Lung cancer remains the leading cause of cancer death in the US, killing more patients each year than colorectal and pancreatic cancer combined, even as targeted therapies and immunotherapies have transformed outcomes for some. A roadmap from the American Association for Cancer Research (AACR) Lung Cancer Task Force, published in Cancer Discovery, lays out where research must go next to close that persistent gap. The document identifies specific areas where progress has stalled, including treatment options for certain subtypes and the failure of high-risk screening to reach all eligible individuals.
Lung cancer’s 5-year survival still trails most other major malignancies despite decades of genomic and immunotherapy advances, with most patients diagnosed after the disease has spread. An estimated 124,990 Americans are projected to die of lung cancer in 2026, more than the combined toll of colorectal and pancreatic cancer, according to the American Cancer Society’s annual statistics report. Five-year survival for metastatic disease climbed from 2% to 10% over the past decade, progress attributed largely to targeted therapy and immunotherapy, although screening uptake remains low, with only a minority of eligible smokers undergoing low-dose CT (LDCT).
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About half of lung adenocarcinomas carry an actionable oncogenic mutation, but squamous cell lung cancer and small cell lung cancer (SCLC) largely lack targeted options, the task force wrote. Antibody-drug conjugates targeting TROP2, HER2, HER3, c-MET, B7-H3, and CEACAM5 are approved or in development for non–small cell lung cancer (NSCLC), while bispecific T-cell engagers have shown particular promise in SCLC. Tarlatamab, which binds CD3 on T cells and DLL3 on cancer cells, improved survival over chemotherapy (HR, 0.60) in patients with recurrent metastatic SCLC and has received FDA approval.
The exceptional clinical activity of T-cell engagers in patients with SCLC versus other solid tumors might relate to the frequent suppression of antigen processing and presentation machinery in SCLC, a mechanism of immune escape associated with resistance to PD-(L)1–directed immunotherapy but bypassed by T-cell engagers, the authors wrote.
Expanding Treatment and Screening
The task force also pointed to protein degraders such as proteolysis-targeting chimeras and molecular glues, which are beginning to make targets like KRAS accessible, as a priority for expanding options beyond adenocarcinoma. The group highlighted trial models built to keep pace with lung cancer’s evolving biomarker setting, noting that centralized genomic screening platforms can reduce screen-fail rates while continuously adding new investigational arms. The FDA’s Project Pragmatica, exemplified by the Pragmatica-Lung trial (NCT05633602), used broad eligibility, minimal data collection, and routine imaging to enroll a more diverse population than typical oncology trials, although the combination tested did not improve overall survival.
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Adaptive designs are already changing practice, according to the task force. The phase 2 umbrella trial CTONG1702 (NCT03574402), testing the tyrosine kinase inhibitor pyrotinib in treatment-naive, HER2-mutant NSCLC, incorporated a compassionate-use arm and produced an objective response rate of 35.7% with a median progression-free survival of 7.3 months. Longitudinal circulating tumor DNA (ctDNA) tracking could similarly guide adaptive escalation or de-escalation of adjuvant therapy based on minimal residual disease status.
Low-dose CT screening has been linked to a mortality reduction in high-risk populations, and US screening has coincided with a 4.6% annual decline in distant-stage disease incidence from 2013 to 2019, the task force noted, but current eligibility criteria, built around age and smoking history, still miss many never-smokers and younger patients. The Taiwan Lung Cancer Screening in Never-Smoker Trial enrolled more than 12,000 people, mostly never-smokers, and found more than 300 carcinomas on baseline LDCT, with more than three-quarters of cases being stage I disease, evidence the task force cited for biology-driven eligibility criteria rather than smoking history alone.
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On prevention, the task force pointed to interleukin-1β (IL-1β) blockade and emerging “preventive vaccines” such as LungVax, designed to train the immune system to recognize common neoantigens in high-risk, ever-smokers, as promising but unproven strategies; no molecular prevention trial has yet been designed specifically to reduce lung cancer incidence. The group also called for greater representation of women, young adults, and Asian never-smokers, populations with distinct disease biology and survivorship needs, in trials and registries.
For clinicians, payers, and patient advocates, the near-term payoff lies in pairing broader trial eligibility and ctDNA-guided monitoring with wider screening access, while longer-term gains depend on prevention research that has so far lagged for lack of a commercial incentive. Lung cancer research, the task force concluded, stands at a critical inflection point requiring sustained, interdisciplinary investment to translate into a cure.
