The efficacy of neoadjuvant immune checkpoint inhibitors in lung squamous cell carcinoma and adenocarcinoma: a systematic review and single-arm meta-analysis
Highlight box
Key findings
• No significant differences in pathological response were observed between squamous cell carcinoma (SCC) and adenocarcinoma (ADC) patients, whether analyzing chemo-immunotherapy and immune checkpoint inhibitor (ICI) monotherapy together or separately.
• Chemo-immunotherapy significantly enhanced the sum of major pathological response and complete pathological response (McPR) in ADC patients compared to ICI monotherapy. Although an improvement was also noted in SCC patients, it was not statistically significant.
• Pembrolizumab exhibited a higher McPR in SCC than in ADC, suggesting its preferential efficacy in treating SCC patients. Toripalimab displayed a higher objective response rate for both SCC and ADC.
What is known and what is new?
• Current studies indicate varying responses to neoadjuvant immunotherapy between SCC and ADC in non-small cell lung cancer, but the limited scale and scope of these studies make definitive conclusions challenging. This systematic review represents the first comprehensive evaluation of the efficacy of neoadjuvant immunotherapy between SCC and ADC. Additionally, it assesses the effectiveness of various immune ICIs and examines the distinct responses of SCC and ADC to the same ICI.
What is the implication, and what should change now?
• SCC and ADC exhibit differential responses to neoadjuvant immunotherapy. This variation is evident across different treatment modalities and medications. Further research is required to elucidate these differences and to devise more appropriate treatment strategies for patients.
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths (1,2). The most common subtypes of NSCLC are adenocarcinoma (ADC) and squamous cell carcinoma (SCC). There are important differences between ADC and SCC, in terms of epidemiology, prognosis, and immunological features.
In recent years, immunotherapies with immune checkpoint inhibitors (ICIs) have demonstrated remarkable therapeutic efficacy against advanced NSCLC, and have been rapidly incorporated into the standard management of advanced NSCLC (3). Many studies have demonstrated improvements in overall survival (OS) with ICI in the first-line setting either alone or in combination with chemotherapy (4,5).
Not only does ICI show advantages in advanced NSCLC, but also in the neoadjuvant immunotherapy setting. Many studies have supported the safety and efficacy of neoadjuvant immunotherapy in resectable NSCLC (6,7). Neoadjuvant immunotherapy can improve pathological response rates with acceptable toxicity. NSCLC patients undergoing neoadjuvant immunotherapy have a lower incidence of treatment related adverse events, surgical complications and surgical delay, compared with neoadjuvant chemotherapy (8).
Current researches suggest potential differences in the effectiveness of neoadjuvant immunotherapy between patients with SCC and ADC in treating NSCLC (9,10). A significant limitation is that most of these studies are single-arm with relatively small participant groups, complicating the ability to make definitive conclusions. Combining study results helps us reliably understand the neoadjuvant immunotherapy response in NSCLC for both SCC and ADC. This understanding is crucial for improving treatment strategies and tailoring therapies to enhance the effectiveness of care for NSCLC patients.
In this study, we carried out a meta-analysis by pooling the publicly available data to investigate the efficacy of neoadjuvant immunotherapy on ADC and SCC, to provide optimal neoadjuvant immunotherapy regimen and treatment plan for NSCLC patients according to histological subtype and for obtaining better survival benefits. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1972/rc).
Methods
Search strategy
In this systematic review and meta-analysis, we carried out a systematic search in PubMed, Embase, and Cochrane databases for articles or abstracts from inception to May 1, 2022. Search terms included “lung cancer” and “neoadjuvant”. No limitation was imposed on the language, region, race, age, or article access cost during search. Furthermore, references of literature reviews, original research, and conference websites including the World Conference on Lung Cancer (WCLC), American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) websites were also scanned, so as not to miss any qualified study. The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO CRD42022328240).
Eligibility criteria
Only studies that provided data on pathological and radiological responses of ADC and SCC NSCLC patients after receiving neoadjuvant immunotherapy were eligible for inclusion in this study. The inclusion criteria were as follows: (I) prospective clinical studies (including randomized control trials and single-arm studies) and retrospective studies. (II) Studies including patients confirmed with NSCLC. (III) Studies involving patients treated with neoadjuvant ICIs, both single-agent therapy and in combination with other agents. (IV) Studies reporting the exact number of SCC and ADC patients receiving neoadjuvant immunotherapy and achieving pathological or radiological response.
Data extraction
Four authors (J.D., Q.W., R.W., K.Y.) independently extracted and entered the data from studies into a standard paper extraction form. A consensus discussion resolved disagreements among the three authors. The following characteristics information were extracted from studies that met the selection criteria for inclusion: authors, year of publication, study phase, study design, sample size, pathological type, NSCLC stages, treatments, primary endpoints. We extracted the number of ADC and SCC patients who received neoadjuvant immunotherapy and achieved pathological or radiological response for further statistical analysis.
Outcome measures
Pathological and radiological response were used to assess the efficacy of neoadjuvant ICI on ADC and SCC. The measures of pathological response included major pathological response (MPR), complete pathological response (cPR) and the sum of major pathological response and complete pathological response (McPR). MPR was defined as less than 10% residual viable tumor cells in resected primary tumor. cPR was defined as no viable tumor cells in all pathologic samples surgically resected after neoadjuvant therapy.
The measures of radiological response included complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with disappearance of the lesion were defined as achieving CR; a greater than 30% decrease in the longest dimension of the target lesion were defined as achieving PR; a greater than 20% increase in the longest dimension or the appearance of new lesions was defined as having PD. All other outcomes were defined as SD. ORR was defined as CR plus PR. DCR was defined as ORR plus the rate of SD.
Statistical analysis
All statistical analyses were performed with R software 4.0.5. The proportion of MPR, cPR, CR, PR, SD, PD, ORR and DCR with 95% confidence intervals (CIs) were calculated. Chi-squared test with I2 statistics was performed to analyze the between-study heterogeneity. Statistical difference was set as P<0.05. Random-effect model was selected if I2>50% or P<0.05, indicating significant heterogeneity. If I2<50% and P>0.05, fixed-effect model was applied. Publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger’s test. Sensitivity analyses were conducted to estimate and validate the impact of each study on the pooled results. Subgroup analyses were carried out to further reduce heterogeneity, if sufficient subgroup data were available.
Assessments of study quality
The quality of the included studies was evaluated according to the MINORS (Methodological Index for Nonrandomized Studies) checklist (11). MINORS is specifically designed to assess the methodological quality of non-randomized studies. A MINORS item would score 0 if not reported, 1 if reported but not adequate and 2 if reported and adequate. MINORS comes with 12 items that give a maximal possible score of 24 points. We considered a study of high quality if the total MINORS score was 17 or more and low quality if the total score was less than 17 (12).
Results
Study characteristics
A total of 4,368 potentially relevant studies were identified from the first search following the research strategy. There were 3,263 studies excluded according to the title and abstract. Seventy-seven studies were selected for comprehensive and detailed examination. After reading the full text carefully, 22 studies were excluded since they did not report the exact number of SCC and ADC patients receiving neoadjuvant immunotherapy and achieving pathological or radiological response. Finally, 22 studies, including a total of 430 patients, were used for the analysis. Details for all included trials are shown in Table 1. The range of MINORS scores among the included studies was 17 to 21, as shown in Table S1. The detailed study selection process is shown in Figure 1.
Table 1
Study | Country | Study type | Sample size | Age (years), median (IQR) | Gender, male/female | Treatment mode | ICI type | Histological type, SCC/ADC | MPR | cPR | ORR | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SCC | ADC | SCC | ADC | SCC | ADC | |||||||||||
Forde et al., 2018 (13) | USA | Single-arm, multicenter | 21 | 67 (55–84) | 11/10 | ICI monotherapy | Nivolumab | 6/12 | 1 | 5 | 1 | 1 | 1 | 1 | ||
Gao et al., 2020 (10) | China | Single-arm, single center, phase 1b | 40 | 62 (47–70) | 33/7 | ICI monotherapy | Sintilimab | 31/5 | 9 | 0 | 6 | 0 | 8 | 0 | ||
Reuss et al., 2020 (14) | USA | Open-label, single-ram, multicenter, phase 1b/2 | 9 | 64 (48–78) | 7/2 | ICI monotherapy | Nivolumab/ipilimumab | 1/8 | 0 | 0 | 0 | 2 | 0 | 1 | ||
Eichhorn et al., 2021 (9) | Germany | Open-label, single-arm, prospective, single center, phase 2 | 15 | 61 (40–83) | 7/8 | ICI monotherapy | Pembrolizumab | 2/13 | 0 | 2 | 1 | 1 | 2 | 2 | ||
Boch et al., 2022 (15) | Germany | Multicenter, retrospective | 13 | 61 (35–78) | 8/5 | ICI monotherapy/chemo-immunotherapy | Pembrolizumab | 1/12 | 0 | 2 | 1 | 6 | NA | NA | ||
Duan et al., 2021 (16) | China | Open-label, single-arm, multicenter | 23 | 61.83 | 22/1 | Chemo-immunotherapy | Nivolumab/pembrolizumab/sintilimab | 19/4 | 4 | 0 | 3 | 3 | 15 | 2 | ||
Sun et al., 2023 (17) | China | Open-label, single center, single-arm, prospective, phase 2 | 16 | 59.5 (34–71) | 18/2 | Chemo-immunotherapy | Sintilimab | 14/2 | 4 | 1 | 5 | 0 | 11 | 1 | ||
Shu et al., 2020 (18) | USA | Open label, multicenter, single-arm, phase 2 | 30 | 67 (62–74) | 15/15 | Chemo-immunotherapy | Atezolizumab | 10/15 | 3 | 3 | 5 | 5 | NA | NA | ||
Provencio et al., 2020 (19) | Spain | Open-label, multicenter, single-arm phase 2 | 46 | 63 (58–70) | 34/12 | Chemo-immunotherapy | Nivolumab | 17/26 | 4 | 4 | 7 | 16 | 13 | 20 | ||
Tfayli et al., 2020 (20) | USA | Open-label, multicenter, single-arm | 15 | 65 (45–80) | 7/8 | Chemo-immunotherapy | Avelumab | 2/13 | 0 | 2 | 1 | 0 | 2 | 2 | ||
Chen et al., 2022 (21) | China | Single center, retrospective | 12 | 61 (55–67) | 9/3 | Chemo-immunotherapy | NA | 6/5 | 1 | 3 | 2 | 2 | NA | NA | ||
Shen et al., 2021 (22) | China | Single-center, single-arm, prospective | 37 | 62.8 (38–76) | 35/2 | Chemo-immunotherapy | Pembrolizumab | 37/0 | 7 | 0 | 17 | 0 | 32 | 0 | ||
Zhao et al., 2021 (23) | China | Single-center, single-arm, phase 2 | 33 | 61 (56–66) | 27/6 | Chemo-immunotherapy | Toripalimab | 18/13 | 2 | 2 | 10 | 4 | 17 | 14 | ||
Wu et al., 2022 (24) | China | Single-center, retrospective | 76 | 62 (56–68) | 72/4 | Chemo-immunotherapy | NA | 11/5 | 6 | 3 | 0 | 0 | NA | NA | ||
Chen et al., 2021 (25) | China | Single-center, retrospective | 35 | NA | 29/6 | Chemo-immunotherapy | Pembrolizumab | 26/7 | 5 | 2 | 15 | 2 | 11 | 6 | ||
Alì et al., 2023 (26) | Italy | Single-center, retrospective | 12 | 67 (58.5–70.5) | 6/6 | Chemo-immunotherapy | NA | 3/8 | 0 | 4 | 1 | 0 | NA | NA | ||
Hou et al., 2023 (27) | China | Single-center, single-arm | 11 | 63 (51–71) | 10/1 | Chemo-immunotherapy | Toripalimab | 9/2 | NA | NA | 5 | 1 | 8 | 2 | ||
Zhao et al., 2023 (28) | China | Single center, retrospective | 25 | 65 (42–74) | 22/3 | Chemo-immunotherapy | Pembrolizumab | 13/4 | 5 | 1 | 3 | 1 | NA | NA | ||
Feng et al., 2022 (29) | China | Single center, two-arm | 8 | 64 (52–68) | 8/0 | Chemo-immunotherapy | NA | 8/0 | 0 | NA | 3 | NA | 8 | NA | ||
Xu et al., 2022 (30) | China | Single-arm, single center | 14 | 60.5 (57–70) | 14/0 | Chemo-immunotherapy | NA | 14/0 | 9 | NA | 2 | NA | 13 | NA | ||
Zhu et al., 2022 (8) | China | Single-arm, open label, single center | 50 | 66.0 (57.8–68.0) | 42/8 | Chemo-immunotherapy | Toripalimab | 19/9 | 5 | 3 | 5 | 1 | 18 | 7 |
IQR, interquartile range; ICI, immune checkpoint inhibitor; SCC, squamous cell carcinoma; ADC, adenocarcinoma; MPR, major pathological response; cPR, complete pathological response; ORR, objective response disease; NA, unavailable.
Efficacy of neoadjuvant immunotherapy on ADC and SCC
Pathological response
For SCC patients, the analysis yields a pooled McPR rate of 0.61 (95% CI: 0.54–0.68), a pooled MPR rate of 0.21 (95% CI: 0.15–0.27), and a pooled cPR rate of 0.31 (95% CI: 0.25–0.38). Conversely, in ADC patients, the pooled McPR rate stands at 0.49 (95% CI: 0.36–0.62), the MPR rate is 0.20 (95% CI: 0.13–0.27), and the cPR rate is found to be 0.20 (95% CI: 0.09–0.33). Comparative analysis reveals no significant differences in McPR, MPR, and cPR rates between SCC and ADC patients (Figure 2).
Radiological response
Within the SCC cohort, the pooled results were as follows: CR at 0.03 (95% CI: 0.00–0.11), PR at 0.66 (95% CI: 0.51–0.79), SD at 0.19 (95% CI: 0.06–0.36), and PD at 0.00 (95% CI: 0.00–0.00). Consequently, the ORR was calculated to be 0.79 (95% CI: 0.62–0.93), with a DCR of 1.00 (95% CI: 1.00–1.00). In contrast, for ADC patients, the pooled metrics indicated a CR of 0.01 (95% CI: 0.00–0.05), PR of 0.42 (95% CI: 0.21–0.65), SD of 0.45 (95% CI: 0.26–0.64), and PD of 0.04 (95% CI: 0.00–0.07). The ORR for ADC was found to be 0.44 (95% CI: 0.21–0.68), and the DCR was 0.98 (95% CI: 0.93–1.00).
Notably, the SCC group demonstrated a significantly higher ORR and lower incidences of PD and SD compared to the ADC group, with statistical significance (P<0.05) (Figure 3).
Subgroup analyses
SCC response to neoadjuvant ICI monotherapy and chemo-immunotherapy
A total of 267 SCC patients were included in this study. Forty-one SCC patients were treated with ICI monotherapy, 226 were treated with chemo-immunotherapy. No significant difference was found in pathological response between ICI monotherapy and chemo-immunotherapy. In terms of radiological response, chemo-immunotherapy outperformed ICI monotherapy, with higher ORR, PR and lower SD (P<0.01) (Table 2).
Table 2
Histological types | Outcome measures | Number of trials | Treatment mode | Pooled estimates (95% CI) |
I2 | P value of heterogeneity | Chi-square test | |
---|---|---|---|---|---|---|---|---|
χ2 | P | |||||||
SCC | McPR | 5 | ICI monotherapy | 0.45 (0.25–0.66) | 0% | 0.69 | 3.21 | 0.07 |
15 | Chemo-immunotherapy | 0.63 (0.56–0.60) | 3% | 0.42 | ||||
MPR | 5 | ICI monotherapy | 0.23 (0.06–0.43) | 0% | 0.55 | 0.49 | 0.49 | |
15 | Chemo-immunotherapy | 0.23 (0.17–0.29) | 41% | 0.05 | ||||
cPR | 5 | ICI monotherapy | 0.13 (0.01–0.32) | 0% | 0.44 | 2.95 | 0.09 | |
16 | Chemo-immunotherapy | 0.34 (0.24–0.45) | 52% | <0.01 | ||||
CR | 4 | ICI monotherapy | 0.00 (0.00–0.00) | 0% | 0.79 | 3.79 | 0.05 | |
11 | Chemo-immunotherapy | 0.07 (0.01–0.17) | 70% | <0.01 | ||||
PR | 4 | ICI monotherapy | 0.22 (0.06–0.41) | 44% | 0.15 | 20.44 | <0.01 | |
11 | Chemo-immunotherapy | 0.70 (0.62–0.77) | 42% | 0.07 | ||||
SD | 4 | ICI monotherapy | 0.72 (0.52–0.89) | 40% | 0.17 | 27.61 | <0.01 | |
11 | Chemo-immunotherapy | 0.13 (0.04–0.24) | 70% | <0.01 | ||||
PD | 4 | ICI monotherapy | 0.00 (0.00–0.07) | 0% | 0.97 | 2.77 | 0.10 | |
11 | Chemo-immunotherapy | 0.00 (0.00–0.01) | 0% | 0.99 | ||||
ORR | 4 | ICI monotherapy | 0.22 (0.06–0.41) | 44% | 0.15 | 33.39 | <0.01 | |
11 | Chemo-immunotherapy | 0.86 (0.75–0.95) | 64% | <0.01 | ||||
DCR | 4 | ICI monotherapy | 1.00 (0.93–1.00) | 0% | 0.97 | 2.77 | 0.10 | |
11 | Chemo-immunotherapy | 1.00 (0.99–1.00) | 0% | 0.99 | ||||
ADC | McPR | 5 | ICI monotherapy | 0.29 (0.14–0.45) | 42% | 0.14 | 4.76 | 0.03 |
13 | Chemo-immunotherapy | 0.57 (0.43–0.71) | 45% | 0.04 | ||||
MPR | 5 | ICI monotherapy | 0.14 (0.03–0.29) | 50% | 0.09 | 1.01 | 0.32 | |
13 | Chemo-immunotherapy | 0.22 (0.14–0.31) | 4% | 0.41 | ||||
cPR | 5 | ICI monotherapy | 0.11 (0.02–0.25) | 30% | 0.22 | 1.77 | 0.18 | |
13 | Chemo-immunotherapy | 0.24 (0.10–0.40) | 65% | <0.01 | ||||
CR | 4 | ICI monotherapy | 0.00 (0.00–0.05) | 0% | 0.99 | 0.45 | 0.50 | |
8 | Chemo-immunotherapy | 0.00 (0.00–0.04) | 0% | 0.95 | ||||
PR | 4 | ICI monotherapy | 0.09 (0.01–0.22) | 0% | 0.83 | 18.69 | <0.01 | |
8 | Chemo-immunotherapy | 0.65 (0.42–0.85) | 60% | 0.01 | ||||
SD | 4 | ICI monotherapy | 0.74 (0.49–0.94) | 53% | 0.10 | 9.14 | <0.01 | |
8 | Chemo-immunotherapy | 0.27 (0.16–0.44) | 18% | 0.29 | ||||
PD | 4 | ICI monotherapy | 0.14 (0.00–0.41) | 68% | 0.03 | 3.43 | 0.06 | |
8 | Chemo-immunotherapy | 0.00 (0.00–0.04) | 3% | 0.40 | ||||
ORR | 4 | ICI monotherapy | 0.09 (0.01–0.22) | 0% | 0.83 | 19.53 | <0.01 | |
8 | Chemo-immunotherapy | 0.68 (0.44–0.88) | 63% | <0.01 | ||||
DCR | 4 | ICI monotherapy | 0.86 (0.59–1.00) | 67% | 0.03 | 3.52 | 0.06 | |
8 | Chemo-immunotherapy | 1.00 (0.96–1.00) | 3% | 0.40 |
ADC, adenocarcinoma; SCC, squamous cell carcinoma; CI, confidence interval; McPR, the sum of major pathological response and complete pathological response; ICI, immune checkpoint inhibitor; MPR, major pathological response; cPR, complete pathological response; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.
ADC response to neoadjuvant ICI monotherapy and chemo-immunotherapy
In this subgroup analysis, 163 patients with ADC are evaluated, of whom 41 received ICI monotherapy, while 122 undergo chemo-immunotherapy. The pooled McPR rates for those treated with ICI monotherapy is 0.29 (95% CI: 0.14–0.45). This rate is significantly lower compared to those observed in patients receiving chemo-immunotherapy, which is 0.57 (95% CI: 0.43–0.71). Chemo-immunotherapy was markedly superior to ICI monotherapy, demonstrating significantly higher PR and ORR, along with a lower rate of SD. No significant differences were noted in other indicators (Table 2).
Comparison of the response between SCC and ADC to neoadjuvant ICI monotherapy
Within the selected research, five studies focused on administering neoadjuvant ICI monotherapy to patients. These investigations revealed no significant differences in either pathological or radiological responses between patients with ADC and SCC who were treated with neoadjuvant ICI monotherapy (Table 3).
Table 3
Treatment mode | Outcome measures | Number of trials | Histological types | Pooled estimates (95% CI) |
I2 | P value of heterogeneity | Chi-square test | |
---|---|---|---|---|---|---|---|---|
χ2 | P | |||||||
ICI monotherapy | McPR | 5 | SCC | 0.45 (0.25–0.66) | 0% | 0.69 | 2.11 | 0.15 |
ADC | 0.29 (0.14–0.45) | 42% | 0.14 | |||||
MPR | 5 | SCC | 0.16 (0.02–0.35) | 0% | 0.90 | 0.15 | 0.70 | |
ADC | 0.26 (0.12–0.43) | 29% | 0.23 | |||||
cPR | 5 | SCC | 0.13 (0.01–0.32) | 0% | 0.44 | 0.87 | 0.35 | |
ADC | 0.11 (0.02–0.25) | 30% | 0.22 | |||||
CR | 4 | SCC | 0.00 (0.00–0.00) | 0% | 0.79 | 0.05 | 0.82 | |
ADC | 0.00 (0.00–0.05) | 0% | 0.99 | |||||
PR | 4 | SCC | 0.22 (0.06–0.41) | 44% | 0.15 | 3.22 | 0.07 | |
ADC | 0.09 (0.01–0.22) | 0% | 0.83 | |||||
SD | 4 | SCC | 0.72 (0.52–0.89) | 40% | 0.17 | 0.46 | 0.50 | |
ADC | 0.74 (0.49–0.94) | 53% | 0.10 | |||||
PD | 4 | SCC | 0.00 (0.00–0.07) | 0% | 0.97 | 1.12 | 0.29 | |
ADC | 0.14 (0.00–0.41) | 68% | 0.03 | |||||
ORR | 4 | SCC | 0.22 (0.06–0.41) | 44% | 0.15 | 3.22 | 0.07 | |
ADC | 0.09 (0.01–0.22) | 0% | 0.83 | |||||
DCR | 4 | SCC | 1.00 (0.93–1.00) | 0% | 0.97 | 1.17 | 0.28 | |
ADC | 0.86 (0.59–1.00) | 67% | 0.03 | |||||
Chemo-immunotherapy | McPR | 15 | SCC | 0.63 (0.56–0.70) | 3% | 0.42 | 0.74 | 0.39 |
13 | ADC | 0.57 (0.43–0.71) | 45% | 0.04 | ||||
MPR | 15 | SCC | 0.23 (0.17–0.29) | 41% | 0.05 | 0.01 | 0.93 | |
13 | ADC | 0.22 (0.14–0.31) | 4% | 0.41 | ||||
cPR | 16 | SCC | 0.34 (0.24–0.45) | 52% | <0.01 | 0.89 | 0.34 | |
14 | ADC | 0.30 (0.21–0.39) | 59% | <0.01 | ||||
CR | 11 | SCC | 0.07 (0.01–0.17) | 70% | <0.01 | 1.56 | 0.21 | |
8 | ADC | 0.00 (0.00–0.04) | 0% | 0.95 | ||||
PR | 11 | SCC | 0.70 (0.62–0.77) | 42% | 0.07 | 0.77 | 0.38 | |
8 | ADC | 0.65 (0.42–0.85) | 60% | 0.01 | ||||
SD | 11 | SCC | 0.13 (0.04–0.24) | 70% | <0.01 | 3.66 | 0.06 | |
8 | ADC | 0.27 (0.16–0.40) | 18% | 0.29 | ||||
PD | 11 | SCC | 0.00 (0.00–0.01) | 0% | 0.99 | 1.43 | 0.23 | |
8 | ADC | 0.00 (0.00–0.04) | 3% | 0.40 | ||||
ORR | 11 | SCC | 0.86 (0.75–0.95) | 64% | <0.01 | 3.07 | 0.08 | |
8 | ADC | 0.68 (0.44–0.88) | 63% | <0.01 | ||||
DCR | 11 | SCC | 1.00 (0.99–1.00) | 0% | 0.99 | 1.43 | 0.88 | |
8 | ADC | 1.00 (0.96–1.00) | 3% | 0.40 |
SCC, squamous cell carcinoma; ADC, adenocarcinoma; CI, confidence interval; ICI, immune checkpoint inhibitor; McPR, the sum of major pathological response and complete pathological response; MPR, major pathological response; cPR, complete pathological response; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.
Comparison of the response between SCC and ADC to neoadjuvant chemo-immunotherapy
Sixteen studies are included in the analysis, focusing on the pathological and radiological responses of ADC and SCC patients to neoadjuvant chemo-immunotherapy. No significant difference is found in the pooled pathological and radiological responses between ADC and SCC patients undergoing neoadjuvant chemo-immunotherapy (Table 3).
Comparison of ICI efficacy in SCC
Studies that did not reported the specific ICI regimen or used dual ICI protocol were not included in this subgroup analyses. Among the included 22 studies, three studies treated SCC patients with nivolumab (13,16,19), six with pembrolizumab (9,15,16,22,25,28), three with sintilimab (16,17), and three with toripalimab (8,23,27) were included in this subgroup analysis. ORR and SD exhibit statistical differences in efficacy among 4 types of ICIs. Further comparison revealed that toripalimab has a significantly higher ORR and a lower SD compared to the other three drugs (Table 4).
Table 4
Histological types | Outcome measures | Number of trials | ICI types | Pooled estimates (95% CI) |
I2 | P value of heterogeneity | Chi-square test | |
---|---|---|---|---|---|---|---|---|
χ2 | P | |||||||
SCC | McPR | 3 | Nivolumab | 0.58 (0.37–0.79) | 0% | 0.44 | 5.50 | 0.14 |
6 | Pembrolizumab | 0.70 (0.58–0.82) | 0% | 0.71 | ||||
3 | Sintilimab | 0.43 (0.18–0.71) | 64% | 0.06 | ||||
2 | Toripalimab | 0.54 (0.37–0.70) | 0% | 0.86 | ||||
MPR | 3 | Nivolumab | 0.25 (0.08–0.46) | 3% | 0.36 | 1.05 | 0.79 | |
6 | Pembrolizumab | 0.16 (0.07–0.27) | 8% | 0.37 | ||||
3 | Sintilimab | 0.26 (0.14–0.39) | 0% | 0.69 | ||||
2 | Toripalimab | 0.18 (0.07–0.33) | 21% | 0.26 | ||||
cPR | 3 | Nivolumab | 0.28 (0.10–0.49) | 26% | 0.26 | 5.93 | 0.12 | |
6 | Pembrolizumab | 0.50 (0.36–0.65) | 0% | 0.70 | ||||
3 | Sintilimab | 0.17 (0.02–0.40) | 60% | 0.08 | ||||
3 | Toripalimab | 0.43 (0.28–0.58) | 47% | 0.15 | ||||
CR | 3 | Nivolumab | 0.01 (0.00–0.14) | 0% | 0.92 | 6.44 | 0.09 | |
4 | Pembrolizumab | 0.03 (0.00–0.23) | 79% | <0.01 | ||||
3 | Sintilimab | 0.00 (0.00–0.03) | 0% | 0.90 | ||||
3 | Toripalimab | 0.15 (0.05–0.28) | 49% | 0.14 | ||||
PR | 3 | Nivolumab | 0.64 (0.15–1.00) | 73% | 0.02 | 2.31 | 0.51 | |
4 | Pembrolizumab | 0.76 (0.39–1.00) | 78% | <0.01 | ||||
3 | Sintilimab | 0.50 (0.18–0.82) | 82% | <0.01 | ||||
3 | Toripalimab | 0.77 (0.63–0.88) | 0% | 0.55 | ||||
SD | 3 | Nivolumab | 0.33 (0.00–0.84) | 76% | 0.02 | 12.45 | <0.01 | |
4 | Pembrolizumab | 0.15 (0.00–0.50) | 85% | <0.01 | ||||
3 | Sintilimab | 0.47 (0.19–0.76) | 76% | 0.02 | ||||
3 | Toripalimab | 0.03 (0.00–0.11) | 5% | 0.35 | ||||
PD | 3 | Nivolumab | 0.00 (0.00–0.05) | 0% | 0.87 | 1.97 | 0.58 | |
4 | Pembrolizumab | 0.00 (0.00–0.00) | 0% | 0.89 | ||||
3 | Sintilimab | 0.02 (0.00–0.10) | 0% | 0.60 | ||||
3 | Toripalimab | 0.01 (0.00–0.08) | 0% | 0.57 | ||||
ORR | 3 | Nivolumab | 0.67 (0.16–1.00) | 76% | 0.02 | 8.69 | 0.03 | |
4 | Pembrolizumab | 0.85 (0.50–1.00) | 85% | <0.01 | ||||
3 | Sintilimab | 0.50 (0.18–0.82) | 82% | <0.01 | ||||
3 | Toripalimab | 0.94 (0.84–1.00) | 0% | 0.82 | ||||
DCR | 3 | Nivolumab | 1.00 (0.95–1.00) | 0% | 0.87 | 3.24 | 0.36 | |
4 | Pembrolizumab | 1.00 (1.00–1.00) | 0% | 0.89 | ||||
3 | Sintilimab | 0.98 (0.90–1.00) | 0% | 0.60 | ||||
3 | Toripalimab | 0.96 (0.90–1.00) | 0% | 0.81 | ||||
ADC | McPR | 3 | Nivolumab | 0.73 (0.56–0.88) | 40% | 0.19 | 4.80 | 0.19 |
4 | Pembrolizumab | 0.39 (0.20–0.61) | 5% | 0.37 | ||||
3 | Sintilimab | 0.13 (0.00–0.50) | 42% | 0.18 | ||||
2 | Toripalimab | 0.45 (0.24–0.67) | 0% | 0.95 | ||||
MPR | 3 | Nivolumab | 0.18 (0.05–0.34) | 38% | 0.20 | 0.67 | 0.88 | |
4 | Pembrolizumab | 0.18 (0.06–0.35) | 0% | 0.88 | ||||
3 | Sintilimab | 0.03 (0.00–0.35) | 14% | 0.31 | ||||
3 | Toripalimab | 0.22 (0.06–0.43) | 0% | 0.32 | ||||
cPR | 3 | Nivolumab | 0.50 (0.02–0.98) | 85% | <0.01 | 2.44 | 0.49 | |
4 | Pembrolizumab | 0.19 (0.04–0.39) | 31% | 0.23 | ||||
3 | Sintilimab | 0.03 (0.00–0.35) | 14% | 0.31 | ||||
3 | Toripalimab | 0.32 (0.12–0.55) | 0% | 0.87 | ||||
CR | 3 | Nivolumab | 0.00 (0.00–0.06) | 0% | 0.82 | 0.52 | 0.91 | |
2 | Pembrolizumab | 0.00 (0.00–0.09) | 0% | 0.84 | ||||
3 | Sintilimab | 0.00 (0.00–0.21) | 0% | 0.95 | ||||
3 | Toripalimab | 0.00 (0.00–0.14) | 0% | 0.47 | ||||
PR | 3 | Nivolumab | 0.56 (0.03–1.00) | 89% | <0.01 | 11.01 | 0.01 | |
2 | Pembrolizumab | 0.48 (0.00–1.00) | 89% | <0.01 | ||||
3 | Sintilimab | 0.03 (0.00–0.35) | 14% | 0.31 | ||||
3 | Toripalimab | 0.78 (0.56–0.95) | 0% | 0.64 | ||||
SD | 3 | Nivolumab | 0.42 (0.00–0.97) | 90% | <0.01 | 8.74 | 0.03 | |
2 | Pembrolizumab | 0.47 (0.00–0.99) | 86% | <0.01 | ||||
3 | Sintilimab | 0.82 (0.43–1.00) | 0% | 0.56 | ||||
3 | Toripalimab | 0.18 (0.02–0.39) | 0% | 0.81 | ||||
PD | 3 | Nivolumab | 0.00 (0.00–0.05) | 9% | 0.33 | 2.38 | 0.50 | |
2 | Pembrolizumab | 0.00 (0.00–0.09) | 0% | 0.84 | ||||
3 | Sintilimab | 0.07 (0.00–0.41) | 0% | 0.79 | ||||
3 | Toripalimab | 0.00 (0.00–0.05) | 0% | 0.88 | ||||
ORR | 3 | Nivolumab | 0.58 (0.03–1.00) | 90% | <0.01 | 12.50 | <0.01 | |
2 | Pembrolizumab | 0.48 (0.00–1.00) | 89% | <0.01 | ||||
3 | Sintilimab | 0.03 (0.00–0.35) | 14% | 0.31 | ||||
3 | Toripalimab | 0.82 (0.61–0.98) | 0% | 0.81 | ||||
DCR | 3 | Nivolumab | 1.00 (0.99–1.00) | 0% | 0.81 | 3.62 | 0.31 | |
2 | Pembrolizumab | 0.96 (0.81–1.00) | 0% | 0.51 | ||||
3 | Sintilimab | 0.93 (0.59–0.35) | 0% | 0.79 | ||||
3 | Toripalimab | 1.00 (0.98–1.00) | 0% | 0.88 |
ICI, immune checkpoint inhibitor; SCC, squamous cell carcinoma; ADC, adenocarcinoma; CI, confidence interval; McPR, the sum of major pathological response and complete pathological response; MPR, major pathological response; cPR, complete pathological response; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.
Comparison of ICI efficacy in ADC
Studies that did not reported the specific ICI regimen or use dual ICI protocol were not included in this subgroup analyses. Among the included 22 studies, three studies treated ADC patients with nivolumab (13,16,19), four with pembrolizumab (9,15,25,28), three with sintilimab (10,16,17), and three with toripalimab (8,23,27) were included in this subgroup analysis. ORR, PR, and SD show statistical differences among 4 types of ICIs. Upon further comparison, it is found that there is no significant difference in ORR between toripalimab and nivolumab, while toripalimab significantly outperforms pembrolizumab and sintilimab in terms of ORR (Table 4).
Comparison of the response between SCC and ADC to different ICIs
The pathological response of pembrolizumab of SCC was better than ADC in the pooled McPR rate and cPR rate (P<0.05). No significant difference was found in the radiological response between ADC and SCC patients treated with pembrolizumab. In addition, no significant difference was found in both pathological and radiological response between ADC and SCC patients treated with nivolumab, sintilimab, and toripalimab (Table 5).
Table 5
ICI type | Outcome measures | Number of trials | Histological types | Pooled estimates (95% CI) |
I2 | P value of heterogeneity | Chi-square test | |
---|---|---|---|---|---|---|---|---|
χ2 | P | |||||||
Nivolumab | McPR | 3 | SCC | 0.54 (0.33–0.75) | 1% | 0.36 | 1.79 | 0.18 |
ADC | 0.73 (0.56–0.88) | 40% | 0.19 | |||||
MPR | 3 | SCC | 0.21 (0.05–0.42) | 0% | 0.86 | 0.05 | 0.82 | |
ADC | 0.18 (0.05–0.34) | 36% | 0.20 | |||||
cPR | 3 | SCC | 0.28 (0.10–0.49) | 26% | 0.26 | 0.66 | 0.42 | |
ADC | 0.50 (0.02–0.98) | 85% | <0.01 | |||||
CR | 3 | SCC | 0.01 (0.00–0.14) | 0% | 0.92 | 0.18 | 0.67 | |
ADC | 0.00 (0.00–0.06) | 0% | 0.82 | |||||
PR | 3 | SCC | 0.64 (0.15–1.00) | 73% | 0.02 | 0.04 | 0.85 | |
ADC | 0.56 (0.03–1.00) | 89% | <0.01 | |||||
SD | 3 | SCC | 0.33 (0.00–0.84) | 76% | 0.02 | 0.04 | 0.84 | |
ADC | 0.42 (0.00–0.97) | 90% | <0.01 | |||||
PD | 3 | SCC | 0.00 (0.00–0.05) | 0% | 0.87 | 0.05 | 0.82 | |
ADC | 0.00 (0.00–0.05) | 9% | 0.33 | |||||
ORR | 3 | SCC | 0.67 (0.16–1.00) | 76% | 0.02 | 0.04 | 0.84 | |
ADC | 0.58 (0.03–1.00) | 90% | <0.01 | |||||
DCR | 3 | SCC | 1.00 (0.95–1.00) | 0% | 0.87 | 0.07 | 0.79 | |
ADC | 1.00 (0.99–1.00) | 0% | 0.81 | |||||
Pembrolizumab | McPR | 6 | SCC | 0.70 (0.58–0.82) | 0% | 0.71 | 5.68 | 0.02 |
4 | ADC | 0.39 (0.20–0.61) | 5% | 0.37 | ||||
MPR | 6 | SCC | 0.15 (0.06–0.26) | 0% | 0.75 | 0.01 | 0.93 | |
4 | ADC | 0.16 (0.02–0.35) | 0% | 0.73 | ||||
cPR | 6 | SCC | 0.45 (0.32–0.58) | 7% | 0.37 | 5.12 | 0.02 | |
4 | ADC | 0.19 (0.04–0.39) | 31% | 0.23 | ||||
CR | 4 | SCC | 0.03 (0.00–0.23) | 79% | <0.01 | 0.67 | 0.41 | |
2 | ADC | 0.00 (0.00–0.09) | 0% | 0.84 | ||||
PR | 4 | SCC | 0.76 (0.39–1.00) | 78% | <0.01 | 0.40 | 0.53 | |
2 | ADC | 0.48 (0.00–1.00) | 89% | <0.01 | ||||
SD | 4 | SCC | 0.15 (0.00–0.50) | 85% | <0.01 | 0.73 | 0.39 | |
2 | ADC | 0.47 (0.00–0.99) | 86% | <0.01 | ||||
PD | 4 | SCC | 0.00 (0.00–0.00) | 0% | 0.89 | 0.15 | 0.70 | |
2 | ADC | 0.00 (0.00–0.09) | 0% | 0.84 | ||||
ORR | 4 | SCC | 0.85 (0.50–1.00) | 85% | <0.01 | 0.77 | 0.38 | |
2 | ADC | 0.48 (0.00–1.00) | 89% | <0.01 | ||||
DCR | 4 | SCC | 1.00 (1.00–1.00) | 0% | 0.89 | 1.93 | 0.16 | |
2 | ADC | 0.96 (0.81–1.00) | 0% | 0.51 | ||||
Sintilimab | McPR | 3 | SCC | 0.43 (0.18–0.71) | 64% | 0.06 | 0.55 | 0.46 |
ADC | 0.13 (0.00–0.50) | 42% | 0.18 | |||||
MPR | 3 | SCC | 0.26 (0.14–0.39) | 0% | 0.69 | 0.16 | 0.69 | |
ADC | 0.13 (0.00–0.50) | 42% | 0.18 | |||||
cPR | 3 | SCC | 0.17 (0.02–0.40) | 60% | 0.08 | 0.35 | 0.56 | |
ADC | 0.03 (0.00–0.35) | 14% | 0.31 | |||||
CR | 3 | SCC | 0.00 (0.00–0.03) | 0% | 0.90 | 0.73 | 0.39 | |
ADC | 0.00 (0.00–0.21) | 0% | 0.95 | |||||
PR | 3 | SCC | 0.50 (0.18–0.82) | 82% | <0.01 | 3.01 | 0.08 | |
ADC | 0.03 (0.00–0.35) | 14% | 0.31 | |||||
SD | 3 | SCC | 0.47 (0.19–0.76) | 76% | 0.02 | 1.76 | 0.18 | |
ADC | 0.82 (0.43–1.00) | 0% | 0.56 | |||||
PD | 3 | SCC | 0.02 (0.00–0.10) | 0% | 0.60 | 1.32 | 0.25 | |
ADC | 0.07 (0.00–0.41) | 0% | 0.79 | |||||
ORR | 3 | SCC | 0.50 (0.18–0.82) | 82% | <0.01 | 3.01 | 0.08 | |
ADC | 0.03 (0.00–0.35) | 14% | 0.31 | |||||
DCR | 3 | SCC | 0.98 (0.90–1.00) | 0% | 0.60 | 1.32 | 0.25 | |
ADC | 0.93 (0.59–1.00) | 0% | 0.79 | |||||
Torilizumab | McPR | 3 | SCC | 0.60 (0.43–0.75) | 0% | 0.40 | 1.01 | 0.31 |
ADC | 0.45 (0.24–0.67) | 0% | 0.95 | |||||
MPR | 3 | SCC | 0.13 (0.04–0.25) | 50% | 0.13 | 0.00 | 0.97 | |
ADC | 0.09 (0.00–0.28) | 0% | 0.93 | |||||
cPR | 3 | SCC | 0.43 (0.28–0.58) | 47% | 0.15 | 0.52 | 0.47 | |
ADC | 0.32 (0.12–0.55) | 0% | 0.87 | |||||
CR | 3 | SCC | 0.15 (0.05–0.28) | 49% | 0.14 | 2.22 | 0.14 | |
ADC | 0.00 (0.00–0.14) | 0% | 0.47 | |||||
PR | 3 | SCC | 0.77 (0.63–0.88) | 0% | 0.55 | 0.02 | 0.89 | |
ADC | 0.78 (0.56–0.95) | 0% | 0.64 | |||||
SD | 3 | SCC | 0.03 (0.00–0.11) | 5% | 0.35 | 4.67 | 0.03 | |
ADC | 0.18 (0.02–0.39) | 0% | 0.81 | |||||
PD | 3 | SCC | 0.01 (0.00–0.08) | 0% | 0.57 | 0.05 | 0.83 | |
ADC | 0.00 (0.00–0.05) | 0% | 0.88 | |||||
ORR | 3 | SCC | 0.94 (0.84–1.00) | 0% | 0.82 | 2.68 | 0.10 | |
ADC | 0.82 (0.61–0.98) | 0% | 0.81 | |||||
DCR | 3 | SCC | 0.98 (0.90–1.00) | 0% | 0.60 | 1.32 | 0.25 | |
ADC | 0.93 (0.59–1.00) | 0% | 0.79 |
ICI, immune checkpoint inhibitor; SCC, squamous cell carcinoma; ADC, adenocarcinoma; CI, confidence interval; McPR, the sum of major pathological response and complete pathological response; MPR, major pathological response; cPR, complete pathological response; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.
Publication bias
The funnel plot was symmetrical (Figure S1), and the result of Egger test suggested no publication bias (P>0.05) (Table S2).
Discussion
This is the first systematic review to evaluate the efficacy of neoadjuvant immunotherapy between SCC and ADC. In this meta-analysis, SCC showed higher ORR and lower SD and PD than ADC. No significant difference was found in pathological response between ADC and SCC patients undergoing, regardless of the treatment mode of either ICI monotherapy or chemo-immunotherapy. In our comparison of the efficacy of neoadjuvant ICI monotherapy vs. chemo-immunotherapy, it was observed that the McPR in ADC was significantly enhanced with the latter approach. Additionally, we evaluated the efficacy of various ICIs, as well as the differential responses of SCC and ADC to the same ICI. Our findings indicated that toripalimab demonstrated a higher ORR for both SCC and ADC, yet none of the ICIs distinctly outperformed others in terms of pathological remission. Notably, pembrolizumab exhibited a substantially higher McPR in SCC compared to ADC, suggesting its potential preferential effectiveness in treating SCC patients.
SCC and ADC are the two most prevalent subtypes of NSCLC with different immunological features, and there has been ongoing controversy over which subtype is more sensitive to neoadjuvant immunotherapy (31). Faruki et al. (32) have noted significant differences in tumor immunity among subtypes of ADC and SCC, which may be an important factor affecting the outcome of neoadjuvant immunotherapy. Li et al. (33) suggested that the MPR rate of SCC was 45.5% (15/33), which is significantly better than that of ADC (0/6). Gao et al. (10) suggested that squamous cell NSCLC exhibited superior response compared to ADC (MPR: 48.4% vs. 0%). However, Tong et al. (34) showed that ADC (50%) had a higher proportion of MPR compared with SCC (12.5%). In this study, we compared the pathological and radiological response rates of SCC and ADC across ICI monotherapy, chemo-immunotherapy, and a comprehensive analysis of both treatment modalities. Upon conducting a comprehensive analysis of both treatment modalities, our findings indicate that SCC showed a higher pathological response compared to ADC, albeit without significant difference, and significantly outperformed ADC in terms of the ORR.
At present, it was generally believed that the therapeutic effect of neoadjuvant chemo-immunotherapy was better than that of neoadjuvant ICI monotherapy (35-37). The advantage of integrating chemotherapy with immunotherapy lied in its ability to boost the immune system’s capacity for antigen presentation, which was crucial in the more effective identification and elimination of cancer cells (38). Reports on the comparative synergetic effects in SCC and ADC were rare. This study revealed that both SCC and ADC exhibited improved pathological response rates when chemotherapy complements immunotherapy. Notably, ADC demonstrated statistically significant pathological differences, unlike SCC. Such findings indicated a potentially greater benefit from neoadjuvant chemo-immunotherapy in ADC cases.
In this study, we also investigated whether there is an optimal ICI type for the efficacy of neoadjuvant immunotherapy on ADC and SCC. The results showed patients treated with toripalimab had higher ORR rate, compared with nivolumab, sintilimab and pembrolizumab. However, superiority in radiological response did not necessarily signify a better treatment option, as the pathological response, which was more closely associated with OS (39,40). The sample size for toripalimab in this study was relatively small, necessitating additional data to validate its therapeutic effects. Additionally, it was noted that patients with SCC showed a more favorable pathological response than those with ADC when both groups were treated with pembrolizumab. This underscores the importance of taking the histological type of the tumor into consideration when choosing immunotherapy plans, to ensure that patients are provided with the treatment most suitable for their specific type of cancer.
There are some limitations in this study. Given the early stage of neoadjuvant treatments at the time of this research, data on long-term outcomes such as 3-year disease-free survival (DFS) and OS for SCC and ADC were scarce. This focus on pre-operative imaging improvements and post-operative pathological response rates, without detailed DFS and OS data by histological subtype, restricts the scope of efficacy indicators that can be explored, highlighting a critical area for future studies.
Conclusions
In conclusion, this systematic review and meta-analysis represented the first to compare the efficacy of neoadjuvant immunotherapy in SCC vs. ADC. Our findings indicate that SCC patients exhibited higher ORR and lower SD and PD than those with ADC. Despite this, no significant differences in pathological response were observed between ADC and SCC patients, regardless of whether they received ICI monotherapy or chemo-immunotherapy. Notably, chemo-immunotherapy significantly improved the McPR in ADC. Among various ICIs, toripalimab showed a higher ORR for both SCC and ADC without a clear advantage in pathological remission across the ICIs. However, pembrolizumab stood out for its higher McPR in SCC than in ADC, suggesting its preferential efficacy in treating SCC patients.
Acknowledgments
Funding: This work was supported by
Footnote
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