The landscape of early-stage non-small cell lung cancer (NSCLC) is undergoing a rapid transformation. Once defined by the modest survival gains of adjuvant chemotherapy, treatment strategies now extend to immunotherapy and targeted therapies in both adjuvant and neoadjuvant settings. At the 36^th ASCOMOS, Dr. Daniel Chan Boon Yeow, medical oncologist from ICON Singapore, reflected on this shift, noting that with immunotherapy, the “ballpark five-year overall survival (OS) benefit is about 10% for unselected patients and as much as 20% when biomarker selection is applied. The latter is a more compelling proposition, especially when we recall that chemotherapy itself only confers about a 5% absolute benefit.”

Early evidence with adjuvant immunotherapy shows significant promise, though its role varies depending on timing and biomarker context. The phase 3 IMpower010 trial randomized patients with completely resected stage II-IIIA NSCLC (who had received adjuvant platinum-based chemotherapy) to adjuvant atezolizumab vs. best supportive care (BSC). The study met its disease-free survival (DFS) primary endpoint, most notably in patients with programmed death-ligand 1 (PD-L1) expression ≥50%. However, Dr. Chan noted that OS outcomes were less definitive, emphasizing the importance of cautious interpretation of DFS as a surrogate endpoint. Similarly, the phase 3 KEYNOTE-091 trial randomized patients with completely resected stage IB-IIIA NSCLC to adjuvant pembrolizumab vs. placebo. The trial reported a statistically significant DFS improvement in the intent-to-treat population, though subgroup analyses revealed variability in responses. This heterogeneity, according to Dr. Chan, together with the still-immature OS data, has tempered enthusiasm for universal adoption. Thus, careful patient selection and consideration of treatment duration remain crucial.

More recently, perioperative immunotherapy has gained traction: The phase 3 CheckMate-816 established neoadjuvant nivolumab + chemotherapy vs. chemotherapy alone as a new standard in resectable stage IB-IIIA NSCLC, reporting marked improvements in pathologic complete response and event-free survival, with larger benefits seen in patients with PD-L1 ≥1%, and greatest effects in those with PD-L1 ≥50%. Building on this, the phase 3 KEYNOTE-671 trial reinforced these findings by comparing neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab vs. placebo. While benefits were consistent, ongoing work such as CheckMate-77T continues to probe whether extending therapy into the adjuvant phase adds incremental benefit, or whether most efficacy is derived from the neoadjuvant component alone. As noted by Dr. Chan, this raises the possibility of sparing patients from prolonged toxicities and financial burden without compromising efficacy—though interpretation is further complicated by evolving American Joint Committee on Cancer (AJCC) staging definitions, which alter eligibility categories and comparability across studies.

Alongside immunotherapy, targeted therapies have also carved out a clear role, particularly in molecularly defined subgroups. In the phase 3 ADAURA trial, patients with completely resected, EGFR-mutated stage IB-IIIA NSCLC (+/- prior chemotherapy) were randomized to receive adjuvant osimertinib vs. placebo for 3 years. Osimertinib produced a sustained and clinically meaningful DFS benefit across all disease stages, regardless of prior chemotherapy. Questions remain about the optimal duration of therapy: TARGET, a phase 2 trial, is now evaluating whether extending adjuvant osimertinib to 5 years confers further benefit. In ALK-positive NSCLC, the phase 3 ALINA trial compared adjuvant alectinib vs. platinum-based chemotherapy in resected stage IB-IIIA disease, demonstrating DFS superiority for alectinib. Yet in the absence of mature OS data, Dr. Chan urged caution, noting that positive DFS signals have not always translated into long-term survival.

In the neoadjuvant setting, targeted therapy appears less developed. The phase 3 NeoADAURA trial examined osimertinib with or without chemotherapy vs. chemotherapy alone in the neoadjuvant setting. Higher rates of major pathologic response were observed in the osimertinib-containing arms (~25% vs. 2% with chemotherapy alone) although pathologic complete responses remain rare and event-free survival results are not yet mature. Dr. Chan observed that responses appear more pronounced in high-risk subgroups, such as patients with TP53 co-mutations, though the long-term significance remains to be defined.

As the field advances, biomarker selection continues to be critical. PD-L1 expression remains a powerful predictor of immunotherapy benefit, while molecular alterations such as EGFR and ALK not only guide targeted therapy but also predict lack of efficacy with immune checkpoint inhibitors. As Dr. Chan emphasized, precise upfront testing and individualized treatment planning are essential.

Reflecting on the breadth of evidence, Dr. Chan highlighted the need to balance efficacy and tolerability, as well as the importance of timing. Immunotherapy appears most effective when integrated early, particularly for PD-L1-positive disease, whereas adjuvant TKIs provide a reliable standard in molecularly defined subgroups. With trials still maturing, including those testing duration and sequencing, the curative-intent treatment of NSCLC is likely to remain in flux. What is clear, according to Dr. Chan, is that the historical nihilism surrounding early lung cancer therapy has given way to a future in which durable survival is increasingly attainable.