The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.

Multiple trials, including PACIFIC-2, have shown no survival benefit from adding immunotherapy concurrently with chemoradiation for unresectable Stage III NSCLC. This suggests that concurrent radiation may disrupt the immune-activating pathways necessary for immunotherapy to work, a critical lesson for future trial designs.

The CheckMate 9LA regimen provides exceptional benefit to PD-L1 negative and squamous histology NSCLC patients. This is significant because these subgroups often respond poorly to other immunotherapy combinations, with Dr. Carbone noting some trials where the control arm outperformed pembrolizumab in these patients.

Despite the success of perioperative chemo-immunotherapy, it is contraindicated for patients with resectable NSCLC harboring EGFR or ALK driver mutations. These molecular markers predict limited benefit from immune checkpoint inhibitors (ICIs), and NCCN guidelines explicitly recommend against using ICI in this population in favor of targeted therapies.

The failure of the concurrent chemo-immuno-radiation approach has not stalled progress. Instead, new clinical trials are actively exploring novel strategies like SBRT boosts, dual checkpoint inhibitors, radiosensitizing nanoparticles, and induction immunotherapy to improve upon the current standard of care.

Data from the KEYNOTE-671 trial demonstrates a meaningful survival benefit from perioperative pembrolizumab even in patients with PD-L1 negative (<1%) tumors. This finding supported broad regulatory approval without PD-L1 restrictions, suggesting the biomarker is not an absolute requirement for benefit in this setting.

A critical design flaw in most perioperative chemo-immunotherapy trials is the lack of a 'contribution of component' analysis. This makes it impossible to determine if the benefit comes from the neoadjuvant phase, the adjuvant phase, or both, thus complicating interpretation and clinical application.

While neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.

The success of perioperative osimertinib means oncologists cannot choose the optimal strategy (targeted therapy vs. chemoimmunotherapy) for resectable lung cancer without first knowing the patient's EGFR, ALK, and PD-L1 status. This elevates biomarker profiling from a metastatic-setting tool to a critical first step in early-stage disease.