Neoadjuvant Immunotherapy or Chemoimmunotherapy in Non-Small Cell Lung Cancer

A Systematic Review and Meta-Analysis

Juan Jiang; Yuling Wang; Yang Gao; Haruhiko Sugimura; Fabrizio Minervini; Junji Uchino; Balazs Halmos; Sai Yendamuri; Jeffrey B. Velotta; Min Li

Disclosures

Transl Lung Cancer Res. 2022;11(2):277-294.

Abstract and Introduction

Abstract

Background: In recent years, a series of clinical trials have explored the application of neoadjuvant immunotherapy or chemoimmunotherapy in non-small cell lung cancer (NSCLC). However, no randomized control trials comparing neoadjuvant immunotherapy with chemoimmunotherapy have yet been reported. This study aimed to summarize and compare the efficacy and safety of neoadjuvant immunotherapy and chemoimmunotherapy in NSCLC.

Methods: Literature focusing on the efficacy and safety of neoadjuvant immunotherapy or chemoimmunotherapy in NSCLC published before June 2021 was retrieved from PubMed, Embase, and the Cochrane Library. Study endpoints included major pathological response (MPR), complete pathological response (pCR), treatment-related adverse events (TRAEs), severe adverse events (SAEs), resection rate, surgical delay rate, and conversion to thoracotomy. The risk of bias was assessed using the Cochrane bias risk assessment tool. Subgroup and sensitivity analyses were further performed.

Results: A total of 988 patients from 16 studies were included in this meta-analysis. For patients who received neoadjuvant immunotherapy with single/combined ICIs or chemoimmunotherapy, the pooled MPR rate was 43.5% and the pooled pCR rate was 21.9%. The pooled incidence of TRAEs and SAEs were 54.8% and 15.3%, respectively. The pooled resection rate was 85.8%, the surgical delay rate was 7.4%, and the conversion rate was 17.4%. Patients who received neoadjuvant chemoimmunotherapy had remarkably improved pathological response (MPR rate: 53.3% vs. 28.6%; pCR rate: 28.6% vs. 9.9%) compared with those receiving neoadjuvant single-agent immunotherapy, while the incidence of SAEs (18.0% vs. 12.3%) and surgical delay rate (3.8% vs. 7.4%) did not significantly increase. Neoadjuvant nivolumab combined with ipilimumab also achieved a high pCR rate (28.6%) with tolerable toxicity. Nivolumab- and pembrolizumab-based neoadjuvant therapy showed a higher MPR rate (nivolumab 51.5%, pembrolizumab 46.8%) and pCR rate (nivolumab 29.1%, pembrolizumab 31.5%). Besides, patients with positive programmed death-ligand 1 (PD-L1) expression [tumor proportion score (TPS) ≥1%] exhibited favorable pathological responses than PD-L1 negative patients.

Discussion: Overall, neoadjuvant immunotherapy or chemoimmunotherapy is effective and safe in NSCLC. Compared with single-agent immunotherapy, neoadjuvant chemoimmunotherapy provides a significant improvement in pathological response without increasing the incidence of SAEs or surgical delay. These results need further confirmation by more large-scale randomized controlled trials.

Introduction

According to the 2020 global cancer statistics, non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers worldwide and remains the leading cause of cancer deaths.^[1] Approximately 70% of NSCLC patients are diagnosed at an advanced stage, leading to a 5-year survival rate less than 18% even after comprehensive treatment.^[2] Over the past decades, the early detection of NSCLC has gradually increased with the wider adoption of chest low-dose CT as a screening modality.^[3] For patients diagnosed with stages I, II, and selected stage III NSCLC, surgical resection with curative intent is considered to be the best treatment option. However, only 20–25% of tumors overall are suitable for potential curative resection. Moreover, these patients have a high risk of postoperative recurrence, ranging from 25% to 70% based on the disease stage.^[4]

Neoadjuvant therapy, defined as systemic anticancer treatment given before surgery, is an accepted practice in NSCLC.^[5] Compared with adjuvant therapy, neoadjuvant therapy has potential advantages including early treatment of micrometastasis, reducing tumor burden before surgery, and better tolerability.^[6,7] Pathological remission, including major pathological response (MPR) and complete pathological response (pCR), is currently used as a surrogate endpoint to predict survival benefit in clinical trials focusing on neoadjuvant chemotherapy.^[8] A meta-analysis conducted by the NSCLC Meta-analysis Collaborative Group involving 15 randomized clinical trials in patients with stages IB–IIIA disease has demonstrated that compared with surgery alone, preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC.^[9] However, the median rate of pCR from 15 trials of neoadjuvant chemotherapy was only 4% (range, 0–16%), which suggests that more effective neoadjuvant therapy modalities are required to further improve prognosis.^[10]

Immunotherapy with immune checkpoint inhibitors (ICIs), which boost antitumor immunity by blocking inhibitory signaling through checkpoint receptors expressed on T lymphocytes and their ligands expressed in tumor cells, has revolutionized the treatment of various cancers, including NSCLC.^[4,11] In recent years, the use of ICIs for the treatment of NSCLC has considerably increased. Monoclonal antibodies that target the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis have been approved as first- and second-line treatments for advanced NSCLC worldwide.^[12] So far, several clinical trials have reported the efficacy and safety of neoadjuvant immunotherapy^[13–18] or chemoimmunotherapy^[19–28] in stages I–III NSCLC. Investigational ICIs included PD-1/PD-L1 inhibitors such as nivolumab,^{[13,18,25,27,28]} pembrolizumab,^[16,20] sintilimab,^[15] durvalumab,^[26] atezolizumab,^[14,19] avelumab,^[23] and a CTLA-4 inhibitor ipilimumab.^[24] In NSCLC patients who receive preoperative immunotherapy, the naive tumor can serve as a "vaccine" boosting the activation of T lymphocytes.^[29] Based on available research data from previous studies, patients who received neoadjuvant immunotherapy or chemoimmunotherapy before surgery had improved pathological response and downstaging of the tumor compared to those who received neoadjuvant chemotherapy. However, most of these studies are single-armed trials with small sample sizes. On the other hand, while neoadjuvant immunotherapy or chemoimmunotherapy offers numerous advantages, immune-related adverse events (irAEs) have attracted significant attention.^[30,31] The occurrence of severe irAEs can lead to delayed surgical resection or even death. Moreover, increasing complexity of the surgical field in the chest, which is caused by fibrosis and nodal flares, has been observed in patients receiving neoadjuvant immunotherapy, even with tumor downstaging.^[13] So far, no data from randomized controlled trials on neoadjuvant immunotherapy and chemoimmunotherapy have been reported. Therefore, in order to improve the knowledge of and compare the clinical benefits between neoadjuvant immunotherapy and chemoimmunotherapy in NSCLC, a meta-analysis on their efficacy and safety, based on current data from clinical trials, is necessary.

Herein, we conducted a systematic review and meta-analysis of clinical trials focusing on neoadjuvant immunotherapy or chemoimmunotherapy in NSCLC. We analyzed efficacy- and safety-related endpoints including MPR, pCR, incidence of treatment-related adverse events (TRAEs) and severe adverse events (SAEs), resection rate, surgical delay rate, and conversion rate in resectable stages I–III NSCLC patients who received neoadjuvant immunotherapy or chemoimmunotherapy. We further compared these endpoints among different treatment modes and ICI types, and summarized the profiles of TRAEs and SAEs. This meta-analysis was conducted and reported in accordance with the PRISMA reporting checklist^[32] (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-75/rc).

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Study characteristics and patient demographics
Treatment mode	First author	Publication year	Clinical trial	NCT number	Study phase	Study design	Main inclusion criteria	Neoadjuvant treatment regimen	Sample size	Proportion of males (%)	Median age, years	Proportion of SCC (%)
ICI + chemo	Forde PM (25)	2021	CheckMate 816	NCT02998528	3	Multicenter, randomized	Stage IB–IIIA resectable NSCLC	Nivolumab + chemotherapy	179	72	64	49
ICI + chemo	Zinner R (27)	2020	–	NCT03366766	2	Single center, single-arm	Stage I–IIIA NSCLC	Nivolumab + pemetrexed/gemcitabine + cisplatin	13	62	65	38
ICI + chemo	Rothschild SI (26)	2021	SAKK 16/14	NCT02572843	2	Multicenter, single-arm	Resectable IIIA (N2) NSCLC	Chemotherapy with cisplatin/docetaxel followed by durvalumab	68	–	–	–
ICI + chemo	Provencio M (28)	2020	NADIM	NCT03081689	2	Multicenter, single-arm	Stage IIIA, N2- resectable NSCLC	3 cycles of nivolumab + paclitaxel + carboplatin	46	74	63	35
ICI + chemo	Shu CA (19)	2020	–	NCT02716038	2	Multicenter, single-arm	Resectable NSCLC	4 cycles of atezolizumab + nab-paclitaxel + carboplatin	30	50	67	40
ICI + chemo	Tfayli A (23)	2020	–	NCT03480230	2	Open label, single-arm	Stage IB–IIIA NSCLC	3 cycles of avelumab + chemotherapy	15	47	65	13
ICI + chemo	Yang CJ (24)	2018	TOP1201	NCT01820754	2	Single center, single-arm	Stage II–IIIA NSCLC	Cycles 2 and 3 ipilimumab + 3 cycles of paclitaxel + platinum	24	50	59	37
ICI + chemo	Wang J (21)	2021	–	–	–	Single center, single-arm	Stage IIIA NSCLC	2 cycles of pembrolizumab + paclitaxel + carboplatin	72	92	62.2	92
ICI + chemo	Shen D (20)	2021	–	–	–	Single center, single-arm	Stage IIB–IIIB resectable SCC	2 cycles of pembrolizumab+ paclitaxel + carboplatin	37	95	62.8	100
ICI + chemo	Duan H (22)	2021	–	–	–	Multicenter, single-arm	Stage IIA–IIIB resectable NSCLC	3–4 cycles of ICIs+ chemotherapy	23	96	61.8	83
Mono-ICI	Carbone D (14)	2021	LCMC3	NCT02927301	2	Multicenter, single-arm	Stage IB–IIIB resectable NSCLC	2 cycles of atezolizumab	181	51	65	38
Mono-ICI	Cascone T (18)	2021	NEOSTAR	NCT03158129	2	Single center, randomized	Stage I–IIIA NSCLC	Nivolumab	23	65	66	43
Mono-ICI	Eichhorn F (16)	2021	NEOMUN	NCT03197467	2	Single center, single-arm	Stage II/IIIA resectable NSCLC	2 cycles of pembrolizumab	15	47	59.8	13
Mono-ICI	Forde PM (13), Bott MJ (17)	2018, 2019	CheckMate159	NCT02259621	2	Two centers, single-arm	Stage I–IIIA NSCLC	2 cycles of nivolumab	22	48	67	29
Mono-ICI	Gao S (15)	2020	–	ChiCTR-OIC-17013726	1b	Multicenter, single-arm	Stage IA–IIIB resectable NSCLC	2 cycles of sintilimab	40	83	62	83
Dual-ICIs	Cascone T (18)	2021	NEOSTAR	NCT03158129	2	Single center, randomized	Stage I–IIIA NSCLC	Nivolumab + ipilimumab	21	62	65	33
Chemo	Forde PM (25)	2021	CheckMate 816	NCT02998528	3	Multicenter, randomized	Stage IB–IIIA resectable NSCLC	Chemotherapy	179	71	65	53

ICI, immune checkpoint inhibitor; chemo, chemotherapy; mono-ICI, single-agent immune checkpoint inhibitor; dual-ICIs, combination of two immune checkpoint inhibitors; NCT number, The National Clinical Trial number; NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma.

Table 2. Research data on endpoints reported in the clinical trials
Treatment mode	First author	ITT	Patients with resection	MPR rate	pCR rate	Incidence of TRAEs	Incidence of SAEs	Surgical delay rate	Conversion rate
ICI + chemo	Forde PM	179	149	37% (66/179)	24% (43/179)	47% (82/176)	19% (34/176)	17% (31/179)	–
ICI + chemo	Zinner R	13	13	85% (11/13)	38% (5/13)	–	15% (2/13)	–	–
ICI + chemo	Rothschild SI	68	55	60% (33/55)	15% (10/68)	–	–	–	–
ICI + chemo	Provencio M	46	41	74% (34/46)	57% (26/46)	93% (43/46)	30% (14/46)	0	–
ICI + chemo	Shu CA	30	26	57% (17/30)	33% (10/30)	–	10% (3/30)	0	–
ICI + chemo	Tfayli A	15	11	20% (3/15)	7% (1/15)	–	27% (4/15)	–	–
ICI + chemo	Yang CJ	24	13	–	8% (2/24)	–	25% (6/24)	8% (2/24)	13% (3/24)
ICI + chemo	Wang J	72	72	–	29% (21/72)	–	4% (3/72)	0	–
ICI + chemo	Shen D	37	37	65% (24/37)	46% (17/37)	70% (26/37)	11% (4/37)	0	–
ICI + chemo	Duan H	23	20	43% (10/23)	26% (6/23)	–	–	–	9% (2/23)
Mono-ICI	Carbone D	181	159	17% (30/181)	6% (10/181)	41% (75/181)	9% (16/181)	–	–
Mono-ICI	Cascone T	23	21	22% (5/23)	9% (2/23)	–	13% (3/23)	–	–
Mono-ICI	Eichhorn F	15	15	27% (4/15)	13% (2/15)	53% (8/15)	33% (5/15)	7% (1/15)	–
Mono-ICI	Forde PM, Bott MJ	22	20	41% (9/22)	14% (3/22)	23% (5/22)	5% (1/22)	0	32% (7/22)
Mono-ICI	Gao S	40	37	38% (15/40)	15% (6/40)	53% (21/40)	10% (4/40)	5% (2/37)	–
Dual-ICIs	Cascone T	21	16	38% (8/21)	29% (6/21)	–	10% (2/21)	–	–
Chemo	Forde PM	179	135	9% (16/179)	2% (4/179)	51% (89/176)	21% (37/176)	13% (24/179)	–

ICI, immune checkpoint inhibitor; chemo, chemotherapy; mono-ICI, single-agent immune checkpoint inhibitor; dual-ICIs, combination of two immune checkpoint inhibitors; ITT, intention-to-treat; MPR, major pathological response; pCR, complete pathological response; TRAE, treatment-related adverse event; SAE, severe adverse event.

Table 3. Comparison of endpoints among different subgroups after neoadjuvant immunotherapy
Subgroups	MPR rate (95% CI)	pCR rate (95% CI)	Incidence of TRAEs (95% CI)	Incidence of SAEs (95% CI)	Resection rate (95% CI)	Surgical delay rate (95% CI)	Conversion rate (95% CI)
Pooled	43.5 (32.4–55.0)	21.9 (15.3–30.6)	54.8 (41.5–67.3)	15.3 (10.7–21.3)	85.8 (80.4–89.8)	7.4 (3.8–12.3)	17.4 (7.4–35.9)
Treatment mode
ICI + chemo	53.3 (40.5–65.8)	28.6 (20.0–38.7)	73.9 (43.2–91.3)	18.0 (12.3–26.5)	84.4 (75.8–90.3)	3.8 (1.0–13.0)	–
Mono-ICI	28.6 (18.7–40.8)	9.9 (5.7–15.3)	42.9 (32.4–53.9)	12.3 (6.5–21.3)	89.2 (84.9–92.4)	7.4 (4.8–11.5)	–
Dual ICIs	38.3 (20.6–59.7)	28.6 (13.8–50.7)	–	9.9 (2.0–31.0)	76.2 (53.9–89.7)	13.0 (9.9–18.0)	–
Chemo	9.1 (5.7–13.8)	2.0 (1.0–5.7)	49.7 (42.5–57.1)	20.6 (15.3–27.0)	75.4 (68.6–81.2)	7.4 (4.8–12.3)	–
P value	<0.001	<0.001	0.15	0.32	0.002	0.02	–
ICI types
Nivolumab	51.5 (32.4–70.0)	29.1 (16.0–46.2)	60.0 (22.5–88.5)	18.7 (12.3–27.5)	84.9 (80.3–88.6)	12.3 (6.5–23.1)	–
Pembrolizumab	46.8 (15.3–81.1)	31.5 (18.0–49.2)	64.4 (47.6–78.2)	12.3 (3.8–35.5)	95.5 (76.0–99.3)	1.0 (0.0–6.5)	–
Durvalumab	48.5 (37.1–60.3)	14.5 (8.3–25.4)	–	–	86.1 (82.6–89.0)	–	–
Atezolizumab	33.3 (7.4–75.9)	14.5 (2.0–58.2)	41.5 (34.6–48.7)	9.1 (5.7–14.5)	87.7 (82.5–91.5)	6.5 (2.0–18.7)	–
Sintilimab	37.5 (24.2–53.3)	15.3 (6.5–29.6)	52.6 (37.1–67.3)	9.9 (3.8–23.7)	92.5 (79.2–97.6)	4.8 (1.0–18.0)	–
Avelumab	20.0 (6.5–47.1)	6.5 (1.0–35.1)	–	26.5 (10.7–53.3)	73.3 (46.8–89.6)	–	–
P value	0.39	0.18	0.06	0.11	0.22	0.07	–

ICI, immune checkpoint inhibitor; chemo, chemotherapy; mono-ICI, single-agent immune checkpoint inhibitor; dual-ICIs, combination of two immune checkpoint inhibitors; MPR, major pathological response; pCR, complete pathological response; TRAE, treatment-related adverse event; SAE, severe adverse event; CI, confidence interval.

Table S1. Sensitivity analysis of efficacy- and safety-related endpoints
Subgroup	Endpoints	Ratio (95% CI)
Mono-ICI	MPR rate	34.2 (25.9–43.2)
ICI + chemo	MPR rate	56.5 (43.2–69.0)^a; 49.5 (37.5–61.4)^b; 50.5 (37.9–62.8)^c
ICI + chemo	pCR rate	25.9 (19.4–34.2)^d; 31.0 (21.9–41.9)^e; 26.5 (18.0–37.1)^f
ICI + chemo	Incidence of TRAEs	58.3 (36.7–77.3)^g; 84.5 (48.5–97.0)^h
ICI + chemo	Incidence of SAEs	21.3 (17.4–26.5)
ICI + chemo	Resection rate	86.0 (79.8–90.5)
ICI + chemo	Surgical delay rate	2.9 (1.0–10.7)

^a,b,crefer to the pooled MPR rate of the ICI + chemo subgroup after removal of the Forde 2021 study, Provencio 2020 study, or Zinner 2020 study, respectively; ^d,e,frefer to the pooled pCR rate of the ICI + chemo subgroup after removal of the Provencio 2020 study, Rothchild 2021 study, or Shen 2021 study, respectively; ^g,hrefer to the pooled incidence of TRAEs of the ICI + chemo subgroup after removal of the Provencio 2020 study and Forde 2021 study, respectively. ICI, immune checkpoint inhibitor; chemo, chemotherapy; mono-ICI, single-agent immune checkpoint inhibitor; MPR, major pathological response; pCR, complete pathological response; TRAE, treatment-related adverse event; SAE, severe adverse event; CI, confidence interval.

Authors and Disclosures

Juan Jiang^1–6, Yuling Wang¹, Yang Gao^2,6,7, Haruhiko Sugimura⁸, Fabrizio Minervini⁹, Junji Uchino^10,11, Balazs Halmos¹², Sai Yendamuri¹³, Jeffrey B. Velotta¹⁴ and Min Li^1–6

¹Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China; ²Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China; ³Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China; ⁴Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, China; ⁵Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Changsha, China; ⁶National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China; ⁷Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China; ⁸Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; ⁹Department of Thoracic Surgery, Cantonal Hospital Lucerne, Lucerne, Switzerland; ¹⁰Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; ¹¹Bannan Central Hospital, Iwata, Shizuoka, Japan; ¹²Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA; ¹³Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; ¹⁴Department of Thoracic Surgery, Kaiser Permanente Oakland Medical Center, Kaiser Permanente Northern California, Oakland, CA, USA

Correspondence to
Min Li. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China. Email: limin2050@csu.edu.cn.

Contributions
(I) Conception and design: M Li; (II) Administrative support: M Li; (III) Provision of study materials or patients: M Li; (IV) Collection and assembly of data: J Jiang, Y Wang, Y Gao; (V) Data analysis and interpretation: J Jiang, M Li; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Conflicts of Interest
All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-75/coif). Prof. SY serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2021 to September 2023. The other authors have no conflicts of interest to declare.

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Neoadjuvant Immunotherapy or Chemoimmunotherapy in Non-Small Cell Lung Cancer

A Systematic Review and Meta-Analysis

Abstract and Introduction

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