Comprehensive molecular testing (PD-L1, EGFR, ALK) is no longer reserved for advanced disease. It is now critical for all patients with stage 1B or higher resectable NSCLC *before* starting any treatment to guide neoadjuvant and adjuvant therapy decisions.

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.

The NeoADURA trial demonstrates that adding osimertinib in the neoadjuvant setting for EGFR-mutated NSCLC results in a 'humongous benefit' in major pathological response and nodal downstaging compared to chemotherapy alone, significantly improving surgical outcomes.

While the feared side effect of severe lung inflammation (pneumonitis) did not increase, other immune-mediated adverse events did. This led to higher rates of treatment discontinuation in the experimental arm, potentially negating any benefits of the concurrent approach and contributing to the trial's failure.

In the HARMONY A study, Ivanesimab plus chemotherapy significantly improved progression-free survival in EGFR-mutant non-small cell lung cancer patients. This is notable because prior trials showed that adding standard PD-1 inhibitors to chemotherapy was ineffective for this specific patient population.

Despite major advances in immunotherapy, patient selection remains crude compared to targeted therapies. PD-L1 is still the primary, yet imperfect, biomarker used. Dr. Carbone highlights an urgent need to develop better predictive biomarkers to customize immunotherapy regimens, as is standard for targeted agents.

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.

Unlike immunotherapy, neoadjuvant osimertinib yields poor pathologic complete response (pCR) rates. However, it significantly improves major pathologic response (MPR) and survival, suggesting pCR may be the wrong efficacy endpoint for cytostatic EGFR TKIs, which have a different mechanism of action than immunotherapy.

While oncologists focus on the low 4% rate of Interstitial Lung Disease (ILD) from neoadjuvant TDXD, surgeons worry this complication could prevent patients from reaching potentially curative surgery, drawing parallels to issues seen with neoadjuvant immunotherapy.