Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer

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]

Metastatic NSCLC with Driver Mutations

^[⁴⁰^].

Trial/Study Name	Phase	Patient N	Neoadjuvant Therapy	Patient Population	Outcomes

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

Adjuvant Immunotherapy
Trial/Study Name		Safety			MPR			PCR
Trial/Study Name	Phase	Patient N	Neoadjuvant Therapy

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.

Unresectable Stage III NSCLC
Trial/Study Name

Table 5.

Clinical Trials: Immuno-, Immuno-Chemo-, Immuno-Chemo-radiotherapy in metastatic NSCLC without driver mutations.

Metastatic NSCLC without Driver Mutations
	Phase	Patient N	Treatment Regimen	Patient Population
Trial/Study Name	Phase		Patient N	Outcomes		Safety	MPR	PCR
	Phase	Patient N	Treatment Regimen	Patient Population	Patient Population Outcomes	Safety
		Outcomes			Safety
		Treatment Regimen		Patient Population	Outcomes	Safety
NEOSTAR [20]^[19]	II

[
44]^[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% [

IMpower010 [41,42,43]

45
]

^38]^[

Nivolumab, Nivolumab ± Ipilimumab

³⁹

IA-IIIA

Median OS and RFS not reached at 22.2 months

⁴⁰

Van Reij et al.

22% vs. 38%

9% vs. 29%

^[
⁴²^].

[54]^[51]

III

1280

CT ± Atezolizumab

IB-IIIA

319

RT ± CT (Sequential vs. concurrent)

IIIA-IIIB

PD-L1 ≥ 50%, EGFR+, ALK+: 3-y DFS 73.8% vs. 48.6%.

PD-L1 ≥ 50%, EGFR−, ALK−: 3-y DFS 75.1% vs. 50.4%.

CheckMate 017 [79

Seq: Median OS 17.4 m OS 5-y 17%, Con: Median OS 18.6 m OS 5-y 19%

]

^69]

79]

III

^[69

272

Nivolumab vs. Docetaxel

IIIB-IV squamous NSCLC

PD-L1 ≥ 1%: 5-y OS 76.8% vs. 67.5%.

PD-L1 ≥ 50%: 5-y OS 84.8% vs. 67.5%.

551

Median PFS: 3.5 m vs. 2.8 m.

ICIs

Median OS 9.2 m vs. 6.0 m

Metastatic NSCLC EGFR+ and ALK+

Median PFS 2.1 m, 2.5 m

Any AE:

LCMC3 [21]^[20]

58% vs. 86%

KEYNOTE-091 [44,45]^[41][42]

181

III

Atezolizumab

1177

IB-IIIB (resectable)

Pembrolizumab vs. Placebo

IB-IIIA

Median DFS 53.6 months vs. 42.0 months.

PD-L1 ≥ 50%: 3-y DFS 65.9% vs. 57.6%.

PD-L1 1–49%: 3-y DFS 54.6% vs. 44.8%.

PD-L1 < 1%: 3-y DFS 55.5% vs. 48.8%

20%

Bradley et al. [55]^[52]

CheckMate 057 [80]^[

Chalmers AW et al.

III

⁷⁰[

544

Concurrent CT + High/low dose RT ± Cetuximab

IIIA-IIIB

High-dose RT Median OS 28.7 m, Standard-dose RT Median OS 20.3 m

III

582

Nivolumab vs. Docetaxel

103]^[86]

IIIB-IV non-squamous NSCLC

Gao et al. [22]^[21]

PACIFIC (Antonia et al.) 2017

[

Sintilimab

IA-IIIB

R0 in 37/40

BR31/IFCT1401 [46]^[43]

III

]

1415

^[53

Durvalumab vs. Placebo

12.5% TRAEs grade 3–5

III

713

Durvalumab vs. placebo

IB-IIIA

IIIA-IIIB

40.50%

16.20%

Not yet

Median PFS 16.8 m vs. 5.6 m, Median time to death or distant metastasis 23.2 m vs. 14.6 m

Not yet

29.9% vs. 26.1% TRAEs grade 3–4

9% vs. 7%

IB-IIIA

Not yet

Median PFS: 2.3 m vs. 4.2 m.

Median OS 12.2 m vs. 9.4 m

Any AE:

69% vs. 88%

KEYNOTE-001 [81]^[71]

III

367

Nivolumab + Pemetrexed/CT or Nivolumab + Ipilimumab vs.

Pemetrexed + CT

Metastatic or Recurrent NSCLC

Nivolumab/ipilimumab + sequential or concurrent SBRT

Metastatic

Not Yet

TRAEs: Treatment-Related Adverse Events, PFS: Progression-Free Survival, OS: Overall Survival, CT: Platinum-based chemotherapy, m: months, ORR: Overall Response Rate, AE: Adverse Effects, NR: Not Reported.

4.3. Metastatic NSCLC with Driver Mutations

The three clinical trials are ongoing, and the results are pending (Table 6).

Table 6.

Clinical Trials: Immuno-, Immuno-Chemo-, Immuno-Chemo-radiotherapy in metastatic NSCLC with driver mutations.


Mazieres et al. [
	14		Ipilimumab + Erlotinib/Crizotinib	Advanced NSCLC EGFR+ and ALK+	Median PFS 17.9 m, 21.4 m; Median OS > 42 m, >47 m	TRAEs 78% vs. 33% grade 3
CheckMate 722 [104]	I	^[87] 550	Pembrolizumab every 2 or 3 weeks	Locally advanced/metastatic NSCLC	Median OS 22.3 m, 10.5 m		Not Yet TRAEs 12% vs. 6% grade 3–5	Not Yet
NEOMUN [23]^[22]	PACIFIC (Spigel et al.) 2022
KEYNOTE-024 [82]^[
Mok et al.	II	⁷²[105 15	^]] Pembrolizumab	^[88 II-IIIA	NR
ANVIL [47]^[44]		33% TRAEs			^] III		III 903	305	Pembrolizumab vs. CT	III	29413%		Nivolumab + Platinum + Pemetrexed vs. CT alone 13%
Nivolumab vs. Observation		Advanced NSCLC		EGFR-mutated NSCLC	Median PFS 10.3 m vs. 6 m, Median OS 30 m vs. 14.2 m		Median PFS 5.6 m, 5.4 m; Median OS 19.4 m, 15.9 m Any AE: 73% vs. 90%	NR	PRINCEPS [24]^[23]	KEYNOTE-042 [83]^[73] II	30	Atezolizumab	IA-IIIA	R0 in 29/30	ALCHEMIST Chemio-IO [48]^[45]
NCT03256136 [106]^[	III	3.3% TRAEs		III 1210	1274 CT ± Nivolumab		Pembrolizumab vs. CT IIA-IIIB	Not yet 14%	Not yet 0%
			Locally advanced/metastatic NSCLC (PD-L1 ≥ 50%, ≥20%, 1%)		Median PFS 7.1 m, 6.2 m, 5.4 m vs. 6.4 m, 6.6 m, 6.5 m. Median OS 20 m, 17.7 m, 16.7 m vs. 12.2 m, 13.0 m, 12.1 m	⁸⁹ NR
^]	II	9	Nivolumab + Carboplatin + Pemetrexed or Nivolumab + Ipilimumab	EGFR+ or ALK+	Not Yet	Not Yet	IONESCO [25]^[24]
MERMAID-1 [49]^[46]	II	Govindan R et al. [84]^[74] III	332	CT ± Durvalumab	II-III, MRD	Not yet
NCT03091491 [107]^[90]	III		Not yet
MERMAID-2 [50]^[47]	III	284	Durvalumab vs. Placebo	II-III, MRD	Not yet	Not yet
[57]^[54]	III	713	Durvalumab vs. placebo	IIIA-IIIB	Median OS 47.5 m vs. 29.1 m, Median PFS 16.9 m vs. 5.6 m	NR	NR	NR
PACIFIC-R [60]^[55]	III	1399	Durvalumab vs. placebo	IIIA-IIIB	Median PFS 21.7 m, Median OS NR	AESIs 27.7%	NR	NR
PACIFIC-6 [61]^[56]	50			II	II 117 956	31 Durvalumab	Durvalumab IB (≥4 cm)-IIIA		Carboplatin + Paclitaxel ± Ipilimumab IIIA-IIIB R0 in 45/50	9% of death in 90 days		Nivolumab ± Ipilimumab Median PFS 10.9 m, 12 m 18.60%	7%
IV or recurrent squamous NSCLC		OS rate 84.1%			4% TRAEs			EGFR+ Median PFS 5.6 m, 5.6 m. Median OS 13.4 m, 12.4 m NR	0.80%		Not Yet TRAEs 51% vs. 35% grade 3–4
	Not Yet		Tong et al. [26]^[25]
PACIFIC-2 [62]^[57]	II	30	Pembrolizumab	IB-IIIA	R0 in 22/25	4% grade 3 TRAEs	III	300	Durvalumab 28%	NEPTUNE IIIA-IIIB	[85 Not yet	]^[75 Not yet	^] Not yet 0%
	Not yet		III	/	Durvalumab + Tremelimumab vs. CT	Metastatic	Not Yet	Not Yet	Altorki et al. [27]^[26]	II		NADIM-ADJUVANT [51]^[48]
COAST [63
MYSTIC [86]^[76	60		III Durvalumab ± radiotherapy	] 210	^[58] IA-IIIA	^]	II Paclitaxel + Carboplatin ± Nivolumab R0 in 26/30 vs. 26/30	17% vs. 20% grade 3–4 TRAEs	189 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.




Durvalumab ± Oleclumab or Monalizumab


IB-IIIA
		III	1118		Durvalumab ± Tremelimumab vs. CT IIIA-IIIB Not yet	Median PFS 6.3 with Durvalumab, NR Oleclumab, 15.1 m Monalizumab Not yet
			Metastatic	TRAEs 39.4% with D, 40.7% with D + O, 27.9% with D + M			NR	3% with D, 1.7% with D + O, 4.8% with D + M	Median PFS 4.3 m, 3.9 m, 5.4 m; Median OS 16.3 m, 11.9 m, 12.9 m	Any AE: 54% vs. 60% vs. 83%	LungMate-008 [52]^[49]
PACIFIC-9 [64]^[59]	III
POSEIDON [87	II	341	]^[77] / CT ± Toripalimab		IIIII-IIIB		/	Not yet	Not yet

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

Durvalumab ± Oleclumab or Monalizumab

Durvalumab + CT ± Tremelimumab followed by Durvalumab ± Tremelimumab; vs. CT

IIIA-IIIB

Not yet

Metastatic

Not yet

Not YetNot yet

Not yet

Not Yet

CITYSCAPE [65]^[60]

KEYNOTE-021 [88]^[78]

I/II

135

44Tiragolumab + Atezolizumab vs. Placebo

IIIA-IIIB

Pembrolizumab ± Ipilimumab

Advanced NSCLCMedian PFS 5.4 m vs. 3.6 m

TRAEs 12% vs. 3% grade 3–4–5

Median PFS 4.1 m,NR

Median OS 10.9 m

TRAEs 29% grade 3–5

KEYNOTE 799 [67]^[61]

KEYNOTE-598 [89]^[79]

III

214

568

Pembrolizumab + cCRT + Paclitaxel + Carboplatin vs. Pembrolizumab + cCRT + Pemetrexed + Cisplatin

Pembrolizumab ± Ipilimumab

IIIA-IIIB

Metastatic

Not yet

TRAEs 64.3% vs. 51% grade 3–4–5

Median PFS 8.2 m, 8.4 m.

Not yet

Median OS 21.4 m, 21.9 m

Not yet

TRAEs 62.4% vs. 50.2% grade 3–5

NICOLAS [69]^[62]

EMPOWER-lung 4 [90]^[80

CRT ± Nivolumab

IIIA-IIIB

Median PFS 12.7 m,

Median OS 38.8 m

TRAEs 9% vs. 18% grade 3–4–5

Cemiplimab (3 weeks) ± Ipilimumab or Cemiplimab (108 weeks)

Advanced NSCLC

PD-L1 1–50%: ORR 45.5%

PD-L1 <1%: ORR 36%

TRAEs 18.2%, 18.2%

Checkmate 73L [71]^[63]

III

Nivolumab + cCRT + Nivolumab ± Ipilimumab vs. cCRT + Durvalumab

Checkmate 012 [91]^[

IIIA-IIIB

^81]

Not yet

Nivolumab + Ipilimumab (every 12 or 6 weeks)

Recurrent IIIB or IV

Median PFS 8.1 m, 3.9 m.

Median OS NR

Any AE:

82%, 72%

BTCRC-LUN16-081 [73]^[64]

Checkmate 227 [92]

^[82]

105

cCRT + Nivolumab ± Ipilimumab

IIIA-IIIB

Not yet

TRAEs 32% vs. 44% grade 3–4

Not yet

III

1739

PD-L1 pos or neg: Nivolumab ± Ipilimumab vs. platinum-based CT

IV or recurrent

Median PFS:

PD-L1 ≥1%: 5.1 m, 4.2 m, 5.6 m,

PD-L1 <1%: 5.1 m, 5.6 m, 4.7 m;

Median OS:

PD-L1 ≥1%: 17.1 m, 15.7 m, 14.9 m,

PD-L1 <1%: 17.2 m, 15.2 m, 12.2 m.

Any AE:

77%, 65.5, 84%, 76%, 92%, 78%

DUART [75]^[65]

Checkmate 9LA [93]

^[83]

150

III

719

RT ± Durvalumab

Platinum-based CT ± Nivolumab + Ipilimumab

IIIA-IIIB

IV or recurrent

Not yet

Median PFS 6.8 m, 5 m.

Median OS 15.6 m, 10.9 m

Not yet

Any AE:

Not yet

91%, 87%

Mazieres et al. [76]^[66]

551

ICIs

IIIA-IIIB (with dGA)

Median OS 13.3 m,

Median PFS 2.8 m

NCT02239900 [94]^[84]

I/II

Ipilimumab + SBRT

Advanced NSCLC

Median PFS 3.2 m,

Median OS 10.2 m

TRAEs 34% grade 3NR

Guisier et al. [77]^[67]

107

NCT03223155 [95]^[

ICIs

^85]

IIIA-IIIB (BRAF-, HER2-, MET-, RET-)

Median OS 4.7 m,

Median PFS 16.2

TRAEs 10% grade 3–4

Not yet

Riudavets et al. [78]^[68]

323

CRT + Durvalumab

IIIA-IIIB

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
[46]^[43].

Median OS 47 m,

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) [47,48,49,50,51,52]^{[44][45][46][47][48][49]}.

Median PFS 17.5 m

TRAEs 6% grade 3–4, 0.5% grade 5

Neoadjuvant Immuno-Chemotherapy
Trial/Study Name	Phase	Patient N	Neoadjuvant Therapy	Patient Population	Outcomes	Safety	MPR	PCR
NADIM [28]^[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. [29]^[28]	II	30	Atezolizumab + Carboplatin + nab-paclitaxel	IB-IIIA	R0 in 26/29 pts	50% TRAEs grade 3–4	57%	33%
NADIM II [30]^[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 [31]^[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 [32]^[31]	III	NR	Pembrolizumab + CT	IIA-IIIA-IIIB (N2)	NR	NR	NR	NR
AEGEAN [33]^[32]	III	NR	CT ± Durvalumab	IIA-IIIA-IIIB (N2)	NR	NR	NR	NR
Checkmate 77T [20]^[19]	III	NR	CT ± Nivolumab	IIA-IIIB (T3N2)	NR	NR	NR	NR
IMPOWER 030 [34]^[33]	III	NR	CT ± Atezolizumab	II-IIIA-IIIB (T3N2)	NR	NR	NR	NR

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 [37]^[34], Gefitinib [38]^[35], or Erlotinib [39]^[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.

As described in the NCCN guidelines, the recommended duration of Atezolizumab as adjuvant therapy is one year [53]^[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.

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).

TRAEs: Treatment-Related Adverse Events, PFS: Progression-Free Survival, OS: Overall Survival, CT: Platinum-based chemotherapy, m: months, ICIs: Immune Checkpoint Inhibitors, NR: Not Reported.

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Ipilimumab and Stereotactic Body Radiation Therapy (SBRT) in Advanced Solid Tumor. Clinical Trial Information: NCT02239900. Available online: https://clinicaltrials.gov/ct2/show/NCT02239900 (accessed on 14 January 2023).
Concurrent or Sequential Immunotherapy and Radiation Therapy in Patients with Metastatic Lung Cancer (COSINR). Clinical Trial Information: NCT03223155. Available online: https://clinicaltrials.gov/ct2/show/NCT03223155 (accessed on 14 January 2023).
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CheckMate722. A Study of Nivolumab + Chemotherapy or Nivolumab + Ipilimumab versus Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) Participants with Epidermal Growth Factor Receptor (EGFR) Mutation Who Failed 1L or 2L EGFR Tyrosine Kinase Inhibitor (TKI) Therapy. Clinical Trial Information: NCT02864251. Available online: https://clinicaltrials.gov/ct2/show/NCT02864251 (accessed on 14 January 2023).
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