Two versus three to four cycles of neoadjuvant immunochemotherapy for stage IB–IIIB non-small cell lung cancer: a real-world study

Introduction

Among malignant tumors, lung cancer has the highest incidence rate—accounting for 12–13% of new invasive cancers—while its mortality rate is also high, with approximately 22–23% of cancer deaths being attributable to lung cancer (1). About 80–85% of cases of lung cancer are non-small cell lung cancer (NSCLC), which mainly consists of the lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large cell carcinoma subtypes (2).

In recent years, immunotherapy based on programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) immune checkpoint inhibitors (ICIs) has made significant progress in the treatment of NSCLC. The findings of KEYNOTE-024, KEYNOTE-042, IMPOWER-110, and CheckMate-017 trialed have revealed that immunotherapy as first-line treatment for patients with metastatic or advanced NSCLC can provide superior survival benefit over chemotherapy (3-6). Meanwhile, the results of the KEYNOTE-189, KEYNOTE-407, IMPOWER-130, IMPOWER-131, and IMPOWER-150 trials demonstrated that immunochemotherapy as first-line treatment for patients with metastatic or advanced NSCLC could yield significantly longer survival than could chemotherapy alone (7-11). Additionally, in the CheckMate-816 and NADIM II trials, immunochemotherapy as first-line treatment for patients with stage IB–IIIB NSCLC resulted in longer survival than did chemotherapy (12,13). Neoadjuvant immunochemotherapy can shrink the tumor, possibly resulting in the downstaging of the disease, and subsequent tumor resection can remove the tumor more thoroughly, providing better outcomes.

Although neoadjuvant immunotherapy has been proven to be effective and safe for the treatment of NSCLC, a consensus regarding the optimal number of cycles of neoadjuvant immunochemotherapy for patients with IB–IIIB NSCLC remains elusive. A short neoadjuvant treatment cycle may not exert a significant therapeutic effect, while an excessive number of treatment cycles may lead to delayed surgery and even disease progression. Most clinical trials related to neoadjuvant immunochemotherapy have employed 2–4 cycles, but few studies have compared the efficacy and safety of different number of neoadjuvant immunochemotherapy cycles in the treatment of stage IB–IIIB NSCLC. The results of the neoSCORE study indicated that 3 cycles of neoadjuvant immunochemotherapy could lead to a higher an MPR compared to two cycles of neoadjuvant immunochemotherapy (14). Moreover, Deng et al. reported that patients subjected to 3 or 4 cycles of neoadjuvant immunochemotherapy had higher MPR rates compared to those treated with 2 cycles (15). The above-mentioned studies consist principally of small-sample clinical studies, and the efficacy of these regimens has not been examined extensively in real-world contexts. Therefore, we conducted this real-world study to compare the efficacy and safety of 3–4 cycles and 2 cycles of neoadjuvant immunochemotherapy in patients with stage IB–IIIB NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2256/rc).

Methods

Study design and patients

This retrospective study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine [2021 Investigator Initiated Trials (IIT) No. 844] and complied with the Helsinki Declaration (revised in 2013) and Good Clinical Practice Guidelines. Informed consent was waived for the retrospective data by the Clinical Research Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. This retrospective study consecutively selected 18 to 80-year-old patients with stage IB–IIIB NSCLC [according to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging (16)] who received 2–4 cycles (3 weeks per cycle) of neoadjuvant immunochemotherapy at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine from our previous clinical studies on neoadjuvant therapy for lung cancer between 2019 and 2022. Patients with incomplete information on hospital records, previous anticancer treatment, and other malignant tumors or distant metastases were excluded. Included patients were divided into two groups according to neoadjuvant treatment courses: a 2-cycle group and a 3 to 4-cycle group. Propensity score matching (PSM) was conducted at a 1:1 ratio according to baseline characteristics [age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, tumor location, T stage, N stage, clinical stage, smoking status, drinking status, comorbidities, pathology, and immunotherapy regimens] to balance the confounding factors between the two groups.

Procedures

Before neoadjuvant therapy and surgery, systematic imaging assessments including chest computed tomography (CT), positron emission tomography-CT (PET-CT), endoscopic ultrasound, brain magnetic resonance imaging (MRI), and abdominal ultrasound, were performed in all patients. During neoadjuvant therapy, chest CT was conducted every cycle until surgery or until the patient abandoned treatment. After surgical resection, we performed imaging evaluations on patients every 1–3 months.

The immunotherapy regimen was comprised of camrelizumab (200 mg), nivolumab (200 mg), durvalumab (1,000 mg), sintilimab (200 mg), tislelizumab (200 mg), or pembrolizumab (200 mg). The chemotherapy regimen consisted of platinum, including cisplatin/carboplatin [75 mg/m²; area under the curve (AUC) of the plasma concentration-time curve after a single dose =5] or nedaplatin (80 mg/m²) combined with paclitaxel (albumin-bound paclitaxel; 260 mg/m²).

Surgery is usually performed 4 weeks after the last neoadjuvant immunochemotherapy. Surgical approaches included open radical surgery, video-assisted thoracoscopic surgery (VATS), and robot-assisted thoracoscopic surgery (RATS) with routine lymph node dissection. Patients continued to receive chemotherapy plus immunotherapy after surgery until the full 6 cycles, and then continued to receive immunotherapy alone for 1–2 years or until disease progression. The follow-up period was required to be at least 1 year after surgery or when the patient decided to cancel treatment.

Assessments

The primary endpoints were objective response rate (ORR) and pathological response [pathological complete remission (pCR) and MPR]. We adopted the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) (17) to evaluate the ORR (no less than 30% reduction in the total diameter of target lesions). MPR was defined as residual viable cancer cells ≤10% in the original tumor area. The definition of pCR was no residual viable cancer cells in the original tumor area.

The secondary endpoints were adverse events (AEs), disease-free survival (DFS), and overall survival (OS). AEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (18). DFS was defined as the time from surgery to disease progression or death. OS was defined as the time from surgery to death for any cause. DFS and OS were evaluated among patients who underwent surgical resection.

Statistical analysis

Categorical variables are expressed as the frequencies (percentages), and differences between groups were compared with the Chi-squared test or the Fisher exact test. Continuous variables are shown the as median and interquartile range (IQR), and differences between groups were compared with the t-test or Wilcoxon test. DFS and OS were evaluated via the Kaplan-Meier method, and differences between groups were compared with the stratified log-rank test. Statistical analyses were performed with R software version 4.1.2 (The R Foundation for Statistical Computing) and GraphPad Prism version 9.0 (GraphPad Software, Boston, MA, USA) was used to plot the results. A two-sided P value <0.05 was considered to be significant.

Results

Baseline characteristics

Characteristics at baseline are listed in Table 1. Our study included 184 patients treated from 2019 to 2022 and were divided into two groups: 2 cycles (n=61) and 3–4 cycles (n=123). There were significant differences between the two groups in terms of smoking status and drinking status. After 1:1 PSM, 108 patients (54 pairs) were analyzed, and no significant differences were observed between the two groups in terms of age, sex, ECOG performance status, tumor location, T stage, N stage, clinical stage, smoking status, drinking status, comorbidities, pathology, or immunotherapy regimens.

Response to neoadjuvant therapy

The maximum diameter of the target tumor was reduced in most patients in the two groups after comparing with the baseline tumor size (Figure 1A,1B). A significant decrease in maximum diameter was observed at the end of cycle 2 (Figure 1C,1D), 3 (Figure 1E,1F), and 4 (Figure 1G,1H) compared to the baseline measure. Tumor diameters also decreased significantly after the third cycle (Figure 1I,1J) and the fourth cycle (Figure 1K,1L) of treatment as compared with the end of the second cycle.

Figure 1 Tumor regression before and after propensity score matching. (A) The percentage change of the maximum diameter in the target lesion from the baseline to the end of the last neoadjuvant immunochemotherapy cycle before matching. (B) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the last neoadjuvant immunochemotherapy cycle after matching. (C) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the second cycle of neoadjuvant immunochemotherapy in patients who received 2 cycles of neoadjuvant immunochemotherapy before matching. (D) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the second cycle of neoadjuvant immunochemotherapy in patients who received 2 cycles of neoadjuvant immunochemotherapy after matching. (E) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the third cycle of neoadjuvant immunochemotherapy in patients who received 3 cycles of neoadjuvant immunochemotherapy before matching. (F) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the third cycle of neoadjuvant immunochemotherapy in patients who received 3 cycles of neoadjuvant immunochemotherapy after matching. (G) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the fourth cycle of neoadjuvant immunochemotherapy in patients who received 4 cycles of neoadjuvant immunochemotherapy before matching. (H) The percentage change of the maximum diameter in the target tumor from the baseline to the end of the fourth cycle of neoadjuvant immunochemotherapy in patients who received 4 cycles of neoadjuvant immunochemotherapy after matching. (I) The percentage change of the maximum diameter in the target tumor from the end of the second cycle to the end of the third cycle of neoadjuvant immunochemotherapy in patients who received 3 cycles of neoadjuvant immunochemotherapy before matching. (J) The percentage change of the maximum diameter in the target tumor from the end of the second cycle to the end of the third cycle of neoadjuvant immunochemotherapy in patients who received 3 cycles of neoadjuvant immunochemotherapy after matching. (K) The percentage change of the maximum diameter in the target tumor from the end of the second cycle to the end of the fourth cycle of neoadjuvant immunochemotherapy in patients who received 4 cycles of neoadjuvant immunochemotherapy before matching. (L) The percentage change of the maximum diameter in the target tumor from the end of the second cycle to the end of the fourth cycle of neoadjuvant immunochemotherapy in patients who received 4 cycles of neoadjuvant immunochemotherapy after matching.

Before matching, there were no cases of progressive disease (PD) (at least 20% enlargement in the total diameter of the target lesion or the emergence of new lesions according to the RECIST 1.1) in the 3 to 4-cycle group and 1 case of PD in the 2-cycle group (Figure 2A). The ORR in the 3 to 4-cycle group and 2-cycle group was 75.6% and 60.7% (P=0.051), respectively. After matching, there were no cases of PD in the two groups (Figure 2B). The ORR in the 3 to 4-cycle group was significantly higher than that in the 2-cycle group (83.3% vs. 63.0%; P=0.01).

Figure 2 Clinical and pathological response before and after propensity score matching. Before matching: (A) CR, PR, SD, and PD; (C) MPR; and (E) pCR. After matching: (B) CR, PR, SD, and PD; (D) MPR; and (F) pCR. Clinical response included CR, PR, SD, and PD; pathological response included MPR and pCR. CR, complete response; MPR, major pathological response; pCR, pathological complete remission; PD, progressive disease; PR, partial remission; SD, stable disease.

AEs

No previously unreported AEs found in this study. The grade 3–4 AEs from neoadjuvant treatment are included in Table 2. Before matching, the incidence of grade 3–4 AEs in the 2-cycle group was 8.2% and 18.7% in the 3 to 4-cycle group (P=0.06), respectively. After matching, the incidence of grade 3–4 AEs in the 2-cycle group and 3 to 4-cycle group was 9.3% and 13.0% (P=0.54), respectively. Before or after matching, there exist no significant differences in the occurrence of grade 3–4 AEs among the two groups, and symptomatic treatment can quickly resolve all AEs.

Surgical outcomes and pathological response

Surgical outcomes and postoperative complications are listed in Table 3. The surgical resection rate in the 3 to 4-cycle group was lower than the 2-cycle group. The reason for patients who did not undergo surgery was that patients were reluctant to receive surgery and chose to maintenance immunotherapy. In the 3 to 4-cycle group, this type of patient accounts for a higher proportion and there were more advanced tumors. Before matching, we observed significant differences in the surgical approach and length of hospital stay (P<0.05). The proportion of minimally invasive surgery in the 3 to 4-cycle group was higher than that in the 2-cycle group. The length of hospital stay in the 3 to 4-cycle group was shorter than that in the 2-cycle group. There were no significant differences in the other surgical outcomes. After matching, there were no significant differences in the surgical approach and method, operation time, blood loss, resection margin, number of lymph node dissections during surgery, length of hospital stay, pathological grade, or post-neoadjuvant pathologic tumor-node-metastasis (ypTNM) stage between the two groups.

Before matching, the rate of MPR in the 3 to 4-cycle group and the 2-cycle group was 60.7% and 67.9%, respectively (P=0.42; Figure 2C). After matching, the rate of MPR in the 3 to 4-cycle group and 2-cycle group was 68.0% and 69.4%, respectively (P=0.90; Figure 2D). Before matching, the rate of pCR in the 3 to 4-cycle group and 2-cycle group was 31.1% and 41.1%, respectively (P=0.26; Figure 2E). After matching, the rate of pCR in the 3 to 4-cycle group and 2-cycle group was 36.0% and 38.8%, respectively (P=0.82; Figure 2F).

Overall, no perioperative deaths occurred. Before matching, the incidence of postoperative complications in the 3 to 4-cycle group and 2-cycle group was 34.4% and 50.0%, respectively (P=0.09). The incidence of hydrothorax in the 2-cycle group was significantly higher than that in the 3 to 4-cycle group (32.1% vs. 14.8%; P=0.03), but there were no significant differences in the other postoperative complications. After matching, the incidence of postoperative complications in the 3 to 4-cycle group and the 2-cycle group was 36.0% and 46.9%, respectively (P=0.33), and there were no significant differences in the incidence of any postoperative complications.

Survival

Before matching, the median DFS (Figure 3A) in the 3 to 4-cycle group and 2-cycle group was not reached [hazard ratio (HR): 1.45, 95% confidence interval (CI): 0.68–3.11; P=0.34]. The 1-year DFS rate, 2-year DFS rate, and 3-year DFS rate in the 2-cycle group were 83.9%, 75.0% and 69.6%, respectively, while those in the 3 to 4-cycle group were 86.9%, 82.0%, and 82.0%, respectively. The median OS (Figure 3B) in the 3 to 4-cycle group and 2-cycle group was not reached (HR: 1.29, 95% CI: 0.53–3.13; P=0.57). The 1-year OS rate, 2-year OS rate, and 3-year OS rate in the 2-cycle group were 92.9%, 80.4%, and 78.6%, respectively, while those in the 3 to 4-cycle group were 93.4%, 86.9%, and 86.9%, respectively.

Figure 3 Kaplan-Meier curves of DFS and OS of the 2-cycle and 3 to 4-cycle groups before and after propensity score matching. Before matching: Kaplan-Meier curves of DFS (A) and OS (B) of the 2-cycle and 3 to 4-cycle groups. After matching: Kaplan-Meier curves of DFS (C) and OS (D) of the 2-cycle and 3 to 4-cycle groups. DFS, disease-free survival; OS, overall survival.

After matching, the median DFS (Figure 3C) in the 3 to 4-cycle group and 2-cycle group was not reached (HR: 1.13, 95% CI: 0.43–2.97; P=0.80). The 1-year DFS rate and 2-year DFS rate in the 2-cycle group were 87.8% and 77.6%, respectively, while those in the 3 to 4-cycle group were 80.0% and 76.0%, respectively. The median OS (Figure 3D) in the 2-cycle group was 42.4 months [95% CI: not arrived (NA)–NA] and was not reached in the 3 to 4-cycle group (HR: 1.56, 95% CI: 0.53–4.59; P=0.42). The 1-year OS rate and 2-year OS rate in the 2-cycle group were 93.9% and 87.8%, respectively, while those in the 3 to 4-cycle group were 88.0% and 80.0%, respectively.

Discussion

In most recent studies on neoadjuvant immunotherapy or immunochemotherapy, only regimens of 2 to 4 cycles have been examined. For instance, the CheckMate159, NEOSTAR, and LCMC3 studies used 2 cycles of neoadjuvant immunotherapy in treating patients with stage IA–IIIA NSCLC (19-21). Wang et al. adopted 2 cycles of neoadjuvant immunochemotherapy for stage IIIA NSCLC treatment (22), while the NADIM, SAKK16/14, NADIM II, and CheckMate-816 trials used 3 cycles of neoadjuvant immunochemotherapy for stage IB–IIIA NSCLC treatment (12,13,23,24). Meanwhile, Shu et al. conducted a study on stage IIA–IIIA NSCLC in which 4 cycles of neoadjuvant immunochemotherapy were used (25). However, there remains no consensus on the optimal number of cycles of neoadjuvant immunochemotherapy for treating patients with stage IB–IIIB NSCLC. Additionally, few studies have compared the efficacy and safety of different numbers of neoadjuvant immunochemotherapy cycles in the treatment of stage IB–IIIB NSCLC. The neoSCORE study compared 3 cycles of neoadjuvant immunochemotherapy with 2 cycles of neoadjuvant immunochemotherapy in stage IB–IIIA NSCLC (14); meanwhile, Deng et al. compared 3–4 cycles of neoadjuvant immunochemotherapy with 2 cycles of neoadjuvant immunochemotherapy in stage III (IIIA, IIIB, IIIC) NSCLC (15). Therefore, in our real-world retrospective analysis, we compared the efficacy and safety between 3–4 cycles and 2 cycles of neoadjuvant immunochemotherapy in patients with stage IB–IIIB NSCLC.

In the neoSCORE study (14), the ORR in the 2-cycle and 3-cycle arm was 50.0% and 55.2% (P=0.701), the MPR rate was 26.9% and 41.4%, (P=0.260), and the pCR rate was 19.2% and 24.1% (P=0.660), respectively. Meanwhile, Deng et al. (15) reported that MPR rates in the neoadjuvant treatment groups treated with 2 cycles, 3 cycles, and 4 cycles were 44.8%, 61.4%, and 66.7% (P=0.189), respectively. In the NADIM study (23), the MPR rate was 76.1% and the pCR rate 54.3% after 3 cycles of neoadjuvant therapy. In Forde et al.’s study (19), the MPR and pCR rates were 45% and 15%, respectively, after 2 cycles of neoadjuvant therapy. Moreover, in Shu et al.’s study (25), the MPR rate was 57% and the pCR rate 33% after 4 cycles of neoadjuvant therapy. These outcomes are generally lower than those in our study, in which we found that 3 to 4 cycles of neoadjuvant immunochemotherapy resulted in more pronounced tumor regression than did 2 cycles. Tumor diameters also shrank significantly after treatment in the third cycle and the fourth cycle as compared to after the second cycle. The ORR in the 3 to 4-cycle group was significantly higher than that in the 2-cycle group (83.3% vs. 63.0%; P=0.01). Therefore, for patients who are able to undergo surgery after 2 cycles of neoadjuvant immunotherapy, surgery should be considered; otherwise, extending the number of cycles to 3–4 is feasible. There were no differences in the rates of MPR and pCR. The MPR rate in the 3 to 4-cycle group and 2-cycle group was 68.0% and 69.4% (P=0.90) while the pCR rate in these groups was 36.0% and 38.8% (P=0.82), respectively, which differed from those reported in previous studies (14,15,23). This discrepancy might be due to the variability in population and immunotherapies applied.

In the study, we found that the survival benefits of neoadjuvant immunochemotherapy were similar in the 3 to 4-cycle group and the 2-cycle group. The 1-year DFS rate and 2-year DFS rate in the 2-cycle group were 87.8% and 77.6%, respectively, while those in the 3 to 4-cycle group were 80.0% and 76.0%, respectively. The 1-year OS rate and 2-year OS rate in the 2-cycle group were 93.9% and 87.8%, respectively, while those in the 3 to 4-cycle group were 88.0% and 80.0%, respectively. Most studies on this subject have compared the short-term efficacy across different cycles of neoadjuvant therapy, but to our knowledge, ours is the first real-world retrospective study to assess the long-term efficacy of 2 and 3–4 cycles of neoadjuvant immunochemotherapy in patients with IB–IIIB NSCLC.

We found no significant differences in the incidence of grade 3–4 AEs between the two groups, with incidences of 7% and 13.6% in the 2-cycle group and 3 to 4-cycle group, respectively. In the neoSCORE study (14), 31.0% of patients in the 2-cycle arm and 29.0% of patients in the 3-cycle arm had grade ≥3 treatment-related AEs. In the CheckMate-816 study (13), the incidence of grade 3–4 AEs was 40.9% after 3 cycles of immunochemotherapy, while in the NADIM II study (12), the incidence was 19% after the same number of cycles. Shen et al. (26) reported an incidence of grade 3 AEs of approximately 10.8% after 4 cycles of immunochemotherapy. The differences in the incidence of AEs between these studies may be due to variability in treatment cycles, populations, and treatment regimens.

Our study has certain limitations, which should be noted. First, we employed a retrospective design with a small sample size, which may limit the statistical power of our findings. Second, there was heterogeneity between patients and treatment regimens, which might have contributed to the difference in outcomes. Therefore, larger-scale, randomized controlled trials and prospective trials are needed to further validate our results, with further follow-up being needed to evaluate the long-term outcomes.

Conclusions

Three to four cycles of neoadjuvant immunochemotherapy can result in more tumor regression in IB–IIIB NSCLC. Extending the number of cycles to 3–4 cycles may be feasible and safe in IB–IIIB NSCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2256/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2256/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2256/prf

Funding: This research was supported by the Key R&D Program of Zhejiang (No. 2023C03172), the National Key Research and Development Program of China (No. 2022YFC2407303), and Research Center for Lung Tumor Diagnosis and Treatment of Zhejiang Province (No. JBZX-202007).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2256/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Informed consent was waived for the retrospective data by the Clinical Research Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. This study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (2021 IIT No. 844) and conducted in accordance with the Declaration of Helsinki (as revised in 2013) and Good Clinical Practice Guidelines.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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