Dao Xin,Yan Song,Lan Mu,Bo Zhang,Ling Qi,Jing Gao,Xingyuan Wang,Jianping Xu,Tao Qu,Jing Huang
The efficacy and safety of nanoparticle albumin bound‐paclitaxel‐based regimen as second‐ or third‐line treatment in patients with advanced esophageal squamous cell carcinoma
chemotherapy,esophageal squamous cell carcinoma,immunotherapy,nanoparticle albumin bound‐paclitaxel
Abstract Background There are limited reports on nanoparticle albumin bound‐paclitaxel (nab‐paclitaxel) regimens as second‐ or third‐line treatments for advanced esophageal squamous cell carcinoma (ESCC). Additionally, its safety and efficacy in ESCC patients after failure of first‐line programmed cell death protein‐1 (PD‐1) blockade plus chemotherapy have not been reported. In this study, we aimed to assess the efficacy and tolerability of nab‐paclitaxel regimens as second‐ or later‐line treatment in advanced ESCC. Methods We retrospectively reviewed clinical data of advanced ESCC patients who participated in a randomized phase III clinical study and received serplulimab or placebo plus chemotherapy at our institution, and consecutive patients who received subsequent nab‐paclitaxel‐based regimens as second‐ or later‐line treatment were included for data collection and analysis. Results A total of 39 patients were included, 25 (64.1%) received serplulimab plus chemotherapy and 14 (35.9%) received chemotherapy alone as first‐line treatment. Treatment strategies included nab‐paclitaxel monotherapy (7/39, 17.9%), or in combination with other chemotherapy (19/39, 48.7%), with anti‐PD‐1 antibodies (12/39, 30.8%) or with nimotuzumab (1/39, 2.6%). Overall, the objective response rate (ORR) and disease control rate (DCR) were 33.3% (13/39) and 61.5% (24/39), respectively. With a median follow‐up of 9.7 months, the median progression‐free survival and median overall survival were 5.0 and 7.9 months, respectively. The most common adverse events were neuropathy peripheral (30.8%), anemia (30.8%), neutrophil count decreased (23.1%), and nausea (20.5%). Conclusions Nab‐paclitaxel‐based regimen could be a safe and effective option as second‐ or later‐line treatment in patients with advanced ESCC, regardless of their previous exposure to PD‐1 inhibitors.
The efficacy and safety of nanoparticle albumin bound‐paclitaxel‐based regimen as second‐ or third‐line treatment in patients with advanced esophageal squamous cell carcinoma

There are limited reports on nanoparticle albumin bound‐paclitaxel (nab‐paclitaxel) regimens as second‐ or third‐line treatments for advanced esophageal squamous cell carcinoma (ESCC). Additionally, its safety and efficacy in ESCC patients after failure of first‐line programmed cell death protein‐1 (PD‐1) blockade plus chemotherapy have not been reported. In this study, we aimed to assess the efficacy and tolerability of nab‐paclitaxel regimens as second‐ or later‐line treatment in advanced ESCC.

We retrospectively reviewed clinical data of advanced ESCC patients who participated in a randomized phase III clinical study and received serplulimab or placebo plus chemotherapy at our institution, and consecutive patients who received subsequent nab‐paclitaxel‐based regimens as second‐ or later‐line treatment were included for data collection and analysis.

A total of 39 patients were included, 25 (64.1%) received serplulimab plus chemotherapy and 14 (35.9%) received chemotherapy alone as first‐line treatment. Treatment strategies included nab‐paclitaxel monotherapy (7/39, 17.9%), or in combination with other chemotherapy (19/39, 48.7%), with anti‐PD‐1 antibodies (12/39, 30.8%) or with nimotuzumab (1/39, 2.6%). Overall, the objective response rate (ORR) and disease control rate (DCR) were 33.3% (13/39) and 61.5% (24/39), respectively. With a median follow‐up of 9.7 months, the median progression‐free survival and median overall survival were 5.0 and 7.9 months, respectively. The most common adverse events were neuropathy peripheral (30.8%), anemia (30.8%), neutrophil count decreased (23.1%), and nausea (20.5%).

Nab‐paclitaxel‐based regimen could be a safe and effective option as second‐ or later‐line treatment in patients with advanced ESCC, regardless of their previous exposure to PD‐1 inhibitors.

Esophageal cancer is the seventh most common cancer and the sixth leading cause of cancer deaths globally, according to the statistics of the World Health Organization in 2020. Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype worldwide. , Early detection of esophageal cancer is difficult given that early‐stage disease is often asymptomatic. As a result, over half of esophageal cancer patients are diagnosed with either locally advanced or distant metastatic disease. Despite advances in multimodality treatment and systemic therapy in the past decade, the prognosis for patients with advanced esophageal cancer remains poor, and the 5‐year survival rate for patients with distant metastasis is only 5.7%. Therefore, more effective and well‐tolerated therapeutic options for esophageal cancer patients are needed. In recent years, the treatment paradigm for advanced ESCC has changed with the progression of immunotherapy. Currently, chemotherapy combined with an anti‐programmed cell death protein‐1 (PD‐1) antibody has become the standard first‐line treatment for advanced ESCC. , , , , , As with patients treated with upfront chemotherapy, PD‐1 blockade is the standard second‐line treatment. , , , However, there remain many unanswered questions. Although several cytotoxic agents are commonly used following failure of first‐line PD‐1 blockade plus chemotherapy, standard second‐line treatment has not been established in this setting. Additionally, the response and survival outcomes are unsatisfactory with single agent anti‐PD‐1 antibodies in the second‐line treatment for patients who have not received prior immunotherapy. The addition of chemotherapy to standard PD‐1 blockade might improve efficacy, and the optimal choice of drug to accompany PD‐1 inhibitors in the second‐ or later‐lines deserves further investigation. Nab‐paclitaxel is a solvent‐free formulation of paclitaxel that utilizes human serum albumin instead of special solvents to encapsulate hydrophobic paclitaxel molecules in approximately 130 nm particles. Albumin has been reported to aid the uptake of paclitaxel by binding to albumin‐binding membrane receptor protein (gp60) in preclinical models, thus enhancing the transendothelial drug transportation, improving delivery efficiency, and increasing the concentrations of paclitaxel within tumor tissues. , Nab‐paclitaxel has been indicated for the treatment of breast, pancreatic, and non‐small cell lung cancers, , , whereas its use in the treatment of esophageal cancer has not been fully investigated. Specifically, the clinical outcomes of nab‐paclitaxel after progression on immunotherapy, or nab‐paclitaxel in combination with immunotherapy for advanced ESCC patients have not been previously reported. We therefore conducted a retrospective study to assess the clinical efficacy and safety of nab‐paclitaxel‐based regimens in the second‐ or later‐line treatment of patients with advanced ESCC. We also analyzed the effect of prior exposure to PD‐1 antibodies on treatment outcomes, in order to provide evidence for the challenges in the immunotherapy era.

In this retrospective study, we reviewed the medical records and follow‐up data for all patients who were enrolled in a randomized, double‐blind, multicenter, phase III clinical trial (NCT03958890) at the Cancer Hospital, Chinese Academy of Medical Sciences. The clinical trial compared serplulimab (a fully humanized, selective immunoglobulin G4 monoclonal antibody against PD‐1 receptor) plus chemotherapy (cisplatin plus 5‐fluorouracil, FP regimen) with placebo plus chemotherapy as first‐line treatment in patients with locally advanced or metastatic ESCC. We included consecutive patients who received nab‐paclitaxel‐based systemic therapies as second‐ or third‐line treatment after the clinical trial for the present study.

Survival data were obtained by regular follow‐up through telephone or outpatient service, and efficacy and safety data were obtained from the medical records. For patients who received subsequent treatment in other hospitals, we also retrospectively collected the medical records for our analysis. The hospitals involved included Yichun Central Hospital, Chengde Medical College Hospital, and Wuhai People's Hospital. The primary endpoints of the present study were the objective response rate (ORR) and the disease control rate (DCR) of advanced ESCC patients receiving nab‐paclitaxel‐based therapy as second‐ or later‐line treatment. Other endpoints included progression‐free survival (PFS) and overall survival (OS) of the patients, and safety of the treatment. We also analyzed if prior exposure of patients to PD‐1 inhibitors, other anticancer drugs that accompany nab‐paclitaxel, and response to first‐line treatment might affect efficacy outcomes. Tumor responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The ORR was defined as the proportion of patients with a complete response (CR) or partial response (PR). The DCR was the proportion of patients with CR, PR, or stable disease (SD). PFS was defined as the time from the initiation of nab‐paclitaxel treatment to disease progression or death from any cause, whichever occurred first. OS was defined as the time from initiation of nab‐paclitaxel treatment to death from any cause. Adverse events (AEs) were graded according to the National Cancer Institute Common Termiy Criteria for AEs Version 4.03 (NCI‐CTCAE 4.03).

Statistical analysis was performed using R software version 4.1.1 and GraphPad Prism 9. The Kaplan–Meier method was used to plot survival curves and calculate the median PFS, OS, and follow‐up time.

A total of 39 patients with advanced ESCC were included in the present study. The median age at diagnosis was 60 years old, and all patients were male. Among them, 25 (64.1%) received serplulimab in combination with chemotherapy and 14 (35.9%) received chemotherapy alone as first‐line treatment. Thirty‐seven (94.9%) patients received nab‐paclitaxel‐based second‐line therapy after progression to first‐line treatment, and two (5.1%) patients received nab‐paclitaxel‐based third‐line therapy. In terms of treatment strategies, seven patients (17.9%) received nab‐paclitaxel monotherapy, 19 (48.7%) received nab‐paclitaxel in combination with other cytotoxic agents, including nedaplatin, fluorouracil, tegafur, and carboplatin, 12 (30.8%) received nab‐paclitaxel in combination with PD‐1 monoclonal antibody, and one patient (2.6%) received nab‐paclitaxel with nedaplatin and nimotuzumab (Table 1).

As of the data cutoff date (October 12, 2022), the median follow‐up duration from the first dose of nab‐paclitaxel‐based therapy was 9.7 months. Treatment responses were assessed in 35 (89.7%) patients while the data was not available in four (10.3%) patients. No CR was observed, and 13 patients achieved a best response of PR, 11 patients had SD, while 11 patients had progressive disease (Table 2). Thus, the ORR and DCR were 33.3% (13/39) and 61.5% (24/39), respectively. With regard to survival outcomes, the median PFS and OS were 5.0 months (range: 0.3–10.8 months) and 7.9 months (range: 0.5–25.2 months), respectively. Twelve of the 39 patients (30.8%) were treated with nab‐paclitaxel in combination with anti‐PD‐1 antibody as second‐ or third‐line treatment. Among them, five patients achieved a best response of PR, three patients had SD, and the ORR and DCR were therefore 41.7% (5/12) and 66.7% (8/12), respectively. With regard to the 27 (69.2%) patients who were treated with nab‐paclitaxel‐based chemotherapy alone, eight patients achieved PR, eight with SD, and the ORR and DCR were 29.6% (8/27) and 59.3% (16/27), respectively. We then investigated the response to continuation of PD‐1 blockade beyond progression in our patients. Among the 25 patients who had received first‐line anti‐PD‐1 antibody plus chemotherapy, seven patients were treated with continuation of immunotherapy plus nab‐paclitaxel in the second‐line treatment. The ORR with these patients was 28.6% (2/7). On the other hand, for the 18 patients who received subsequent nab‐paclitaxel‐based chemotherapy alone, the ORR was 38.9% (7/18). We also analyzed the response to PD‐1 blockade plus nab‐paclitaxel‐based regimen in patients who had not received prior immunotherapy. A total of 14 patients received chemotherapy alone in the first‐line, and five received a combination of anti‐PD‐1 antibody plus nab‐paclitaxel, with an ORR of 60.0%. The other nine patients received nab‐paclitaxel‐based chemotherapy only, with a lower ORR of 11.1% (1/9). Moreover, we assessed patients' response to nab‐paclitaxel‐based therapy according to their responses to first‐line treatment. A total of 24 patients responded to first‐line treatment, and the ORR with subsequent nab‐paclitaxel‐based therapy was 50.0% (12/24). For the other 15 patients whose best response was SD or PD in the first‐line, the ORR with nab‐paclitaxel‐based therapy was only 6.7% (1/15).

All 39 patients were included in the safety analysis. Hematological and nonhematological toxicities are summarized in Table 3. Overall, treatment with nab‐paclitaxel was well tolerated, and no unexpected toxicities or treatment‐related deaths were observed. The most common AEs were neuropathy peripheral (30.8%), anemia (30.8%), neutrophil count decreased (23.1%), and nausea (20.5%). Grade 3 or higher treatment‐related AEs included neutrophil count decreased (15.4%), white blood cell count decreased (2.6%), neuropathy peripheral (2.6%), anemia (2.6%), nausea (2.6%), decreased appetite (2.6%), and rash (2.6%). Alopecia data was not collected in this study.

In this retrospective study, we assessed the clinical outcomes of patients with advanced ESCC treated with nab‐paclitaxel‐based systemic therapy beyond failure of first‐line chemotherapy or chemotherapy plus immunotherapy. Among the 39 patients included in our analysis, the ORR and DCR were 33.3% (13/39) and 61.5% (24/39), and the median PFS and OS were 5.0 and 7.9 months, respectively. Reports on the efficacy and safety of nab‐paclitaxel for the treatment of advanced ESCC are few, and our study is, to the best of our knowledge, the first to include patients who had prior exposure to PD‐1 blockade. Until now, only one study has explored treatment outcomes of nab‐paclitaxel as a second‐ or later‐line treatment for ESCC. This retrospective study enrolled 29 advanced ESCC patients who received nab‐paclitaxel in combination with capecitabine or oxaliplatin after progressing to front‐line chemotherapy. The ORR and DCR for the 27 patients evaluated for response were 37% and 44.4%, respectively, and the median PFS was 6.6 months. The efficacy outcomes observed in our study were comparable to those in the previous report. The toxicities associated with nab‐paclitaxel in the present study were consistent with the safety profile of the drug in other malignancies, with peripheral sensory neuropathy being the most common AE. Taken together, these data suggest that nab‐paclitaxel‐based regimens could be a safe and effective treatment option for previously treated advanced ESCC patients, regardless of whether they had previously received PD‐1 inhibitors. With the recent progress in cancer immunotherapy, several large randomized controlled trials have established PD‐1 inhibitors as second‐line standard of care for advanced ESCC patients treated with first‐line chemotherapy. Nevertheless, the response rates reported in randomized controlled trials with different PD‐1 inhibitors were approximately 16.7% to 20.3%. , , , In our study, for patients who were immunotherapy‐naive with their first‐line treatment, nab‐paclitaxel plus immunotherapy in later‐lines resulted in a promising ORR of 60.0% (3/5). Due to the highly limited sample size, the efficacy of nab‐paclitaxel plus immunotherapy in the later‐line and whether this objective response could translate into survival benefit needs to be further investigated. Upon disease progression with first‐line immunotherapy plus chemotherapy for advanced ESCC patients, salvage chemotherapy with a different regimen is routinely adopted without solid evidence from prospective clinical trials. Due to the limited choices for pretreated advanced ESCC, the continuation of the first‐line PD‐1 inhibitor plus a different anticancer agent might be another option, especially for those patients who initially responded to first‐line treatment. In a retrospective study that included 82 advanced ESCC patients who received PD‐1 monoclonal antibody as first‐line therapy, 61 patients continued immunotherapy by combining antiangiogenic drugs in their second‐line treatment, and the ORR and DCR were 22.9% and 75.4%, respectively. In contrast, antiangiogenic drugs as a single agent had limited efficacy in pretreated advanced ESCC patients, with ORRs around 7%. , Therefore, a proportion of patients might benefit from the continuation of immunotherapy after first progression. In the present study, 25 patients were treated with serplulimab plus chemotherapy. Of these patients, the ORR in patients treated with continuation of immunotherapy plus chemotherapy was numerically lower than the ORR in patients treated with chemotherapy alone (28.6%, 2/7 vs. 38.9%, 7/18). Since our analysis was retrospective, the value of this continuation immunotherapy after the failure of first‐line immunotherapy plus chemotherapy needs further investigation. Our study had some limitations. The retrospective nature and the limited sample size did not draw any definite conclusions. Additionally, the anticancer regimens used in our study were heterogeneous, which may have caused bias and impacted upon our results. In conclusion, nab‐paclitaxel‐based therapy could be a safe and effective treatment option for second‐ or third‐line treatment in patients with advanced ESCC, whether or not they had received first‐line immunotherapy. In addition, for patients previously treated with chemotherapy alone, the addition of nab‐paclitaxel to the PD‐1 blockade might be a feasible choice in the second‐ or later‐line.

Material preparation, data collection, and data analysis were performed and the first draft of the manuscript was written by Dao Xin and Bo Zhang. Yan Song, Bo Zhang, Tao Qu, Xingyuan Wang, and Jianping Xu contributed to research direction and patient management. Dao Xin, Lan Mu, Ling Qi, and Jing Gao contributed to patient management. Jing Huang designed the study and contributed to funding support, and patient management, and reviewed the final manuscript. All authors read and approved the final manuscript.

The authors declare no competing interests.