Sintilimab With Chemotherapy as First-line Treatment for Locally Advanced or Metastatic Squamous Non-small-cell Lung Cancer: Real-world Data Study

The ORIENT-12 study demonstrated the promising results of sintilimab combined with gemcitabine and platinum (GP) therapy in squamous non-small-cell lung cancer (sqNSCLC) patients. However, the ecacy of sintilimab plus paclitaxel/nab-paclitaxel and platinum (TP) in sqNSCLC is not yet known. Methods: Real-life data were collected from patients with untreated locally advanced or metastatic sqNSCLC who were treated with sintilimab plus TP (arm A) or sintilimab plus GP (arm B) between January 2019 and January 2021. Results: A total of 52 patients were included (arm A, n=32 and arm B, n=20). After a median follow-up of 12.1 months, the median PFS was 10.9 months (95% condence interval [CI], 5.0 to 16.7) in arm A and 7.5 months (95% CI, 4.0–10.9) in arm B (hazard ratio [HR], 0.64; 95% CI, 0.30 to 1.4; P = 0.24). The median overall survival was 20.1 months (95% CI, 13.6 to 26.6) in arm A and 16.3 months (95% CI, 2.9 to 29.6) in arm B (HR, 0.69; 95% CI, 0.26–1.84; P = 0.46). The overall response rate was 59.4% in arm A and 40.0% in arm B. Adverse events of grade 3 or higher occurred in 37.5% of the patients in arm A and 55.0% of the patients in arm B. Conclusions: Sintilimab-TP exhibits similar clinical benets compared with sintilimab-GP in patients with untreated advanced or metastatic sqNSCLC.

The present study aimed to investigate the e cacy and safety of sintilimab with chemotherapy (paclitaxel/nab-paclitaxel+platinum or gemcitabine+platinum) in real-world patients with locally advanced or metastatic sqNSCLC.

Patients
The present study was a retrospective study conducted at the First A liated Hospital of Guangzhou Medical University. The medical records of patients who received their initiated therapy between January 2019 and January 2021 were reviewed. The patients were eligible for enrollment if they had pathologically con rmed sqNSCLC without sensitizing epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations, incurable stage IIIB-IV tumors (according to the 8th edition AJCC/IASLC classi cation (Goldstraw et al. 2016)) or at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Eisenhauer et al. 2009). Patients who were treated with sintilimab plus paclitaxel/nab-paclitaxel and platinum (sintilimab-TP, arm A) or sintilimab plus gemcitabine and platinum (sintilimab-GP, arm B) in the rst line were recruited. Patients younger than 18 years old, who had received previous therapies for locally advanced or metastatic disease, or had the active autoimmune disease were excluded.

Data collection and outcome assessment
The patient data were collected retrospectively from medical les and included patient demographics, the ECOG PS, PD-L1 expression levels, tumor response to ICIs, and adverse events (AEs).
The ECOG PS was evaluated prior to treatment initiation. The evaluations of the clinical responses were performed by investigators according to the RECIST version 1.1. ORR was de ned as the proportion of patients achieving complete response (CR) and partial response (PR). The disease control rate (DCR) corresponds to all cases with CR, PR and stable disease (SD). The time to response (TTR) was de ned as the time from the initiation of sintilimab to the rst documented CR or PR. PFS was estimated as the duration from the initiation of sintilimab to disease progression or patient death. The overall survival (OS) was de ned as the time from the initiation of sintilimab to patient death. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). PFS was the primary endpoint. OS, ORR, DCR and TTR were the secondary endpoints. The nal follow-up time was April 31, 2021.

Statistical analysis
The clinical and tumor characteristics were summarized as medians and ranges for continuous variables and as frequencies and percentages for categorical variables. An independent-samples t-test or the  Table 2 and gure 1). In addition, 6.4% of the patients who received sintilimab-TP and 5.0% of those who received sintilimab-GP exhibited disease progression (Table 2 and Fig.1). The DCR was 93.6% in arm A and 95.0% in arm B. The median TTR was 2.0 months (range: 0.8-6.7) with arm A and 1.9 months (range: 0.7-3.0), respectively (Table 2).
A total of 28 events of progression or death were noted and the median PFS was estimated to 10 (Fig.3a), with a total of 19 events in the treatment population. The OS rate at 1 year was 72.9% in arm A and 53.3% in arm B. Similar OS bene ts were observed in all prespeci ed subgroups of the two treatment groups (Fig.3b).

Safety
AEs of any cause occurred in all patients in the two treatment groups ( Table 3). AEs of grade 3 or higher occurred in 37.5% of the patients in arm A and 55.0% of the patients in the arm B. The AEs led to the discontinuation of all treatment components in 3.1% and 10.0% of arms A and B, respectively and to the discontinuation of sintilimab in 12.5% and 10.0% of arms A and B, respectively. No toxicity-related deaths occurred. The most common AEs in arm A were anemia (68.8%), decreased white blood cell count (37.5%), increased alanine aminotransferase (31.3%) and decreased neutrophil count (25.0%), whereas the most common AEs in arm B were anemia (75.0%), decreased white blood cell count (40.0%), decreased neutrophil count (30.0%) and decreased platelet count (20.0%).
Immune-mediated adverse events (irAEs) occurred in 12 of 32 patients (40.6%) in arm A and in 9 of 20 patients (45.0%) in arm B; grade 3 or higher AEs occurred in 3 patients (9.1%) and one patient (5.0%), respectively. A higher number of hematological AEs was noted in arm B than in arm A, while the number of cases with hyperthyroidism, myositis, peripheral neuropathy and immune-mediated pneumonitis was higher in arm A than that in arm B. Sintilimab with TP or GP therapy was well tolerated, with a low proportion of grade 3 or higher AEs and discontinuation of treatment due to AEs. In addition, the rate of discontinuation of treatment due to AEs was lower in the sintilimab-TP group than that in the sintilimab-GP group (3.1% vs. 10.0%). The high frequencies of AEs in both groups included anemia, decreased white blood cell count and decreased neutrophil count. The incidence of these hematological AEs was considered to be related to chemotherapy and a lower number of patients were treated with sintilimab-TP than with sintilimab-GP.

Discussion
However, non-hematological AEs were higher in arm A than arm B. A previous study reported higher number of cases with anemia, neutropenia and thrombocytopenia in the TP group than that of the GP group. Notably the number of cases with grade 3 or 4 anemia and neutropenia was signi cantly higher in the TP group compared with that of the GP group (Mudad et al. 2017). The AE pro le observed in the present study was consistent with our expectations and no new adverse events were observed. The majority of AEs were resolved or improved and were manageable.
The present study exhibits certain limitations. Firstly, it was a retrospective observational study with a small sample size. A large-scale prospective cohort study should be conducted to further explore these ndings. Secondly, the results provided only a narrow time window with limited follow-up for certain patients. Our follow-up results will provide a more comprehensive analysis.
In conclusion, the present study revealed that the effectiveness of sintilimab plus platinum and gemcitabine or paclitaxel/nab-paclitaxel in a real-world setting was comparable to that reported in clinical trials. The treatment groups exhibited similar e cacy with regard to patients with untreated advanced or metastatic sqNSCLC, with safety pro les. Sintilimab combined with paclitaxel/nab-paclitaxel and platinum may be a novel option for the treatment of sqNSCLC patients. Abbreviations GP, gemcitabine+platinum; sqNSCLC, squamous non-small-cell lung cancer;TP, paclitaxel/nab-paclitaxel and platinum; PFS, progression-free survival; HR, hazard ratio; CI, con dence interval; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; ORR, objective response rate; ICIs, immune checkpoint inhibitors; EGFR, epidermal growth factor receptor; ALK, Anaplastic Lymphoma Kinase; RECIST, Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; DCR, disease control rate; SD, stable disease; TTR, time to response; OS, overall survival; AEs,     Kaplan-Meier curves of estimated progression-free survival (PFS) (a) and a Cox proportional hazards regression analysis of PFS in prespeci ed subgroups (b). CI, con dence interval; HR, hazard ratio; Sint, sintilimab; GP, gemcitabine and platinum; TP, paclitaxel/nab-paclitaxel and platinum; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1 TPS, programmed death-ligand 1 tumor proportion score.