The last 10 years have witnessed remarkable advances in the treatment of metastatic non–small cell lung cancer (NSCLC). Therapy is tailored not only to the individual patient’s molecular status but also, importantly, to the individual patient.

The initial conversation with a patient who has metastatic disease usually focuses on helping the patient understand the extent of the disease, explaining what stage IV means, and discussing the goals and intent of treatment. Typically, the intent of therapy for stage IV lung cancer is palliative and supportive, aimed at controlling the disease and maintaining quality of life, and it is important to communicate this clearly and honestly. During those first discussions, I will also explain that there are 2 main categories of lung cancer—NSCLC and SCLC—and I dedicate some time to explain biomarker testing and PD-L1 testing, as these results can significantly guide treatment decisions in NSCLC.

Comprehensive biomarker results, including driver mutations and PD-L1, may still be pending initially, so the structure of the discussion depends on test result availability. When results are in hand, the conversation can be more precise and tailored to the specific circumstances. But when results remain outstanding, I still generally outline potential treatments in broad categories, including chemoimmunotherapy, single-agent immunotherapy, targeted therapy, and targeted therapy plus chemotherapy.

When results are available at the initial consultation, and no driver mutation is identified, I will often discuss PD-L1 expression levels, explaining that a higher PD-L1 Tumor Proportion Score (TPS) correlates with greater benefit from ICI monotherapy. In patients with a PD-L1 TPS of greater than or equal to 50%, I generally recommend avoiding chemotherapy, instead opting for ICI monotherapy (unless the patient is highly symptomatic). For patients with a PD-L1 TPS of less than 50%, I typically favor chemoimmunotherapy.

For patients who are driver negative and PD-L1 negative, particularly those with co-occurring STK11 or KEAP1 mutations, I consider quadruplet therapy with dual immune checkpoint inhibition. Retrospective and subgroup data indicate poorer outcomes with chemoimmunotherapy alone in these molecular subsets, so there is a rationale for offering dual PD-1/CTLA-4 blockade. The 2 main US Food and Drug Administration (FDA)–approved regimens in this category are durvalumab plus tremelimumab plus platinum-based doublet chemotherapy (based on results from the POSEIDON study) and nivolumab plus ipilimumab plus 2 cycles of platinum-based doublet chemotherapy (based on results from the CheckMate 9LA study).

In the driver-positive setting, another point of discussion is the possible addition of chemotherapy in the first line. Broadly, in patients with oncogenic driver mutations, integrating chemotherapy with targeted therapy in the first line represents a nuanced and often challenging decision, particularly when molecular information is incomplete. This situation highlights the importance of comprehensive biomarker testing beyond standard gene-specific panels, with careful attention to TP53 alterations and comutational profiles.

For those with EGFR-activating mutations, combination therapy has demonstrated clear benefit in subgroups with brain metastases, TP53 mutations, high circulating tumor DNA shedding, or extensive visceral involvement. In the presence of an EGFR-activating mutation plus any of these features, I routinely offer combination treatment in the frontline setting. Available combination strategies include chemotherapy plus osimertinib or the amivantamab-plus-lazertinib regimen that was evaluated in the MARIPOSA study. For these higher-risk patients, I most commonly favor chemotherapy combined with osimertinib as first-line therapy.

More generally, among patients with driver-positive tumors, it has been well established that many can be successfully treated without chemotherapy, offering patients significant quality-of-life advantages. Moreover, newer TKIs continue to emerge. We now have a new first-line indication for HER2-mutant NSCLC with an oral targeted inhibitor. The expanded expedited FDA approval of zongertinib in the first line was based on data from a treatment-naive cohort in the ongoing Beamion LUNG-1 trial. This expedited approval is for patients with metastatic nonsquamous NSCLC with HER2 (ERBB2) TKD mutations, as identified by an FDA-approved test. Both patients and physicians value these oral regimens, as they eliminate the need for infusions, reduce scheduling burdens, and minimize treatment-related delays.