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Mohamed, S.; Bertolaccini, L.; Casiraghi, M.; Galetta, D.; Petrella, F.; De Marinis, F.; Spaggiari, L. Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/43768 (accessed on 20 April 2024).
Mohamed S, Bertolaccini L, Casiraghi M, Galetta D, Petrella F, De Marinis F, et al. Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/43768. Accessed April 20, 2024.
Mohamed, Shehab, Luca Bertolaccini, Monica Casiraghi, Domenico Galetta, Francesco Petrella, Filippo De Marinis, Lorenzo Spaggiari. "Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer" Encyclopedia, https://encyclopedia.pub/entry/43768 (accessed April 20, 2024).
Mohamed, S., Bertolaccini, L., Casiraghi, M., Galetta, D., Petrella, F., De Marinis, F., & Spaggiari, L. (2023, May 04). Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer. In Encyclopedia. https://encyclopedia.pub/entry/43768
Mohamed, Shehab, et al. "Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer." Encyclopedia. Web. 04 May, 2023.
Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer
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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].
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][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]. 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].
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

Trial/Study Name

Phase

Patient N

Neoadjuvant Therapy

Patient Population

Outcomes

Safety

MPR

PCR

NEOSTAR [19]

II

88

Nivolumab, Nivolumab ± Ipilimumab

IA-IIIA

Median OS and RFS not reached at 22.2 months

NR

22% vs. 38%

9% vs. 29%

LCMC3 [20]

II

181

Atezolizumab

IB-IIIB (resectable)

NR

NR

20%

7%

Gao et al. [21]

Ib

40

Sintilimab

IA-IIIB

R0 in 37/40

12.5% TRAEs grade 3–5

40.50%

16.20%

NEOMUN [22]

II

15

Pembrolizumab

II-IIIA

NR

33% TRAEs

13%

13%

PRINCEPS [23]

II

30

Atezolizumab

IA-IIIA

R0 in 29/30

3.3% TRAEs

14%

0%

IONESCO [24]

II

50

Durvalumab

IB (≥4 cm)-IIIA

R0 in 45/50

9% of death in 90 days

18.60%

7%

Tong et al. [25]

II

30

Pembrolizumab

IB-IIIA

R0 in 22/25

4% grade 3 TRAEs

28%

0%

Altorki et al. [26]

II

60

Durvalumab ± radiotherapy

IA-IIIA

R0 in 26/30 vs. 26/30

17% vs. 20% grade 3–4 TRAEs

6.7% vs. 26.6%

0% vs. 26.6%

MPR: Major Pathological Response, PCR: Pathological Complete Response. TRAEs: Treatment-Related Adverse Events, OS: Overall Survival, NR: Not Reported.

Table 2. Clinical Trials: Neoadjuvant Immuno-Chemotherapy in resectable NSCLC. 

Neoadjuvant Immuno-Chemotherapy

Trial/Study Name

Phase

Patient N

Neoadjuvant Therapy

Patient Population

Outcomes

Safety

MPR

PCR

NADIM [27]

II

46

Nivolumab + Carboplatin + Paclitaxel

IIIA

PFS 77%, OS 12–18-24 m: 97.8–93.5–89.9%

30% TRAEs grade 3–4

83%

71%

Shu et al. [28]

II

30

Atezolizumab + Carboplatin + nab-paclitaxel

IB-IIIA

R0 in 26/29 pts

50% TRAEs grade 3–4

57%

33%

NADIM II [29]

II

86

Paclitaxel + Carboplatin ± Nivolumab

IIIA-IIIB

Median OS 81.9% at 36 m

25% vs. 10.3% TRAEs grade 3–4

52.6% vs. 13.8%

36.8% vs. 6.9%

CheckMate 816 [30]

III

358

CT ± Nivolumab

IB-IIIA

R0 in 83% vs. 75%

11% vs. 15% TRAEs grade 3–4

37% vs. 9%

24% vs. 2%

KEYNOTE 671 [31]

III

NR

Pembrolizumab + CT

IIA-IIIA-IIIB (N2)

NR

NR

NR

NR

AEGEAN [32]

III

NR

CT ± Durvalumab

IIA-IIIA-IIIB (N2)

NR

NR

NR

NR

Checkmate 77T [19]

III

NR

CT ± Nivolumab

IIA-IIIB (T3N2)

NR

NR

NR

NR

IMPOWER 030 [33]

III

NR

CT ± Atezolizumab

II-IIIA-IIIB (T3N2)

NR

NR

NR

NR

MPR: Major Pathological Response, PCR: Pathological Complete Response. TRAEs: Treatment-Related Adverse Events, PFS: Progression-Free Survival, OS: Overall Survival, CT: Platinum-doublet chemotherapy, m: months, NR: Not Reported.

3. Adjuvant Immunotherapy

Chemotherapy has been the standard of care for patients with NSCLC as adjuvant therapy, improving the 5-year survival rates by only 4–5%.
Adjuvant therapy plays an essential role in preventing recurrence and eliminating micrometastases. To date, new targeted therapies have been described that showed better DFS than chemotherapy, such as Osimertinib [34], Gefitinib [35], or Erlotinib [36].
Wu et al. reported in ADAURA that 90% of patients with stage II to IIIA were alive at 24 months in the Osimertinib group and only 44% in the placebo group.
In recent years, ICIs have become more and more utilized for unresectable locally advanced or metastatic stages with very promising results, as described in the following paragraphs. Based on these results, several new trials are studying the efficacy of ICIs also in early-stage NSCLC patients.
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) [37]. Due to these promising results, the FDA approved Atezolizumab as adjuvant monotherapy in patients with PD-L1 positive in October 2021 [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 [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 [40].
  • KEYNOTE-091: phase III trial with a sample size of 1177 patients with stage IB-IIIA. In this study, patients after adjuvant chemotherapy are randomized to receive adjuvant Pembrolizumab or placebo for one year [41]. Preliminary results showed an improved DFS of 53.6 months in the Pembrolizumab group compared to 42.0 months in the placebo group. At the ESMO Congress 2022, Peters et al. reported based on the PD-L1 status, the 3-year median DFS which was 65.9% vs. 57.6% in PD-L1 ≥ 50%, 54.6% vs. 44.8% in PD-L1 1–49% and 55.5% vs. 48.8% in PD-L1 < 1% [42].
  • BR31/IFCT1401: phase III trial with a sample size of 1415 patients with a stage IB-IIIA NSCLC. After adjuvant chemotherapy, patients are randomized to receive Durvalumab or a placebo for one year. The outcome studied is DFS in patients with PD-L1 ≥ 25% without EGFR mutations or ALK rearrangements [43].
  • ANVIL, ALCHEMIST Chemo-IO, MERMAID-1, MERMAID-2, NADIM-ADJUVANT, and LungMate-008 are ongoing trials studying efficacy, the DFS and the OS of adjuvant ICIs (Nivolumab, Pembrolizumab, Durvalumab, Toripalimab) in patients with resectable NSCLC (see Table 3 for details) [44][45][46][47][48][49].
As described in the NCCN guidelines, the recommended duration of Atezolizumab as adjuvant therapy is one year [50]. In the previously reported ongoing trials, the adjuvant ICIs treatment ranges from 6 months to 2 years. Future results will better define the efficacy and duration of adjuvant therapy, as well as the predictors of response and the combination of multiple therapies.
Table 3. Clinical Trials: Adjuvant Immunotherapy, Immuno-Chemotherapy in resectable NSCLC.

OS: Overall Survival, CT: Platinum-doublet chemotherapy, MRD: Minimal Residual Disease, y: years, NR: Not Reported.

4. Immunotherapy or Immuno-Chemotherapy in Unresectable NSCLC

For unresectable NSCLC, several therapeutic strategies have been proposed in the last decade. these treatments could range from local therapies (such as radiotherapy) to systemic therapies (such as standard chemotherapy, target therapy, and immunotherapy), which may be used alone or in association with each other.

4.1. Unresectable Stage III NSCLC

The studies show no benefit for immunotherapy (Durvalumab) in dGA-NSCLC patients, except for NSCLC patients harboring KRAS mutation (Table 4).
Table 4. Clinical Trials: Immuno-, Immuno-Chemo-, Immuno-Chemo-Radiotherapy in unresectable NSCLC.

MPR: Major Pathological Response, PCR: Pathological Complete Response. TRAEs: Treatment-Related Adverse Events, PFS: Progression-Free Survival, OS: Overall Survival, CT: Chemotherapy, RT: Radiotherapy, cCRT: concurrent Chemo-Radiotherapy, D: Durvalumab, O: Oleclumab, M: Monalizumab, m: months, ICIs: Immune-checkpoint Inhibitors, dGA: driver Genic Alteration, NR: Not Reported.

4.2. Metastatic NSCLC without Driver Mutations

Several studies and trials reported the outcomes of anti-PD-1/PD-L1 monotherapy alone or in combination with platinum doublet chemotherapy or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody against standard platinum doublet chemotherapy in advanced NSCLC patients (Table 5).
Table 5. Clinical Trials: Immuno-, Immuno-Chemo-, Immuno-Chemo-radiotherapy in metastatic NSCLC without driver mutations.

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