Paclitaxel liposome for injection (Lipusu) plus cisplatin versus gemcitabine plus cisplatin in the first-line treatment of locally advanced or metastatic lung squamous cell carcinoma: A multicenter, randomized, open-label, parallel controlled clinical study

Jie Zhang, Yueyin Pan, Qin Shi, Guojun Zhang, Liyan Jiang, Xiaorong Dong, Kangsheng Gu, Huijuan Wang, Xiaochun Zhang, Nong Yang, Yuping Li, Jianping Xiong, Tienan Yi, Min Peng, Yong Song, Yun Fan, Jiuwei Cui, Gongyan Chen, Wei Tan, Aimin Zang, Qisen Guo, Guangqiang Zhao, Ziping Wang, Jianxing He, Wenxiu Yao, Xiaohong Wu, Kai Chen, Xiaohua Hu, Chunhong Hu, Lu Yue, Da Jiang, Guangfa Wang, Junfeng Liu, Guohua Yu, Junling Li, Jianling Bai, Wenmin Xie, Weihong Zhao, Lihong Wu, Caicun Zhou, Jie Zhang, Yueyin Pan, Qin Shi, Guojun Zhang, Liyan Jiang, Xiaorong Dong, Kangsheng Gu, Huijuan Wang, Xiaochun Zhang, Nong Yang, Yuping Li, Jianping Xiong, Tienan Yi, Min Peng, Yong Song, Yun Fan, Jiuwei Cui, Gongyan Chen, Wei Tan, Aimin Zang, Qisen Guo, Guangqiang Zhao, Ziping Wang, Jianxing He, Wenxiu Yao, Xiaohong Wu, Kai Chen, Xiaohua Hu, Chunhong Hu, Lu Yue, Da Jiang, Guangfa Wang, Junfeng Liu, Guohua Yu, Junling Li, Jianling Bai, Wenmin Xie, Weihong Zhao, Lihong Wu, Caicun Zhou

Abstract

Background: Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small-scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first-line treatment in locally advanced or metastatic LSCC.

Methods: Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.

Results: The median duration of follow-up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF-α, IFN-γ, IL-6, and IL-8, demonstrating an overlapping trend.

Conclusion: The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.

Trial registration: ClinicalTrials.gov NCT02996214.

Keywords: chemotherapy; cisplatin; clinical trial; gemcitabine; liposomal paclitaxel (Lipusu); locally advanced; lung squamous cell carcinoma; metastatic; multicenter; plasma cytokines.

© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

Figures

FIGURE 1
FIGURE 1
Study flowchart illustrating patients’ randomization and group allocation for the cisplatin plus lipusu and cisplatin plus gemcitabine arms
FIGURE 2
FIGURE 2
The Kaplan‐Meir curves of progression‐free survival (A) and overall survival (B) of the full analysis set stratified by treatment with LP and GP. (C) Forest plots for effects related to the bodyweight reduction (≥ 5% vs. < 5% within 6 months), age (≥ 65 vs. < 65 years; ≥ 70 vs. < 70 years), and TNM stage (IIIB vs. IV), and ECOG PS (0 versus 1) on progression‐free survival. Abbreviations: LP, cisplatin plus Lipusu; GP, cisplatin plus gemcitabine; ECOG PS, Eastern Cooperative Oncology Group performance status; ys, years; HR, hazard ratio; CI, confidence interval
FIGURE 3
FIGURE 3
The association between baseline plasma cytokines and clinical outcomes of LSCC patients from the cisplatin plus Lipusu group. (A) Heatmap of 45 cytokines in 86 treatment‐naïve LSCC patients from the cisplatin plus Lipusu group. Each row represents one cytokine and each column one patient. Patients were arranged based on the duration of PFS and were grouped by measurement of efficacy during the first evaluation. Effect_1st, efficacy during the first evaluation. Dark green, SD; yellow‐green: PR; purple, PD. The cytokine levels are log2 transformed. Darker red indicates higher cytokine levels. (B) Twenty‐seven cytokines were differentially expressed between 45 patients who achieved PR and 41 patients who had SD (n = 27) or PD (n = 14) during the first efficacy evaluation. Wilcoxon rank‐sum test, P < 0.05. (C) Forest plot of correlation between 15 cytokine levels and PFS of 86 patients from the cisplatin plus Lipusu group. Abbreviations: PFS, progression‐free survival; PR, partial response; SD, stable disease; PD, progression disease
FIGURE 4
FIGURE 4
Dynamic changes of plasma cytokines and cytokine signatures at baseline and after two cycles of cisplatin plus Lipusu therapy. (A) Plasma cytokine levels at baseline and after two cycles of cisplatin plus Lipusu therapy. (B) Plasma cytokine levels at baseline and after two cycles of cisplatin plus Lipusu therapy in 39 patients who achieved PR and 18 patients who had SD or PD. (C) Complex heatmap of plasma cytokine signatures at baseline and the dynamic changes after two cycles of cisplatin plus Lipusu therapy in 57 patients. Each row represents one cytokine signature and each column one patient. Patients were arranged based on the duration of PFS and were grouped by measurement of efficacy during the first evaluation. Effect_1st means efficacy during the first evaluation. Baseline shows the heatmap of cytokine signatures scores at baseline. All data were standardized by the Z‐score method according to row. Difference (C2‐BL) was calculated as the difference score of each cytokine signature between two cycles of cisplatin plus Lipusu therapy and baseline. Fraction was calculated as the percentage of each cytokine signature in all six signatures in one patient. Abbreviations: PFS, progression‐free survival; BL, baseline; C2, two cycles of cisplatin plus Lipusu therapy; PR, partial response; SD, stable disease; PD, progression disease

References

    1. Youlden DR, Cramb SM, Baade PD. The International Epidemiology of Lung Cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3(8):819–31.
    1. Castellanos E, Feld E, Horn L. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR‐Mutated Non‐Small Cell Lung Cancer. J Thorac Oncol. 2017;12(4):612–23.
    1. Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR‐inhibitor‐resistant patients with non‐small‐cell lung cancer. Lancet Oncol. 2015;16(9):e447–e59.
    1. Wang J, Shen Q, Shi Q, Yu B, Wang X, Cheng K, et al. Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry. J Exp Clin Cancer Res. 2014;33(1):109.
    1. Guidelines of Chinese Society of Clinical Oncology (CSCO) Non‐Small Cell Lung Cancer, 2020.
    1. NCCN Guidelines Version 5.2021 Non‐Small Cell Lung Cancer.
    1. Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, et al. Hypersensitivity reactions from taxol. J Clin Oncol. 1990;8(7):1263–8.
    1. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590–8.
    1. Straubinger RM, Sharma A, Murray M, Mayhew E. Novel Taxol formulations: Taxol‐containing liposomes. J Natl Cancer Inst Monogr. 1993(15):69–78.
    1. Sharma A, Mayhew E, Straubinger RM. Antitumor effect of taxol‐containing liposomes in a taxol‐resistant murine tumor model. Cancer Res. 1993;53(24):5877–81.
    1. Sharma A, Sharma US, Straubinger RM. Paclitaxel‐liposomes for intracavitary therapy of intraperitoneal P388 leukemia. Cancer Lett. 1996;107(2):265–72.
    1. Sharma A, Mayhew E, Bolcsak L, Cavanaugh C, Harmon P, Janoff A, et al. Activity of paclitaxel liposome formulations against human ovarian tumor xenografts. Int J Cancer. 1997;71(1):103–7.
    1. Cabanes A, Briggs KE, Gokhale PC, Treat JA, Rahman A. Comparative in vivo studies with paclitaxel and liposome‐encapsulated paclitaxel. Int J Oncol. 1998;12(5):1035–40.
    1. Xu X, Wang L, Xu HQ, Huang XE, Qian YD, Xiang J. Clinical comparison between paclitaxel liposome (Lipusu(R)) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac J Cancer Prev. 2013;14(4):2591–4.
    1. Chen G, Sheng L, Du X. Efficacy and safety of liposome‐paclitaxel and carboplatin based concurrent chemoradiotherapy for locally advanced lung squamous cell carcinoma. Cancer Chemother Pharmacol. 2018;82(3):505–10.
    1. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Perez‐Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019;120(1):6–15.
    1. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218–28.
    1. Koufos N, Michailidou D, Xynos ID, Tomos P, Athanasiadou K, Kosmas C, et al. Modulation of peripheral immune responses by paclitaxel‐ifosfamide‐cisplatin chemotherapy in advanced non‐small‐cell lung cancer. J Cancer Res Clin Oncol. 2013;139(12):1995–2003.
    1. Jia Y, Li X, Zhao C, Jiang T, Zhao S, Zhang L, et al. Impact of serum vascular endothelial growth factor and interleukin‐6 on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non‐small‐cell lung cancer. Lung Cancer. 2018;125:22–8.
    1. Suwinski R, Giglok M, Galwas‐Kliber K, Idasiak A, Jochymek B, Deja R, et al. Blood serum proteins as biomarkers for prediction of survival, locoregional control and distant metastasis rate in radiotherapy and radio‐chemotherapy for non‐small cell lung cancer. BMC Cancer. 2019;19(1):427.
    1. Lu Z, Zou J, Hu Y, Li S, Zhou T, Gong J, et al. Serological Markers Associated With Response to Immune Checkpoint Blockade in Metastatic Gastrointestinal Tract Cancer. JAMA Netw Open. 2019;2(7):e197621.
    1. Ji S, Chen H, Yang K, Zhang G, Mao B, Hu Y, et al. Peripheral cytokine levels as predictive biomarkers of benefit from immune checkpoint inhibitors in cancer therapy. Biomed Pharmacother. 2020;129:110457.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.
    1. Zhang Q, Huang XE, Gao LL. A clinical study on the premedication of paclitaxel liposome in the treatment of solid tumors. Biomed Pharmacother. 2009;63(8):603–7.
    1. Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first‐line therapy in patients with stage IV squamous non‐small‐cell lung cancer (SQUIRE): an open‐label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763–74.
    1. Paz‐Ares L, Socinski MA, Shahidi J, Hozak RR, Soldatenkova V, Kurek R, et al. Correlation of EGFR‐expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open‐label, phase III study of gemcitabine‐cisplatin plus necitumumab versus gemcitabine‐cisplatin alone in the first‐line treatment of patients with stage IV squamous non‐small‐cell lung cancer. Ann Oncol. 2016;27(8):1573–9.
    1. Wang Z, Huang C, Yang JJ, Song Y, Cheng Y, Chen GY, et al. A randomised phase II clinical trial of nab‐paclitaxel and carboplatin compared with gemcitabine and carboplatin as first‐line therapy in advanced squamous cell lung carcinoma (C‐TONG1002). Eur J Cancer. 2019;109:183–91.
    1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non‐small‐cell lung cancer. N Engl J Med. 2002;346(2):92–8.
    1. Bakouny Z, Choueiri TK. IL‐8 and cancer prognosis on immunotherapy. Nat Med. 2020;26(5):650–1.
    1. Sanmamed MF, Perez‐Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez‐Ruiz ME, et al. Changes in serum interleukin‐8 (IL‐8) levels reflect and predict response to anti‐PD‐1 treatment in melanoma and non‐small‐cell lung cancer patients. Ann Oncol. 2017;28(8):1988–95.
    1. Yuen KC, Liu LF, Gupta V, Madireddi S, Keerthivasan S, Li C, et al. High systemic and tumor‐associated IL‐8 correlates with reduced clinical benefit of PD‐L1 blockade. Nat Med. 2020;26(5):693–8.
    1. Schalper KA, Carleton M, Zhou M, Chen T, Feng Y, Huang SP, et al. Elevated serum interleukin‐8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune‐checkpoint inhibitors. Nat Med. 2020;26(5):688–92.
    1. Paz‐Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus Chemotherapy for Squamous Non‐Small‐Cell Lung Cancer. N Engl J Med. 2018;379(21):2040–51.
    1. Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, et al. Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First‐line Treatment for Advanced Squamous Non‐Small‐Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021.
    1. Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodriguez‐Abreu D, Hussein M, et al. Atezolizumab in Combination With Carboplatin and Nab‐Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J Thorac Oncol. 2020;15(8):1351–60.
    1. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune‐based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale‐based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25.
    1. Salas‐Benito D, Perez‐Gracia JL, Ponz‐Sarvise M, Rodriguez‐Ruiz ME, Martinez‐Forero I, Castanon E, et al. Paradigms on Immunotherapy Combinations with Chemotherapy. Cancer Discov. 2021.
    1. Ozga AJ, Chow MT, Luster AD. Chemokines and the immune response to cancer. Immunity. 2021.

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