Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer: Comparison
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Luca Bertolaccini.

Surgical resections remain the gold standard for early stages non-small-cell carcinoma (NSCLC) and may be considered for locally advanced tumors. Medical treatment has changed drastically, especially for advanced stages, for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. The addition of radical surgical resection following immunotherapy or immuno-chemotherapy is feasible and safe with low surgical-related mortality and morbidity in selected patients with initially unresectable NSCLC.

  • lung cancer
  • immunotherapy
  • thoracic surgery

1. Introduction

Lung cancer is the leading cause of cancer death worldwide. Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades, introducing thoracic surgery to a multimodality approach [1]. Surgical resections remain the gold standard for early stages (I-II) and are considered in a multidisciplinary approach for stage IIIA. Medical treatment has changed drastically in recent years, especially for advanced stages (IIIB-IV). For unresectable or metastatic diseases, the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life in lung cancer patients.
Early-stage NSCLC is defined as localized cancer and refers to stages I, II, and IIIA as described by the 8th edition of TNM [2]. Locally advanced tumors include those with direct invasions, such as Pancoast’s tumors, chest wall infiltrating neoplasia, and tumors with invasion of the main bronchus, the carina, or the pulmonary artery, which require extended pulmonary resections and complex reconstructions of the chest wall, airways, or vessels [3,4][3][4].
However, locally advanced tumors also include those with a mediastinal lymph node involvement defining a very heterogeneous group of patients (stage IIIA-IIIB). For locally advanced tumors, surgery may be considered. However, optimal therapeutic management requires an interdisciplinary approach in order to evaluate the extension of the disease at the diagnosis, the patient’s comorbidities and the performance status before the operation, surgical operability, and a systemic induction treatment (also referred to as neo-adjuvant treatment) when indicated for the disease stage, including its potentially toxic effects. In this case, to improve long-term outcomes, the treatment could include platinum-based chemotherapy and, in selected cases, a specific radiotherapy program to reduce tumor size and lymph node involvement before complete resection. Several studies compared survival and outcomes between definitive chemo-radiotherapy and surgery after induction treatment (chemotherapy or chemo-radiotherapy) [5].
Chemotherapy drugs, especially platinum-based compounds, are associated with side effects [6]. In this view, numerous molecular mutations in cancer biology have been searched and identified in NSCLC patients to develop new therapeutic strategies with lesser adverse reactions and better oncological outcomes in recent years. Specific molecular mutations may classify new therapies as tyrosine kinase inhibitors (target therapy) or immune checkpoint inhibitors (immunotherapy).
Regarding tyrosine kinase inhibitors (TKI), the most commonly identified targets in the adenocarcinoma setting are activating gene K-RAS and EGFR [7], re-arranged genes ALK and ROS-1 [8[8][9],9], and many others. Though molecularly targeted therapies in the neo-adjuvant setting are associated with a decrease in the risk of recurrence and an increase in the mediastinal downstaging rate, they are not associated with a complete pathological response [10].
In the last decade, different retrospective studies have shown significant outcome changes in previously unresectable diseases treated with tyrosine kinase inhibitors followed by lung resections for residual disease when feasible [11,12][11][12]. Based on these promising results, the latest National Association of Medical Oncology guidelines confirmed that all patients with non-squamous histology or mixed and young non-smoker patients with squamous histology should be tested for ALK and EGFR [13,14][13][14].
Erlotinib safety, tolerability, and pathological responses were evaluated in patients with EGFR-mutated NSCLC in a phase II study which showed encouraging results [15]. A reasonable response rate was found on using Lorlatinib and Crizotinib as neoadjuvant therapy in a significant phase III trial in patients with advanced rearranged-ALK NSCLC [16].
Regarding the role of the immune checkpoint inhibitors, Durvalumab has been established in the PACIFIC trial as the standard of care for stage III unresectable NSCLC patients as consolidation therapy after concurrent chemoradiation [17]. This role has been questioned in patients affected by EGFR-mutated NSCLC after definitive chemo-radiotherapy [18].

2. Neoadjuvant Immunotherapy or Immuno-Chemotherapy in Resectable NSCLC

Administering immune checkpoint inhibitors alone or in combination with chemotherapy and followed by surgical resections can benefit patients in terms of OS and DFS. Despite surgical resection being the standard of care for early-stage NSCLC, micrometastases, and isolated tumor cells are very challenging to detect by current technologies. Immune checkpoint inhibitors with or without chemotherapy combined with surgery can lower the probability of recurrence eradicating the micrometastases (Table 1 and Table 2).
Table 1.
Clinical Trials: Neoadjuvant immunotherapy in resectable NSCLC.

Neoadjuvant Immunotherapy

Most of the ongoing clinical trials in this field are evaluating the benefits of ICIs associated with chemotherapy as adjuvant treatment for resectable NSCLC (Stage IB-IIIA and resectable IIIB) (Table 3):
  • IMpower 010: open-label phase III study with a sample size of 1280 patients from 22 countries. This trial includes EGFR mutations and ALK rearrangements. A total of 1005 patients were randomized to receive adjuvant Atezolizumab (507) or best supportive care (498). In patients with stage II-IIIA NSCLC and an expression of PD-L1 ≥ 1%, the patients who had disease progression were 35% of patients receiving Atezolizumab and 46% of patients receiving best supportive care, reducing the risk of recurrence by 34% (HR = 0.66; 95% CI: 0.50–0.88) [40][37]. Due to these promising results, the FDA approved Atezolizumab as adjuvant monotherapy in patients with PD-L1 positive in October 2021 [41][38]. At the 2022 European Lung Cancer Congress (ELCC 2022), Felip et al. presented the updated preliminary results for DFS in patients with PD-L1 ≥ 50% stage II-IIIA NSCLC, with or without EGFR mutations or ALK rearrangements. In patients with EGFR mutations or ALK rearrangements, the 3-year DFS rates were 73.8% in the Atezolizumab group compared to 48.6% in the control group. In patients without EGFR mutations or ALK rearrangements, the 3-year DFS was 75.1% in the Atezolizumab group and 50.4% in the control group [42][39]. Adjuvant Atezolizumab was associated with a 22% recurrence rate compared to 44%, a median recurrence of 18.1 months vs. 10.1 months, and a lower rate of distant metastasis of 9% vs. 26%. The analyses of OS were presented at the 2022 World Conference on Lung Cancer (WCLC 2022). In the PD-L1 ≥ 1% patients, the Atezolizumab group showed a 5-year OS rate of 76.8% vs. 67.5% in the control group. Furthermore, in the PD-L1 ≥ 50% of patients, the 5-year OS rates were 84.8% in the Atezolizumab group compared to 67.5% in the control group [43]

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