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Table of Contents

    Topic review

    Surgically Resectable NSCLC

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    Submitted by: Ping Chih Hsu

    Definition

    Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC.

    1. Introduction

    The global incidence of lung cancer has prominently increased among the various cancers in the last three decades. Lung cancer has become the leading cause of cancer-related deaths in both males and females [1][2]. It is histologically classified as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); NSCLC accounts for 85% of cases [3][4]. Surgery remains the main treatment for early-stage NSCLC (stages I and II, and some IIIA diseases), and approximately 30% of NSCLC patients present with the surgically resectable disease at initial diagnosis [5]; however, the risk of disease recurrence and cancer-related mortality are high, even for those NSCLC patients receiving complete resection [5][6]. Previous studies focusing on the long-term follow-up of post-operative NSCLC have shown that the five-year survival rate is lower than 70% for IB and about 35% for IIIA diseases [6][7]. Platinum-based chemotherapy has been recommended as a post-operative adjuvant therapy for stages II to IIIA patients in the past 20 years [6][7]. Post-operative adjuvant chemotherapy decreases the disease recurrence rate by about 15% and the mortality rate at five years by about 5% [6][7]. Platinum-based chemotherapy, with or without radiation therapy, has been used as induction neoadjuvant therapy before surgery; however, the improvement of survival in resectable NSCLC patients is still limited [6][7]. A recent pivotal clinical study (ADAURA) showed that the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) osimertinib significantly reduced the disease recurrence rate in stage IB to IIIA resected EGFR-mutated NSCLC patients [8]; however, the advances in neoadjuvant and post-operative adjuvant therapies for surgically resectable NSCLC have been very limited over the last three decades.
    Immunotherapies are a new therapeutic modality, which has been studied and used for the treatment of advanced NSCLC in the past 10 years [9][10]; for example, anti-programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have been developed and widely studied in clinical trials, and have been used to treat advanced NSCLC. The clinical trials showed that immunotherapies targeting the PD-1/PD-L1 axis have a promising response (~45%) and can significantly prolong the survival of metastatic NSCLC patients [9][10]. Therefore, the application of immunotherapy in early-stage NSCLC has been explored in recent studies [11].

    2. Neoadjuvant and Adjuvant Immunotherapy in Surgically Resectable NSCLC

    2.1. Immune Checkpoints Inhibitors (ICIs) in Neoadjuvant Therapy

    Uncompleted resection by surgery is always considered in NSCLC with locally advanced disease or mediastinal lymph node metastasis (stage II and III disease), where neoadjuvant therapies, e.g., chemotherapy, radiation therapy, or concurrent chemoradiotherapy, are suggested before surgery [12][13]. Recently, ICIs have been applied and investigated for neoadjuvant therapy in NSCLC. In a previous preclinical study, Cascone et al. established a mouse model by inoculating NSCLC 344SQ-OVA+ cells into the flank of syngeneic mice, where the mice were divided into four groups to compare the efficacy of different neoadjuvant immunotherapies. The mice were treated with 3 doses of the neoadjuvant anti-PD-1 antibody, anti-CTLA-4 antibody, or anti-PD-1 plus anti-CTLA-4 antibodies, or observation, followed by surgical resection of primary tumors in all mice. The observational mice received post-surgery adjuvant therapies with anti-PD-1 antibody, anti-CTLA-4 antibody, or anti-PD-1 plus anti-CTLA-4 antibodies. The results of this study showed that either single-agent or combination neoadjuvant therapies contributed to significantly longer survival than all adjuvant therapies in the mouse model. In a subgroup analysis of mice receiving neoadjuvant therapies, the combination was significantly superior to a single agent in prolonging survival. In addition, the neoadjuvant combination therapy significantly reduced lung metastasis, when compared with a single agent and all treatment modalities, in the adjuvant setting (single and combination) [14]. Based on the promising results of this pre-clinical study, several clinical trials investigating neoadjuvant immunotherapy have been initiated [14][15]. A previous study has shown that neoadjuvant therapy with single nivolumab before surgery had a 45% major pathological response (MPR), acceptable toxicity, and no delay of surgery [16]. A previous report found that nivolumab plus ipilimumab therapy had the trend of more effective in current or former smokers than never smokers based on the results of the CheckMate 227 trial [17]. Another clinical study showed that neoadjuvant nivolumab plus ipilimumab in resectable NSCLC is feasible, and all the patients enrolled in the study were active and former smokers [18]. A previous meta-analysis review showed that neoadjuvant immunotherapy was more effective than neoadjuvant chemotherapy regarding the MPR and pathological complete response (PCR) in resectable NSCLC. In the same analysis, the surgical resection rate was also similar between neoadjuvant immunotherapy and neoadjuvant chemotherapy (88.7% vs. 70–90%) [19].
    In a recent phase 2 clinical trial (NEOSTAR), stages I to IIIA NSCLC patients were randomized to receive neoadjuvant therapies with nivolumab alone or nivolumab plus ipilimumab, followed by surgery. In the analysis of 37 patients with surgical resection, the MPR was 24% for nivolumab alone, and 50% for nivolumab combined with ipilimumab. The NEOSTAR trial indicated that neoadjuvant therapy, with either nivolumab alone or the combination of nivolumab and ipilimumab, achieved pathological response in surgery. The results of the same trial showed that the neoadjuvant combination of nivolumab and ipilimumab produced significantly higher pathologic responses, immune infiltrations, and immunologic memory in the resected tumor than nivolumab alone [20]. Cytotoxic chemotherapy augments the immunogenicity of cancer cells by inducing antigenicity and adjuvanticity [21]. Immunogenic cell death (ICD) is associated with adaptive stress response which promotes the maturation of dendritic cells (DCs). In a lung cancer mouse model, chemotherapy promotes the ICD pathway to enhance the anti-tumor ability of anti-PD-1 and anti-CTLA4 antibodies [21][22]. In addition, chemotherapy might have off-target effects on suppressing myeloid-derived suppressor cells (MDSCs) or regulatory T (Treg) cells to stimulate anti-tumor immunity [23]. Together, these indicated that chemotherapy in combination with ICIs successfully improved the survival of metastatic NSCLC patients [24][25][26][27][28][29]. The addition of ICIs to conventional chemotherapy in neoadjuvant therapy for resectable NSCLC has been tested in two previous clinical trials. Nivolumab in combination with conventional chemotherapy as neoadjuvant therapy for resectable stage IIIA NSCLC was explored in phase 2 clinical study (NADIM), where the results of this trial showed 77.1% 24-month PFS in patients receiving tumor resection after neoadjuvant therapy [30]. Another phase 2 clinical trial investigated the efficacy of neoadjuvant atezolizumab plus chemotherapy in stage II-IIIA NSCLC. A total of thirty patients were enrolled in this phase 2 clinical trial, of which 29 finally received surgery and 17 (57%) had MPR, which was achieved with the neoadjuvant atezolizumab in combination with chemotherapy [31]. Single atezolizumab and pembrolizumab monotherapy as neoadjuvant therapy has been also tested in two previous clinical studies. Both clinical trials recruited potentially resectable stage I to III NSCLC [15][32]. Neoadjuvant single atezolizumab achieved 18% MPR in the LCMC3 clinical trial [15][32]. Ready et al. showed that neoadjuvant single pembrolizumab had 28% MPR in the other phase 2 clinical trial [20].
    There are remaining some early-stage NSCLC patients who do not receive surgery because of reasons including poor cardiopulmonary reserve, extremely old age, poor performance status, and personal refusal. Therefore, radiotherapy such as stereotactic ablative radiotherapy (SABR) can be an alternative treatment for early-stage NSCLC patients who are unable to receive surgery [33][34]. Previous studies had shown that local radiation therapy can stimulate the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). The TAAs and DAMPs promote immune cell priming and destruct immunosuppressive tumor-supporting stroma and these result in the enhancement of the anti-cancer effect of ICIs in NSCLC [22][35]. The efficacy of ICIs enhanced by radiotherapy is also called the abscopal effect [22][35], and compatible with the promising results shown in the PACIFIC trial. Using the combination of local radiation therapy and ICIs to improve local control and survival in early-stage NSCLC is warranted in future clinical trials. The results of trials using immunotherapy, with or without chemotherapy, as neoadjuvant therapy in surgically resectable NSCLC patients are summarized in Table 1.
    Table 1. Results of clinical trials using immunotherapy with or without chemotherapy as neoadjuvant therapy for resectable NSCLC patients.
    Trial
    [Reference]
    Stage Number of Patients Recruited Drugs Used in Neoadjuvant Therapy Primary Endpoint MPR (%)
    Forde et al. (NCT02259621)
    [16]
    Stages I-IIIA 21 Nivolumab (monotherapy) Safety and feasibility 45
    NEOSTAR
    (NCT03158129)
    [20]
    Stages IA-IIIA 44 Nivolumab or
    nivolumab + ipilimumab
    MPR 24 in nivolumab group
    50 in nivolumab + ipilimumab group
    NADIM
    (NCT03081689)
    [30]
    Stages IIIA 46 Nivolumab + carboplatin + paclitaxel 24-month PFS
    (77.1%)
    83
    Shu et al.
    (NCT02716038)
    [31]
    Stages II-IIIA 30 Atezolizumab + carboplatin +
    nab-paclitaxel
    MPR 57
    LCMC3
    (NCT02927301)
    [15][32]
    Stages IB-IIIB 82 Atezolizumab (monotherapy) MPR 18
    Ready et al.
    (NCT02818920)
    [32]
    Stages IB-IIIB 25 Pembrolizumab (monotherapy) MPR 28
    PRINCEPS
    (NCT02994576)
    [36]
    Stages IA (>2 cm)-IIIA 30 Atezolizumab (monotherapy) Toxicity Not available
    Gao et al.
    (ChiCTR-OIC-17013726)
    [37]
    Stages IA-IIIB 40 Sintilimab (monotherapy) MPR 40.5
    Abbreviations: MPR, major pathological response; PFS, progression-free survival.
    At present, several ongoing clinical trials are investigating the use of ICIs with or without chemotherapy as neoadjuvant therapy in resectable NSCLC (Table 2.). Several previous early-phase (phases I & II) had shown that ICIs with or without chemotherapy were feasible and effective as a neoadjuvant therapy before surgery [15][16][17][18][19][20][21][22][23][30][31][32][33][34][35][36][37][38][39][40]. Therefore, four main phase III clinical trials (KEYNOTE 617, CheckMate 816, IMpower 030, AEGEAN) are conducted and ongoing now. All four trials enrolled control groups, and explore the consolidation ICIs therapy after surgery. These four clinical trials are expected to be completed in 2024 [15][41][42][43].
    Table 2. Ongoing clinical trials using immunotherapy with or without chemotherapy as neoadjuvant therapy for resectable NSCLC patients.
    Trial
    [Reference]
    Phase Stage Number of Patients Recruited or
    Target Number
    Drugs Used in the Trial Primary Endpoint
    NEOMUN (NCT03197467)
    [38]
    II Stages II-IIIA 30 Pembrolizumab (monotherapy) Safety and feasibility
    IFCT-1601 IONESCO (NCT03030131)
    [39]
    II Stages IB (>4 cm)-IIIA 50 Durvalumab (monotherapy) Complete surgical resection (R0)
    ACTS-30 (NCT03694236)
    [40]
    Ib Resectable Stage IIIA 14 Durvalumab + chemoradiotherapy Safety and feasibility
    KEYNOTE 617 (NCT03425643)
    [15]
    III Stages II-IIIB 786 Chemotherapy + pembrolizumab/placebo
    × 4 cycles → surgery →
    pembrolizumab/placebo × 13 cycles
    Event-free survival (EFS) and OS
    CheckMate 816 (NCT02998528)
    [41]
    III Stages IB-IIIA 350 Chemotherapy + nivolumab × 3 cycles vs. chemotherapy alone × 3 cycles → surgery EFS and pathological complete response (pCR)
    IMpower 030 (NCT03456063)
    [42]
    III Stages II-IIIB 374 Chemotherapy + atezolizumab/placebo × 4 cycles → surgery →
    pembrolizumab/placebo × 16 cycles
    MPR, EFS
    AEGEAN
    (NCT03800134)
    [43]
    III Stages IIA-IIIB 300 Chemotherapy + durvalumab/placebo × 3 cycles → surgery →
    durvalumab/placebo × 12 cycles
    MPR
    Abbreviations: EFS, even-free survival; pCR, pathological complete response; MPR, major pathological response.

    2.2. Immune Checkpoint Inhibitors (ICIs) in Post-Operation Adjuvant Therapy

    Some early-stage NSCLC patients receive surgical resection without neoadjuvant therapy, and post-operation adjuvant chemotherapy is generally recommended for those with high risks of recurrence [21]. The risks of post-operation recurrence in NSCLC include lymph node metastases, the main tumor size being larger than 4 cm, and extensive local invasion [44]. The use of anti-PD-1/PD-L1 ICIs with or without chemotherapy as post-surgery adjuvant therapy in NSCLC is under investigation, and no mature study result is available to date [15][45]. There are four ongoing phase 3 clinical trials considering anti-PD-1/PD-L1 ICIs for early-stage NSCLC patients after receiving complete tumor resection (ANVIL, PEARLS, IMpower010, and BR31) [15][45][46][47]. The details of these four clinical trials are summarized in Table 3. The four phase 3 clinical trials are planning to recruit about 4600 NSCLC patients receiving surgery, and are expected to be completed between 2024 and 2027. Disease-free survival (DFS) is the main primary endpoint of all four trials [15][45][46][47]. The results of these phase 3 clinical trials may bring a substantial impact on the clinical practice of NSCLC patients receiving complete resection in the future. Though the design of the four ongoing trials is similar, there is little difference among the 4 ongoing trials. First, post-operative platinum-based chemotherapy before randomized to atezolizumab or best supportive care group is a required treatment for participants of the IMpower010 trial whether post-operative chemotherapy is optional for the participants of the other 3 ongoing trials. Second, the patients in the control group of IMpower010 and ANVIL trials receive the best supportive care or observation, and the patients in the control group of the other 2 ongoing trials (PEARLS and BR31) receive placebo [15][45][46][47]. Patients in the BR31 trial would have the tests EGFR mutation and ALK rearrangement for further subgroup analysis. Patients with EGFR mutation or ALK rearrangement would be excluded from the ANVIL trial. The tests of EGFR mutation and ALK rearrangement are not mandatory in PEARLS and IMpower010 trials. All the trials have the test of tumor tissue PD-L1 expressions for further subgroup analysis in the future [15][45][46][47]. The results of the four ongoing trials will provide information on ICIs with or without chemotherapy as post-operative adjuvant therapy for clinical practice.
    Table 3. Ongoing clinical trials using ICIs as adjuvant therapy for post-surgery NSCLC patients.
    Trial Stage Estimated Enrollment Treatment Procedure Primary Endpoint
    ANVIL (NCT02595944) Stages IB-IIIA 903 Surgery +/− chemotherapy → nivolumab vs. observation DFS, OS
    PEARLS
    (NCT02504372)
    Stages IB-IIIA 1177 Surgery +/− chemotherapy → pembrolizumab vs. placebo DFS
    IMpower010
    (NCT02486718)
    Stages IB-IIIA 1280 Surgery +/− chemotherapy → atezolizumab vs. best supportive care DFS
    BR31
    (NCT02273375)
    Stages IB-IIIA 1360 Surgery +/− chemotherapy → durvalumab vs. placebo DFS
    Abbreviations: ICIs, immune checkpoint inhibitors; NSCLC, non-small cell lung cancer; DFS, disease-free survival; OS, overall survival.

    2.3. Immune Checkpoint Inhibitors (ICIs) in Neoadjuvant Therapy or Adjuvant Therapy

    According to the results of a pre-clinical study by Cascone et al., the neoadjuvant ICIs seem to contribute better survival benefits than the adjuvant setting has in the mouse model [14]. The complete clinical trials showed that ICIs with or without chemotherapy as neoadjuvant therapy achieved pathological response and contribute to complete surgical resection. However, there were remaining some NSCLC patients receiving neoadjuvant therapy who did not receive surgical resection finally because of complication or disease progression in neoadjuvant therapy [15][16][20][30][31][32][36][37]. In the main four ongoing trials investigating ICIs as adjuvant therapy for post-surgery NSCLC patients, the enrolled patients were required to have complete surgical resection (R0) [15][45][46][47]. However, some NSCLC patients have incomplete surgical resection in real-world clinical practice [48]. Post-operative adjuvant therapy such as chemotherapy and radiotherapy are suggested for incomplete resection NSCLC patients. However, the survival benefit of post-operative conventional chemotherapy and radiotherapy is limited for incomplete resection NSCLC patients, and the prognosis of these patients are not well [49]. ICIs in addition to chemotherapy or radiotherapy may provide survival benefits for incomplete resection NSCLC patients, but the 4 ongoing trials of adjuvant ICIs cannot answer this clinical query [15][45][46][47].
    In currently ongoing four main phase III clinical trials (KEYNOTE 617, CheckMate 816, IMpower 030, AE-GEAN) with neoadjuvant chemotherapy plus ICIs or placebo, post-operative consolidation ICIs therapy is administrated in the treatment group patients [15][41][42][43]. These four clinical trials will provide clear evidence on the efficacy of ICIs administrated before and after surgery in early-stage and resectable NSCLC.

    The entry is from 10.3390/vaccines9070689

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