Lung cancer remains a significant health challenge. Historically, surgery has been a primary approach for resectable lung cancer. To improve patient outcomes, researchers now combine therapies before surgical intervention. This article focuses on neoadjuvant nivolumab plus chemotherapy for resectable lung cancer, a pre-surgical approach designed to enhance treatment effectiveness.
Understanding the Treatment Components
Neoadjuvant therapy refers to treatments given before the main intervention, typically surgery for resectable lung cancer. This approach aims to shrink tumors, making them easier to remove, or to eliminate microscopic cancer cells that may have already spread but are not yet detectable. This can improve the chances of a complete surgical removal.
Nivolumab is an immunotherapy drug, a PD-1 (programmed death-1) checkpoint inhibitor. It helps the body’s immune system recognize and fight cancer cells more effectively. This drug targets a pathway cancer cells exploit to evade immune detection, thereby “unleashing” the immune response.
Chemotherapy uses powerful drugs to kill rapidly dividing cells, a characteristic of cancer. These treatments interfere with cell growth and multiplication. While chemotherapy targets cancer directly, it can also affect healthy, fast-growing cells.
Resectable lung cancer indicates the tumor is confined enough for surgical removal with an aim for cure. This applies to specific stages of non-small cell lung cancer (NSCLC) where the disease has not spread extensively to distant parts of the body.
The Mechanism of Combined Therapy
Nivolumab blocks the PD-1 receptor on T-cells. Normally, PD-1 binds to ligands (PD-L1 or PD-L2) on tumor cells, sending an inhibitory signal to the T-cell. This “brakes” the immune response, allowing cancer cells to evade detection. By blocking this interaction, nivolumab removes these inhibitory signals, reactivating T-cells to attack the cancer.
Chemotherapy, besides directly killing cancer cells, can induce immunogenic cell death (ICD). When cancer cells undergo ICD, they release specific molecules called damage-associated molecular patterns (DAMPs). These DAMPs, such as calreticulin and HMGB1, act as “danger signals” that alert and activate the immune system.
This activation primarily involves antigen-presenting cells, like dendritic cells, which engulf the released tumor antigens. These activated dendritic cells then present tumor antigens to T-cells, making the cancer cells more visible to the immune system. This heightened visibility, induced by chemotherapy, significantly enhances nivolumab’s effectiveness, leading to a more robust anti-tumor response before surgical removal.
Anticipated Outcomes and Advantages
The combination of neoadjuvant nivolumab and chemotherapy has shown promising outcomes in clinical trials, particularly the CheckMate 816 study. A significant advantage is the improved rate of pathological response, meaning the reduction or elimination of cancer cells in surgically removed tissue. Pathological complete response (pCR), where no viable tumor cells remain, increased from 2.2% with chemotherapy alone to 24% with nivolumab in CheckMate 816. Major pathological response (MPR), defined as 10% or less residual viable tumor cells, also improved substantially.
The therapy can also lead to tumor downstaging, where the tumor shrinks or cancer in nearby lymph nodes diminishes. This makes surgical removal easier, potentially allowing for less extensive surgery, such as a lobectomy instead of a pneumonectomy. In CheckMate 816, 77% of patients in the combination arm underwent lung-sparing lobectomy compared to 61% in the chemotherapy-alone arm.
Studies show promising results for event-free survival (EFS), which measures the time until disease progression, recurrence, or death. The CheckMate 816 trial reported a median EFS of 59.6 months for the combination therapy compared to 21.1 months for chemotherapy alone, representing a considerable extension. Recent analyses from CheckMate 816 also indicate a significant improvement in overall survival (OS) with the neoadjuvant combination, showing a nearly 30% reduction in the risk of death at 5 years compared to chemotherapy alone. Treating before surgery also targets micrometastases, which are tiny clusters of cancer cells that may have spread beyond the primary tumor but are too small to be detected by imaging. Addressing these microscopic cells early reduces the risk of cancer recurrence after surgery.
Managing Potential Side Effects
Patients undergoing neoadjuvant nivolumab plus chemotherapy may experience side effects from both components. Nivolumab, an immunotherapy, can cause immune-related adverse events (irAEs) due to an overactive immune system attacking healthy tissues. These include fatigue, skin rashes, itching, and diarrhea. More serious, though less common, irAEs involve inflammation in organs like the lungs (pneumonitis), colon (colitis), or liver (hepatitis). Endocrine issues, such as thyroid dysfunction, can also occur.
Chemotherapy contributes its own side effects, related to its action on rapidly dividing cells. Common chemotherapy side effects include nausea, vomiting, hair loss, and fatigue. It can also lead to lowered blood counts, such as reduced white blood cells (neutropenia), increasing infection risk, or red blood cells (anemia), causing fatigue.
Peripheral neuropathy, characterized by numbness or tingling in the hands and feet, is another potential side effect. The medical team closely monitors patients for these reactions. Side effects are often manageable with supportive medications or temporary adjustments to the treatment plan. Prompt reporting of any new or worsening symptoms by the patient is important for effective management.
Patient Eligibility and Treatment Pathway
Patients considered for neoadjuvant nivolumab plus chemotherapy have resectable non-small cell lung cancer (NSCLC) at specific stages, often IB (tumors 4 cm or larger) to IIIA. Eligibility also depends on overall health, including performance status, which assesses a patient’s ability to perform daily activities. Patients with certain genetic alterations, like EGFR or ALK mutations, might be considered for other targeted therapies first, as immunotherapy benefits can differ.
The treatment schedule involves a short course of neoadjuvant therapy, consisting of three to four cycles of nivolumab combined with platinum-based chemotherapy. These cycles are administered every three weeks. The neoadjuvant phase lasts for approximately 9 to 12 weeks.
Following neoadjuvant therapy, patients undergo re-evaluation to assess tumor response and confirm readiness for surgery. Surgical resection of the lung tumor occurs within six weeks of finishing treatment. This plan is managed through a multidisciplinary approach, involving a team of specialists including oncologists, surgeons, radiologists, and pathologists, who collaborate to tailor the best strategy for each patient.