Immunotherapy in Early-Stage Non-Small Cell Lung Cancer (NSCLC): Current Evidence and Perspectives

Abstract

Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.

Cemiplimab combined with chemotherapy versus chemotherapy in advanced non-small cell lung cancer: an updated EMPOWER-Lung 3 trial-based cost-effectiveness analysis

“…26 Immunotherapy, specifically ICIs, has emerged as a promising therapeutic strategy for the treatment of various tumors. 27,28 Given the rising incidence of lung cancer, there is growing interest among clinicians in the potential therapeutic benefits of combining cemiplimab with chemotherapy, as demonstrated in the EMPOWER-Lung 3 clinical trial. A recent 2-year follow-up analysis from part 2 of the EMPOWER-Lung 3 trial demonstrated sustained benefits of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC after 28.4 months of follow-up.…”

Neoadjuvant and Adjuvant Immunotherapy in Resectable NSCLC

“…The synergistic combination of chemotherapy and immunotherapy was becoming rather evident, with preclinical data from Martin-Ruiz et al demonstrating a significant difference in tumor regression rates in the arm that received immunotherapy plus cisplatin versus immunotherapy alone [49]. In light of NADIM's results and building upon them, the NADIM II trial followed [50]. In this randomized, phase 2, open-label trial, 86 patients clinically staged IIIA-B, 35% of which presented with multi-stationed N2 disease, were randomly assigned to receive three cycles of doublet chemotherapy compared to nivolumab plus chemotherapy, followed by surgery and then adjuvant nivolumab for six months.…”

“…Around 40% of early NSCLC patients seem to gain no benefit from chemo-immunotherapy regimens, highlighting the unmet need for customized patient care [50]. Amongst other similar parameters, such as tumor mutational burden (TMB), CD8+ invasion rates, and absence of immunosuppressive cell subsets, PD-L1 expression has emerged as the most clinically significant biomarker to assess response to immunotherapy [16].…”

Characterization of the tumor microenvironment by single-cell RNA sequencing in non-small cell lung cancer treated with neo-adjuvant immunotherapy

“…Neo-adjuvant and perioperative therapies are an emerging topic in the multi-modal treatment landscape of early-stage NSCLCs ( 1 ). A growing number of clinical trials evaluates the use of either IO, or combined IO-chemotherapy (IO-CTx) or targeted therapies in this particular setting ( Table 1 ).…”

“…A growing number of clinical trials evaluates the use of either IO, or combined IO-chemotherapy (IO-CTx) or targeted therapies in this particular setting ( Table 1 ). Biologically, systemic therapy before surgery (including perioperative strategies) induces profound and long-lasting changes of the tumor microenvironment (TME), encompassing multi-faceted immune cells, cancer-associated fibroblast (CAF) and tumor vasculature ( 1 , 8 ).…”