around a third of all oncogene-driven lung cancers and are diagnosed in thousands of patients each year. Advances in our understanding of tumour biology, diagnosis and the development of novel therapies are enabling increasing use of specific therapies targeting these alterations. In this Review, the authors provide an overview of the epidemiology, diagnosis, prognosis and treatment of patients with lung cancers harbouring these rare alterations. The importance of expedited drug approval pathways and cooperation between multiple stakeholders is also emphasized.

    • Guilherme Harada
    • , Soo-Ryum Yang
    •  & Alexander Drilon

  • Review Article |

    Immune-checkpoint inhibitors (ICI) constitute a paradigm shift in the treatment of non-small-cell lung cancer (NSCLC); however, identifying the minority of patients who derive long-term benefit remains problematic, particularly among those with targetable oncogenic drivers who have typically been under-represented in or excluded from clinical trials of ICIs. This Review summarizes the associations of common oncogenic drivers of NSCLC with sensitivity or resistance to ICIs as well as the underlying effects on the immune tumour microenvironment. Potential vulnerabilities that could potentially be exploited to overcome primary resistance to ICIs conferred by certain oncogenic drivers are also highlighted.

    • Itziar Otano
    • , Alvaro C. Ucero
    •  & Luis Paz-Ares

  • Review Article |

    Neuroendocrine neoplasms (NENs), which can develop in almost any organ and range from indolent neuroendocrine tumours (NETs) to rapidly progressive and fatal neuroendocrine carcinomas (NECs), have historically been approached in a siloed manner according to their specific tissue of origin. However, NETs and NECs across different sites of origin often share genomic and phenotypic characteristics. In this Review, the authors discuss both the clinical and biological commonalities as well as key organ-specific differences of NENs, with a focus on those of the gastrointestinal system and lung. Moreover, they advocate for a cross-cutting, tissue-agnostic approach to drug development for these rare tumours that might enable advances in one disease entity to accelerate research in others, ultimately improving patient care.

    • Kenta Kawasaki
    • , Natasha Rekhtman
    •  & Charles M. Rudin

  • News & Views |

    A high tumour mutational burden (≥10 mutations per megabase) is a companion biomarker in the histology-agnostic approval of pembrolizumab for treatment-refractory advanced-stage solid tumours, and continues to be an exploratory predictive biomarker for immune-checkpoint inhibitors in non-small-cell lung cancer. Herein, we discuss recent results from the first phase III trial evaluating blood-based tumour mutational burden in patients with treatment-naive advanced-stage non-small-cell lung cancer.

    • So Yeon Kim
    •  & Roy S. Herbst

  • News & Views |

    The development of covalent, allele-specific inhibitors of KRASG12C represents a major breakthrough in precision oncology. Herein we discuss recent data from the phase II KRYSTAL-1 trial of adagrasib in KRASG12C-mutated non-small-cell lung cancer (NSCLC). This trial showed responses in a subset of patients, including among those with brain metastases, and offers exploratory insights into potential biomarkers of response.

    • Yonina R. Murciano-Goroff
    •  & Piro Lito

  • News & Views |

    Tracking circulating tumour DNA (ctDNA) after surgery holds promise for patient management and therapeutic intervention in non-small-cell lung cancer (NSCLC). A study published by Zhang and colleagues tracks ctDNA from 261 patients with stages I–III NSCLC and suggests that the likelihood of disease relapse decreases for high-risk stage II/III patients after 18 months without ctDNA detection.

    • Alexander Frankell
    •  & Mariam Jamal-Hanjani

  • News & Views |

    Immune-checkpoint inhibitors have revolutionized the treatment of patients with non-small-cell lung cancer (NSCLC). Recently, indications for immune-checkpoint inhibitors have expanded from advanced-stage NSCLC to adjuvant, and now neoadjuvant, therapy for resectable NSCLC, with three cycles of preoperative chemoimmunotherapy achieving superior pathological complete response rates and event-free survival compared with chemotherapy alone in the phase III CheckMate 816 trial.

    • Boris Sepesi
    •  & Stephen G. Swisher

  • Review Article |

    Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area.

    • Alissa J. Cooper
    • , Lecia V. Sequist
    •  & Jessica J. Lin

  • Comment |

    Randomized controlled trials (RCTs) are conducted when clinical equipoise between treatment options exists. However, some RCTs in patients with non-small-cell lung cancer continue to use chemotherapy as the control arm several years after chemotherapy was proven inferior to anti-PD-1 antibodies. Here, we highlight why the justifications for using an inferior treatment in the control arm are invalid and offer solutions that are applicable across tumour types.

    • Adi Kartolo
    •  & Bishal Gyawali

  • News & Views |

    Efforts are being made to incorporate immune-checkpoint inhibitors into therapy for early stage non-small-cell lung cancer. The IMpower010 trial of adjuvant atezolizumab has recently become the first study to demonstrate that this strategy can improve disease-free survival in a subset of patients. This trial opens a new area of research in the quest for the optimal perioperative strategy to increase overall survival.

    • Jordi Remon
    •  & Benjamin Besse

  • News & Views |

    Advances in cancer immunotherapy have led to clinical trials of immunotherapy-based neoadjuvant treatments for early stage non-small-cell lung cancer. Evidence for priming of the immune system using both preoperative short-course radiotherapy and immunotherapy in this setting has now emerged from a randomized phase II study incorporating pathological and immunological end points.

    • Famke L. Schneiders
    •  & Suresh Senan

  • Review Article |

    Immune-checkpoint inhibitors (ICIs) are now standard-of-care therapies for patients with advanced-stage non-small-cell lung cancer (NSCLC) without a targetable driver alteration. Various ICIs or combination regimens have been approved in this setting, relative to chemotherapy, although no prospective data are available comparing the various ICI-based approaches. Here, the authors provide guidance on selecting the optimal ICI-based therapy and highlight several future research directions that will probably further improve the outcomes of patients with advanced-stage NSCLC.

    • Michael J. Grant
    • , Roy S. Herbst
    •  & Sarah B. Goldberg

  • Review Article |

    The authors of this Review present the current considerations in the treatment of patients with early-stage lung cancer, discussing the critical determination of resectability by thoracic surgical oncologists and the management of both resectable and unresectable disease with a focus on systemic therapy selection. They also address innovations in drug development, trial design and efforts to identify early-stage cancers.

    • Jamie E. Chaft
    • , Andreas Rimner
    •  & Tina Cascone

  • Review Article |

    PD-L1 expression is currently the best available biomarker for the prediction of responsiveness to immune-checkpoint inhibitors. However, several immunohistochemical assays are now approved for clinical use in various settings, despite imperfect inter-assay concordance, with important implications for pathology services and, potentially, for clinical outcomes. In this Review, the authors compare the performance of the various FDA-approved PD-L1 assays, discuss the varying implications of PD-L1 expression across different tumour types and provide guidance on possible novel approaches that might optimize the clinical utility of PD-L1 as a biomarker.

    • Deborah Blythe Doroshow
    • , Sheena Bhalla
    •  & Fred R. Hirsch

  • Perspective |

    Genotyping is recommended for all patients with metastatic non-squamous non-small-cell lung cancers (NSCLC), both to enable patients to receive targeted therapies and to avoid therapies they are unlikely to benefit from. However, obtaining tumour biopsy material for genotyping is often challenging and is unfeasible in some patients, indicating the need to incorporate liquid biopsy approaches. In this Perspective, the authors provide guidance on how analysis of ctDNA from liquid biopsy samples in patients with metastatic NSCLC prior to first-line therapy has the potential to extend the benefits of genotyping to virtually all patients.

    • Charu Aggarwal
    • , Christian D. Rolfo
    •  & David R. Gandara

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