Nab-paclitaxel plus capecitabine as a first-line regimen for advanced biliary tract cancers: Feasible or not feasible?

Abstract

A clinical trial of nab-paclitaxel plus capecitabine as a first-line treatment for advanced biliary tract cancers was conducted. We analyzed the development of systemic therapy recommended by the National Comprehensive Cancer Network guidelines and the development of nab-paclitaxel combination chemotherapy for advanced biliary tract cancers (BTCs) and concluded that nab-paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs.

Key Words: Nab-paclitaxel; Capecitabine; Biliary tract cancers; Systemic therapy; First-line regimen

Core Tip: We investigated the development and efficacy of systemic therapy for advanced biliary tract cancers (BTCs) and concluded that paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs.

TO THE EDITOR

Biliary tract cancers (BTCs), which include intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder cancer, constitute approximately 4% of all malignant gastrointestinal tract neoplasms and are considered rare forms of tumors[1]. However, the prognosis of BTC is poor, with a 5-year overall survival (OS) of less than 20%[2]. Patients are usually diagnosed with advanced-stage BTCs when they have tumors, and systemic therapy has become the only choice for these patients.

More than 10 years ago, the combination of chemotherapy with gemcitabine and cisplatin became the standard-of-care first-line therapy for advanced biliary tract cancer. Nevertheless, the median OS of patients receiving this doublet chemotherapy is still less than 1 year[3,4]. In recent years, immune checkpoint inhibitors, including durvalumab and pembrolizumab, have been proven effective in advanced BTCs. Chemotherapy involving triple-drug treatment, including durvalumab plus gemcitabine and cisplatin and pembrolizumab plus gemcitabine and cisplatin, has been accepted as the first-line therapy for advanced BTCs, with median OS times of 12.8 months and 12.7 months, respectively. Recently, Xu et al[5] finished a phase II clinical trial of nab-paclitaxel plus capecitabine as first-line treatment for advanced BTCs, with a median OS of 14.1 months[5]. To identify the efficacy of nab-paclitaxel plus capecitabine as a first-line regimen for advanced BTCs, we retrospectively examined the development of systemic therapy for advanced BTCs and attempted to reach a conclusion.

DEVELOPMENT OF SYSTEMIC THERAPY FOR ADVANCED BTCS

Before the results of the randomized phase II study of gemcitabine plus cisplatin were published by Valle et al[6] in 2009, the majority of chemotherapy regimens were based on 5-fluorouracil combination chemotherapy, and the function of chemotherapy remained uncertain. In 2009, in the randomized phase 2 trial known as the Advanced Biliary Cancer ABC-01 trial, which included 86 patients, Valle et al[6] reported an increase in the 6-month progression-free survival (PFS) rate, from 45.5% to 57.1%, when the combination therapy of cisplatin and gemcitabine to gemcitabine used alone was compared[6]. In 2010, the ABC-02 trial set the first-line standard of care for advanced biliary tract cancer and reported that the median OS was 11.7 months (for details, Table 1) with the combination of gemcitabine and cisplatin, as opposed to 8.1 months with gemcitabine alone[4]. Over the next decade, the use of gemcitabine plus cisplatin as a first-line treatment remained unchanged. In 2022, the results of the double-blind phase III TOPAZ-1 trial of durvalumab plus gemcitabine and cisplatin vs placebo plus gemcitabine and cisplatin were published. The TOPAZ-1 trial results indicated that the combination of durvalumab plus gemcitabine and cisplatin notably extended OS compared with placebo plus gemcitabine and cisplatin, for which the median OS times were 12.8 months and 11.5 months, respectively. Additionally, the trial revealed that both treatment groups presented similar safety profiles[7]. The TOPAZ-1 trial indicated that the triple-drug regimen based on durvalumab has become the first-line standard treatment for advanced BTCs, and immune checkpoint inhibitors have become a promising research direction. In 2023, the results of the KEYNOTE-966 trial indicated that pembrolizumab plus gemcitabine and cisplatin prolonged OS compared with placebo plus gemcitabine and cisplatin, with median OS rates of 12.7 months and 10.9 months, respectively (for brief contents, Figure 1).

Figure 1 History of systemic therapy for advanced biliary tract cancers. 5-FU: 5-fluorouracil combination chemotherapy; G: Gemcitabine; C: Cisplatin; D: Durvalumab P: Pembrolizumab.

Table 1 First-line systemic therapy for advanced biliary tract cancers recommended by the National Comprehensive Cancer Network guidelines.

Ref.	Regimen	Median OS (months)	Median PFS (months)	ORR (%)	DCR (%)	n
Valle et al[4] 2010	Gemcitabine + cisplatin	11.7	8.0	/	81.4	410
Sahai et al[14], 2018	Nab-paclitaxel + gemcitabine	12.4	7.7	30	66	74
André et al[15], 2008	Gemcitabine + oxaliplatin	8.8	3.4	14.9	50.7	67
Kim et al[16], 2019	Capecitabine + oxaliplatin	10.6	5.8	15.7	58.3	114
Knox et al[17], 2005	Gemcitabine + capecitabine	14.0	7.0	31	73	45
Oh et al[7], 2022	Durvalumab + gemcitabine + cisplatin	12.8	7.2	26.7	85.3	685
Kelley et al[3], 2023	Pembrolizumab + gemcitabine + cisplatin	12.7	6.5	29	75	1069

OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; DCR: Disease control rate.

To date, gemcitabine plus cisplatin remains the standard first-line regimen for advanced BTCs. However, the OS of patients receiving this regimen is dismal, and more effective chemotherapy regimens need to be explored. Since 2022, two immune checkpoint inhibitors have been proven effective for advanced BTCs and provide a new research direction for systemic therapy.

DEVELOPMENT OF NAB-PACLITAXEL COMBINATION CHEMOTHERAPY FOR ADVANCED BTCS

Nab-paclitaxel combination therapies are increasingly recognized as potentially effective systemic therapies for treating BTCs. In the past few years, the results of 4 nab-paclitaxel combination chemotherapies (for details, Table 2), including nab-paclitaxel plus gemcitabine and cisplatin, nab-paclitaxel plus gemcitabine and oxaliplatin, nab-paclitaxel plus capecitabine, and nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1), have been published, and the median OS of the 4 trials was greater than 1 year[5,8-10]. In the 4 chemotherapy trials involving nab-paclitaxel, nab-paclitaxel plus gemcitabine and cisplatin achieved the longest median OS of 19.2 months and the highest objective response rate of 45% in the triple-drug regimens, and nab-paclitaxel plus capecitabine achieved the longest median OS of 14.1 months in the double-drug regimens. However, the median PFS of the nab-paclitaxel plus capecitabine regimen is only 4.4 months, which indicates that the PFS of this regimen is shorter than that of other published combinations of chemotherapy with nab-paclitaxel. In addition, there are no double-blind, placebo-controlled, randomized trials on nab-paclitaxel combination chemotherapy. We cannot conclude that nab-paclitaxel combination chemotherapy is better than gemcitabine plus cisplatin. Furthermore, conducting a randomized controlled trial is an ideal way to further validate the efficacy and safety of nab-paclitaxel plus capecitabine, but this approach is extremely difficult. If a three-arm study is designed, the trial groups will include an experimental group of nab-paclitaxel plus capecitabine, a control group of gemcitabine plus cisplatin, and a control group of placebo, which is problematic for ethics committees to permit. In addition, if a two-arm study is designed, the trial groups include an experimental group of nab-paclitaxel plus capecitabine and gemcitabine plus cisplatin and a control group of placebo plus gemcitabine and cisplatin, which may cause unacceptable toxicity. Hence, a real-world evidence study can be employed to provide further evidence about the efficacy and safety of nab-paclitaxel plus capecitabine.

Table 2 Published results of nab-paclitaxel combination chemotherapy.

Ref.	Regimen	Median OS (months)	Median PFS (months)	ORR (%)	DCR (%)	n
Shroff et al[8], 2019	Nab-paclitaxel + gemcitabine + cisplatin	19.2	11.8	45	84	60
Zhang et al[9], 2023	Nab-paclitaxel + S-1	13.2	6	27.5	70.6	54
Pressiani et al[10], 2024	Nab-paclitaxel + gemcitabine + oxaliplatin	12.4	6.3	20.89	67.15	67
Xu et al[5], 2024	Nab-paclitaxel + capecitabine	14.1	4.4	23.26	69.77	44

OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; DCR: Disease control rate.

To date, there has been no basic medical research on the mechanism of nab-paclitaxel combination chemotherapy for advanced BTCs. However, the phase 3 trials TOPAZ-1[7] and KEYNOTE-966[3] have shown that durvalumab or pembrolizumab in combination with gemcitabine and cisplatin can improve the OS of patients with advanced biliary tract cancer compared with gemcitabine plus cisplatin, which indicates that immune checkpoint inhibitors in combination with chemotherapy are promising options for improving the survival rate. In addition, in the majority of BTCs, the tumor microenvironment is characterized by properties that either suppress the immune response or cause immune rejection[3], Although the tumors respond to inhibitors of programmed cell death protein 1 (PD-1) and its ligand, PD-L1, the efficacy of monotherapy is poor[11,12]. Furthermore, several chemotherapies, are recognized for their ability to influence the immune system through direct immunostimulatory mechanisms, reducing the suppressive nature of the microenvironment and enhancing the immunogenicity of tumors[3,13]. The immunomodulatory effects of these treatments offer a compelling reason to integrate immunotherapy with chemotherapy, which suggests that immune checkpoint inhibitors such as durvalumab or pembrolizumab in combination with chemotherapy based on nab-paclitaxel may improve the survival rate of patients with advanced biliary tract cancer.

Therefore, a real-world evidence study must be conducted in the future. Furthermore, clinical trials of immune checkpoint inhibitors in combination with nab-paclitaxel can be considered.

CONCLUSION

Nab-paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs. There is not enough evidence to support the conclusion that the efficacy of nab-paclitaxel plus capecitabine is better than that of gemcitabine plus cisplatin. Further trials need to be conducted to validate the efficacy of nab-paclitaxel plus capecitabine.