Day Two: ISOPT Annual Meeting

Lung cancer has become the working model for precision oncology, and the number of actionable targets in early-stage disease is growing faster than the trials to test them. Professor Fred Hirsch walks through that acceleration and lands on the harder question underneath it: with immunotherapy, only about 40 percent of lung cancer patients see significant benefit, and we still do not select the right ones well.

Hirsch traces the move of targeted therapy and immunotherapy from advanced disease into the adjuvant, neoadjuvant, and perioperative settings, then Professor Oscar Arrieta adds a note of restraint on when a randomized trial is truly required. The through-line is a field advancing quickly on drugs while the questions that matter to patients, cure and treatment duration, are still open.

Key points for clinicians:

• In early-stage EGFR-positive disease, adjuvant osimertinib (ADAURA) showed a clear disease-free survival benefit and, so far, an overall survival benefit. Adjuvant alectinib (ALINA) is now standard of care for ALK-positive patients.

• Fourth-generation EGFR TKIs are being designed for better CNS penetration than third-generation osimertinib, with early data presented at ASCO this year. In unresectable stage 3 EGFR disease, the LAURA study favored osimertinib.

• The proliferation of rare targets, some at 1 to 2 percent of patients, raises a real design question: is a randomized trial needed for every actionable mutation before moving it into early-stage disease?

• With immunotherapy, roughly 40 percent of patients benefit meaningfully. PD-L1 remains the working selector: above 50 percent, IO monotherapy; below 50 percent, chemo plus IO; below 1 percent, chemo plus IO or chemo plus dual IO.

• Neoadjuvant or perioperative immunotherapy carries benefit even in PD-L1 negative tumors, about 20 percent of patients, though the PD-L1 negative space is still unsettled.

• After neoadjuvant therapy, about 20 percent of US patients reach a complete pathologic response, higher in Asia. The SWOG-initiated INSIDE trial tests adjuvant IO versus surveillance in those patients, with a separate ETOP trial for non-pCR.

• Arrieta's caution: not all actionable mutations carry the same magnitude of benefit, and some may not change survival if the same therapy can be given at recurrence.

Early-stage lung cancer is curable. That is not in dispute. Professor Fred Hirsch put the real problem plainly: at best 15 percent of eligible Americans are screened, and among those who are, only 40 to 50 percent come back the following year. The tools work. The question is whether we choose to look.

Hirsch walks through why screening matters and why so little of its benefit reaches people. He covers the evidence base behind low-dose CT, the tightening of the USPSTF eligibility criteria from 2013 to 2021, and a growing group the criteria still miss: never-smokers and younger patients whose lung cancer is rising and who do not qualify for screening at all. He closes on where detection is headed, from liquid biopsy and multi-cancer early detection assays to a multi-omics approach that combines molecular signals with low-dose CT and AI-assisted reading.

Key points for clinicians:

• The scale is large and the timing is late. More than 238,000 lung cancers are diagnosed each year in the United States and 1.8 million globally, and most are still found at an advanced stage where prognosis is poor.
  
  

• Randomized trials established the screening criteria. The 2013 USPSTF guidance (ages 55 to 80, at least 30 pack-years, quit within 15 years) reduced lung cancer mortality by more than 20 percent, with a larger benefit seen in women.
  
  

• The 2021 revision widened eligibility to ages 50 and above and 20 pack-years, but Hirsch argues the movement was modest and still leaves a clear gap.
  
  

• The fastest-growing groups are outside the criteria. Lung cancer in never-smokers and in younger patients is increasing, and current pack-year-and-age thresholds do not capture them.
  
  

• Implementation, not evidence, is the failure point. Screening uptake sits at 15 percent of the eligible population at best, and only 40 to 50 percent of those screened return annually, so few people receive the full benefit.
  
  

• The future is multi-omics. Liquid biopsy and multi-cancer early detection assays currently show high specificity but low sensitivity and are not yet fully FDA approved. Hirsch expects detection to combine ctDNA, methylation, fragmentomics, and proteomics with clinical data and low-dose CT, aided by AI. Mount Sinai, host of the International I-ELCAP consortium, is already extending its low-dose CT program to include cardiovascular disease.