The treatment of lung cancer has been reshaped by personalized medicine. We now understand lung cancer is a collection of distinct conditions, leading to the use of specific biomarkers to create tailored treatment plans. These markers, found on or within tumor cells, allow for the selection of therapies based on the specific molecular profile of a person’s cancer.
Understanding PD-L1 Negative Status
The immune system has checks and balances to prevent it from attacking the body’s healthy cells. One such mechanism is the PD-1/PD-L1 pathway. PD-1 is a receptor on active immune cells, like T-cells, while its partner, PD-L1, is a protein that can be on other cells. When PD-L1 binds to PD-1, it acts as a brake, signaling the T-cell to stand down and preventing an immune attack.
Some cancer cells exploit this system by expressing high levels of PD-L1 on their surface, pressing the “off” switch on approaching T-cells. This allows the tumor to hide from the immune system. To determine if a cancer is using this mechanism, a tumor tissue sample is analyzed using immunohistochemistry (IHC). This test uses antibodies to measure the amount of PD-L1 protein on the cancer cells.
The result is reported as a Tumor Proportion Score (TPS), which is the percentage of tumor cells showing PD-L1 staining. A diagnosis of “PD-L1 negative” means very few cancer cells have this protein, corresponding to a TPS of less than 1%. This result indicates the cancer is not heavily relying on this specific signal to protect itself.
Impact on Immunotherapy Decisions
The level of PD-L1 expression on a tumor has direct implications for treatment choices, specifically for a class of drugs known as immune checkpoint inhibitors. These drugs are antibodies designed to block either the PD-1 receptor or the PD-L1 protein. By blocking this interaction, the “brake” on the immune system is released, allowing T-cells to recognize and attack cancer cells.
For these drugs to work most effectively as a single agent, the PD-L1 target needs to be present in sufficient quantities. In PD-L1 negative lung cancer, where the protein is largely absent, single-agent immunotherapy has limited targets and results in a lower response rate compared to patients with high PD-L1 expression. Therefore, a PD-L1 negative status means that using an immune checkpoint inhibitor by itself is not the preferred initial strategy, and oncologists will instead consider combination approaches.
Primary Treatment Strategies
For patients with PD-L1 negative non-small cell lung cancer (NSCLC) who lack other specific genetic mutations, the most common first-line treatment is a combination of chemotherapy and immunotherapy. The two treatments work together to enhance each other’s effects. Chemotherapy kills rapidly dividing cancer cells and can also induce a type of cell death that makes the tumor more visible to the immune system by increasing the presentation of tumor antigens.
This increased visibility helps the immunotherapy component work more effectively, even with low PD-L1 levels. Clinical trials have shown this combination improves outcomes for patients with PD-L1 negative NSCLC compared to chemotherapy alone. Several regimens combining platinum-based chemotherapy with an immune checkpoint inhibitor, such as pembrolizumab or atezolizumab, are now standard care.
In some cases, a combination of two different immunotherapy types may be used, such as an anti-PD-1 drug with an anti-CTLA-4 drug. CTLA-4 is another protein on T-cells that acts as an immune checkpoint, and this combination offers a “chemo-free” option that stimulates the immune system through two distinct pathways. Radiation therapy is also a treatment, often used with chemotherapy for earlier-stage disease or to manage specific symptomatic areas.
Beyond PD-L1 with Targeted Therapies
PD-L1 status is just one piece of the puzzle. Comprehensive biomarker testing of the tumor tissue is standard practice and looks for a wide array of genetic alterations, called driver mutations, that can fuel a cancer’s growth. These tests are performed alongside the PD-L1 analysis.
Common mutations sought in non-small cell lung cancer include those in the following genes:
- EGFR
- ALK
- ROS1
- BRAF
- MET
- RET
If a tumor tests positive for one of these driver mutations, the most effective first-line treatment is a targeted therapy. These are often oral medications designed to block the specific signaling pathway that the mutation has activated. For example, a patient with an EGFR mutation would receive an EGFR inhibitor like osimertinib. When an actionable driver mutation is identified, targeted therapy is the preferred treatment regardless of the tumor’s PD-L1 status.
Prognosis and Long-Term Outlook
The prognosis for an individual with PD-L1 negative lung cancer is influenced by multiple factors beyond the PD-L1 result. The cancer’s stage at diagnosis is one of the most significant predictors of outcome. A patient’s overall health, or performance status, also plays a role in their ability to tolerate and respond to treatment, as does the presence of other targetable mutations.
While some studies suggest PD-L1 negative status can be associated with a poorer prognosis compared to PD-L1 positive status, this is not a definitive rule. The effectiveness of combination therapies has improved survival rates for many patients, and the introduction of chemotherapy-immunotherapy combinations has provided durable responses for a subset of this population.
The field of lung cancer treatment is in a state of constant evolution, with new research continually identifying novel biomarkers and developing innovative strategies. Ongoing disease management, including regular monitoring, allows the medical team to track the cancer’s response and adapt the treatment strategy as needed.