Immunotherapy for Early-Stage Lung Cancer: A Game Changer
Lung cancer has long been one of the most challenging cancers to treat, often diagnosed at advanced stages when treatment options are limited. However, the treatment landscape is rapidly evolving with the introduction of immunotherapy for early-stage lung cancer. This breakthrough transforms outcomes and offers new hope to patients and their families.
Lung cancer remains one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80-85% of cases.1 Traditionally, early-stage NSCLC treatment involved surgery followed by chemotherapy, which is associated with a modest improvement in overall survival of just 5%. Over the past decade, advancements in treatment strategies have aimed to improve survival rates and reduce recurrence risk. Recent clinical trials have led to a paradigm shift, incorporating immunotherapy in both neoadjuvant and adjuvant treatment settings, in combination with chemotherapy in the neoadjuvant setting or given after chemotherapy.
Immunotherapy in Neoadjuvant Treatment: Boosting the Immune Response
Preclinical studies first demonstrated the potential for immunological benefits of neoadjuvant immunotherapy instead of adjuvant immunotherapy. Research showed that immune checkpoint inhibitors (ICIs) administered before surgery enhance the immune response by activating tumour-specific CD8+ T cells while the primary tumour remains intact. These T cells circulate, expand, and infiltrate distant organs, targeting micrometastases and lowering recurrence risk.2 The process also promotes antigen presentation, stimulating naïve T cells and sustaining long-term immune surveillance. It is thought that the optimal immune response may occur with the tumour in situ rather than post surgical resection.
Neoadjuvant Immunotherapy Combined with Chemotherapy: A New Standard of Care
Over the last decade, extensive research has explored combining neoadjuvant immunotherapy with chemotherapy. The CheckMate-816 trial marked a major advancement in this area, becoming the first phase III clinical trial to assess the safety and efficacy of neoadjuvant chemoimmunotherapy versus chemotherapy alone in resectable NSCLC. The study evaluated neoadjuvant nivolumab combined with chemotherapy, without post-operative adjuvant treatment. Results showed that adding immunotherapy reduced the risk of death and distant metastasis. This led to a shift in clinical practice in Ireland in May 2024, with more patients now receiving this innovative treatment approach.3
The IMpower010 trial explored the impact of immunotherapy in the adjuvant setting. This phase III study evaluated adjuvant atezolizumab versus best supportive care in patients with completely resected stage IB-IIIA NSCLC who had received prior platinum-based chemotherapy. The results demonstrated that atezolizumab significantly improved disease-free survival, particularly in patients with PD-L1-positive tumors.3 These findings, combined with those from CheckMate-816, suggest that a combination of neoadjuvant and adjuvant immunotherapy offers a promising treatment strategy for early-stage NSCLC.
Several phase III clinical trials are have investigated the prognostic effect of perioperative immunotherapy combined with chemotherapy versus chemotherapy alone in resectable non-small cell lung cancer. These trials differed in the characteristics of immunotherapy selection, dosing patterns, and primary endpoints. The figure on page 76 provides a summary of the study characteristics and endpoints.
The results demonstrate that patients with or without pCR may benefit from perioperative immunotherapy plus chemotherapy. CheckMate 816 showed that neoadjuvant nivolumab plus chemotherapy significantly improved event-free survival (EFS) and pathological complete response (pCR) rates, leading to better surgical outcomes and reduced recurrence risk. CheckMate 77T reinforced these benefits, demonstrating prolonged disease-free survival (DFS) and overall survival (OS) with adjuvant nivolumab following neoadjuvant chemoimmunotherapy.3 KEYNOTE-671 supported perioperative pembrolizumab plus chemotherapy, showing significant improvements in EFS, OS, and pCR, while the AEGEAN trial highlighted durvalumab’s potential in improving pCR and DFS when combined with neoadjuvant chemotherapy and continued postoperatively. The NEOTORCH and RATIONALE 315 trials showed that toripalimab and tislelizumab, respectively, enhanced pCR and DFS when combined with neoadjuvant chemotherapy.
Long-Term Survival Benefits: The NADIM Trial
The NADIM phase II trial provided the most impressive evidence of immunotherapy’s long-term benefits. It assessed the efficacy of neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy in patients with resectable stage IIIA NSCLC. At the 5-year follow-up, 65% of patients remained disease-free, and 69.3% were still alive.4 Notably, no further tumour-related relapses were observed beyond the 29-month mark, suggesting that patients who remain disease-free beyond three years may be considered cured.
One of the key advantages of immunotherapy over traditional chemotherapy is its improved tolerability. While chemotherapy is associated with significant side effects such as nausea, fatigue, and low blood counts, immunotherapy tends to have a more manageable side effect profile. Immune-related adverse effects remain a concern, but overall, the treatment is better tolerated. Additionally, the substantial survival benefits observed in clinical trials suggest that integrating immunotherapy into early-stage NSCLC treatment could lead to a higher cure rate.
The Future of Lung Cancer Treatment
With ongoing research and continued clinical trials, the role of immunotherapy in lung cancer treatment is expanding. Future studies will focus on optimizing the combination of immunotherapy with surgery, radiation, and other treatments to maximize patient outcomes. Immunotherapy is shifting the focus from disease management to potential cure, making lung cancer a more treatable condition than ever before. As advancements continue, the prospects for lung cancer patients are becoming increasingly hopeful.
References available on request
Written by Professor Jarushka Naidoo, Consultant Medical Oncologist and Dr Janet Moyle, Beaumont RCSI Cancer Centre, Beaumont Hospital, Beaumont Road, Dublin
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