Expert Consensus on Neoadjuvant Immunotherapy for Non-Small Cell Lung Cancer

Wenhua Liang; Kaican Cai; Chun Chen; Haiquan Chen; Qixun Chen; Junke Fu; Jian Hu; Tao Jiang; Wenjie Jiao; Shuben Li; Changhong Liu; Deruo Liu; Wei Liu; Yang Liu; Haitao Ma; Xiaojie Pan; Guibin Qiao; Hui Tian; Li Wei; Yi Zhang; Song Zhao; Xiaojing Zhao; Chengzhi Zhou; Yuming Zhu; Ran Zhong; Feng Li; Rafael Rosell; Mariano Provencio; Erminia Massarelli; Mara B. Antonoff; Toyoaki Hida; Marc de Perrot; Steven H. Lin; Massimo Di Maio; Antonio Rossi; Dirk De Ruysscher; Robert A. Ramirez; Wolfram C. M. Dempke; D. Ross Camidge; Nicolas Guibert; Raffaele Califano; Qi Wang; Shengxiang Ren; Caicun Zhou; Jianxing He

Disclosures

Transl Lung Cancer Res. 2020;9(6):2696-2715.

Abstract and Introduction

Introduction

Lung cancer is the leading cause of cancer-related death worldwide and in China.^[1] According to the statistics of the National Cancer Center of China, there were 733,300 new cases of non-small cell lung cancer (NSCLC) and approximately 610,200 related deaths in 2015.^[2] For patients with early staged disease, surgery is the mainstay of treatment, and it is commonly followed by adjuvant chemotherapy for patients with locally advanced resectable NSCLC. Although complete surgical resection may be curative for NSCLC, 25–70% of patients (with different proportion according to stage) eventually relapse despite complete resection.^[3] Platinum-based adjuvant chemotherapy has been shown to marginally increase the 5-year survival rate of patients by 4–8%.^[4–6] Even after treatment with surgery and indicated adjuvant therapies in eligible cases, approximately 20–30% of stage I, 50% of stage II, and 60% of stage IIIA patients still die within 5 years.^[7] In the past decade, experts have conducted a number of investigations on the perioperative management of resectable NSCLC; however, progress remains slow, and patients still have a high risk of recurrence and death.

Neoadjuvant therapy is defined as any therapy delivered prior to definitive local therapy intended to increase the cure rate. It provides several theoretical benefits in managing such patients with NSCLC. In the setting of, neoadjuvant therapy given prior to radical surgery this approach can also have the goals of downstaging, improving the resection rate, and more promptly treating subclinical micro-metastases than adjuvant approaches, delivered after the definitive local therapy. In addition, the compliance with neoadjuvant therapy has been shown to be better than in the adjuvant setting, and the biological effect of the neoadjuvant therapy can be analyzed directly in the resected tumor specimens.^[8] A meta-analysis on patients with stage IB-IIIA NSCLC that compared chemotherapy plus subsequent surgery vs. surgery alone showed that the 5-year survival rate was 5% higher after receiving neoadjuvant chemotherapy (NCT).^[9] Therefore, the comprehensive NSCLC data suggest that, for resectable NSCLC, NCT improves survival compared with surgery alone but appear to show no significant survival benefit compared with adjuvant chemotherapy.^[10]

In the last 5 years, immune checkpoint inhibitors (ICIs) have profoundly changed the treatment paradigm for patients with advanced NSCLC.^[11–15] Immunotherapy has provided hope for long-term survival benefits to a minority of patients with metastatic lung cancer. For treatment-naive patients with driver mutation-negative NSCLC, the 5-year survival rate of single agent pembrolizumab was 23.2%; for the previously treated patients with driver mutation-negative NSCLC, the 5-year survival rates of single agent pembrolizumab and nivolumab were 15.5% and 16%, respectively.^[16,17] Given the profound impact made by immunotherapy drugs for patients with advanced disease, significant attention has been directed in recent years toward investigating the potential role for early-stage NSCLC patients, and whether they, too, can achieve long-term benefits from the inclusion of immunotherapy into their treatment algorithms.

Many phase Ib/II clinical trials have reported promising results, and a series of large-scale phase III clinical trials are underway. However, these various investigations have employed different strategies of neoadjuvant immunotherapy, in terms of the specific regimens as well as number of treatment cycles.^[18] To better guide Chinese thoracic surgeons in the neoadjuvant immunotherapy of NSCLC, well-known thoracic surgeons in China participated in an in-depth discussion on the hot topics and controversial issues of neoadjuvant immunotherapy and formed the Expert consensus on neoadjuvant immunotherapy for non-small-cell lung cancer by incorporating the latest evidence on neoadjuvant immunotherapy.

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Next Section

Table 1. The results of trials of neoadjuvant immunotherapy
Study title	NCT.no	Key inclusion and exclusion criteria	Drug	Major result
A Randomized, Double-Blind, Phase III Study of Platinum + Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-189)	NCT02578680	Patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations	Cisplatin; carboplatin; pemetrexed; dexamethasone; pembrolizumab	(I) OS at 12 months was 69.2% in the pembrolizumab-combination group versus 49.4% in the placebo-combination group. (II) PFS was 8.8 months in the pembrolizumab-combination group and 4.9 months in the placebo-combination group. (III) Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group
A Randomized, Double-Blind, Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)	NCT02775435	Untreated metastatic squamous NSCLC	Paclitaxel; nab-paclitaxel; carboplatin; pembrolizumab	(I) OS was 15.9 months in the pembrolizumab-combination group and 11.3 months in the placebo-combination group. (II) PFS was 6.4 months in the pembrolizumab-combination group and 4.8 months in the placebo-combination group. (III) Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group
A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab (MK-3475) Versus Platinum Based Chemotherapy in Treatment Naïve Subjects With PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer (Keynote 042)	NCT02220894	Patients with previously untreated metastatic NSCLC without EGFR or ALK mutations and with an ECOG performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater.	Carboplatin; paclitaxel; pemetrexed; pembrolizumab	(I) The median survival values by TPS population (≥50%, ≥20%, ≥1%) were 20.0 months for pembrolizumab versus 12.2 months for chemotherapy, 17.7 months versus 13.0 months, and 16.7 months versus 12.1 months, respectively. (II) Treatment-related adverse events of grade 3 or worse occurred in 18% of the patients in the pembrolizumab group and in 41% of those in the chemotherapy group and led to death in 2% and 2% patients, respectively
Phase I Study of Single Agent Pembrolizumab (MK-3475) in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (KEYNOTE 001)	NCT01295827	Patients had confirmed locally advanced/metastatic NSCLC and provided a contemporaneous tumor sample for PD-L1 evaluation by immunohistochemistry using the 22C3 antibody.	Pembrolizumab	(I) Median OS was 22.3 months in treatment-naive patients and 10.5 months in previously treated patients. (II) Estimated 5-year OS was 23.2% for treatment-naive patients and 15.5% for previously treated patients. (III) In patients with a PD-L1 tumor proportion score of 50% or greater, 5-year OS was 29.6% and 25.0% in treatment-naive and previously treated patients, respectively. (IV) Compared with analysis at 3 years, only three new-onset treatment-related grade 3 adverse events occurred
A Phase 1, Open-Label, Multicenter, Multidose, Dose Escalation Study of BMS-936558 (Nivolumab) in Subjects With Selected Advanced or Recurrent Malignancies	NCT00730639	Advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011	Nivolumab	OS was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months) or grade 3 or more (median, 20.3 months) compared with those without treatment-related AEs (median, 5.8 months)
Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable Non-Small- Cell Lung Cancer.	NCT02259621	Adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC	Nivolumab	Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors
A Randomized Open-Label Phase III Trial of MK-3475 Versus Platinum Based Chemotherapy in 1L Subjects With PD-L1 Strong Metastatic Non- Small Cell Lung Cancer	NCT02142738	Previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and without EGFR or ALK mutations	Paclitaxel; carboplatin; pemetrexed; cisplatin; gemcitabine; pembrolizumab	(I) PFS was 10.3 months in the pembrolizumab group versus 6.0 months in the chemotherapy group. (II) OS at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group. (III) The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%). (IV) Treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%)
An Open-Label, Randomized Phase 3 Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum Doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Subjects With Chemotherapy-Naïve Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)	NCT02477826	Patients with stage IV or recurrent NSCLC that was not previously treated	Nivolumab; ipilimumab; carboplatin; cisplatin; gemcitabine; pemetrexed; paclitaxel	(I) The 1-year PFS rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median PFS was 7.2 months versus 5.5 months. (II) The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. (III) The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy
An Open-Label Randomized Phase III Trial of BMS-936558 (Nivolumab) Versus Docetaxel in Previously Treated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC)	NCT01673867	Patients with nonsquamous NSCLC that had progressed during or after platinum-based doublet chemotherapy	Nivolumab; docetaxel	(I) The OS was 12.2 months in the nivolumab group and 9.4 months in the docetaxel group. At 1 year, the OS rate was 51% with nivolumab versus 39% with docetaxel. OS rate at 18 months was 39% with nivolumab versus 23% with docetaxel. (II) The response rate was 19% with nivolumab versus 12% with docetaxel. (III) The rate of PFS at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). (IV) Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.
A Phase II/III Randomized Trial of Two Doses of MK-3475 (SCH900475) Versus Docetaxel in Previously Treated Subjects With Non-Small Cell Lung Cancer	NCT01905657	Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells	Pembrolizumab; docetaxel	(I) OS was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. (II) PFS was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel (III) Among patients with at least 50% of tumour cells expressing PD-L1, OS was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (14.9 vs. 8.2 months) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 vs. 8.2 months). PFS was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (5.0 vs. 4.1 months) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 vs. 4.1 months) (IV) Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (13% of the patients given 2 mg/kg, 16% of given 10 mg/kg, and 35% of 309 given docetaxel)
A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab (MK-3475) Versus Platinum Based Chemotherapy in Treatment Naïve Subjects With PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer (Keynote 042)-China Extension Study	NCT03850444	Chinese participants with PD-L1-positive NSCLC	Pembrolizumab; carboplatin; paclitaxel; pemetrexed	(I) OS (TPS of ≥50%)was 20.0 months in the pembrolizumab group and 14.0 months in the Chemotherapy group. OS (TPS of ≥20%) was 20.0 months in the pembrolizumab group and 13.7 months in the Chemotherapy group. OS (TPS of ≥1%) was 20.0 months in the pembrolizumab group and 13.7 months in the Chemotherapy group. (II) PFS (TPS of ≥50%) was 8.3 months in the pembrolizumab group and 6.5 months in the Chemotherapy group. PFS (TPS of ≥20%) was 6.3 months in the pembrolizumab group and 6.5 months in the Chemotherapy group. PFS (TPS of ≥1%) was 6.3 months in the pembrolizumab group and 6.4 months in the Chemotherapy group
A Randomized, Double-Blind, Phase III Study of Platinum + Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-189)	NCT03950674	Adult Japanese participants with advanced or metastatic nonsquamous NSCLC who have not previously received systemic therapy for advanced disease	Dexamethasone; cisplatin; carboplatin; pemetrexed	(I) PFS was 16.5 months in the pembrolizumab group and 7.1 months in the Chemotherapy group. (II) ORR was 56% in the pembrolizumab group and 33.3% in the Chemotherapy group
An Open-label Randomized Multinational Phase 3 Trial of Nivolumab Versus Docetaxel in Previously Treated Subjects With Advanced or Metastatic Non-small Cell Lung Cancer (CheckMate 078: CHECK point Pathway and nivoluMAb Clinical Trial Evaluation 078)	NCT02613507	Advanced or Metastatic NSCLC who have failed prior platinum-based doublet chemotherapy	Nivolumab; docetaxel	(I) OS was 11.99 months in the Nivolumab group and 9.63 months in the Docetaxel group. (II) ORR was 16.6% in the Nivolumab group and 4.2% in the Docetaxel group
A Phase 3, Randomized Study of Nivolumab Plus Ipilimumab in Combination With Chemotherapy vs. Chemotherapy Alone as First Line Therapy in Stage IV Non-Small Cell Lung Cancer	NCT03215706	Stage IV NSCLC have not previously received systemic therapy	Ipilimumab; Nivolumab; Carboplatin; Paclitaxel; Pemetrexed; Cisplatin	(I) OS was 14.13 months in the Nivolumab + Ipilimumab + Chemotherapy group and 10.74 months in the Chemotherapy group. (II) PFS was 6.83 months in the Nivolumab + Ipilimumab + Chemotherapy group and 4.96 months in the Chemotherapy group. (III) ORR was 37.7% in the Nivolumab + Ipilimumab + Chemotherapy group and 25.1% in the Chemotherapy group
An Open-Label, Randomized, Phase 3 Trial of Nivolumab Versus Investigator's Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer	NCT02041533	Stage IV or Recurrent PD-L1⁺ NSCLC	Nivolumab; Gemcitabine; Cisplatin; Carboplatin; Paclitaxel; Pemetrexed	(I) PFS was 4.21 months in the Nivolumab group and 5.82 months in the Chemotherapy group. PFS (TPS of ≥5%) was 4.21 months in the Nivolumab group and 5.88 months in the Chemotherapy group. (II) OS was 13.73 months in the pembrolizumab group and 13.80 months in the Chemotherapy group. OS (TPS of ≥5%) was 14.36 months in the pembrolizumab group and 13.21 months in the Chemotherapy group
A Dose Frequency Optimization, Phase IIIB/IV Trial of Nivolumab 240 mg Every 2 Weeks vs. Nivolumab 480 mg Every 4 Weeks in Subjects With Advanced or Metastatic Non-small Cell Lung Cancer Who Received up to 12 Months of Nivolumab at 3 mg/kg or 240 mg Every 2 Weeks	NCT02713867	Advanced/metastatic (Stage IIIb/IV) NSCLC	Nivolumab	(I) PFSR at 6 months was 0.76 in the Nivolumab 480mg Q4W group and 0.79 in the Nivolumab 240 mg Q2W group. (II) OS was at 6 months 0.966 of 180 patients in the Nivolumab 480 mg Q4W group and 0.956 183 patients in the Nivolumab 240 mg Q2W group

Table S1. The ongoing trials of neoadjuvant immunotherapy
Study title	NCT.no	Key inclusion and exclusion criteria	Drug	Control group	Primary and secondary endpoint
A Single-arm, Phase II Study of Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in Resectable Non-small Cell Lung Cancer (NSCLC)	NCT02716038	Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an ECOG performance status of 0–1, and a history of smoking exposure	Atezolizumab; carboplatin; nab-paclitaxel	Carboplatin + nab-paclitaxel	The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery
Randomized, Open-label, Controlled Phase III Trial Comparing Pembrolizumab-platinum Based Chemotherapy Combination With Pembrolizumab Monotherapy in First Line Treatment of Non-small-cell Lung Cancers (NSCLC) With PDL1 Expression ≥50%	NCT04547504	Advanced NSCLC molecularly defined by a PDL1 expression ≥50% of tumour cells and no EGFR mutations or ALK rearrangement	Pembrolizumab; cisplatin; carboplatin AUC	Pembrolizumab alone	The primary endpoint was PFS. The secondary endpoints were PFS, iPFS, ORR, OS, DOT, DOR, AE and AESI
A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) in Participants With Treatment-naïve, Metastatic Non-small Cell Lung Cancer (NSCLC) Whose Tumors Have a Tumor Proportion Score (TPS) Greater Than or Equal to 1% (LEAP-007)-China Extension Study	NCT04676412	No prior systemic therapy for their metastatic NSCLC whose tumors has a PD-L1 TPS ≥1%	Lenvatinib; pembrolizumab	Pembrolizumab + placebo	The primary endpoints were PFS and OS. The secondary endpoints were ORR, AE, GHS, QoL, EORTC and TTD
A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) in Participants With Treatment-naïve, Metastatic Non-small Cell Lung Cancer (NSCLC) Whose Tumors Have a Tumor Proportion Score (TPS) Greater Than or Equal to 1% (LEAP-007)	NCT03829332	No prior systemic therapy for their metastatic NSCLC whose tumors has a PD-L1 TPS ≥1%	Lenvatinib; pembrolizumab	Pembrolizumab + placebo	The primary endpoints were PFS and OS. The secondary endpoints were ORR, AE, GHS, QoL, EORTC and TTD
A Randomized, Phase 3 Trial With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo for Patients With Early Stage NSCLC After Resection and Completion of Standard Adjuvant Therapy (PEARLS)	NCT02504372	Stage IB/II–IIIA NSCLC who have undergone surgical resection	Pembrolizumab	Placebo	The primary endpoint was DFS. The secondary endpoints were OS and LCSS
A Phase 3, Randomized, Placebo-Controlled Clinical Study to Evaluate the Safety and Efficacy of Stereotactic Body Radiotherapy (SBRT) With or Without Pembrolizumab (MK-3475) in Participants With Medically Inoperable Stages I or IIA Non Small Cell Lung Cancer (NSCLC) (KEYNOTE-867)	NCT03924869	Medically inoperable Stage I or IIA NSCLC	Pembrolizumab; SBRT	SBRT + placebo	The primary endpoints were EFS and OS. The secondary endpoints were TDDM, AE and EORTC QLQ-LC13/-C30 SCORE
A Phase 3, Multicenter, Randomized, Open-label Trial to Compare the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Lenvatinib (E7080/MK-7902) Versus Docetaxel in Previously Treated Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) and Progressive Disease (PD) After Platinum Doublet Chemotherapy and Immunotherapy (LEAP-008)	NCT03976375	Metastatic NSCLC and progressive disease (PD) after platinum doublet chemotherapy and treatment with one prior anti-PD-1/PD-L1	Pembrolizumab; lenvatinib; docetaxel	Docetaxel	The primary endpoints were OS and PFS. The secondary endpoints were ORR, DOR, AE, EORTC QLQ-LC13/-C30 SCORE and TTD in EORTC QLQ-LC13 Cough (Item 31) Scale Score
A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)	NCT03515837	Adults with the following types of TKI-resistant, EGFR-mutated, metastatic NSCLC tumors: (I) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, (II) T790M-positive mutation tumors with prior exposure to osimertinib, and (III) first-line osimertinib failure regardless of T790M mutation status	Pembrolizumab; pemetrexed; carboplatin; cisplatin	Placebo + pemetrexed + carboplatin+ cisplatin	The primary endpoints were OS and PFS. The secondary endpoints were ORR, DOR, AE, EORTC QLQ-LC13/-C30 SCORE and TTD in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea
An Adaptive Phase III, Multicenter, Randomized, Open-Label, Controlled Study of M7824 (Bintrafusp Alfa) Versus Pembrolizumab as a First-line Treatment in Patients With PD-L1 Expressing Advanced Non-small Cell Lung Cancer	NCT03631706	Advanced NSCLC with high PD-L1-tumor expression, with no EGFR mutation or ALK translocation	M7824; pembrolizumab	Pembrolizumab	The primary endpoints were OS and PFS. The secondary endpoint were TEAEs, NCI-CTCAE, CR, PR and Immunogenicity
A Phase III, Randomized, Double-blind Trial of Platinum Doublet Chemotherapy +/-Pembrolizumab (MK-3475) as Neoadjuvant/Adjuvant Therapy for Participants With Resectable Stage II, IIIA, and Resectable IIIB (T3–4N2) Non-small Cell Lung Cancer (NSCLC) (KEYNOTE-671)	NCT03425643	Resectable stage II, IIIA, and resectable IIIB (T3-4N2) NSCLC	Pembrolizumab; cisplatin; gemcitabine; pemetrexed	NAC + neoadjuvant/adjuvant placebo	The primary endpoints were EFS and OS. The secondary endpoints were mPR rate, pCR rate, AE and EGHS/QoL SCORE
A Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Pembrolizumab Plus Platinum-based Doublet Chemotherapy With or Without Canakinumab as First Line Therapy for Locally Advanced or Metastatic Non-squamous and Squamous Non-small Cell Lung Cancer Subjects (CANOPY-1)	NCT03631199	Previously untreated locally advanced or metastatic non-squamous and squamous NSCLC subjects	Canakinumab; pembrolizumab; carboplatin; cisplatin; paclitaxel; nab-paclitaxel; pemetrexed	Canakinumab matching-placebo	The primary endpoint were DLTs, PFS and OS. The secondary endpoints were ORR, DCR, DOR and TTR
A Phase 3 Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) as First-line Intervention in Participants With Metastatic Nonsquamous Non-small Cell Lung Cancer (LEAP-006)	NCT03829319	Adults with metastatic nonsquamous NSCLC	Pembrolizumab; carboplatin; cisplatin; pemetrexed; lenvatinib	Pemetrexed + platinum chemotherapy + pembrolizumab + placebo	The primary endpoints were DLTs, AES, PFS and OS. The secondary endpoints were ORR, DOR and EORTC QLQ-LC13/-C30 SCORE
LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy With or Without Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer	NCT04194944	Participants with RET fusion-positive non-squamous NSCLC that has spread to other parts of the body	Selpercatinib; carboplatin; cisplatin; pemetrexed; pembrolizumab	Pemetrexed with or without pembrolizumab	The primary endpoint was PFS. The secondary endpoints were ORR, DCR, PFS, OS, DOR and Time to Deterioration of Pulmonary Symptoms
A Randomized, Double-Blind, Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)	NCT03875092	Chinese adults with first line metastatic squamous NSCLC	Pembrolizumab; paclitaxel; nab-paclitaxel; carboplatin	Chemotherapy	The primary endpoints were PFS and OS. The secondary endpoints were ORR, DOR and AE
A Phase 3 Study of Pembrolizumab in Combination With Carboplatin/Taxane (Paclitaxel or Nab-paclitaxel) Followed by Pembrolizumab With or Without Maintenance Olaparib in the First-line Treatment of Metastatic Squamous Non-small Cell Lung Cancer (NSCLC)	NCT03976362	Have not received prior systemic treatment for their advanced/metastatic NSCLC	Pembrolizumab; carboplatin; paclitaxel; nab-paclitaxel; olaparib	Pembrolizumab + carboplatin + taxane + olaparib placebo	The primary endpoints were PFS and OS. The secondary endpoints were AE, EORTC QLQ-C30/LC13 score and TTD in EORTC QLQ-C30/LC13
PD-1 Inhibitors and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer	NCT03774732	Patients with advanced (stage IIIB/IV) NSCLC	Radiotherapy; pembrolizumab; chemotherapy	Pembrolizumab + chemotherapy	The primary endpoint was OS. The secondary endpoints were Tumour response, PFS, Acute/Late toxicities and Quality of life of the patients using EORTC-QLQ-C30
A Phase 3 Study of Pembrolizumab (MK-3475) in Combination With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib vs. Concurrent Chemoradiation Therapy Followed by Durvalumab in Participants With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer (NSCLC)	NCT04380636	Participants with unresectable, locally advanced NSCLC	Pembrolizumab; olaparib; etoposide; carboplatin; cisplatin; paclitaxel; pemetrexed; thoracic radiotherapy; durvalumab	Chemoradiation→durvalumab	The primary endpoints were PFS and OS. The secondary endpoints were AE, DOR, ORR and EORTC-QLQ-C30 score
A Phase 3 Study of Pembrolizumab in Combination With Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by Pembrolizumab and Maintenance Olaparib vs. Maintenance Pemetrexed in the First-Line Treatment of Participants With Metastatic Nonsquamous Non-Small-Cell Lung Cancer	NCT03976323	Advanced NSCLC with no EGFR mutation, ALK translocation or ROS1-directed therapy	Pembrolizumab; pemetrexed; carboplatin; cisplatin; olaparib	Pembrolizumab + pemetrexed + platinum therapy + pemetrexed	The primary endpoints were PFS and OS. The secondary endpoints were AE, EORTC-QLQ-C30 score and TTD in EORTC QLQ-LC13 Cough (Item 31) Scale Score
A Randomized Trial of Consolidative Immunotherapy With vs. Without Thoracic Radiotherapy and/or Stereotactic Body Radiation Therapy (SBRT) After First-Line Systemic Therapy for Metastatic NSCLC	NCT03867175	Stage IV NSCLC with no EGFR mutation, ROS1 or ALK gene rearrangements	Stereotactic body radiation therapy; pembrolizumab	Body radiation therapy	The primary endpoint was PFS. The secondary endpoints were Time of Progression, AE, Rate of Failure and Number of Participants with New Sites of Disease
A Randomized, Phase 3, Open-Label Study of Combinations of REGN2810 (Anti-PD-1 Antibody), Platinum-based Doublet Chemotherapy, and Ipilimumab (Anti-CTLA-4 Antibody) Versus Pembrolizumab Monotherapy in First-Line Treatment of Patients With Advanced or Metastatic Non-Small Cell Lung Cancer With Tumors Expressing PD-L1 ≥50%	NCT03515629	Patients with advanced squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor cells	REGN2810/ipi; REGN2810/chemo/ipi; Pembrolizumab	Pembrolizumab	The primary endpoint was PFS. The secondary endpoints were OS, ORR, TEAEs, SAEs, DLTs and Quality of life
QUILT 2.023: A Phase 3, Open-Label, 3-Cohort Randomized Study of N-803, in Combination With Current Standard of Care vs. Standard of Care as First-Line Treatment for Patients With Advanced or Metastatic NSCLC.	NCT03520686	Stage III/IV advanced or metastatic NSCLC	N-803; pembrolizumab; carboplatin; nab-paclitaxel	Control A: pembrolizumab; Control B: carboplatin + nab-paclitaxel or paclitaxel + pembrolizumab; control c: cisplatin or carboplatin + pembrolizumab + pemetrexed	The primary endpoint was PFS. The secondary endpoints were OS, ORR, PFS, DCR and Quality of life
A Randomized, Open-Label, Phase 3 Study of Pralsetinib Versus Standard of Care for First Line Treatment of RET Fusion-positive, Metastatic Non-Small Cell Lung Cancer	NCT04222972	Patients with RET fusion-positive metastatic NSCLC who have not previously received systemic anticancer therapy for metastatic disease	Pralsetinib; carboplatin; cisplatin; pemetrexed; pembrolizumab; gemcitabine	Platinum doublet with or without pembrolizumab	The primary endpoint was PFS. The secondary endpoints were OS, ORR, AE, DCR and CBR
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants Whose Disease Has Remained Stable or Responded to First-Line Platinum Based Chemotherapy With Pembrolizumab for Stage IIIB or IV Non-Small Cell Lung Cancer	NCT04475939	Participants with Stage IIIB or IV NSCLC who have achieved Stable disease (SD), Partial response (PR), or complete response (CR) following completion of platinum-based first-line induction chemotherapy with pembrolizumab	Niraparib; pembrolizumab	Placebo + pembrolizumab	The primary endpoints were PFS and OS. The secondary endpoints were AE, TTD in Lung Symptoms and TPP
A Randomized Non-inferiority Trial Evaluating the Length of Treatment With PD-1/PD-L1 Inhibitors in Patients With Advanced Solid Tumors	NCT04157985	Patients who have disease stability to stop treatment at 1 year or continue treatment until disease progression	Pembrolizumab; nivolumab; atezolizumab; ipilimumab	Continue Treatment with PD-1/PD-L1 inhibitor	The primary endpoint was Time to next treatment. The secondary endpoints were OS, irAEs and BOR
An Open-label, Randomized Phase III Study of Early Switch Maintenance vs. DElayed Second-line Nivolumab in Advanced Stage Squamous Non Small-cell Lung Cancer (NSCLC) Patients After Standard First-line Platinum-based Chemotherapy - EDEN Trial	NCT03542461	Patients with advanced stage squamous NSCLC without immunotherapy	Nivolumab	Best supportive care	The primary endpoint was OS. The secondary endpoints were PFS, TTF, OSind and PFSind
A Phase 3, Randomized, Open Label Study to Compare Nivolumab Plus Concurrent Chemoradiotherapy (CCRT) Followed by Nivolumab Plus Ipilimumab or Nivolumab Plus CCRT Followed by Nivolumab vs. CCRT Followed by Durvalumab in Previously Untreated, Locally Advanced Non-small Cell Lung Cancer (LA NSCLC)	NCT04026412	Participants with untreated locally advanced NSCLC	Nivolumab; ipilimumab; durvalumab	Nivolumab/durvalumab + CCRT	The primary endpoints were PFS and OS. The secondary endpoints were AE, ORR and TTR
A Phase IIIb/IV Safety Trial of Nivolumab (BMS-936558) in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed During or After Receiving At Least One Prior Systemic Regimen	NCT02066636	Advanced or metastatic NSCLC (subjects with non-squamous histology must be tested for EGFR mutations and ALK rearrangement)	Nivolumab		The primary endpoint was AEs. The secondary endpoint were AEs and Median time to onset and median time to resolution
An Open-Label, Randomized Phase 3 Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum Doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Subjects With Chemotherapy-Naïve Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)	NCT02477826	Stage IV or recurrent NSCLC, with no prior systemic anticancer therapy	Nivolumab; ipilimumab; carboplatin; cisplatin; gemcitabine; pemetrexed; paclitaxel	Platinum doublet chemotherapy	The primary endpoints were PFS and OS. The secondary endpoints were ORR and LCSS
Open-Label, Randomized Trial of Nivolumab (BMS-936558) Plus Pemetrexed/Platinum or Nivolumab Plus Ipilimumab (BMS-734016) vs. Pemetrexed Plus Platinum in Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Subjects With Epidermal Growth Factor Receptor (EGFR) Mutation Who Failed 1L or 2L EGFR Tyrosine Kinase Inhibitor Therapy	NCT02864251	Patients with EGFR mutation, NSCLC who failed first line (1L) or second-line (2L) EGFR TKI therapy	Nivolumab; ipilimumab; pemetrexed; cisplatin; carboplatin	Platinum doublet chemotherapy	The primary endpoint was PFS. The secondary endpoints were PFS, ORR, OS and DOR
Randomized, OpenLabel, Phase 3 Trial of Nivolumab Plus Ipilimumab or Nivolumab Plus Platinum Doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Early Stage NSCLC	NCT02998528	Early stage IB-IIIA, operable NSCLC	Nivolumab; cisplatin; vinorelbine; gemcitabine; docetaxel; pemetrexed; carboplatin; paclitaxel; ipilimumab	Platinum doublet chemotherapy	The primary endpoints were EFS and pCR. The secondary endpoints were OS, MPR and TTDM
An Open-Label Randomized Phase III Trial of BMS-936558 (Nivolumab) Versus Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC)	NCT01642004	Subjects with squamous cell NSCLC, after failure of prior platinum-based chemotherapy	Nivolumab; docetaxel	Docetaxel	The primary endpoint was OS. The secondary endpoints were PFS, ORR, OS and TTR
Randomized Phase III Study Testing Nivolumab and Ipilimumab Versus a Carboplatin Based Doublet in First Line Treatment of PS 2 or Elderly (More Than 70 Years Old) Patients With Advanced Non-small Cell Lung Cancer	NCT03351361	Patients already have metastatic disease and a systemic, palliative treatment is the primary therapeutic option	Nivolumab; ipilimumab; chemotherapy	Chemotherapy	The primary endpoint was OS. The secondary endpoints were PFS, ORR, Quality of life score and PD-L1
An Open Label, Safety Study of Participants With Non-Small Cell Lung Cancer Receiving Second-Line Nivolumab Monotherapy in Asia	NCT03195491	Patients in Asia with NSCLC who are treated with Nivolumab monotherapy as a second line or third line treatment	Nivolumab		The primary endpoint was AE. The secondary endpoints were AE and Laboratory test abnormalities
A Randomized Phase 3 Study of Sitravatinib in Combination With Nivolumab Versus Docetaxel in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer With Disease Progression On or After Platinum-Based Chemotherapy and Checkpoint Inhibitor Therapy SAPPHIRE	NCT03906071	Patients with advanced non-squamous NSCLC who have previously experienced disease progression on or after platinum-based chemotherapy and checkpoint inhibitor therapy	Nivolumab; sitravatinib; docetaxel	Docetaxel	The primary endpoint was OS. The secondary endpoints were AEs, PFS and ORR
A Randomized Phase 3 Trial Comparing Continuation Nivolumab-Ipilimumab Doublet Immunotherapy Until Progression Versus Observation in Treatment-naive Patients With PDL1-positive Stage IV Non-Small Cell Lung Cancer (NSCLC) After Nivolumab-Ipilimumab Induction Treatment	NCT03469960	Stage IV NSCLC, with no prior systemic anticancer therapy, PD-L1 tumor content ≥1% and <50%	Ipilimumab; nivolumab	Standard treatment:6 months of treatment by nivolumab + ipilimumab then nivolumab + ipilimumab then in case of progression platinum-based doublet recommended	The primary endpoint was PFS. The secondary endpoints were OS, PFS and Quality of life
Adjuvant Nivolumab in Resected Lung Cancers (ANVIL) - A Randomized Phase III Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-Small Cell Lung Cancers	NCT02595944	Patients with stage IB–IIIA NSCLC	Nivolumab	No intervention	The primary endpoints were DFS and OS. The secondary endpoint was AE
Randomized Phase III Trial of Local Consolidation Therapy (LCT) After Nivolumab and Ipilimumab for Immunotherapy-Naive Patients With Metastatic Non-Small Cell Lung Cancer (LONESTAR) -Strategic Alliance: BMS	NCT03391869	Patients with stage IV NSCLC	Radiation therapy; local consolidation therapy; nivolumab; ipilimumab	Ipilimumab + nivolumab	The primary endpoint was OS. The secondary endpoints were PFS, TANM and Quality of life
A Phase III Clinical Trial of Adjuvant Chemotherapy vs. Chemoimmunotherapy for Stage IB-IIIA Completely Resected Non-small Cell Lung Cancer (NSCLC) Patients.	NCT04564157	Stage IB–IIIA, completely resected, NSCLC patients	Carboplatin; paclitaxel; nivolumab	Carboplatin + paclitaxel	The primary endpoint was DFS. The secondary endpoints were OS and AE
A Phase 3, Randomized, Double-blind Study of Neoadjuvant Chemotherapy Plus Nivolumab Versus Neoadjuvant Chemotherapy Plus Placebo, Followed by Surgical Resection and Adjuvant Treatment With Nivolumab or Placebo for Participants With Resectable Stage II-IIIB Non-small Cell Lung Cancer	NCT04025879	Early-stage NSCLC with no prior systemic anti-cancer treatment	Nivolumab; carboplatin; cisplatin; paclitaxel; pemetrexed; docetaxel	Neoadj. Plac. + Pt-based doublet chemo followed by Adj.Plac.	The primary endpoint was EFS. The secondary endpoints were OS, pCR, MPR and AE
A Multicenter, Randomized, Double-Blind Trial in Subjects With Non-Squamous Non-Small Cell Lung Cancer (TASUKI-52)	NCT03117049	Stage IIIB/IV or recurrent non-squamous NSCLC unsuitable for radical radiation	ONO-4538; carboplatin; paclitaxel; bevacizumab	Placebo group	The primary endpoint was PFS. The secondary endpoints were OS, PFS, ORR and AE

Authors and Disclosures

Wenhua Liang¹, Kaican Cai², Chun Chen³, Haiquan Chen⁴, Qixun Chen⁵, Junke Fu⁶, Jian Hu⁷, Tao Jiang⁸, Wenjie Jiao⁹, Shuben Li¹, Changhong Liu¹⁰, Deruo Liu¹¹, Wei Liu¹², Yang Liu¹³, Haitao Ma¹⁴, Xiaojie Pan¹⁵, Guibin Qiao¹⁶, Hui Tian¹⁷, Li Wei¹⁸, Yi Zhang¹⁹, Song Zhao²⁰, Xiaojing Zhao²¹, Chengzhi Zhou¹, Yuming Zhu²², Ran Zhong¹, Feng Li¹, Rafael Rosell²³, Mariano Provencio²⁴, Erminia Massarelli²⁵, Mara B. Antonoff²⁶, Toyoaki Hida²⁷, Marc de Perrot²⁸, Steven H. Lin²⁹, Massimo Di Maio³⁰, Antonio Rossi³¹, Dirk De Ruysscher³², Robert A. Ramirez³³, Wolfram C. M. Dempke³⁴, D. Ross Camidge³⁵, Nicolas Guibert³⁶, Raffaele Califano³⁷, Qi Wang³⁸, Shengxiang Ren³⁹, Caicun Zhou³⁹ and Jianxing He¹

¹Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, Guangzhou, China; ²Nanfang Hospital, Guangzhou, China; ³Fujian Medical University Union Hospital, Fuzhou, China; ⁴Fundan University Shanghai Cancer Center, Shanghai, China; ⁵Zhejiang Cancer Hospital, Hangzhou, China; ⁶The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; ⁷The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China; ⁸Tangdu Hospital, Xi'an, China; ⁹The Affiliated Hospital of Qingdao University, Qingdao, China; ¹⁰The Second Hospital of Dalian Medical University, Dalian, China; ¹¹China-Japan Friendship Hospital, Beijing, China; ¹²The First Bethune Hospital of Jilin University, Changchun, China; ¹³Chinese PLA General Hospital, Beijing, China; ¹⁴The Affiliated Hospital of Soochow University, Suzhou, China; ¹⁵Fujian Provincial Hospital, Fuzhou, China; ¹⁶Guangdong Provincial People's Hospital, Guangzhou, China; ¹⁷Qilu Hospital of Shandong University, Ji'nan, China; ¹⁸Henan Provincial People's Hospital, Zhengzhou, China; ¹⁹Xuanwu Hospital Capital Medical University, Beijing, China; ²⁰The Affiliated Hospital of Zhengzhou University, Zhengzhou, China; ²¹Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; ²²Shanghai Pulmonary Hospital, Shanghai, China; ²³Department of Medical Oncology, University of Barcelona, Hospital de Badalona Germans Trias i Pujol, Barcelona, Spain; ²⁴Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain; ²⁵City of Hope National Cancer Center, Duarte, CA, USA; ²⁶Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA; ²⁷Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; ²⁸Toronto Mesothelioma Research Program, Toronto General Hospital, Toronto, ON, Canada; ²⁹Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; ³⁰Department of Oncology, University of Turin/Division of Medical Oncology, Ordine Mauriziano Hospital, Turin, Italy; ³¹Oncology Center of Excellence, Therapeutic Science & Strategy Unit, IQVIA, Milan, Italy; ³²Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; ³³Department of Internal Medicine, Section of Hematology/Oncology, Ochsner Medical Center, Kenner, LA, USA; ³⁴Department of Hematology and Oncology, University Medical School, Munich, Germany; ³⁵Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ³⁶Thoracic Oncology Department, Larrey Hospital, University Hospital of Toulouse, Toulouse, France; ³⁷Department of Medical Oncology, The Christie NHS Foundation Trust, and Division of Cancer Sciences, The University of Manchester, Manchester, UK; ³⁸Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China; ³⁹Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

Correspondence to
Jianxing He. National Center for Respiratory Medicine, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Email: drjianxing.he@gmail.com.

Conflicts of Interest
All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-2020-63). The authors have no conflicts of interest to declare. The authors have no conflicts of interest to declare.