Sintilimab and Docetaxel Treatment Comparison in Advanced Lung Cancer
Lung cancer is the leading cause of cancer death worldwide. In China, it is estimated that there were 815,563 new cases of lung cancer and 714,699 deaths in 2020. Squamous-cell non-small-cell lung cancer (sqNSCLC) accounts for about 30% of all NSCLC cases. Most targeted therapies are ineffective for sqNSCLC because it does not have any actionable genetic changes. The standard treatment for advanced sqNSCLC is platinum-based chemotherapy. However, there are limited options for patients who do not respond to first-line chemotherapy. Docetaxel is the standard second-line treatment for sqNSCLC, but it has a median overall survival (OS) of only about 6 months. Immune checkpoint inhibitors, such as PD-1 or PD-L1 inhibitors, have been shown to improve OS compared to docetaxel in patients with second-line advanced NSCLC.
However, no randomized clinical trials have been conducted in Chinese patients with sqNSCLC who are receiving second-line anti-PD-1/PD-L1 treatment. Sintilimab is a fully human IgG4 monoclonal PD-1 antibody that has shown improved survival benefits when combined with platinum-based chemotherapy for both sqNSCLC and non-sqNSCLC patients in the first-line setting.
The Study
The ORIENT-3 study was conducted to assess the effectiveness and safety of sintilimab compared to docetaxel as a second-line treatment for Chinese patients with locally advanced or metastatic sqNSCLC. The ORIENT-3 trial was a phase 3, open-label, randomized controlled trial conducted at 39 medical centers in China. The trial enrolled patients with locally advanced, metastatic, or recurrent squamous-cell non-small-cell lung cancer (sqNSCLC) of stages IIIB, IIIC, or IV who had progressed or recurred after first-line platinum-based chemotherapy.
The inclusion criteria were:
- Confirmed histological or cytological diagnosis of sqNSCLC
- Age 18 to 75 years
- At least one measurable lesion by RECIST v1.1
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of at least 12 weeks
- Satisfactory major organ functions
The exclusion criteria were:
- EGFR-sensitive mutation or ALK rearrangement
- Adenosquamous carcinoma of the lung
- Previous treatment with anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies, or docetaxel
- Symptomatic central nervous system metastasis and/or carcinomatous meningitis
- Active autoimmune disease (whether inherited or acquired)
- Interstitial lung disease
Patients were randomized 1:1 to receive sintilimab or docetaxel. The randomization was performed using a centralized system called Medidata-rtsm. A statistician, who was independent of the study sponsor, generated the randomization list. Minimization was used to ensure balance between the groups, with ECOG performance status (0 or 1) as a stratification factor. The treatment assignments were not disclosed to the participants or investigators to maintain the study’s integrity.
Procedure
Patients were administered intravenous infusions of either sintilimab or docetaxel. Treatment continued until disease progression, death, intolerable toxicity, consent withdrawal, initiation of new anti-cancer therapy, or other protocol-specified reasons. Sintilimab treatment after initial radiographic disease progression was possible if clinically justified by investigators. The primary trial endpoint was overall survival (OS), which referred to the time from randomization to death from any cause. Secondary endpoints encompassed progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR).
Safety evaluation encompassed the following aspects:
- Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0.
- Adverse event severity was assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
- The PD-L1 tumor proportion score (TPS) was determined using the 22C3 pharmDx assay.
- Quality of life (QoL) was gauged through EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 questionnaires.
- RNA and cell-free DNA (cfDNA) were extracted from tumor and blood samples, respectively, and underwent sequencing.
Statistical analysis utilized SAS version 9.4 and R version 3.6.1. Normal distribution continuous data were presented as mean ± standard deviation or median (min, max). Categorical data were expressed as numbers and percentages. The Kaplan-Meier method estimated median and 95% CI for OS, PFS, and DoR, with survival curves plotted. The stratified log-rank test compared groups, and the stratified Cox proportional hazard regression model estimated hazard ratios (HR), including randomization’s stratification factors. Fisher’s exact test evaluated ORR and DCR differences.
Exploratory biomarker analysis was conducted using tissue/blood sequencing data. Among 157 sequenced patients, 110 samples comprised the biomarker evaluable population (BEP) for downstream analysis. Survival-related gene screening involved dividing BEP into high/low expression groups based on gene median values. Cox regression analysis derived HR and unadjusted P values for each treatment arm’s high/low BEP groups. Genes with P < 0.05 were considered potential survival-related genes. Gene set signature scores were calculated using the GSVA algorithm for screening survival-related gene signatures. Survival curves were generated using the R survminer package.
Results
A total of 368 patients were screened for the ORIENT-3 trial, and 290 were randomized to receive sintilimab or docetaxel. The median follow-up duration was 23.56 months. The efficacy analysis was based on the Full Analysis Set (FAS), which included 280 patients: 145 in the sintilimab group and 135 in the docetaxel group.
Ten patients from the docetaxel group were excluded from the FAS because they received anti-PD-1/PD-L1 therapy before documented disease progression after randomization. The safety set included 144 patients from the sintilimab arm and 130 from the docetaxel arm who had received at least one dose of study treatment. The median treatment duration was 8 cycles for sintilimab and 2 cycles for docetaxel. The reasons for treatment discontinuation were mainly disease progression and adverse events. The median overall survival (OS) was 11.79 months for sintilimab and 8.25 months for docetaxel. Sintilimab demonstrated a significant OS improvement compared to docetaxel, with a hazard ratio of 0.74. The 12-month OS rate was 49% for sintilimab and 38% for docetaxel, while the 24-month OS rate was 27% for sintilimab and 16% for docetaxel. Subgroup analysis indicated survival benefits with sintilimab across various groups, including those aged over 60 years.
Conclusion
Sintilimab exhibited a notable and statistically significant advantage in terms of survival when compared to docetaxel in the context of second-line treatment for Chinese patients grappling with advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC). Importantly, this was accompanied by a safety profile that can be effectively managed. Given these promising outcomes, sintilimab might emerge as a promising and novel treatment alternative for individuals diagnosed with locally advanced or metastatic sqNSCLC who have undergone progression, recurrence, or faced intolerance following initial platinum-based chemotherapy.
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