The North Star study shows local therapy like radiation or surgery improves survival in stage IV patients on osimertinib, but only if every site of residual disease is treated. Treating some but not all spots provides no additional benefit over standard TKI therapy.

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.

The FLORA two study's overall survival benefit was so compelling that clinicians should now default to osimertinib plus chemotherapy for most first-line EGFR-mutant NSCLC patients, only opting out for specific reasons like comorbidities or patient preference.

Features like brain metastases or p53 co-mutations are considered high-risk. However, about 75% of patients have at least one such factor, making the "high-risk" profile the norm, not the exception, and reinforcing the need for upfront combination therapy.

Due to a 10-11 month overall survival benefit shown in the FLORA two regimen, leading oncologists now consider osimertinib plus chemotherapy the standard first-line treatment for metastatic EGFR-mutant NSCLC. Monotherapy is reserved only for patients who cannot tolerate or refuse chemotherapy.

Zongertinib shows a meaningful intracranial response rate of ~44% in HER2-mutant NSCLC. This efficacy supports initiating systemic TKI therapy for patients with small, asymptomatic brain metastases and monitoring closely with short-interval scans, potentially avoiding or delaying brain radiation and its associated toxicities.

For EGFR-mutated NSCLC patients with brain metastases, even numerous ones (>30), potent systemic therapy like osimertinib plus chemotherapy is often initiated first. This can achieve high rates of complete intracranial response, allowing clinicians to delay or entirely avoid whole-brain radiation and its long-term toxicities.

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.