Precision oncology has changed the management of advanced non-small-cell lung cancer (NSCLC). Biomarker-matched therapies now improve outcomes in an increasing number of molecularly defined subgroups. In this second paper in a Series on therapeutics in lung cancer, we summarise recent advances in NSCLC with established alterations, including EGFR, ALK, ROS1, KRAS, BRAF, RET, HER2, MET, and NTRK, and discuss emerging targets, such as NRG1 fusions, MTAP loss, and SMARCA4 deficiency. Newer generations of tyrosine kinase inhibitors, the introduction of bispecific antibodies, and antibody-drug conjugates have improved response durability, intracranial disease control, and in some settings, overall survival. However, durable benefit can remain limited by acquired resistance, tumour heterogeneity, lineage plasticity, and off-target escape, supporting repeat tissue biopsy and circulating-tumour DNA profiling to guide subsequent treatment. With several options available such as monotherapy and combination approaches, individualised treatment selection is becoming increasingly complex. We discuss these choices, including the management of CNS disease and oligoprogression, and long-term tolerability. As drug development extends beyond canonical drivers to rarer alterations and adverse co-mutations, the range of targetable disease is increasing. Further progress will depend on more effective and adaptive treatment strategies together with equitable access to comprehensive molecular profiling, timely biomarker testing, and next-generation targeted therapies.
The treatment of early-stage non-small-cell lung cancer (NSCLC) has evolved substantially in recent years. For decades, curative-intent surgery followed by platinum-based chemotherapy remained the standard of care (SOC), despite delivering only modest gains in long-term survival. Current evidence from randomised trials incorporating immunotherapy as a neoadjuvant or perioperative approach, along with targeted therapies, have defined a new SOC treatment approach for patients with resectable early-stage NSCLC. However, these advances have introduced uncertainties regarding optimal sequencing, treatment duration, patient selection, and the role of treatment escalation or de-intensification with immunotherapy and targeted therapies. The advances and uncertainties are discussed in this Series paper, along with the role of radiotherapy in this setting.
BACKGROUND:Crizotinib is an established first-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of advanced ALK-positive non-small-cell lung cancer (NSCLC). E4512 aimed to evaluate the effect of adjuvant crizotinib on disease-free survival (DFS) in patients with resected, early-stage ALK-positive NSCLC. METHODS:In this randomised, controlled, phase 3 trial conducted in 1618 sites across the USA, Guam, and Puerto Rico, patients were randomly assigned 1:1 by computer-generated sequence to receive crizotinib 250 mg orally twice daily or observation (changed from initial double-blind placebo) for up 2 years. Eligible patients had resected NSCLC tumours that were 4 cm or larger in diameter or lymph node-positive, negative surgical margins, no neoadjuvant therapy, ALK positivity by local or central testing, and an Eastern Cooperative Oncology Group performance status of 0-1. Adjuvant chemotherapy was allowed but not required. Stratification factors were stage, previous radiation therapy, and sex. The primary endpoint was disease-free survival (DFS) in the centrally tested ALK-positive intention-to-treat population and presented as hazard ratio with 90% and 95% CI. The trial was registered at ClinicalTrials.gov (NCT02201992) and is completed. Safety was assessed in all patients whose tumours tested ALK-positive and who received the study drug. FINDINGS:Between Aug 18, 2014, and May 10, 2024, 166 patients (of 168 planned) were enrolled (85 to crizotinib and 81 to observation). Accrual was stopped when the US Food and Drug Administration approved adjuvant alectinib for resected ALK-positive NSCLC. Overall, 153 (92%) patients had centrally confirmed ALK-positive tumours. Among these 153 individuals, 99 (65%) were female, 54 (35%) were male, and 121 (79%) were White. After a median follow-up of 65·7 months (IQR 37·5-85·6), median DFS was 74·6 (95% CI 71·2 to not assessable) months in the crizotinib group and 106·2 (67·8 to NA) months in the observation group (HR 1·08 [90% CI 0·67-1·73; 95% CI 0·61-1·90; p=0·80). In the crizotinib group, 46 (58%) patients had grade 3 or higher adverse events of any attribution (most commonly diarrhoea, in eight [10%] patients; oedema, in four [5%] patients; and hypertension, in four [5%] patients), including one death that was not deemed treatment-related. 21 (27%) patients had serious adverse events, most commonly dyspnoea (three [4%] patients), abdominal pain (two [3%] patients), thromboembolic event (two [3%] patients), diarrhoea (two [3%] patients), dehydration (two [3%] patients), and hypertension (two [3%] patients). INTERPRETATION:Adjuvant crizotinib does not prolong DFS in patients with surgically resected ALK-positive NSCLC. These findings suggest that crizotinib should not be recommended as an adjuvant therapy for patients with resected ALK-positive NSCLC. FUNDING:National Cancer Institute of the US National Institutes of Health.
BACKGROUND:The Surviving Sepsis Campaign guidelines stratify antibiotic urgency in suspected sepsis by shock status, recommending treatment within 1 h for patients with shock and within 3 h for possible sepsis without shock. UK National Institute for Health and Care Excellence (NICE) guidelines use National Early Warning Score 2 (NEWS2) risk categories, with a window of 1 h for the group at highest risk of mortality (aggregate score ≥7). We aimed to compare these strategies for identifying patients in whom antibiotic delays are associated with mortality. METHODS:We conducted a retrospective cohort study between May 31, 2015, and Feb 28, 2024, of adults (age ≥18 years) admitted via the emergency departments of nine hospitals within the Mass General Brigham health-care system (MA, USA) and treated for suspected infection, defined as blood culture sampling and intravenous antibiotic administration within 6 h of emergency department arrival. Exclusion criteria included transition to palliative care or death within 6 h of arrival to emergency department, transfer from acute care hospitals, psychiatric or obstetric admissions, missing vital signs or key laboratory test results within 12 h of arrival, oral or intravenous antibiotic receipt before arrival, insufficient data to calculate NEWS2 scores, and positive SARS-CoV-2 PCR test results within 2 days of arrival. We estimated hourly associations between time to antibiotic administration and hospital mortality using multivariable logistic regression with generalised estimating equations, stratified by shock (defined as persistent hypotension and lactate >2 mmol/L) and by laboratory-upgraded NEWS2 scores (NEWS2+), which were calculated per UK NICE guidance by shifting patients up one category if they had neutropenia, lactate concentration higher than 2 mmol/L, or laboratory evidence of new organ dysfunction within 3 h of arrival. FINDINGS:115 464 encounters with suspected infection were identified, of which 15 797 were ineligible based on exclusion criteria. The final analysis cohort included 71 593 patients who contributed 99 667 encounters (52 835 [53%] male, 46 828 [47%] female). 4867 (4·9%) encounters had shock. NEWS2+ scores were 0 in 9672 (9·7%) encounters, 1-4 in 37 310 (37·4%) encounters, 5-6 in 26 134 (26·2%) encounters, and ≥7 in 26 551 (26·6%) encounters. Each additional hour to antibiotic administration was associated with higher mortality in encounters with shock (adjusted odds ratio [OR] 1·15, 95% CI 1·07-1·25; 1·5% absolute increase per hour, 95% CI 0·5-2·4), but not in those without shock (1·03, 1·00-1·05). Delays were also associated with higher mortality in encounters with NEWS2+ ≥7 (1·07, 1·04-1·11; 0·5% absolute increase per hour, 95% CI 0·3-0·8), including 22 902 (86·3%) of 26 551 encounters without shock (1·05, 1·01-1·09; 0·4% absolute increase per hour, 95% CI 0·1-0·6%). No association was observed in encounters with NEWS2+ scores less than 7. INTERPRETATION:The NICE-defined high-risk NEWS2 category (scores ≥7) identified patients in whom each additional hour to antibiotic administration was associated with increased mortality, including many without shock, whereas no association was observed for lower NEWS2 scores. These findings suggest that NEWS2 might better target urgent antibiotic therapy beyond shock-based assessment alone. FUNDING:US Agency for Healthcare Research and Quality and US Centers for Disease Control and Prevention.
BACKGROUND:Diagnostic yield for peripheral pulmonary lesions using conventional bronchoscopic sampling remains suboptimal. We evaluated whether stand-alone cryobiopsy using single-use cryoprobes improves diagnostic yield during bronchoscopy guided by radial endobronchial ultrasound. METHODS:This international, open-label, randomised trial was done across six centres in Japan, Malaysia, South Korea, and Taiwan. Patients aged 18 years or older with peripheral pulmonary lesions up to and including 30 mm visualised using radial endobronchial ultrasound were included. Patients with within (ie, concentric) findings or adjacent-to or eccentric findings were randomly assigned (1:1) to stand-alone cryobiopsy or conventional sampling. In the cryobiopsy group, bronchoscopists used a single-use cryoprobe and aimed to obtain 1-3 specimens, with en bloc removal of the bronchoscope and cryoprobe for each biopsy. In the conventional sampling group, bronchoscopists aimed to obtain five or more specimens when feasible using standard bronchoscopic sampling instruments, including forceps, aspiration needles, or both. The primary endpoint was histology-based diagnostic yield (definitive histological diagnosis consistent with the final diagnosis), which was assessed in all randomly assigned patients with confirmed lesion visualisation who were evaluable for the primary endpoint and tested hierarchically in the prespecified adjacent-to or eccentric cohort, followed by the overall cohort. Safety was assessed in all eligible randomly assigned patients. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000049329, and is completed. FINDINGS:Between Nov 1, 2022, and March 25, 2025, 660 patients were enrolled; 627 were randomly assigned (314 [50%] to cryobiopsy and 313 [50%] to conventional sampling). Two patients in the conventional sampling group were excluded from the primary analysis after randomisation. Median age was 70 years (IQR 61-76), 287 (46%) of 625 patients were female and 338 (54%) were male. In the adjacent-to or eccentric cohort, histology-based diagnostic yield was 77% (128 of 167 patients) with cryobiopsy and 65% (108 of 167) with conventional sampling (estimated difference 12·4% [95% CI 2·8-22·0]; p=0·0060). In the overall cohort, diagnostic yield was 83% (262 of 314) and 75% (233 of 311; estimated difference 8·9% [95% CI 2·8-15·0]; p=0·0023). Moderate bleeding occurred in 120 (38%) of 314 patients in the cryobiopsy group and 60 (19%) of 312 patients in the conventional sampling group; severe bleeding was uncommon (two [1%] vs three [1%]). Pneumothorax occurred in six (2%) patients in the cryobiopsy group and one (<1%) patient in the conventional sampling group (chest-tube drainage was required in five [2%] patients vs none). Serious adverse events were infrequent (seven [2%] in the cryobiopsy group vs five [2%] in the conventional sampling group). INTERPRETATION:In patients with peripheral pulmonary lesions undergoing radial endobronchial ultrasound-guided bronchoscopy, cryobiopsy achieved a higher histology-based diagnostic yield than conventional sampling, although moderate bleeding and pneumothorax were more frequent. These findings support cryobiopsy as a valuable tissue-acquisition strategy for peripheral pulmonary lesions, particularly when the probe-lesion relationship is adjacent to or eccentric. FUNDING:JSPS KAKENHI.
