Carboplatin

The MTT colorimetric assay, which measures metabolic activity of viable cells, was used to generate growth curves and determine the chemosensitivity of the cell lines.
First, growth curves were generated in duplicate to determine the optimal number of cells to use for the drug sensitivity assay. This was done to avoid growth inhibition due to seeding not enough cells or depletion of the medium after seeding too many cells. The highest number of cells showing continuing exponential growth after five days was selected for the drug response MTT assays (Table S1, File S1).
Response curves were generated for Carboplatin, Cisplatin, Oxaliplatin, Doxorubicin and 5-Fluorouracil (Intravenous solutions, Pharmachemie, The Netherlands), Paclitaxel (Intravenous solution, Ebewe Pharma, Austria), Docetaxel (dissolved in DMSO, Sigma), and Gemcitabin (for intravenous use, dissolved in PBS, Sun Pharmaceutical Industries Europe BV, The Netherlands). Cell viability was assessed in quadruplicate using the MTT assay after a five day exposure to 18 concentrations of the compound. Phoenix WinNonLin 1.1 software (Pharsight) was used to fit a dose response curve and to calculate the 50% growth inhibition values (GI50) with error and 95% confidence intervals (see also File S1).

The target population was Chinese adults (aged ≥ 18 years) who had pathologically confirmed stage IIIB–IV wild-type sq-NSCLC with unlimited PD-L1 expression. The population received no previous systemic therapy. We modeled a hypothetical cohort with the same baseline characteristics as the patients enrolled in the original clinical trials. For dosage calculation, the body surface area and creatinine clearance rate were assumed as 1.72 m² and 70 ml/min (22 (link)). According to the CSCO 2022 (21 ), the first-level recommended first-line regimens for performance status (PS) 0–1 patients with advanced sq-NSCLC and unlimited PD-L1 expression include cisplatin or carboplatin combined with gemcitabine, docetaxel, or paclitaxel (standard chemotherapy), nedaplatin combined with docetaxel (N + C), paclitaxel and platinum combined with pembrolizumab (P + C), paclitaxel and platinum combined with tislelizumab (T + C), paclitaxel and platinum combined with camrelizumab (CA + C), platinum combined with gemcitabine and sintilimab (SI + C), paclitaxel and platinum combined with sugemalimab (SU + C). Among these seven first-line therapies, T + C, CA + C, SI + C, and SU + C were newly approved for sq-NSCLC since 2021 in China. Nivolumab, tislelizumab and docetaxel are first-level recommended second-line treatments options for these patients, and tislelizumab was newly approved in 2022 for second-line treatment of sq-NSCLC. Because of the possible resistance among PD-1/PD-L1 drugs, few clinical applications and evidence, we did not consider cases where immune checkpoint inhibitors were used in the first- and second-line treatments simultaneously. Therefore, we assessed 11 treatment strategies (see Figure 1): 1. first-line N + C followed by second-line docetaxel (ND); 2. first-line N + C followed by second-line tislelizumab (NT); 3. first-line N + C followed by second-line nivolumab (NN) (16 (link)); 4. first-line standard chemotherapy followed by second-line docetaxel (CD); 5. first-line standard chemotherapy followed by second-line tislelizumab (CT); 6. first-line standard chemotherapy followed by second-line nivolumab (CN) (10 (link)–13 (link), 16 (link), 20 (link)); 7. first-line P + C followed by second-line docetaxel (PED) (13 (link)); 8. first-line SI + C followed by second-line docetaxel (SID) (12 (link)); 9. first-line CA + C followed by second-line docetaxel (CAD) (11 (link)); 10. first-line T + C followed by second-line docetaxel (TID) (20 (link)); 11. first-line SU + C followed by second-line docetaxel (SUD) (10 (link)). According to randomized clinical trials (RCTs) (23 (link), 24 (link)), clinical diagnosis, and treatment experience (25 (link), 26 (link)), the PS of patients with advanced sq-NSCLC tends to be poor after two-line active treatments. Therefore, the best supportive treatment (BSC) accounts for the largest proportion of third-line treatment, surpassing sum of other active treatments' proportions. Thus, patients with disease progression after the first- and second-line treatments were assumed to receive the BSC in this model. Standard chemotherapy and docetaxel were used as comparators for first-line and second-line treatments, respectively. We explored the impact of uncertainty about the third-line treatment on the results by scenario analysis. Specific medication, dosages, treatment durations are provided in the Supplementary material 1.

The costs of implementing each treatment were derived the perspective of Chinese healthcare system. All cost data were inflated to 2022, shown as 2022 US dollars (1 USD = 6.36 Chinese Yuan). We considered only direct medical costs, including drug costs, follow-up costs, monitoring costs, death costs, and costs for treatment of adverse reactions (AEs). Drug prices were obtained from the latest local public bid-winning price or public databases (41 –43 ). The prices of camrelizumab used in first-line or tislelizumab used in second-line were assumed to be the same as other indications of them which have entered the NRDL, considering the newly approved indication of sq-NSCLC would likely to be included in the list and the price is the same for all indications of the same drug in the NRDL. Prices for paclitaxel and gemcitabine were from the fifth batch of bids for centralized drug procurement of drugs in China in 2021 (41 –43 ). Because carboplatin, cisplatin, paclitaxel, docetaxel, and nedaplatin have multiple dosage forms in the Chinese market, we chose the commonly used dosage combination under the principle of minimizing cost. Follow-up costs and monitoring costs were derived from the healthcare documents (44 ), which included CT examination, blood test, urinalysis, and blood biochemical examination, as wells as diagnosis fee, injection fee, nursing fee, and bed fee. Costs of BSC and end-of-life were extracted from published literature. We considered only severe AEs (≥grade 3) with rates >5%. AE related treatment costs and durations of AE were extracted from published articles. All AEs were assumed to occur during the first cycle (45 (link)). Details are listed in Table 1.

Relative efficacy of the different treatments compared to the reference treatments were assessed by network meta-analysis (NMA). Briefly, we systematically searched PubMed, Embase, ClinicalTrials.Gov, European Society for Medical Oncology, American Society of Clinical Oncology, and World Conference on Lung Cancer databases as of May 2022 (27 –31 ). Bayesian parametric survival NMA was used to synthesize survival data from eligible trials. Details of the eligibility criteria, search strategies are provided in Supplementary material 2. We conducted three NMAs in our study. For the NMA of first-line PFS, we estimated the time-varying hazard ratios (HRs) between the combination therapies N + C, P + C, T + C, CA + C, SI + C or SU + C and standard chemotherapy. Then, the expected survival curves for the combination therapies were derived by applying the HRs to the Kaplan-Meier survival curves for standard chemotherapy (reference treatment). The reference PFS curve for the first-line was derived from the CameL-sq, in which the final rate of the PFS was 5% (11 (link)). For this analysis, in the platinum- and paclitaxel-based chemotherapy regimens, cisplatin and carboplatin, and paclitaxell, gemcitabine, and docetaxel were not differentiated because their prices were similarly low and their survival outcomes were almost the same, and these drugs were used in similar capacities in common clinical practice (6 (link), 32 (link), 33 (link)). Similar to the first-line NMA, for the second-line NMAs of PFS and OS, we estimated the HRs between nivolumab, tislelizumab and docetaxel. The referred PFS and OS curves were extracted from the docetaxel in Checkmate-078 China (final rates of PFS and OS were < 3 and 5% for docetaxel) (23 (link), 24 (link)). We also considered natural mortality after the plateau at the end of the survival curves, which were extracted from China's 6th National Census (34 ). The original PFS and OS curves used in this study are presented in Supplementary material 2.