Neoadjuvant chemoimmunotherapy, comprising an anti-PD-(L)1 antibody and platinum-doublet chemotherapy, given alone or as part of a perioperative regimen with the addition of adjuvant anti-PD-(L)1 therapy, has become the standard of care for patients with early-stage, resectable non-oncogene-driven non-small-cell lung cancer (NSCLC). This approach has demonstrated substantial increases in pathological response rates and improvements in long-term outcomes, including overall survival. However, these advances have largely been achieved through uniform treatment application across biologically heterogeneous tumours. As a result, a central challenge in contemporary perioperative management is how to identify which patients require escalation or de-escalation of treatment following surgery and which individuals could safely avoid unnecessary treatment. In this Review, we summarize current evidence supporting pathological response, and particularly pathological complete response (pCR), as a robust and clinically meaningful surrogate for durable benefit in patients with NSCLC. We then consider how complementary tools, including circulating tumour DNA, radiomics and metabolic imaging approaches, and baseline molecular and immune biomarkers, can be integrated to refine patient selection and dynamically adapt perioperative strategies.
Neoadjuvant chemoimmunotherapy, comprising an anti-PD-(L)1 antibody and platinum-doublet chemotherapy, given alone or as part of a perioperative regimen with the addition of adjuvant anti-PD-(L)1 therapy, has become the standard of care for patients with early-stage, resectable non-oncogene-driven non-small-cell lung cancer (NSCLC). This approach has demonstrated substantial increases in pathological response rates and improvements in long-term outcomes, including overall survival. However, these advances have largely been achieved through uniform treatment application across biologically heterogeneous tumours. As a result, a central challenge in contemporary perioperative management is how to identify which patients require escalation or de-escalation of treatment following surgery and which individuals could safely avoid unnecessary treatment. In this Review, we summarize current evidence supporting pathological response, and particularly pathological complete response (pCR), as a robust and clinically meaningful surrogate for durable benefit in patients with NSCLC. We then consider how complementary tools, including circulating tumour DNA, radiomics and metabolic imaging approaches, and baseline molecular and immune biomarkers, can be integrated to refine patient selection and dynamically adapt perioperative strategies. Finally, we describe potential therapeutic strategies to intensify perioperative treatment in biologically high-risk populations, with the dual objective of increasing the likelihood of a pCR and improving disease control in patients with an insufficient pathological response.
Pathological complete response (pCR) determined using standardized assessments provides a robust surrogate for durable benefit after neoadjuvant chemoimmunotherapy in patients with resectable non-oncogene-driven non-small-cell lung cancer, and provides an important anchor to guide decisions regarding escalation or de-escalation in the adjuvant phase.
Baseline immune biomarkers such as high tumour PD-L1 expression increase the likelihood of achieving a pCR but have not been tested prospectively and, in isolation, are insufficient to guide escalation or de-escalation, underscoring the need for dynamic, on-treatment biomarkers.
Circulating tumour DNA clearance is prognostic and captures early treatment response but provides clinical value that is complementary to pCR only in selected contexts (such as biomarker discordance or minimal residual disease positivity following surgery), and currently lacks sufficient robustness to guide de-escalation strategies.
Integrative approaches combining radiomics with circulating and immune biomarkers might enable improved patient stratification and support future biomarker-driven treatment decisions, including the potential to inform local treatment strategies.
Emerging intensified neoadjuvant strategies, including those involving antibody–drug conjugates and novel immunotherapy combinations, have the potential to overcome primary resistance but will probably require biomarker-enriched trial designs to define their optimal clinical niche.
Patients with clinical features suggesting an inferior prognosis, including a lack of a pCR and/or minimal residual disease positivity, might benefit from escalated adjuvant strategies within a response-adaptive perioperative framework integrating pathological response with dynamic tumour–host monitoring.
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