For never-smokers with HER2 mutations, immunotherapy is largely ineffective and risks severe immune-related adverse events when the patient is later switched to the correct TKI. This paradigm mirrors the approach for EGFR and ALK mutations, where targeted therapy is the standard upfront, even with high PD-L1 expression.

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.

When a lung cancer patient is too symptomatic to wait for genomic testing results, the expert consensus is to initiate treatment with chemotherapy alone. Adding immunotherapy upfront is ill-advised, as its use in EGFR-mutated patients (a common finding) can be detrimental.

The standard of care for newly diagnosed EGFR-mutated non-small cell lung cancer has shifted from osimertinib monotherapy to combination regimens. Experts agree that combinations (e.g., osimertinib/chemo) should be the default choice, with monotherapy now reserved for cases with significant tolerability concerns.

When treating EGFR-mutated NSCLC that has progressed on osimertinib, leading oncologists advocate for continuing the TKI even when adding a new agent like datopotamab deruxtecan. This off-label practice is based on strong biological rationale and consistent trial data showing benefit from maintaining EGFR inhibition.

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.

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.

For patients with actionable mutations like EGFR or ALK, targeted therapy is the priority, regardless of PD-L1 score. Starting immunotherapy first in these patients can significantly increase the risk of developing severe pneumonitis (ILD) when they later switch to targeted therapy like osimertinib.