{"id":"lung-cancer-evidence-roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/","eras":[{"era":"1950 to 1965","title":"The cause is named, and cancer epidemiology is invented to name it","description":"Wynder and Graham's 684 proven cases appeared in JAMA in May 1950 and Doll and Hill's British case-control study in the BMJ in September. Both were attacked as artefacts of how cases were chosen, so Doll and Hill built a prospective cohort of British doctors in 1951 and followed it for fifty years. The method they used, exposure recorded before outcome with a measured dose-response, is the foundation of modern cancer epidemiology; the 1964 United States Surgeon General's report and everything in tobacco control since rests on it.","status":"historic","refs":[{"id":"paper-wynder-graham-tobacco-bronchiogenic-carcinoma-jama-1950","kind":"paper","name":"Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases","route":"/key-papers/paper-wynder-graham-tobacco-bronchiogenic-carcinoma-jama-1950/","tldr":"One of the two 1950 studies that first tied cigarettes to lung cancer. Wynder and Graham compared the smoking histories of 684 people with proven lung cancer against people without it, and found heavy smoking almost everywhere in the cancer group."},{"id":"paper-doll-hill-smoking-lung-cancer-bmj-1950","kind":"paper","name":"Doll and Hill 1950: the case-control study that tied smoking to lung cancer","route":"/key-papers/paper-doll-hill-smoking-lung-cancer-bmj-1950/","tldr":"Comparing 649 men with lung cancer to matched hospital controls in London, Doll and Hill found that almost none of the cancer patients were non-smokers and that risk rose steeply with the amount smoked."},{"id":"paper-doll-hill-mortality-of-doctors-smoking-bmj-1954","kind":"paper","name":"The mortality of doctors in relation to their smoking habits; a preliminary report","route":"/key-papers/paper-doll-hill-mortality-of-doctors-smoking-bmj-1954/","tldr":"Doll and Hill wrote to every doctor in Britain in 1951 asking how much they smoked, then waited to see who died. This first report, after two and a half years, is where the prospective evidence on smoking begins."},{"id":"paper-doll-peto-50-year-doctors-bmj-2004","kind":"paper","name":"Fifty years of the British Doctors Study: smokers lose ten years of life, quitting gives most of it back","route":"/key-papers/paper-doll-peto-50-year-doctors-bmj-2004/","tldr":"After following 34,439 male doctors for 50 years, lifelong smokers died on average about 10 years earlier than never-smokers, and stopping at 60, 50, 40 or 30 recovered about 3, 6, 9 or the full 10 years."},{"id":"prevention-roadmap","kind":"roadmap","name":"Cancer prevention roadmap: tobacco control and vaccines → biomarker-guided chemoprevention → interception in carriers","route":"/roadmaps/prevention-roadmap/","tldr":"About four in ten cancers could be prevented with tools that already exist: vaccines against the viruses that cause them, tobacco and alcohol control, weight, aspirin for the right people, and finding the families who carry a high-risk gene. The roadmap is mostly about deployment, with interception vaccines as the long-range bet."}],"trials":[],"papers":[{"id":"paper-wynder-graham-tobacco-bronchiogenic-carcinoma-jama-1950","name":"Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases","route":"/key-papers/paper-wynder-graham-tobacco-bronchiogenic-carcinoma-jama-1950/","journal":"Journal of the American Medical Association","year":1950,"whatItMeans":"Half of the evidence base on which every tobacco control policy in the world rests. Lung cancer was a rare disease at the start of the twentieth century and the commonest cancer killer by its end; this paper and Doll and Hill's are where the cause was named."},{"id":"paper-doll-hill-smoking-lung-cancer-bmj-1950","name":"Doll and Hill 1950: the case-control study that tied smoking to lung cancer","route":"/key-papers/paper-doll-hill-smoking-lung-cancer-bmj-1950/","journal":"BMJ","year":1950,"whatItMeans":"Doll and Hill's 1950 study is where the evidence that smoking causes cancer begins. Everything from cigarette warnings and tax to smoke-free laws and lung screening eligibility descends from this study and the cohort that followed it."},{"id":"paper-doll-hill-mortality-of-doctors-smoking-bmj-1954","name":"The mortality of doctors in relation to their smoking habits; a preliminary report","route":"/key-papers/paper-doll-hill-mortality-of-doctors-smoking-bmj-1954/","journal":"BMJ","year":1954,"whatItMeans":"The methodological ancestor of modern cancer epidemiology. Cohort design, exposure recorded before outcome, and a dose-response relationship measured rather than asserted: this is the template every later study of a cancer risk factor follows."},{"id":"paper-doll-peto-50-year-doctors-bmj-2004","name":"Fifty years of the British Doctors Study: smokers lose ten years of life, quitting gives most of it back","route":"/key-papers/paper-doll-peto-50-year-doctors-bmj-2004/","journal":"BMJ","year":2004,"whatItMeans":"Smoking is the single largest preventable cause of cancer death, and quitting at any age helps, with the greatest gain from quitting young. Cessation support belongs in every cancer service, including lung screening programmes."}]},{"era":"1970 to 2006","title":"Cytotoxic chemotherapy, and the ceiling it hit","description":"Therapeutic nihilism was the default until the Non-small Cell Lung Cancer Collaborative Group pooled individual data on 9,387 patients from 52 trials in 1995 and found a 27 percent reduction in the risk of death when chemotherapy was added to supportive care. E1594 then randomised 1,207 patients between four platinum doublets and found no difference: a 19 percent response rate and a median survival of 7.9 months, whichever drugs were used. LACE later pooled 4,584 resected patients and fixed the adjuvant rule, a 5.4 percent absolute survival gain concentrated in stage II and III disease. The first crack in the ceiling was biological rather than cytotoxic: ECOG 4599 added bevacizumab in 2006 and took median survival past twelve months for the first time, at 12.3 against 10.3 months, in the non-squamous patients without brain metastases who were allowed into the trial.","status":"historic","refs":[{"id":"paper-nsclc-collaborative-group-chemotherapy-meta-analysis-bmj-1995","kind":"paper","name":"Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials","route":"/key-papers/paper-nsclc-collaborative-group-chemotherapy-meta-analysis-bmj-1995/","tldr":"Before 1995 many doctors thought chemotherapy did nothing for lung cancer. Pooling 9,387 patients from 52 trials showed it did something: a 27 percent reduction in the risk of death when added to supportive care, worth about 10 percent more people alive at one year."},{"id":"paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002","kind":"paper","name":"Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer","route":"/key-papers/paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002/","tldr":"1,207 patients were randomised between four platinum doublets. All four gave the same result: about one in five responded and median survival was just under eight months. Chemotherapy had reached a ceiling."},{"id":"paper-lace-adjuvant-cisplatin-pooled-analysis-jco-2008","kind":"paper","name":"Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group","route":"/key-papers/paper-lace-adjuvant-cisplatin-pooled-analysis-jco-2008/","tldr":"Pooling 4,584 patients from the five big trials of chemotherapy after lung cancer surgery gave a clear answer: it helps, by about 5 percent at five years, and the benefit is in stage II and III rather than stage IA."},{"id":"paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006","kind":"paper","name":"Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer","route":"/key-papers/paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006/","tldr":"Adding an antibody against the tumour's blood supply to chemotherapy pushed median survival past a year for the first time in advanced lung cancer, at the cost of more treatment-related deaths."},{"id":"chemotherapy-roadmap","kind":"roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","route":"/roadmaps/chemotherapy-roadmap/","tldr":"Chemotherapy went from a poison that sometimes worked to the backbone of most cures, and is now being given more precisely: to fewer people, at better doses, and increasingly delivered inside an antibody so that it reaches the tumour and not the whole body."}],"trials":[],"papers":[{"id":"paper-nsclc-collaborative-group-chemotherapy-meta-analysis-bmj-1995","name":"Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials","route":"/key-papers/paper-nsclc-collaborative-group-chemotherapy-meta-analysis-bmj-1995/","journal":"BMJ","year":1995,"whatItMeans":"The paper that ended therapeutic nihilism in lung cancer. The effect was small, and saying so honestly is what made it credible; every later trial in advanced disease is measured against the platinum doublet this analysis justified."},{"id":"paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002","name":"Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer","route":"/key-papers/paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002/","journal":"New England Journal of Medicine","year":2002,"whatItMeans":"The ceiling of undirected cytotoxic chemotherapy, measured precisely. Everything that came afterwards, from histology-directed pemetrexed to EGFR inhibitors to checkpoint blockade, is an attempt to break a plateau this trial demonstrated could not be broken by changing the drugs."},{"id":"paper-lace-adjuvant-cisplatin-pooled-analysis-jco-2008","name":"Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group","route":"/key-papers/paper-lace-adjuvant-cisplatin-pooled-analysis-jco-2008/","journal":"Journal of Clinical Oncology","year":2008,"whatItMeans":"The rule that a patient with a resected stage II or III lung cancer is offered chemotherapy and a patient with a small stage I tumour is not. Everything added to adjuvant treatment since has had to beat, or be added to, this 5 percent."},{"id":"paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006","name":"Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer","route":"/key-papers/paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006/","journal":"New England Journal of Medicine","year":2006,"whatItMeans":"The first time a targeted biological agent extended survival in lung cancer, and the first time median survival in the advanced setting crossed twelve months. It also set the pattern that a drug's exclusion criteria can matter as much as its mechanism."}]},{"era":"2004 to 2013","title":"EGFR, ALK, and the invention of precision oncology in solid tumours","description":"Gefitinib worked spectacularly in about one patient in ten and was close to being abandoned. In May 2004 Lynch in the NEJM and Paez in Science independently reported that the responders had activating EGFR mutations; Paez also explained the geography, finding the mutation in 15 of 58 Japanese tumours and 1 of 61 American ones. IPASS in 2009 randomised 1,217 clinically selected patients and showed the benefit lived entirely in the mutation-positive subgroup. In 2007 Soda found the EML4-ALK fusion in 5 of 75 tumours; Kwak screened 1,500 patients to enrol 82 and got a 57 percent response rate with crizotinib, a drug built for a different target. Resistance came with it: Kobayashi's single re-biopsied patient in 2005 carried T790M, and Sequist's 37 patients in 2011 showed resistance could be genetic, histological or even reversible.","status":"historic","refs":[{"id":"paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","kind":"paper","name":"Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/","tldr":"A drug that worked spectacularly in about one patient in ten and did nothing in the rest. Sequencing the tumours of nine responders found the answer: eight of them had a mutation in the gene the drug targets."},{"id":"paper-paez-egfr-mutations-gefitinib-science-2004","kind":"paper","name":"EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy","route":"/key-papers/paper-paez-egfr-mutations-gefitinib-science-2004/","tldr":"The second of the two 2004 papers that found EGFR mutations. It also explained why Japanese patients responded to gefitinib far more often than American ones: the mutation was simply much more common in Japan."},{"id":"paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009","kind":"paper","name":"Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma","route":"/key-papers/paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009/","tldr":"IPASS randomised 1,217 East Asian never-smokers and light former smokers between a tablet and chemotherapy. The tablet won, but only in the patients whose tumour carried an EGFR mutation; in the rest chemotherapy was better."},{"id":"paper-soda-eml4-alk-fusion-nature-2007","kind":"paper","name":"Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer","route":"/key-papers/paper-soda-eml4-alk-fusion-nature-2007/","tldr":"A small inversion on chromosome 2 fuses two genes and makes a kinase that drives lung cancer. Soda and Mano found it in 5 of 75 tumours, and a drug for it was approved four years later."},{"id":"paper-kwak-crizotinib-alk-nsclc-nejm-2010","kind":"paper","name":"Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer","route":"/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/","tldr":"1,500 tumours were screened to find 82 patients with an ALK fusion. Of those, 57 percent responded to crizotinib, a drug originally developed against a different target."},{"id":"paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","kind":"paper","name":"EGFR mutation and resistance of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/","tldr":"One patient, two years in complete remission on gefitinib, then relapse. Sequencing the new biopsy found a second mutation in the same gene, at position 790, that stopped the drug binding."},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/","tldr":"37 patients were re-biopsied when their EGFR drug stopped working. Some had the expected resistance mutation; five had turned into small-cell lung cancer. In three, the resistance disappeared when the drug was stopped."},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/","tldr":"Targeted drugs switch off the specific broken protein a cancer depends on. The first ones turned a leukaemia into a chronic condition; the field then learned that resistance is the rule, designed drugs around it, and has now reached the drivers that were called impossible to target."}],"trials":[],"papers":[{"id":"paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","name":"Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"The template for every driver mutation since: find the responders, sequence them, and give the drug only to people whose tumour carries the lesion it was built for. Gefitinib had been close to abandonment on the strength of unselected trials."},{"id":"paper-paez-egfr-mutations-gefitinib-science-2004","name":"EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy","route":"/key-papers/paper-paez-egfr-mutations-gefitinib-science-2004/","journal":"Science","year":2004,"whatItMeans":"Why a drug can look useless in one trial and transformative in another: the trials had different proportions of the patients the drug was for. It is the argument for genotyping before drawing conclusions from a response rate."},{"id":"paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009","name":"Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma","route":"/key-papers/paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009/","journal":"New England Journal of Medicine","year":2009,"whatItMeans":"The trial that turned EGFR testing into a standard of care rather than a research assay, and the clearest demonstration in oncology that a clinically selected population can hide two opposite treatment effects inside one positive result."},{"id":"paper-soda-eml4-alk-fusion-nature-2007","name":"Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer","route":"/key-papers/paper-soda-eml4-alk-fusion-nature-2007/","journal":"Nature","year":2007,"whatItMeans":"The second driver in lung cancer, and the one that proved the first was not a special case. It also established mutual exclusivity as a working assumption: a tumour usually has one driver, so finding it tells you what to give."},{"id":"paper-kwak-crizotinib-alk-nsclc-nejm-2010","name":"Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer","route":"/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/","journal":"New England Journal of Medicine","year":2010,"whatItMeans":"The trial that made ALK testing worth doing. It is also the clearest case in oncology of a drug finding its disease after the fact: crizotinib entered the clinic as a MET inhibitor and became an ALK drug because somebody checked."},{"id":"paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","name":"EGFR mutation and resistance of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/","journal":"New England Journal of Medicine","year":2005,"whatItMeans":"Resistance to a targeted drug usually has a cause you can read off a sequence, which means it can be targeted in turn. Osimertinib exists because of this paper."},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/","journal":"Science Translational Medicine","year":2011,"whatItMeans":"The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became."}]},{"era":"2011 to 2020","title":"Low-dose computed tomography earns its place, and chest radiography loses its","description":"PLCO randomised 154,901 people to four annual chest radiographs or usual care and after 13 years found 1,213 lung cancer deaths against 1,230: no effect at all. NLST the same year and NELSON in 2020 showed that low-dose computed tomography does reduce lung cancer mortality, and the United States task force widened eligibility in 2021 from age 55 and 30 pack-years to age 50 and 20. Aldrich had already shown what a pack-year threshold does: in a southern United States cohort, 31 percent of white smokers qualified against 17 percent of Black smokers, who develop the disease at lower cumulative exposure.","status":"historic","refs":[{"id":"paper-plco-chest-radiograph-lung-cancer-mortality-jama-2011","kind":"paper","name":"Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial","route":"/key-papers/paper-plco-chest-radiograph-lung-cancer-mortality-jama-2011/","tldr":"154,901 people were randomised to yearly chest X-rays or usual care. After 13 years the number who died of lung cancer was the same in both groups. The test that had been used for decades did not work."},{"id":"paper-nlst-nejm-2011","kind":"paper","name":"NLST: yearly low-dose CT scans cut lung cancer deaths in heavy smokers","route":"/key-papers/paper-nlst-nejm-2011/","tldr":"Three annual low-dose CT scans reduced lung cancer deaths by a fifth compared with chest X-rays in current and former heavy smokers."},{"id":"paper-nelson-nejm-2020","kind":"paper","name":"NELSON: volume-based CT screening reduces lung cancer deaths with fewer false alarms","route":"/key-papers/paper-nelson-nejm-2020/","tldr":"In a Dutch-Belgian trial, CT screening using nodule volume rather than diameter cut lung cancer deaths in men by about a quarter at 10 years, with a far lower false-positive rate than NLST."},{"id":"paper-uspstf-lung-cancer-screening-jama-2021","kind":"paper","name":"Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement","route":"/key-papers/paper-uspstf-lung-cancer-screening-jama-2021/","tldr":"In 2021 the United States task force lowered the age at which lung screening starts from 55 to 50 and halved the smoking history needed from 30 to 20 pack-years, roughly doubling the number of people eligible."},{"id":"paper-aldrich-uspstf-screening-african-american-smokers-jama-oncol-2019","kind":"paper","name":"Evaluation of USPSTF Lung Cancer Screening Guidelines Among African American Adult Smokers","route":"/key-papers/paper-aldrich-uspstf-screening-african-american-smokers-jama-oncol-2019/","tldr":"The screening rules were written from a trial in which only 4 percent of participants were Black. In a southern United States cohort, 31 percent of white smokers qualified for screening but only 17 percent of Black smokers, even though Black smokers develop lung cancer at fewer cigarettes."},{"id":"early-detection-roadmap","kind":"roadmap","name":"Early detection roadmap: organ screening → blood tests for many cancers","route":"/roadmaps/early-detection-roadmap/","tldr":"From mammograms and colonoscopies to a single blood draw that might screen for dozens of cancers, with the FDA's first decision imminent."}],"trials":[],"papers":[{"id":"paper-plco-chest-radiograph-lung-cancer-mortality-jama-2011","name":"Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial","route":"/key-papers/paper-plco-chest-radiograph-lung-cancer-mortality-jama-2011/","journal":"JAMA","year":2011,"whatItMeans":"A negative screening trial that saved a generation from a useless test, and the reason low-dose computed tomography had to be proved separately rather than assumed to work because it saw more."},{"id":"paper-nlst-nejm-2011","name":"NLST: yearly low-dose CT scans cut lung cancer deaths in heavy smokers","route":"/key-papers/paper-nlst-nejm-2011/","journal":"New England Journal of Medicine","year":2011,"whatItMeans":"For people with a heavy smoking history, an annual low-dose CT scan is one of the few screening tests proven to reduce cancer deaths. Most abnormal scans are not cancer, so screening must be paired with careful nodule management. It does not apply to never-smokers or light smokers."},{"id":"paper-nelson-nejm-2020","name":"NELSON: volume-based CT screening reduces lung cancer deaths with fewer false alarms","route":"/key-papers/paper-nelson-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"Lung screening works when it uses volumetric nodule management, and it works against a no-screening control. The protocol underpins the UK Targeted Lung Health Check programme and European recommendations. Benefit in women remains less precisely estimated."},{"id":"paper-uspstf-lung-cancer-screening-jama-2021","name":"Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement","route":"/key-papers/paper-uspstf-lung-cancer-screening-jama-2021/","journal":"JAMA","year":2021,"whatItMeans":"The document that defines who is offered a scan in the United States, and therefore the document any argument about the screening eligibility gap has to engage with. Eligibility is still defined by pack-years and years since quitting rather than by an individual risk estimate."},{"id":"paper-aldrich-uspstf-screening-african-american-smokers-jama-oncol-2019","name":"Evaluation of USPSTF Lung Cancer Screening Guidelines Among African American Adult Smokers","route":"/key-papers/paper-aldrich-uspstf-screening-african-american-smokers-jama-oncol-2019/","journal":"JAMA Oncology","year":2019,"whatItMeans":"The clearest published demonstration that a screening eligibility rule can be accurate on average and systematically wrong for a group. It is the empirical core of the argument for replacing pack-year thresholds with individual risk models."}]},{"era":"2012 to 2019","title":"Immunotherapy, and the trouble with PD-L1 as a gate","description":"Topalian's 2012 phase 1 found durable responses to PD-1 blockade in 18 percent of lung cancer patients and the first hint that PD-L1 expression predicted them. CheckMate 017 and 057 and KEYNOTE-010 established second-line nivolumab and pembrolizumab; KEYNOTE-024 moved pembrolizumab in front of chemotherapy for PD-L1-high tumours; KEYNOTE-189 and KEYNOTE-407 combined it with chemotherapy for everybody else. IMpower110 reproduced the PD-L1-high result with atezolizumab and a different assay, which is where the assay problem became unavoidable: SP142, 22C3 and SP263 do not select the same patients.","status":"historic","refs":[{"id":"paper-topalian-anti-pd1-nejm-2012","kind":"paper","name":"Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer","route":"/key-papers/paper-topalian-anti-pd1-nejm-2012/","tldr":"Nivolumab shrank tumours in roughly a fifth to a quarter of patients with three different advanced cancers, with responses that lasted more than a year and a hint that PD-L1 on the tumour predicted benefit."},{"id":"paper-keynote-001-pembrolizumab-nsclc-nejm-2015","kind":"paper","name":"KEYNOTE-001 (Garon 2015): pembrolizumab in non-small-cell lung cancer and the 50% PD-L1 cut-off","route":"/key-papers/paper-keynote-001-pembrolizumab-nsclc-nejm-2015/","tldr":"The large early trial that showed pembrolizumab shrinks about a fifth of advanced lung cancers, with responses that last, and that identified a PD-L1 score of 50% or more as the group most likely to benefit."},{"id":"paper-checkmate-017-nejm-2015","kind":"paper","name":"CheckMate 017: nivolumab beats docetaxel in squamous lung cancer after chemotherapy","route":"/key-papers/paper-checkmate-017-nejm-2015/","tldr":"In squamous non-small-cell lung cancer that had progressed after platinum chemotherapy, the PD-1 antibody nivolumab prolonged life compared with docetaxel with far fewer severe side effects, regardless of PD-L1 status."},{"id":"paper-checkmate-057-nejm-2015","kind":"paper","name":"CheckMate 057: nivolumab beats docetaxel after chemotherapy in non-squamous lung cancer","route":"/key-papers/paper-checkmate-057-nejm-2015/","tldr":"After platinum chemotherapy had failed, the PD-1 antibody nivolumab prolonged life compared with docetaxel in non-squamous lung cancer with far fewer severe side effects, and the benefit was largest in tumours expressing PD-L1."},{"id":"paper-keynote-024-nejm-2016","kind":"paper","name":"KEYNOTE-024: pembrolizumab alone beats chemotherapy in PD-L1-high lung cancer","route":"/key-papers/paper-keynote-024-nejm-2016/","tldr":"In patients whose lung tumours carried PD-L1 on at least half their cells, pembrolizumab alone held the cancer back longer than chemotherapy and caused fewer serious side effects, making immunotherapy the first treatment for this group."},{"id":"paper-keynote-189-nejm-2018","kind":"paper","name":"KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation","route":"/key-papers/paper-keynote-189-nejm-2018/","tldr":"Adding pembrolizumab to standard chemotherapy roughly halved the risk of death in newly diagnosed non-squamous lung cancer, whatever the PD-L1 level, making chemo-immunotherapy the default first treatment."},{"id":"paper-keynote-407-n-engl-j-med-2018","kind":"paper","name":"Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer","route":"/key-papers/paper-keynote-407-n-engl-j-med-2018/","tldr":"Published report from the KEYNOTE-407 trial registered as NCT02775435, in New England Journal of Medicine (2018), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","kind":"paper","name":"Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC","route":"/key-papers/paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020/","tldr":"In the patients whose tumours showed the most PD-L1, immunotherapy alone gave a median survival of 20.2 months against 13.1 on chemotherapy, with far fewer severe side effects."},{"id":"immunotherapy-roadmap","kind":"roadmap","name":"Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity","route":"/roadmaps/immunotherapy-roadmap/","tldr":"The immunotherapy roadmap is a 130-year arc from injecting bacteria into tumours to releasing immune brakes, and now to designing the immune response itself with vaccines, engagers, and cells."}],"trials":[],"papers":[{"id":"paper-topalian-anti-pd1-nejm-2012","name":"Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer","route":"/key-papers/paper-topalian-anti-pd1-nejm-2012/","journal":"New England Journal of Medicine","year":2012,"whatItMeans":"This study is why PD-1 inhibitors were developed across cancers rather than in melanoma alone: unexpected activity in lung cancer, historically thought immune-resistant, changed drug development priorities industry-wide. It also introduced PD-L1 immunohistochemistry as a candidate biomarker and pneumonitis as a signature toxicity. Within five years PD-1 blockade was approved in more than ten cancers."},{"id":"paper-keynote-001-pembrolizumab-nsclc-nejm-2015","name":"KEYNOTE-001 (Garon 2015): pembrolizumab in non-small-cell lung cancer and the 50% PD-L1 cut-off","route":"/key-papers/paper-keynote-001-pembrolizumab-nsclc-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"This trial gave lung cancer its immunotherapy biomarker. The 50% PD-L1 cut-off decides today whether a patient with advanced lung cancer can start immunotherapy alone or needs chemotherapy added, and the five-year follow-up later showed long-term survivors among first-line responders."},{"id":"paper-checkmate-017-nejm-2015","name":"CheckMate 017: nivolumab beats docetaxel in squamous lung cancer after chemotherapy","route":"/key-papers/paper-checkmate-017-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"With CheckMate 057 this trial ended docetaxel's role as the default second-line treatment in lung cancer and gave the first phase 3 proof that PD-1 blockade extends life in a common carcinoma. Its PD-L1-independent benefit in squamous disease still shapes how the biomarker is used."},{"id":"paper-checkmate-057-nejm-2015","name":"CheckMate 057: nivolumab beats docetaxel after chemotherapy in non-squamous lung cancer","route":"/key-papers/paper-checkmate-057-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"With CheckMate 017 in squamous disease, this trial ended docetaxel's reign as the default second-line treatment for lung cancer and established PD-1 blockade as standard after chemotherapy. Its PD-L1 finding shaped how later first-line trials were designed and how the biomarker is used in the clinic."},{"id":"paper-keynote-024-nejm-2016","name":"KEYNOTE-024: pembrolizumab alone beats chemotherapy in PD-L1-high lung cancer","route":"/key-papers/paper-keynote-024-nejm-2016/","journal":"New England Journal of Medicine","year":2016,"whatItMeans":"This trial is why PD-L1 is measured on every new advanced lung cancer and why a patient with a high score can start immunotherapy without chemotherapy. Together with KEYNOTE-189 for the rest of the population, it moved checkpoint inhibitors from second-line rescue to the first treatment most lung cancer patients receive."},{"id":"paper-keynote-189-nejm-2018","name":"KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation","route":"/key-papers/paper-keynote-189-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"Most patients with newly diagnosed advanced non-squamous lung cancer that lacks a targetable mutation should receive chemotherapy plus pembrolizumab; those with PD-L1 of 50% or more may reasonably receive pembrolizumab alone. About one in five patients is alive at five years, compared with roughly one in ten with chemotherapy alone. Patients with EGFR or ALK alterations were excluded and should have targeted therapy first."},{"id":"paper-keynote-407-n-engl-j-med-2018","name":"Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer","route":"/key-papers/paper-keynote-407-n-engl-j-med-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT02775435 with the most citations, so it is the natural first reading for anyone following the KEYNOTE-407 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","name":"Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC","route":"/key-papers/paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"For the minority of patients whose tumours express a lot of PD-L1, a single antibody outperforms chemotherapy and is far easier to take. The word minority is the point: the same drug in the same disease at lower PD-L1 gives much less."}]},{"era":"2017 to 2024","title":"Stage III, and treatment moving to either side of the operation","description":"PACIFIC put a year of durvalumab after chemoradiotherapy in unresectable stage III disease; the five-year update found 42.9 percent alive against 33.4 percent and a third still free of progression. Resectable disease followed: CheckMate 816 gave nivolumab before surgery, KEYNOTE-671, AEGEAN and CheckMate 77T on both sides, IMpower010 afterwards, and NADIM II showed 93 percent of patients reaching the operating theatre against 69 percent. Targeted drugs made the same move: ADAURA for EGFR, ALINA for ALK, and LAURA for EGFR-mutant stage III disease, where a hazard ratio of 0.16 replaced durvalumab consolidation that had never worked well in that genotype.","status":"current","refs":[{"id":"paper-pacific-nejm-2017","kind":"paper","name":"PACIFIC: a year of durvalumab after chemoradiotherapy for stage III lung cancer","route":"/key-papers/paper-pacific-nejm-2017/","tldr":"Giving the immunotherapy durvalumab for a year after chemoradiotherapy for unresectable stage III lung cancer tripled the time to progression and raised five-year survival from about a third to over 40%."},{"id":"paper-spigel-pacific-five-year-survival-jco-2022","kind":"paper","name":"Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer","route":"/key-papers/paper-spigel-pacific-five-year-survival-jco-2022/","tldr":"Five years after the PACIFIC trial, 42.9 percent of patients given a year of immunotherapy after chemoradiotherapy were still alive, against 33.4 percent of those given placebo. A third of them had never relapsed."},{"id":"paper-checkmate-816-nejm-2022","kind":"paper","name":"CheckMate 816: three cycles of nivolumab plus chemotherapy before lung cancer surgery","route":"/key-papers/paper-checkmate-816-nejm-2022/","tldr":"Just three cycles of chemotherapy with the immunotherapy nivolumab before surgery wiped out all viable tumour in a quarter of patients and reduced relapse or death by about a third, without making surgery harder."},{"id":"paper-keynote-671-n-engl-j-med-2023","kind":"paper","name":"Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer","route":"/key-papers/paper-keynote-671-n-engl-j-med-2023/","tldr":"Published report from the KEYNOTE-671 trial registered as NCT03425643, in New England Journal of Medicine (2023), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-heymach-aegean-perioperative-durvalumab-nejm-2023","kind":"paper","name":"Perioperative durvalumab for resectable non-small-cell lung cancer","route":"/key-papers/paper-heymach-aegean-perioperative-durvalumab-nejm-2023/","tldr":"Giving immunotherapy both before and after lung cancer surgery cut the risk of recurrence by about a third, and left 17.2 percent of tumours with no viable cancer at all in the specimen."},{"id":"paper-felip-impower010-adjuvant-atezolizumab-lancet-2021","kind":"paper","name":"Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010)","route":"/key-papers/paper-felip-impower010-adjuvant-atezolizumab-lancet-2021/","tldr":"The first trial to show that immunotherapy after lung cancer surgery delays recurrence. The benefit was concentrated in patients whose tumours expressed PD-L1."},{"id":"paper-provencio-nadim-ii-perioperative-nivolumab-stage-iii-nejm-2023","kind":"paper","name":"Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer","route":"/key-papers/paper-provencio-nadim-ii-perioperative-nivolumab-stage-iii-nejm-2023/","tldr":"A Spanish trial of 86 patients with stage III lung cancer. Adding immunotherapy before surgery left 37 percent with no viable tumour in the specimen against 7 percent, and 85 percent were alive at two years against 64."},{"id":"paper-adaura-nejm-2020","kind":"paper","name":"ADAURA: three years of osimertinib after surgery for EGFR-mutated lung cancer","route":"/key-papers/paper-adaura-nejm-2020/","tldr":"After surgery for early-stage EGFR-mutated lung cancer, three years of osimertinib cut recurrences by about 80% and later reduced deaths by half."},{"id":"paper-wu-alina-adjuvant-alectinib-nejm-2024","kind":"paper","name":"Alectinib in resected ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-wu-alina-adjuvant-alectinib-nejm-2024/","tldr":"After surgery for ALK-positive lung cancer, two years of alectinib kept 93.8 percent of patients disease-free at two years against 63.0 percent on chemotherapy."},{"id":"paper-lu-laura-osimertinib-stage-iii-nejm-2024","kind":"paper","name":"Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC","route":"/key-papers/paper-lu-laura-osimertinib-stage-iii-nejm-2024/","tldr":"For stage III lung cancer with an EGFR mutation, the standard consolidation immunotherapy works poorly. LAURA gave the EGFR tablet instead and pushed median time to progression from 5.6 months to 39.1."}],"trials":[],"papers":[{"id":"paper-pacific-nejm-2017","name":"PACIFIC: a year of durvalumab after chemoradiotherapy for stage III lung cancer","route":"/key-papers/paper-pacific-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"Patients with stage III lung cancer that cannot be removed surgically should receive a year of durvalumab after completing chemoradiotherapy, provided they have not progressed. This roughly doubles the chance of being alive without progression at five years. Whether the benefit extends to PD-L1-negative tumours is contested, and the EGFR-mutated subgroup is better served by osimertinib (LAURA)."},{"id":"paper-spigel-pacific-five-year-survival-jco-2022","name":"Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer","route":"/key-papers/paper-spigel-pacific-five-year-survival-jco-2022/","journal":"Journal of Clinical Oncology","year":2022,"whatItMeans":"The current standard for unresectable stage III lung cancer, and the clearest evidence in the disease that consolidation immunotherapy converts responses into cures for some patients rather than merely delaying relapse."},{"id":"paper-checkmate-816-nejm-2022","name":"CheckMate 816: three cycles of nivolumab plus chemotherapy before lung cancer surgery","route":"/key-papers/paper-checkmate-816-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Patients with operable stage II-III lung cancer without EGFR or ALK alterations should have chemo-immunotherapy discussed before surgery rather than only afterwards. Three pre-operative cycles do not compromise the operation and improve cure rates. Whether to continue immunotherapy after surgery, as the perioperative trials do, and whether patients with pCR need any further treatment, remain open questions."},{"id":"paper-keynote-671-n-engl-j-med-2023","name":"Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer","route":"/key-papers/paper-keynote-671-n-engl-j-med-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03425643 with the most citations, so it is the natural first reading for anyone following the KEYNOTE-671 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-heymach-aegean-perioperative-durvalumab-nejm-2023","name":"Perioperative durvalumab for resectable non-small-cell lung cancer","route":"/key-papers/paper-heymach-aegean-perioperative-durvalumab-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Perioperative immunotherapy is now standard for resectable lung cancer without a targetable driver. The updated overall survival hazard ratio of 0.89, with a confidence interval crossing one, is the honest state of the evidence on whether it cures more people."},{"id":"paper-felip-impower010-adjuvant-atezolizumab-lancet-2021","name":"Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010)","route":"/key-papers/paper-felip-impower010-adjuvant-atezolizumab-lancet-2021/","journal":"The Lancet","year":2021,"whatItMeans":"Adjuvant immunotherapy entered lung cancer here, and with it the question that still divides practice: whether it is better given before the operation, after it, or on both sides."},{"id":"paper-provencio-nadim-ii-perioperative-nivolumab-stage-iii-nejm-2023","name":"Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer","route":"/key-papers/paper-provencio-nadim-ii-perioperative-nivolumab-stage-iii-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"The strongest signal that neoadjuvant immunotherapy makes stage III lung cancer operable as well as more often curable. Twenty-four percentage points more patients reaching surgery is a result that only a neoadjuvant design can produce."},{"id":"paper-adaura-nejm-2020","name":"ADAURA: three years of osimertinib after surgery for EGFR-mutated lung cancer","route":"/key-papers/paper-adaura-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"Every resected non-squamous lung cancer should be tested for EGFR mutations, because patients who carry one live longer if they take osimertinib for three years after surgery. The trial does not tell us whether adjuvant chemotherapy can be omitted, nor what happens on relapse after osimertinib, and the three-year duration was chosen empirically."},{"id":"paper-wu-alina-adjuvant-alectinib-nejm-2024","name":"Alectinib in resected ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-wu-alina-adjuvant-alectinib-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"Adjuvant treatment for lung cancer is now chosen by genotype. A resected ALK-positive tumour is treated with two years of a tablet instead of four cycles of platinum, which is a different life as well as a different outcome."},{"id":"paper-lu-laura-osimertinib-stage-iii-nejm-2024","name":"Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC","route":"/key-papers/paper-lu-laura-osimertinib-stage-iii-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"Stage III lung cancer is now treated by genotype as well as by stage: an EGFR mutation moves a patient from durvalumab consolidation to osimertinib consolidation. It is also the strongest hazard ratio in the lung cancer literature, which is a reason to read the overall survival data carefully when they arrive."}]},{"era":"2020 to 2026","title":"The driver list grows, and first-line treatment starts to be intensified","description":"ALK moved from crizotinib to alectinib (ALEX) to lorlatinib (CROWN, 78 percent progression-free at 12 months against 39). MET exon 14 got capmatinib, RET got selpercatinib, ROS1 got crizotinib then entrectinib, BRAF V600E got dabrafenib and trametinib, HER2 got trastuzumab deruxtecan and zongertinib, and KRAS G12C, undruggable for thirty years, got sotorasib and adagrasib, with CodeBreaK 200 showing a 1.1-month gain over docetaxel. In EGFR-mutant disease, FLAURA2 added chemotherapy to osimertinib and MARIPOSA beat it outright with amivantamab and lazertinib, 23.7 months against 16.6, at the cost of ten times the treatment discontinuation.","status":"current","refs":[{"id":"paper-peters-alex-alectinib-crizotinib-nejm-2017","kind":"paper","name":"Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/","tldr":"A newer ALK drug that gets into the brain beat the original one, and did it with fewer side effects. ALEX is why nobody starts an ALK-positive patient on crizotinib any more."},{"id":"paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","kind":"paper","name":"First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer","route":"/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/","tldr":"CROWN's third-generation ALK drug kept 78 percent of patients free of progression at a year against 39 percent on crizotinib, and controlled disease inside the brain far better."},{"id":"paper-wolf-geometry-mono-1-capmatinib-nejm-2020","kind":"paper","name":"Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer","route":"/key-papers/paper-wolf-geometry-mono-1-capmatinib-nejm-2020/","tldr":"MET exon 14 skipping is found in 3 to 4 percent of lung cancers. Untreated patients given capmatinib responded 68 percent of the time; those already treated, 41 percent. Order of treatment mattered more than usual."},{"id":"paper-libretto-001-selpercatinib-nsclc-nejm-2020","kind":"paper","name":"LIBRETTO-001: selpercatinib in RET fusion-positive non-small-cell lung cancer","route":"/key-papers/paper-libretto-001-selpercatinib-nsclc-nejm-2020/","tldr":"The selective RET inhibitor selpercatinib shrank tumours in 64 percent of previously treated and 85 percent of untreated patients with RET fusion-positive lung cancer, including brain metastases, and led to the first approval for this driver."},{"id":"paper-de-langen-codebreak-200-sotorasib-docetaxel-lancet-2023","kind":"paper","name":"Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial","route":"/key-papers/paper-de-langen-codebreak-200-sotorasib-docetaxel-lancet-2023/","tldr":"The first randomised test of a KRAS inhibitor. Sotorasib beat docetaxel on time to progression by about a month, with fewer serious side effects. A real but modest win against the commonest driver in lung cancer."},{"id":"paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","kind":"paper","name":"Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC","route":"/key-papers/paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023/","tldr":"FLAURA2 added chemotherapy to the standard EGFR tablet in 557 patients and cut the risk of the cancer growing by 38 percent, at the cost of chemotherapy's side effects for everybody."},{"id":"paper-cho-mariposa-amivantamab-lazertinib-nejm-2024","kind":"paper","name":"Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC","route":"/key-papers/paper-cho-mariposa-amivantamab-lazertinib-nejm-2024/","tldr":"MARIPOSA beat osimertinib, the standard first treatment, by about seven months before the cancer grew again. It is the first trial to do so, and the first to show that hitting EGFR two ways at once is better than one."},{"id":"paper-beamion-lung-1-zongertinib-nejm-2025","kind":"paper","name":"Beamion LUNG-1: zongertinib in previously treated HER2-mutant non-small-cell lung cancer","route":"/key-papers/paper-beamion-lung-1-zongertinib-nejm-2025/","tldr":"The oral HER2-selective kinase inhibitor zongertinib shrank tumours in about seven in ten patients with previously treated HER2-mutant lung cancer with little of the diarrhoea and rash that plagued earlier HER2 pills, becoming the first oral drug approved for this driver."},{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/","tldr":"The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer."}],"trials":[],"papers":[{"id":"paper-peters-alex-alectinib-crizotinib-nejm-2017","name":"Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"First-line ALK treatment moved to a drug designed for the brain, and brain metastasis prevention became an explicit design goal rather than a hoped-for side effect. ALK-positive lung cancer is now among the longest-surviving metastatic solid tumours."},{"id":"paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","name":"First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer","route":"/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"The current first choice for ALK-positive lung cancer in most guidelines, and the strongest evidence in solid tumour oncology that a drug can be designed to work inside the brain. Five-year follow-up has since shown the majority of patients still progression-free."},{"id":"paper-wolf-geometry-mono-1-capmatinib-nejm-2020","name":"Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer","route":"/key-papers/paper-wolf-geometry-mono-1-capmatinib-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"A rare driver with a real drug, and a warning about biomarker thresholds: the same gene, tested the same way, predicts response or does not depending on a copy-number cut-off that has to be measured rather than assumed."},{"id":"paper-libretto-001-selpercatinib-nsclc-nejm-2020","name":"LIBRETTO-001: selpercatinib in RET fusion-positive non-small-cell lung cancer","route":"/key-papers/paper-libretto-001-selpercatinib-nsclc-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"RET fusion testing is standard in lung adenocarcinoma and selpercatinib the preferred first-line RET inhibitor, confirmed against chemo-immunotherapy in LIBRETTO-431."},{"id":"paper-de-langen-codebreak-200-sotorasib-docetaxel-lancet-2023","name":"Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial","route":"/key-papers/paper-de-langen-codebreak-200-sotorasib-docetaxel-lancet-2023/","journal":"The Lancet","year":2023,"whatItMeans":"KRAS is druggable, and the first generation of drugs is not very good. The gap between the biological achievement and the clinical gain is what the next generation of KRAS inhibitors, and the combination trials around them, exist to close."},{"id":"paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","name":"Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC","route":"/key-papers/paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Adding chemotherapy to osimertinib delays progression. Whether it extends life, and whether the same benefit could be had by giving the chemotherapy later to the patients who need it, is what the overall survival analysis and the registry watch on this roadmap are for."},{"id":"paper-cho-mariposa-amivantamab-lazertinib-nejm-2024","name":"Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC","route":"/key-papers/paper-cho-mariposa-amivantamab-lazertinib-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"The first regimen to beat osimertinib as first-line treatment for EGFR-mutant lung cancer. It sets up the choice that now faces every newly diagnosed patient: a more effective but harder combination now, or a simpler tablet with something held back for later."},{"id":"paper-beamion-lung-1-zongertinib-nejm-2025","name":"Beamion LUNG-1: zongertinib in previously treated HER2-mutant non-small-cell lung cancer","route":"/key-papers/paper-beamion-lung-1-zongertinib-nejm-2025/","journal":"New England Journal of Medicine","year":2025,"whatItMeans":"Zongertinib gives HER2-mutant lung cancer an oral targeted option with brain activity, used after platinum chemotherapy and increasingly before or after trastuzumab deruxtecan."}]},{"era":"1999 to 2026","title":"Small-cell lung cancer, static for twenty-five years and then not","description":"Turrisi's twice-daily thoracic radiotherapy in 1999 raised five-year survival from 16 to 26 percent, and the Aupérin overview showed that irradiating a brain with no detectable disease in it extends life. Then nothing, for a quarter of a century. George's 110 genomes explained why: the disease is defined by losing both copies of TP53 and RB1, and a loss cannot be inhibited. Rudin's four transcription-factor subtypes gave the field something to design around, the NOTCH finding pointed at DLL3, and in 2023 tarlatamab produced a 40 percent response rate in twice-treated patients. ADRIATIC then lifted median survival in limited-stage disease from 33.4 to 55.9 months.","status":"current","refs":[{"id":"paper-turrisi-twice-daily-thoracic-radiotherapy-limited-sclc-nejm-1999","kind":"paper","name":"Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide","route":"/key-papers/paper-turrisi-twice-daily-thoracic-radiotherapy-limited-sclc-nejm-1999/","tldr":"Giving the same total radiation dose twice a day over three weeks instead of once a day over five raised five-year survival from 16 to 26 percent, at the cost of a much sorer gullet."},{"id":"paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999","kind":"paper","name":"Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission","route":"/key-papers/paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999/","tldr":"Pooling 987 patients from seven trials showed that irradiating the brain of people whose small-cell lung cancer had gone into remission, before any brain secondaries appeared, made them live longer."},{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/","tldr":"Sequencing 110 small-cell lung cancers found that losing both copies of TP53 and RB1 is obligatory. That is a loss of two brakes, not a gain of a target, which is why the disease has been so hard to drug."},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/","tldr":"Small-cell lung cancer, treated as one disease for fifty years, is at least four. The subtypes are named after the transcription factor each one leans on: ASCL1, NeuroD1, YAP1 and POU2F3."},{"id":"paper-impower133-n-engl-j-med-2018","kind":"paper","name":"First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer","route":"/key-papers/paper-impower133-n-engl-j-med-2018/","tldr":"Published report from the IMpower133 trial registered as NCT02763579, in New England Journal of Medicine (2018), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019","kind":"paper","name":"Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)","route":"/key-papers/paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019/","tldr":"Adding immunotherapy to chemotherapy for advanced small-cell lung cancer raised median survival from 10.3 to 13.0 months. Small, but it was the second positive first-line trial in the disease in thirty years."},{"id":"paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023","kind":"paper","name":"Tarlatamab for patients with previously treated small-cell lung cancer","route":"/key-papers/paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023/","tldr":"The first drug in decades built specifically for small-cell lung cancer. Tarlatamab grabs a protein called DLL3 on the tumour with one arm and a T cell with the other; 40 percent of heavily pretreated patients responded."},{"id":"paper-cheng-adriatic-durvalumab-limited-stage-sclc-nejm-2024","kind":"paper","name":"Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer","route":"/key-papers/paper-cheng-adriatic-durvalumab-limited-stage-sclc-nejm-2024/","tldr":"ADRIATIC gave immunotherapy after chemoradiotherapy for limited-stage small-cell lung cancer and lifted median survival from 33.4 to 55.9 months, the largest gain the disease has seen."}],"trials":[],"papers":[{"id":"paper-turrisi-twice-daily-thoracic-radiotherapy-limited-sclc-nejm-1999","name":"Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide","route":"/key-papers/paper-turrisi-twice-daily-thoracic-radiotherapy-limited-sclc-nejm-1999/","journal":"New England Journal of Medicine","year":1999,"whatItMeans":"The standard of care in limited-stage small-cell lung cancer from 1999 until ADRIATIC added immunotherapy in 2024, and a rare example of a curative gain in a disease that has had almost none."},{"id":"paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999","name":"Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission","route":"/key-papers/paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999/","journal":"New England Journal of Medicine","year":1999,"whatItMeans":"Treating the brain before the cancer gets there works in small-cell lung cancer, and it is the proof of principle behind every later attempt to prevent rather than treat brain metastases."},{"id":"paper-george-sclc-genomic-profiles-nature-2015","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/","journal":"Nature","year":2015,"whatItMeans":"Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab."},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/","journal":"Nature Reviews Cancer","year":2019,"whatItMeans":"The organising framework for every small-cell lung cancer trial designed since. It is also why the slow progress in the disease is now attributed to treating four diseases as one rather than to the biology being intractable."},{"id":"paper-impower133-n-engl-j-med-2018","name":"First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer","route":"/key-papers/paper-impower133-n-engl-j-med-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT02763579 with the most citations, so it is the natural first reading for anyone following the IMpower133 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019","name":"Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)","route":"/key-papers/paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019/","journal":"The Lancet","year":2019,"whatItMeans":"Immunotherapy is now part of first-line treatment for extensive-stage small-cell lung cancer everywhere, on the strength of a gain measured in weeks. The size of that gain is the reason small-cell lung cancer remains the clearest unmet need in thoracic oncology."},{"id":"paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023","name":"Tarlatamab for patients with previously treated small-cell lung cancer","route":"/key-papers/paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Small-cell lung cancer got its first targeted drug, and the mechanism is a T-cell engager rather than a kinase inhibitor. It also brought cytokine release syndrome, and the inpatient monitoring that goes with it, into thoracic oncology for the first time."},{"id":"paper-cheng-adriatic-durvalumab-limited-stage-sclc-nejm-2024","name":"Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer","route":"/key-papers/paper-cheng-adriatic-durvalumab-limited-stage-sclc-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"The biggest single advance in small-cell lung cancer since twice-daily radiotherapy in 1999, and the strongest argument that the disease responds to immunotherapy when it is given at a lower tumour burden."}]},{"era":"2017 to 2027","title":"Reading the tumour over time: heterogeneity, ctDNA and resistance-directed treatment","description":"TRACERx sequenced 327 regions from 100 resected tumours and found that drivers are almost always clonal while later alterations are heterogeneous in more than three quarters of tumours, with copy-number heterogeneity carrying a hazard ratio of 4.9 for recurrence or death. Abbosh built a per-patient phylogenetic ctDNA assay from the same tumours and identified the patients who would relapse before any scan did. Neither is yet a clinical test in lung cancer: no randomised trial has shown that acting on a positive minimal residual disease result improves survival, which is the gap the ctDNA-guided adjuvant trials are designed to close.","status":"emerging","refs":[{"id":"paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017","kind":"paper","name":"Tracking the evolution of non-small-cell lung cancer","route":"/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/","tldr":"TRACERx sequenced several regions of 100 lung tumours instead of one. The driver mutations were usually everywhere in the tumour, but three quarters had later mutations present in only part of it, and the messier the tumour, the worse the outcome."},{"id":"paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017","kind":"paper","name":"Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution","route":"/key-papers/paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017/","tldr":"By building a family tree of each tumour's mutations first, the TRACERx team could find the cancer's DNA in blood after surgery and tell which patients would relapse, before any scan showed anything."},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/","tldr":"37 patients were re-biopsied when their EGFR drug stopped working. Some had the expected resistance mutation; five had turned into small-cell lung cancer. In three, the resistance disappeared when the drug was stopped."},{"id":"ctdna-tests","kind":"roadmap","name":"ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment","route":"/roadmaps/ctdna-tests/","tldr":"Blood carries fragments of tumour DNA. This roadmap follows the tests that read them, from the first sighting in 1948 to blood tests that now choose a drug, spare chemotherapy, or screen for many cancers at once, and it lists the readouts to watch next."},{"id":"diagnostics-roadmap","kind":"roadmap","name":"Diagnostics roadmap: stains → gene panels → blood tests that decide treatment","route":"/roadmaps/diagnostics-roadmap/","tldr":"Cancer diagnosis moved from what a tumour looks like under a microscope to what is driving it, and now to reading it from a blood sample. The next step is tests that tell the doctor what to do, not only what is there."}],"trials":[],"papers":[{"id":"paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017","name":"Tracking the evolution of non-small-cell lung cancer","route":"/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"Why targeting a clonal driver works and targeting a subclonal one usually does not, and why a single-site biopsy can mislead. Chromosomal instability is now a candidate prognostic marker in its own right."},{"id":"paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017","name":"Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution","route":"/key-papers/paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017/","journal":"Nature","year":2017,"whatItMeans":"The foundation of minimal residual disease testing in lung cancer: a blood test that says a patient will relapse months before a scan does, and says which part of the tumour is doing it. Whether acting on that signal changes outcome is what the ctDNA-guided trials are for."},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/","journal":"Science Translational Medicine","year":2011,"whatItMeans":"The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became."}]},{"era":"2021 to 2030","title":"Never-smoker disease and the air people breathe","description":"About one lung cancer in five worldwide occurs in someone who never smoked, and the proportion is rising as smoking falls. Sherlock-Lung's 232 whole genomes found three subtypes with no tobacco signature, the dominant one slow-growing with drivers datable to years before diagnosis. Hill and Swanton then proposed a mechanism for at least part of it: fine particulate matter does not create the EGFR mutation, which is already present in 18 percent of histologically normal lungs, but inflames the tissue enough to let it grow. That makes air quality a cancer intervention with a measurable endpoint, and makes the screening eligibility criteria, which exclude never-smokers entirely, the wrong instrument for a growing share of the disease.","status":"emerging","refs":[{"id":"paper-zhang-lung-cancer-never-smokers-nat-genet-2021","kind":"paper","name":"Genomic and evolutionary classification of lung cancer in never smokers","route":"/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/","tldr":"The Sherlock-Lung study sequenced 232 lung cancers from people who never smoked and found three distinct types, none of them carrying the tobacco damage signature. One type appears to begin decades before it is diagnosed."},{"id":"paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","kind":"paper","name":"Lung adenocarcinoma promotion by air pollutants","route":"/key-papers/paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023/","tldr":"Healthy lungs already carry cancer-causing mutations. This study argues that fine particles in polluted air do not create the mutation but wake it up, which is why lung cancer happens in people who never smoked."},{"id":"paper-uspstf-lung-cancer-screening-jama-2021","kind":"paper","name":"Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement","route":"/key-papers/paper-uspstf-lung-cancer-screening-jama-2021/","tldr":"In 2021 the United States task force lowered the age at which lung screening starts from 55 to 50 and halved the smoking history needed from 30 to 20 pack-years, roughly doubling the number of people eligible."},{"id":"prevention-roadmap","kind":"roadmap","name":"Cancer prevention roadmap: tobacco control and vaccines → biomarker-guided chemoprevention → interception in carriers","route":"/roadmaps/prevention-roadmap/","tldr":"About four in ten cancers could be prevented with tools that already exist: vaccines against the viruses that cause them, tobacco and alcohol control, weight, aspirin for the right people, and finding the families who carry a high-risk gene. The roadmap is mostly about deployment, with interception vaccines as the long-range bet."},{"id":"idea-prev-clean-air-never-smoker-endpoints","kind":"idea","name":"Evaluate clean-air policies using lung cancer in never-smokers","route":"/ideas/idea-prev-clean-air-never-smoker-endpoints/","tldr":"Air pollution causes lung cancer in people who never smoked. Clean air zones and coal phase-outs should be tracked against never-smoker lung cancer rates."}],"trials":[],"papers":[{"id":"paper-zhang-lung-cancer-never-smokers-nat-genet-2021","name":"Genomic and evolutionary classification of lung cancer in never smokers","route":"/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/","journal":"Nature Genetics","year":2021,"whatItMeans":"Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find."},{"id":"paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","name":"Lung adenocarcinoma promotion by air pollutants","route":"/key-papers/paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023/","journal":"Nature","year":2023,"whatItMeans":"It reframes air quality as cancer policy rather than respiratory policy, and it explains the shape of lung cancer in never-smokers: the mutations are common and mostly silent, and what differs is whether something inflames the tissue enough to let one of them grow."},{"id":"paper-uspstf-lung-cancer-screening-jama-2021","name":"Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement","route":"/key-papers/paper-uspstf-lung-cancer-screening-jama-2021/","journal":"JAMA","year":2021,"whatItMeans":"The document that defines who is offered a scan in the United States, and therefore the document any argument about the screening eligibility gap has to engage with. Eligibility is still defined by pack-years and years since quitting rather than by an individual risk estimate."}]},{"era":"2026 to 2032","title":"What would have to be true for lung cancer mortality to halve again","description":"Four things, none of them a new drug class. Screening reaching the people at highest risk rather than the people easiest to enrol, which means risk-model eligibility and delivery into deprived areas rather than wider pack-year thresholds. Resistance treated as a diagnosis, with a re-biopsy or a ctDNA profile choosing the next line rather than a default. Brain metastasis prevention measured as a primary endpoint rather than counted as a secondary one. And small-cell lung cancer trialled as the four diseases Rudin's subtypes describe, in a platform with shared controls, rather than as one disease with a 62 percent grade 3 toxicity rate and a two-month gain.","status":"speculative","refs":[{"id":"idea-lung-screening-eligibility-by-risk-not-pack-years","kind":"idea","name":"Decide who is screened for lung cancer by individual risk, not by pack-years","route":"/ideas/idea-lung-screening-eligibility-by-risk-not-pack-years/","tldr":"The rules that decide who gets a lung scan count cigarettes. A risk model that also uses age, sex, family history, deprivation and lung disease would find more cancers in the same number of scans, and would stop excluding people who smoke less but are more likely to get the disease."},{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/","tldr":"When a targeted drug stops working, the tumour has usually changed in a way you can read. Most patients still move to the next treatment on a protocol rather than on a test of what actually happened."},{"id":"idea-lung-brain-metastasis-prevention-as-a-primary-endpoint","kind":"idea","name":"Measure brain metastasis prevention as a primary endpoint, not as a secondary one","route":"/ideas/idea-lung-brain-metastasis-prevention-as-a-primary-endpoint/","tldr":"Lung cancer spreads to the brain more than any other common cancer, and the newest drugs seem to stop it happening. Almost no trial is designed to prove that, so the claim stays a footnote."},{"id":"idea-lung-small-cell-platform-with-shared-controls-and-subtypes","kind":"idea","name":"Run small-cell lung cancer as one platform with shared controls and subtype stratification","route":"/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/","tldr":"Small-cell lung cancer has had two real advances in twenty-five years. It is probably four diseases being tested as one, in separate small trials that each need their own control group."},{"id":"idea-lung-deprivation-gradient-treated-as-a-defect-in-delivery","kind":"idea","name":"Treat the deprivation gradient in lung cancer as a defect in delivery that can be fixed and measured","route":"/ideas/idea-lung-deprivation-gradient-treated-as-a-defect-in-delivery/","tldr":"Poorer patients with lung cancer are less likely to be offered surgery or chemotherapy, at the same stage, in systems that are free at the point of use. That is a fixable problem in how care is delivered, not a fact about the disease."}],"trials":[],"papers":[]}],"watch":[{"item":"ADRIATIC: final analysis of durvalumab, and the unblinding of the durvalumab plus tremelimumab arm, in limited-stage small-cell lung cancer","expected":"Study completion 23 October 2026 (estimated, ClinicalTrials.gov NCT03703297)","source":"https://clinicaltrials.gov/study/NCT03703297","refs":[{"id":"paper-cheng-adriatic-durvalumab-limited-stage-sclc-nejm-2024","kind":"paper","name":"Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer","route":"/key-papers/paper-cheng-adriatic-durvalumab-limited-stage-sclc-nejm-2024/","tldr":"ADRIATIC gave immunotherapy after chemoradiotherapy for limited-stage small-cell lung cancer and lifted median survival from 33.4 to 55.9 months, the largest gain the disease has seen."},{"id":"adriatic","kind":"trial","name":"ADRIATIC","route":"/trials/adriatic/","status":"positive","tldr":"ADRIATIC brought the first improvement in curative-intent small-cell lung cancer treatment in 30 years: a year or two of immunotherapy after chemoradiation lengthens life."}]},{"item":"IMpower010: final overall survival for adjuvant atezolizumab after chemotherapy in resected disease","expected":"Study completion 31 August 2027 (estimated, ClinicalTrials.gov NCT02486718)","source":"https://clinicaltrials.gov/study/NCT02486718","refs":[{"id":"paper-felip-impower010-adjuvant-atezolizumab-lancet-2021","kind":"paper","name":"Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010)","route":"/key-papers/paper-felip-impower010-adjuvant-atezolizumab-lancet-2021/","tldr":"The first trial to show that immunotherapy after lung cancer surgery delays recurrence. The benefit was concentrated in patients whose tumours expressed PD-L1."}]},{"item":"FLAURA2: overall survival for osimertinib with chemotherapy against osimertinib alone","expected":"Study completion 30 September 2027 (estimated, ClinicalTrials.gov NCT04035486)","source":"https://clinicaltrials.gov/study/NCT04035486","refs":[{"id":"paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","kind":"paper","name":"Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC","route":"/key-papers/paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023/","tldr":"FLAURA2 added chemotherapy to the standard EGFR tablet in 557 patients and cut the risk of the cancer growing by 38 percent, at the cost of chemotherapy's side effects for everybody."},{"id":"flaura2","kind":"trial","name":"FLAURA2","route":"/trials/flaura2/","status":"positive","tldr":"Adding chemotherapy to osimertinib extended both progression-free and, in 2025, overall survival."}]},{"item":"LAURA: overall survival for osimertinib after chemoradiotherapy in stage III EGFR-mutated disease","expected":"Study completion 29 October 2027 (estimated, ClinicalTrials.gov NCT03521154)","source":"https://clinicaltrials.gov/study/NCT03521154","refs":[{"id":"paper-lu-laura-osimertinib-stage-iii-nejm-2024","kind":"paper","name":"Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC","route":"/key-papers/paper-lu-laura-osimertinib-stage-iii-nejm-2024/","tldr":"For stage III lung cancer with an EGFR mutation, the standard consolidation immunotherapy works poorly. LAURA gave the EGFR tablet instead and pushed median time to progression from 5.6 months to 39.1."},{"id":"laura","kind":"trial","name":"LAURA","route":"/trials/laura/","status":"positive","tldr":"For stage III lung cancers with an EGFR mutation, a targeted pill after chemoradiation cut progression by more than 80%."}]},{"item":"MARIPOSA: final overall survival for amivantamab plus lazertinib against osimertinib in first line","expected":"Study completion 16 February 2028 (estimated, ClinicalTrials.gov NCT04487080)","source":"https://clinicaltrials.gov/study/NCT04487080","refs":[{"id":"paper-cho-mariposa-amivantamab-lazertinib-nejm-2024","kind":"paper","name":"Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC","route":"/key-papers/paper-cho-mariposa-amivantamab-lazertinib-nejm-2024/","tldr":"MARIPOSA beat osimertinib, the standard first treatment, by about seven months before the cancer grew again. It is the first trial to do so, and the first to show that hitting EGFR two ways at once is better than one."},{"id":"mariposa","kind":"trial","name":"MARIPOSA","route":"/trials/mariposa/","status":"positive","tldr":"The first regimen to beat osimertinib in EGFR-mutant lung cancer, with a survival benefit exceeding a year."}]},{"item":"DeLLphi-304: final analysis of tarlatamab against chemotherapy in relapsed small-cell lung cancer","expected":"Study completion 26 March 2028 (estimated, ClinicalTrials.gov NCT05740566)","source":"https://clinicaltrials.gov/study/NCT05740566","refs":[{"id":"paper-tarlatamab-sclc-n-engl-j-med-2025","kind":"paper","name":"Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy","route":"/key-papers/paper-tarlatamab-sclc-n-engl-j-med-2025/","tldr":"Phase 2 or 3 results paper on Tarlatamab in Small-cell lung cancer, in New England Journal of Medicine (2025), one of the most cited Europe PMC records with Tarlatamab in its title."},{"id":"paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023","kind":"paper","name":"Tarlatamab for patients with previously treated small-cell lung cancer","route":"/key-papers/paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023/","tldr":"The first drug in decades built specifically for small-cell lung cancer. Tarlatamab grabs a protein called DLL3 on the tumour with one arm and a T cell with the other; 40 percent of heavily pretreated patients responded."},{"id":"dellphi-304","kind":"trial","name":"DeLLphi-304","route":"/trials/dellphi-304/","status":"positive","tldr":"DeLLphi-304 was the first trial in which a T-cell engager improved survival in a common solid tumour."}]},{"item":"AEGEAN: final overall survival for perioperative durvalumab in resectable disease","expected":"Study completion 11 September 2028 (estimated, ClinicalTrials.gov NCT03800134)","source":"https://clinicaltrials.gov/study/NCT03800134","refs":[{"id":"paper-heymach-aegean-perioperative-durvalumab-nejm-2023","kind":"paper","name":"Perioperative durvalumab for resectable non-small-cell lung cancer","route":"/key-papers/paper-heymach-aegean-perioperative-durvalumab-nejm-2023/","tldr":"Giving immunotherapy both before and after lung cancer surgery cut the risk of recurrence by about a third, and left 17.2 percent of tumours with no viable cancer at all in the specimen."}]},{"item":"CROWN: final analysis of first-line lorlatinib against crizotinib, including long-term intracranial control","expected":"Study completion 31 December 2028 (estimated, ClinicalTrials.gov NCT03052608)","source":"https://clinicaltrials.gov/study/NCT03052608","refs":[{"id":"paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","kind":"paper","name":"First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer","route":"/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/","tldr":"CROWN's third-generation ALK drug kept 78 percent of patients free of progression at a year against 39 percent on crizotinib, and controlled disease inside the brain far better."},{"id":"crown","kind":"trial","name":"CROWN","route":"/trials/crown/","status":"positive","tldr":"The trial with the longest disease control ever seen for a targeted lung cancer pill: most patients still progression-free at five years."}]},{"item":"ALINA: overall survival for adjuvant alectinib against chemotherapy in resected ALK-positive disease, the longest-dated of the practice-changing perioperative trials","expected":"Study completion 19 November 2031 (estimated, ClinicalTrials.gov NCT03456076)","source":"https://clinicaltrials.gov/study/NCT03456076","refs":[{"id":"paper-wu-alina-adjuvant-alectinib-nejm-2024","kind":"paper","name":"Alectinib in resected ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-wu-alina-adjuvant-alectinib-nejm-2024/","tldr":"After surgery for ALK-positive lung cancer, two years of alectinib kept 93.8 percent of patients disease-free at two years against 63.0 percent on chemotherapy."},{"id":"alina","kind":"trial","name":"ALINA","route":"/trials/alina/","status":"positive","tldr":"Showed that giving an ALK pill after surgery, instead of chemotherapy, sharply reduces recurrence, including in the brain."}]},{"item":"TRACERx: the full evolutionary and ctDNA dataset on 814 patients, the deepest longitudinal study of lung cancer evolution","expected":"Study completion November 2035 (estimated, ClinicalTrials.gov NCT01888601)","source":"https://clinicaltrials.gov/study/NCT01888601","refs":[{"id":"paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017","kind":"paper","name":"Tracking the evolution of non-small-cell lung cancer","route":"/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/","tldr":"TRACERx sequenced several regions of 100 lung tumours instead of one. The driver mutations were usually everywhere in the tumour, but three quarters had later mutations present in only part of it, and the messier the tumour, the worse the outcome."},{"id":"paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017","kind":"paper","name":"Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution","route":"/key-papers/paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017/","tldr":"By building a family tree of each tumour's mutations first, the TRACERx team could find the cancer's DNA in blood after surgery and tell which patients would relapse, before any scan showed anything."}]}]}