Diagnosis: If you have been diagnosed with non-small cell lung cancer, including stage 3 inoperable NSCLC or stage 4 NSCLC, you might qualify for participation in innovative and promising clinical trials.

Non-Small Cell Lung Cancer (NSCLC): NSCLC accounts for about 80-85% of all lung cancer cases, with prognosis varying by stage; early-stage NSCLC has higher survival rates, while advanced stages have a poorer prognosis. Key biomarkers for NSCLC include EGFR, ALK, TP53, MDM2, PD-L1, and KRAS, which guide targeted and immunotherapy options. Clinical trials for NSCLC either mutated or non-mutated genes to be eligible for their trials.

Small Cell Lung Cancer (SCLC): SCLC represents 10-15% of lung cancer cases and is known for its aggressive nature and rapid spread, resulting in a generally poorer prognosis. Biomarkers for SCLC include neuroendocrine markers (chromogranin A, synaptophysin, NSE), PD-L1, and MYC amplification. SCLC trials typically explore new chemotherapy regimens and options targeting neuroendocrine markers.

Patients with both NSCLC and SCLC can find numerous clinical trials offering access to the latest and most advanced options tailored to their specific cancer characteristics.

Squamous Cell Carcinoma:

Originates in the squamous cells lining the airways, commonly associated with a history of smoking and typically found in the central part of the lungs near the main airway (bronchi).

Non-Squamous Cell Carcinoma:

Adenocarcinoma lung cancer starts in the cells that produce mucus in the outer part of the lungs. Is the most common lung cancer in non-smokers and is more often found in women. Clinical trials offering Adenocarcinoma Lung Cancer treatment often require specific genetic mutations for enrollment, as this subtype frequently harbors genetic mutations.

Large Cell Carcinoma: Can appear in any part of the lung and tends to grow and spread quickly, making it a more aggressive subtype.

Other Less Common Non-Squamous Types: Includes rare subtypes like sarcomatoid carcinoma and adenosquamous carcinoma, each with unique cellular characteristics and behaviors.

Most clinical trials for advanced non-squamous NSCLC, including Stage 3 non-squamous NSCLC or Stage 4 non-squamous NSCLC, focus on patients with unresectable tumors. These trials offer a crucial opportunity to explore innovative solutions for those with limited options, motivating patients to enroll and potentially benefit from cutting-edge options.

Knowing the 2 main different NSCLC types, it is important to know that most clinical trials focus on discovering Advanced NSCLC treatments thats why is important to know that into two main stages belong to the definition based on extent of the disease:

• Locally advanced NSCLC (Stage 3 Lung Cancer): is characterized by the spread of cancer to nearby tissues and lymph nodes, but not to distant parts of the body. Trials aimed at Stage 3 Non Small Cell Lung Cancer focus on patients with unresectable tumors because these patients have limited options and a higher need for innovative solutions to manage their disease.
• Metastatic NSCLC (Stage 4 Lung Cancer): is characterized by the spread of cancer to distant parts of the body, such as the brain, bones, liver, or other organs. Most trials for Stage 4 Non-Small Cell Lung Cancer focus on patients with unresectable tumors due to their limited options and the urgent need for innovative solutions to manage the disease.

Clinical trials play a crucial role in advancing the options of both Stage 3 NSCLC trials and Stage 4 NSCLC trials (also known as Stage III NSCLC trials and Stage IV NSCLC trials respectively). They offer patients access to cutting-edge solutions that may provide better outcomes and improved quality of life.

Treated NSCLC is cancer that has been treated with surgery, chemotherapy, radiation, targeted solution, or immunotherapy. These options are used to manage and control the disease. Some clinical trials may require patients to have received prior options to be eligible for innovative new solutions.

Untreated NSCLC: Refers to Lung Cancer that has not yet received any form of oncologic option, including systemic approaches or specific medications. This can apply to any stage of the disease, from early to advanced stages.

Cancer treatment is tailored to each patient’s needs, depending on the stage and type of cancer. Below are key treatment approaches you may encounter:

Neoadjuvant Therapy: Refers to treatment given before surgery or radiation to shrink the tumor, making it easier to remove or treat effectively. It can include chemotherapy, targeted therapy, immunotherapy, or radiation.

Adjuvant Therapy: Refers to treatment given after surgery or radiation to destroy any remaining cancer cells and reduce the risk of recurrence. It may involve chemotherapy, hormone therapy, radiation, or targeted therapy.

Definitive Therapy: Refers to the main or primary treatment intended to eliminate cancer. This may include surgery, radiation, chemotherapy, or a combination of treatments.

Palliative Therapy: Refers to treatment aimed at relieving symptoms and improving quality of life, rather than curing the cancer. It helps manage pain, discomfort, and other side effects, and can be used at any stage of the disease.

Resectable Lung Cancer: Refers to cancer that can be surgically removed, typically confined to the lungs and nearby lymph nodes without extensive spread. This generally includes Early (Stage I), Localized (Stage II) and some cases of Stage IIIA.

Unresectable Lung Cancer: Refers to cancer that cannot be surgically removed due to its size, location, or extent of spread to other parts of the body. This usually includes stages IIIB and IV, and some cases of stage IIIA, requiring alternative treatments such as chemotherapy, radiation, or targeted approaches.

Clinical trials for unresectable NSCLC explore advanced approaches such as targeted drugs and immunotherapy, providing patients access to the latest treatments. These trials aim to improve survival rates and quality of life.

NGS Biomarkers and Their Importance in NSCLC
Next-Generation Sequencing (NGS) is crucial for identifying key biomarkers in Non-Small Cell Lung Cancer (NSCLC), which help guide personalized options and determine eligibility for clinical trials. These are some important biomarkers:

• EGFR (Epidermal Growth Factor Receptor): is a protein found on the surface of some cells in your body. It plays a key role in regulating cell growth and division. In certain types of lung cancer, the EGFR protein is mutated or overactive, causing cells to grow and divide uncontrollably, leading to tumor growth. Targeted approaches have been developed to specifically block the activity of EGFR, thereby slowing down or stopping the cancer’s progression. This makes EGFR a crucial target in addressing cancers with these specific genetic characteristics.
• ALK (Anaplastic Lymphoma Kinase) Rearrangement Positive: ALK rearrangements lead to abnormal cell signaling and growth.
• BRAF V600E Mutation Positive: BRAF V600E mutations result in uncontrolled cell division.
• METex14 Skipping Mutation Positive: MET exon 14 skipping mutations lead to prolonged MET signaling, promoting cancer growth.
• KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog): KRAS mutations drive cancer cell proliferation and are common in NSCLC.
• ROS1 Rearrangement Positive: ROS1 rearrangements cause abnormal cell growth similar to ALK rearrangements. Trials focus on ROS1 inhibitors for these patients.
• NTRK1/2/3 Gene Fusion Positive: NTRK gene fusions create abnormal proteins that drive cancer growth.
• RET Rearrangement Positive: RET rearrangements activate abnormal cell signaling pathways.
• ERBB2 (HER2) Mutation Positive: HER2 mutations cause excessive cell growth and division.
• MTAP deletion: Present in 14.3% of lung cancers, and in NSCLC it occurs in about 21% of cases (19% in adenocarcinomas, 25% in squamous cell carcinomas). This deletion frequently accompanies CDKN2A/B loss, eliminating critical tumor-suppressor “brakes” and disrupting normal DNA methylation, which together fuel uncontrolled cancer cell growth. Importantly, MTAP loss creates a distinct biological vulnerability, opening the door to innovative targeted therapies for tumors with this genetic profile.

IHC Biomarkers and Their Importance in NSCLC
Immunohistochemistry (IHC) biomarkers are crucial in diagnosing and determining the appropriate treatment for non-small cell lung cancer (NSCLC). Some of the most significant IHC biomarkers for the NSCLC treatment and relevant for clinical trials include:

• PD-L1 (Programmed Death-Ligand 1): is a protein expressed on the surface of cancer cells that binds to the PD-1 receptor on T-cells, turning off the immune response against the cancer. High PD-L1 expression suggests that the tumor may respond well to immunotherapies anti PD-L1 approaches.
• MMR (Mismatch Repair): MMR proteins are involved in the repair of DNA replication errors. Deficiency in MMR leads to microsatellite instability (MSI), which can result in increased mutation rates within tumors. MMR deficiency is associated with high levels of MSI (MSI-H), which can make tumors more responsive to immunotherapy.

Knowing this helps doctors decide which treatments to use and enhance the possibility of getting targeted treatment like the ones offered in clinical trials.