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Nimotuzumab combined with docetaxel and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: a multicenter, phase 2 trial

BMC Medicine volume 23, Article number: 264 (2025) Cite this article

Abstract

Background

To evaluate the efficacy and safety of nimotuzumab combined with docetaxel and cisplatin (TPN) as the first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC).

Methods

In this multicenter, open-label, phase 2 trial (ClinicalTrials.gov identifier: NCT03708822), patients with RM-NPC received intravenous nimotuzumab (200 mg on days 1, 8, and 15), docetaxel (75 mg/m2 on day 1), and cisplatin (75 mg/m2 on day 1) every 3 weeks for 6 cycles. The primary endpoint was the objective response rate (ORR), and the secondary endpoints included the disease control rate (DCR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety.

Results

Between October 15, 2018, and July 20, 2022, 52 patients were enrolled. The ORR and DCR in the intention-to-treat population were 65.4% and 90.4%, respectively. With a median follow-up of 38.1 months, the median PFS and OS were 7.4 and 40.4 months, respectively. The majority of adverse events were grades 1–2. Grade 3/4 adverse events were neutropenia (42.3%), leukopenia (32.7%), febrile neutropenia (11.5%), nausea (7.7%), fatigue (5.8%), infection (5.8%), thrombocytopenia (1.9%), and anorexia (1.9%). There was no treatment-related death. Low baseline plasma Epstein-Barr virus (EBV) DNA level and the clearance of plasma EBV DNA after 2 cycles of treatment were associated with longer PFS. Additionally, patients who received ≥ 2400 mg of nimotuzumab and ≥ 4 cycles of docetaxel plus cisplatin had superior ORR and survival.

Conclusions

First-line therapy with the TPN regimen showed promising efficacy with a well-tolerated safety profile in RM-NPC patients.

Trial registration

ClinicalTrials.gov: NCT03708822.

Peer Review reports

Background

Nasopharyngeal carcinoma (NPC) is a relatively uncommon carcinoma in most regions worldwide but prevails in East and Southeast Asia [1, 2]. Non-keratinizing NPC constitutes the majority of cases in endemic areas and is associated with Epstein-Barr virus (EBV) infection [1]. Approximately 5–11% of patients are initially diagnosed with metastatic disease, while an additional 15–30% of patients treated with chemo-radiotherapy encounter distant recurrence [3, 4]. Palliative systemic treatments are the primary therapeutic approach for recurrent or metastatic NPC (RM-NPC).

Addition of immune checkpoint inhibitor (ICI) to chemotherapy as the first-line therapy has resulted in dramatic improvement in treatment response as well as survival outcomes in RM-NPC patients [5, 6]. The combination of gemcitabine plus cisplatin (GP) with ICI is now recommended as the preferred first-line regimen for RM-NPC. However, not all patients are suitable candidates for ICI therapy. The objective response rate (ORR) for platinum-based doublet chemotherapeutic regimens was 42 to 66% with median overall survival (OS) of only 12.4–29.1 months [5, 7, 8]. Accordingly, the exploration novel treatment regimens not based on ICI are needed.

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein belonging to the human epidermal growth factor receptor (HER) family involved in the regulation of various cellular functions, including apoptosis, angiogenesis, cell proliferation, migration, and invasion [9]. Elevated EGFR expression has been demonstrated in distant metastatic NPC tissues [10]. EGFR overexpression has also been recognized as an independent prognostic indicator for disease-free survival and OS in patients with NPC [11]. These results provide rationality for targeting EGFR therapy in NPC.

Monoclonal antibodies against EGFR have shown promising efficacy in patients with NPC. Nimotuzumab, a humanized EGFR-targeting monoclonal antibody (mAb), inhibits proliferation and promotes apoptosis of tumor cells [12]. Compared with other EGFR-targeting mAb (e.g., cetuximab), nimotuzumab has longer half-life and larger area under the curve (AUC) at the same dose levels [13]. Two retrospective analyses reported clinical benefits of nimotuzumab plus chemotherapy versus chemotherapy alone as first-line treatment in RM-NPC patients [14, 15]. A phase 2 trial reported 71.4% ORR and 7.0-month median PFS in RM-NPC patients receiving nimotuzumab combined with cisplatin and 5-fluorouracil as the first-line therapy [16]. A retrospective analysis of 12 RM-NPC patients receiving cetuximab plus paclitaxel and carboplatin as first-line treatment reported 58.3% ORR and 4.1-month median PFS [17]. A phase 2 trial in 43 RM-NPC patients undergoing first-line treatment with cetuximab plus docetaxel and cisplatin followed by concurrent chemoradiotherapy with cetuximab and cisplatin, and capecitabine maintenance reported 79.1% ORR [18]. Furthermore, in a preliminary retrospective analysis of 40 RM-NPC patients from this research group, nimotuzumab combined with docetaxel and cisplatin (TPN) regimen was associated with 72.5% ORR (unpublished data). These findings suggested that the combination of anti-EGFR mAb and docetaxel with cisplatin may be an effective therapeutic strategy for RM-NPC.

Therefore, this multicenter, open-label, phase 2 trial was conducted to evaluate the efficacy and safety of TPN regimen as first-line treatment for RM-NPC.

Methods

Study design and patients

Patients (18–70 years of age) with newly diagnosed, untreated stage IVB NPC according to the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control staging system, or with recurrent NPC beyond 6 months after radical chemoradiotherapy and unsuitable for local therapy were eligible. Other requirements for enrolment included (1) ECOG PS of 0–2; (2) at least one measurable disease according to the RECIST v1.1 [19]; (3) estimated life expectancy exceeding 3 months; (4) adequate bone marrow function (absolute neutrophil count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 90 g/L), renal function (creatinine ≤ the upper limit of normal [ULN] and creatinine clearance ≥ 60 mL/min), and hepatic function (total bilirubin ≤ ULN, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤ 2.5 times ULN, and alkaline phosphatase ≤ 5 times ULN).

Patients were excluded if they were eligible for local therapy; were allergic to any drugs in the TPN regimen; were pregnant or lactating; had other malignant neoplasms; had participated in other clinical trials within 3 months; had serious infections, comorbidities, or vital organ dysfunction. More details on the inclusion and exclusion criteria are shown in the protocol (Additional file 1: Study protocol).

This trial was approved by the institutional ethics committees of the institution, and conducted per the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. All participants provided written informed consent.

Procedures

All eligible patients received intravenous nimotuzumab (200 mg on days 1, 8, and 15) plus docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1) every 3 weeks for a maximum of 6 cycles, or until disease progression, or death, or intolerable toxicity, or treatment delay of more than 14 days, whichever occurred earlier. Given the highly emetic nature of cisplatin, a three-drug antiemetic strategy, including neurokinin 1 receptor blockers, 5-hydroxytryptamine-3 receptor blockers, and dexamethasone, was recommended. Diuretics and adequate hydration were used to mitigate cisplatin-induced nephrotoxicity.

The EBV DNA level was detected using a real-time quantitative polymerase chain reaction method [20]. EGFR expression was assessed using immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) tumor specimens at baseline, and classified into four levels: negative, weak (+, light brown staining only under high magnification), intermediate (+ +, between weak membrane staining and strong membrane staining), and strong (+ + +, dark brown staining under low magnification).

Tumor response was assessed according to RECIST v1.1. Computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scans were performed every 2 cycles during the TPN treatment. Nasopharyngoscopy and biopsy were optional.

Treatment-related adverse events (TRAEs) were evaluated based on patient report, physical examinations, and laboratory testing at the trial visits. All TRAEs were graded for severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE 4.0). Serious adverse events (SAEs) were defined as those leading to death, life-threatening events, hospitalization or prolonged hospitalization, permanent disability, secondary tumor, congenital malformations, or birth defect.

Follow-up visit was conducted 1 month after completing TPN treatment, once every 3 months during the first 3 years, once every 6 months in the fourth and fifth years, and annually thereafter.

Outcomes

The primary endpoint was ORR, defined as the proportion of patients who achieved partial response (PR) and complete response (CR) according to RECIST v1.1. Secondary endpoints were DCR (the proportion of patients who achieved CR, PR, or stable disease [SD]), duration of response (DOR, time interval from the first day of documented response to PD or death from any cause), time to response (TTR, time interval from the enrolled date to the first CR or PR), PFS (time interval from the enrolled date to the documented PD or death from any cause or censored at the last follow-up), OS (time interval from the enrolled date to death from any cause or last follow-up), and TRAEs. Exploratory endpoints were the relationship between clinical characteristics and response, PFS, and OS.

Statistical analysis

The sample size requirement was estimated based on the Simon two-stage design [21]. The ORR (45%) of cetuximab combined with docetaxel and cisplatin was used as the reference for the null hypothesis testing [22]. We assumed that the targeted ORR of the TPN regimen was 65% with 80% power at a significance level of 0.05. In the initial stage, if a response was observed in at least 7 out of the 15 evaluable patients, the trial would proceed to the second stage; otherwise, the trial would be stopped. The estimated total sample size for the study was 48 patients with a dropout rate of 10%.

Statistical analysis was performed using SPSS version 25.0 and GraphPad Prism 8 software. The two-sided 95% confidence interval (CI) for a response was calculated using the Clopper-Pearson exact method. For exploratory analysis, Pearson’s chi-square test or Fisher’s exact test was used to compare responses and other categorical variables among different subgroups. Survival curves were plotted using the Kaplan–Meier method for survival outcomes. The univariate comparison of the difference was performed by log-rank test. Multivariate Cox proportional hazards regression analysis was performed to identify factors that were independently associated with the PFS and OS. A two-sided P value of < 0.05 was considered statistically significant.

Results

Demographics and baseline characteristics of the participants

A total of 56 patients with RM-NPC were screened between October 15, 2018, and July 20, 2022; 52 were enrolled (Fig. 1). The median age was 44 years (range 25–63 years) (Table 1). Twenty-nine (55.8%) patients had primary metastatic disease, and 44.2% of the patients were recurrent after radical concurrent chemoradiotherapy.

Fig. 1
figure 1

Trial profile

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Table 1 Baseline demographics and disease characteristics of participants (n = 52)
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Treatment

The median number of treatment cycles of TPN regimen was 6 (IQR 4–6). Most patients (36/52, 69.2%) received 6 cycles of docetaxel/cisplatin, with 8 patients (15.4%) receiving 1–2 cycles and 8 patients (15.4%) receiving 4–5 cycles. The median exposure to nimotuzumab was 3600 mg (IQR 2400–3600 mg).

Twenty-seven (51.9%) patients received second-line treatment after failure of TPN therapy, mostly ICI-containing regimens (25 out of the 27 patients) (Additional file 2: Table S1). These included ICI plus anlotinib (n = 11), ICI plus gemcitabine and tegafur/gimeracil/oteracil potassium (S-1) (n = 10), ICI plus gemcitabine and platinum (n = 2), ICI plus gemcitabine and capecitabine (n = 1), and ICI plus transforming growth factor-β (TGF-β) inhibitor (n = 1).

Treatment response

In the initial stage, 9 of 15 (60.0%) patients had PR, allowing continued enrollment onto the second stage. In the intention-to-treat (ITT) population, the ORR was 65.4% (34/52; 95% CI 50.9–78.0) (Table 2). In the 48 patients with at least one post-treatment assessment, the ORR was 70.8% (34/48; 95% CI 55.9–83.0) (Table 2, Fig. 2).

Table 2 Antitumor activity
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Fig. 2
figure 2

Swimmer plot of the intention-to-treat population. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease

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Post hoc exploratory analyses showed higher ORR in the patients who were female (versus male), who received ≥ 2400 mg nimotuzumab (versus < 2400 mg), and who received ≥ 4 cycles of docetaxel/cisplatin (versus 3 or less) (Additional file 3: Fig. S1). The ORR was 75.0% in patients with intermediate/strong EGFR expression versus 66.7% in those with negative/weak EGFR expression (P = 0.426) (Additional file 3: Fig. S2).

The median DOR was 6.1 months (95% CI 5.5–6.7) in the overall cohort (Fig. 3A), 5.8 months in patients with liver metastases versus 7.1 months in those without liver metastases (P = 0.091). The median TTR was 1.4 months (95% CI 1.4–1.5).

Fig. 3
figure 3

Kaplan-Meier survival curves. A Duration of response of 34 responding patients. B PFS of 52 patients. C PFS of patients with versus those without liver metastases. D PFS of patients who received ≥2400 mg nimotuzumab versus those who received <2400 mg nimotuzumab. E PFS of patients at initial diagnosis with EBV DNA ≥10,000 copies/mL versus those with EBV DNA <10,000 copies/mL. F PFS of patients whose EBV DNA declined to zero after 2 cycles versus those whose EBV DNA did not. Abbreviations: DOR, duration of response; EBV, Epstein-Barr virus; HR, hazard ratio; PFS, progression-free survival

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Survival outcomes

At the cutoff date (July 25, 2023), 36 patients experienced PFS events, and 24 deaths were reported. With a median follow-up of 38.1 months (IQR 23.6–47.1), the median PFS and OS were 7.4 months (95% CI 6.5–8.4) and 40.4 months (95% CI 24.7—not reached), respectively (Figs. 3B and 4A). The 1- and 2-year PFS rate was 28.8% (95% CI 17.9–46.2) and 17.3% (95% CI 8.6–34.6), respectively. The 1-year, 2-year, and 3-year OS rate was 83.6% (95% CI 73.9–94.7), 67.9% (95% CI 55.6–82.9), and 50.4% (95% CI 40.7–71.8), respectively.

Fig. 4
figure 4

Kaplan-Meier curves for the OS. A OS of 52 patients. B OS of patients aged ≥50 years versus those aged <50 years. C OS of patients who received ≥2400 mg nimotuzumab versus those who received <2400 mg nimotuzumab. D OS of patients who received ≥4 cycles of docetaxel plus cisplatin versus those who received <4 cycles of docetaxel plus cisplatin. Abbreviations: HR, hazard ratio; OS, overall survival; TP, docetaxel plus cisplatin

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In the 27 patients who received the next-line treatment, 18 (66.7%) progressive disease (PD) events were reported. The median PFS2 was 8.9 months (95% CI 5.7–12.1) (Additional file 3: Fig. S3 A). The PFS2 in the 11 patients who received ICI plus anlotinib as the next-line therapy was significantly longer than that in the 14 patients who received ICI plus other regimens (median PFS2: not reached versus 7.4 months; hazard ratio [HR] 0.3, 95% CI 0.1–1.0, P = 0.032) (Additional file 3: Fig. S3B). In the 11 patients who received ICI plus anlotinib, the 1-year PFS2 rate was 68.2%, and the 1- year and 2-year OS rate was 100.0 and 81.8%, respectively (Additional file 3: Fig. S3 C, 3D).

In the subgroup analyses, the median PFS was significantly longer in patients without liver metastases (8.3 versus 6.5 months in those with liver metastases, HR 0.5, 95% CI 0.2–0.9, P = 0.028), and in patients who received ≥ 2400 mg nimotuzumab (7.5 versus 4.4 months in those who received < 2400 mg, HR 0.3, 95% CI 0.1–0.8, P = 0.011) (Fig. 3C, D). The median PFS was 7.5 and 7.2 months in patients who received ≥ 4 and < 4 cycles of docetaxel plus cisplatin (P = 0.072). The median PFS did not differ in patients with different gender (P = 0.418), age (P = 0.759), Eastern Cooperative Oncology Group performance status (ECOG PS) (P = 0.235), smoking status (P = 0.845), disease status (P = 0.976), EGFR expression (P = 0.936), lung metastases (P = 0.843), and bone metastases (P = 0.470).

The median OS was significantly longer in patients aged < 50 years (52.8 versus 24.7 months in those aged ≥ 50 years; HR 0.4; 95% CI 0.2–1.0; P = 0.035), in patients who received ≥ 2400 mg nimotuzumab (42.3 versus 17.9 months, HR 0.4, 95% CI 0.2–1.0, P = 0.045) and in patients who received ≥ 4 cycles of docetaxel plus cisplatin (42.3 versus 17.9 months, HR 0.3, 95% CI 0.1–0.8, P = 0.010) (Fig. 4B–D). The median OS did not differ in patients with different gender (P = 0.628), ECOG PS (P = 0.372), smoking status (P = 0.816), disease status (P = 0.721), EGFR expression (P = 0.604), lung metastases (P = 0.497), liver metastases (P = 0.428), and bone metastases (P = 0.184).

Clinical significance of plasma EBV DNA level

Patients were divided into a high-EBV DNA group (n = 25) and a low-EBV DNA group (n = 27) using a cutoff value of 10,000 copies/mL [23, 24]. Compared with the high-EBV DNA group, the low-EBV DNA group had longer median PFS (7.9 versus 7.0 months; HR 0.5; 95% CI 0.2–0.9; P = 0.030) (Fig. 3E). However, the two groups did not differ in either ORR (70.4% versus 60.0%; P = 0.432) or median OS (40.4 versus 36.3 months; P = 0.740).

EBV DNA level was available in 39 patients upon completion of two treatment cycles. Patients whose EBV DNA declined to 0 copies/mL after 2 cycles of treatment (n = 15) had a better median PFS (14.0 versus 7.0 months; HR 0.4; 95% CI 0.2–0.9; P = 0.023) than patients whose EBV DNA did not (n = 24) (Fig. 3F). The ORR was 86.7% (13/15) in the patients whose EBV DNA declined to 0 copies/mL versus 62.5% (15/24) in patients with detectable EBV DNA after 2 cycles of treatment (P = 0.206). OS did not differ between the two groups (not reached versus 52.8 months; P = 0.641).

Furthermore, in multivariate Cox proportional hazards regression analysis, longer PFS was associated with ≥ 2400 mg nimotuzumab (HR 0.2; 95% CI 0.1–0.6; P = 0.003) and low-EBV DNA level (HR 0.4; 95% CI 0.2–0.8; P = 0.010) after adjustment. Longer OS was associated with ≥ 4 cycles of docetaxel plus cisplatin (HR 0.3; 95% CI 0.1–0.8; P = 0.014) after adjustment.

Treatment-related adverse events

Among the 52 patients, 50 (96.2%) had any grade TRAEs, and the majority of TRAEs were grades 1–2. TRAEs with ≥ 20% rate included anemia, leukopenia, neutropenia, hypertriglyceridemia, hypercholesterolemia, nausea, limb numbness, hyperglycemia, fatigue, thrombocytopenia, rash, and creatinine elevated (Table 3). Grade ≥ 3 TRAEs included neutropenia, leukopenia, febrile neutropenia, nausea, fatigue, infection, thrombocytopenia, and anorexia (Table 3). All TRAEs were reversible with standard supportive care or dose interruptions.

Table 3 Treat-related adverse events (n = 52)
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Twelve patients required dose interruptions of nimotuzumab owing to febrile neutropenia (n = 4), infection (n = 3), fatigue (n = 2), COVID-19 (n = 2), and dyspnea (n = 1). SAEs were reported in 3 patients due to infection. No treatment-related deaths were reported.

Discussion

To the best of our knowledge, this is the first study to report the efficacy and safety of the TPN regimen as a first-line treatment in RM-NPC. Our primary endpoint was achieved, with an ORR of 65.4% in the ITT population, and the adverse event profile was manageable, underscoring the substantial efficacy and well-tolerated safety profile of the TPN regimen in treating RM-NPC in the first-line setting.

GP regimen has been recommended as the first-line chemotherapy for RM-NPC based on evidence from a phase 3 trial, with an ORR of 64.0% and median PFS of 7 months [8]. In the current study, the ORR was 65.4% with median PFS of 7.4 months and median OS of 40.4 months. In contrast, the median OS in patients treated with GP regimen in previous trials was 14.6–22.1 months [4, 25, 26]. Such an apparent difference could be largely attributed to the high proportion of patients receiving ICI-containing regimen as next-line therapy in this trial. The extent of true differences between the two chemotherapeutic regimens needs further investigation. Furthermore, GP combined with ICI has been established as the first-line regimen based on three phase 3 trials [6, 27, 28], but options in patients with contraindications to ICI, such as severe auto-immune diseases, history of organ transplantation, and known intolerance to ICI are limited. The TPN regimen may represent an alternative first-line therapy in this subpopulation.

Docetaxel plus cisplatin regimen is also recommended as one of the first-line regimens for RM-NPC by the National Comprehensive Cancer Network (NCCN) Guidelines. Based on the results in this trial (ORR 65.4%; median PFS 7.4 months) as opposed to that reported by a previous phase 2 trial of docetaxel/cisplatin alone in 19 patients with RM-NPC (ORR 52.6%; median PFS 5.6 months) [7], we speculate that adding nimotuzumab to docetaxel/cisplatin may be beneficial. Cross-trial comparison in different eras, however, is subject to potential biases.

Twenty-five patients in this trial received ICI-contained regimens as the next-line treatment, with a median PFS2 of 8.9 months, which is superior to that in RM patients who received ICI monotherapy [24, 29, 30] or ICI plus bevacizumab [31]. Intriguingly, the 1-year PFS2 rate was 68.2% in patients who received ICI plus anlotinib, which was numerically longer than that reported for RM-NPC who received ICI plus anti-angiogenic treatments [32,33,34]. Clearly, ICI is an essential component in the treatment of RM-NPC, whether given in first-line or in second-line. However, the optimal sequence of ICI use requires further investigation.

The TPN regimen was well-tolerated in this trial. The rate of hematological toxicities and elevation of AST or ALT was similar to that reported with the GP regimen [8]. Notably, the rate of TRAEs was comparable to that reported for docetaxel and cisplatin chemotherapy alone in a previous study [7]. Consistent with prior studies of nimotuzumab [15, 16], there were no grade 3/4 skin lesions in this trial. In contrast, cetuximab plus docetaxel/cisplatin was associated with grade 3/4 skin lesions in 16% of the patients [22]. Our finding provides the evidence supporting the superior cutaneous safety profile of nimotuzumab, consistent with the result reported by Takeda et al. [35].

NPC is closely associated with EBV infection in the process of tumorigenesis and development [1, 36]. Plasma EBV DNA plays a vital role in screening for early asymptomatic NPC, facilitating clinical decision-making, monitoring treatment response, predicting tumor relapse, and evaluating prognosis in patients with NPC [37,38,39]. Consistent with previous studies [40], low EBV DNA level at baseline (< 10,000 copies/mL) was associated with longer PFS (HR 0.5; P = 0.030), as well as a statistically non-significantly higher ORR (70.4% versus 60.0%, P = 0.432), which is similar to finding in previous studies [24, 33].

The dynamic change in the EBV titer is closely linked to the response to systemic therapy [24, 40]. Consistent with a previous study [41], the median PFS was longer in patients whose EBV DNA declined to zero after two treatment cycles in this trial. Also consistent with the previous study [16], higher ORR and longer PFS were associated with ≥ 2400 mg nimotuzumab and ≥ 4 cycles of docetaxel plus cisplatin. However, no significant correlations were found between EGFR expression with either ORR or survival outcomes.

This trial had several limitations. First, there was no built-in control group of docetaxel/cisplatin alone. The potential benefits of adding nimotuzumab, thus requires further investigation. Second, treatment response and survival outcomes seemed to differ between patients with different EBV DNA level at the baseline as well as after two treatment cycles, but EBV DNA was not available after treatment cycles in all patients. Finally, the clinical values of the EGFR expression status were not elucidated because of the high proportion of weak staining. Hence, the relationship between EGFR expression and the efficacy of nimotuzumab warrants further exploration.

Conclusions

First-line therapy with the TPN regimen showed promising efficacy with a well-tolerated safety profile in RM-NPC patients.

Data availability

All data used or analyzed in the study are available from the lead contact upon reasonable request.

Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

AUC:

Area under the curve

CI:

Confidence interval

CR:

Complete response

CT:

Computed tomography

DCR:

Disease control rate

DOR:

Duration of response

EBV:

Epstein-Barr virus

ECOG PS:

Eastern Cooperative Oncology Group performance status

EGFR:

Epidermal growth factor receptor

FFPE:

Formalin-fixed paraffin embedded

GP:

Gemcitabine plus cisplatin

HER:

Human epidermal growth factor receptor

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

IQR:

Interquartile range

ITT:

Intention-to-treat

mAb:

Monoclonal antibody

MRI:

Magnetic resonance imaging

NCCN:

National Comprehensive Cancer Network

NCI-CTCAE 4.0:

National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

NE:

Not evaluable

NPC:

Nasopharyngeal carcinoma

ORR:

Objective response rate

OS:

Overall survival

PD:

Progressive disease

PET:

Positron emission tomography

PFS:

Progression-free survival

PR:

Partial response

RECIST v1.1:

Response Evaluation Criteria in Solid Tumors version 1.1

RM:

Recurrent or metastatic

S-1:

Tegafur/gimeracil/oteracil potassium

SAEs:

Serious adverse events

SD:

Stable disease

TGF-β:

Transforming growth factor-β

TP:

Docetaxel plus cisplatin

TPN:

Nimotuzumab combined with docetaxel and cisplatin

TRAEs:

Treatment-related adverse events

TTR:

Time to response

ULN:

Upper limit of normal

References

  1. Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80.

    Article  PubMed  Google Scholar 

  2. Fang Y, Su N, Zou Q, Cao Y, Xia Y, Tang L, Tian X, Liu P, Cai Q. Anlotinib as a third-line or further treatment for recurrent or metastatic nasopharyngeal carcinoma: a single-arm, phase 2 clinical trial. BMC Med. 2023;21(1):423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol. 2015;33(29):3356–64.

    Article  PubMed  Google Scholar 

  4. Hong S, Zhang Y, Yu G, Peng P, Peng J, Jia J, Wu X, Huang Y, Yang Y, Lin Q, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin as first-line therapy for recurrent or metastatic nasopharyngeal carcinoma: final overall survival analysis of GEM20110714 phase III study. J Clin Oncol. 2021;39(29):3273–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, Li J, Shi YR, Jin F, Xu R, et al. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. Nat Med. 2021;27(9):1536–43.

    Article  CAS  PubMed  Google Scholar 

  6. Yang Y, Qu S, Li J, Hu C, Xu M, Li W, Zhou T, Shen L, Wu H, Lang J, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22(8):1162–74.

    Article  CAS  PubMed  Google Scholar 

  7. Chua DT, Sham JS, Au GK. A phase II study of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic nasopharyngeal carcinoma. Oral Oncol. 2005;41(6):589–95.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, Peng P, Wu X, Lin Q, Xi X, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016;388(10054):1883–92.

    Article  CAS  PubMed  Google Scholar 

  9. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;110(6):669–72.

    Article  CAS  PubMed  Google Scholar 

  10. Li F, Zhao X, Sun R, Ou J, Huang J, Yang N, Xu T, Li J, He X, Li C, et al. EGFR-rich extracellular vesicles derived from highly metastatic nasopharyngeal carcinoma cells accelerate tumour metastasis through PI3K/AKT pathway-suppressed ROS. J Extracell Vesicles. 2020;10(1):e12003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sun W, Long G, Wang J, Mei Q, Liu D, Hu G. Prognostic role of epidermal growth factor receptor in nasopharyngeal carcinoma: a meta-analysis. Head Neck. 2014;36(10):1508–16.

    Article  PubMed  Google Scholar 

  12. Talavera A, Friemann R, Gómez-Puerta S, Martinez-Fleites C, Garrido G, Rabasa A, López-Requena A, Pupo A, Johansen RF, Sánchez O, et al. Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. Cancer Res. 2009;69(14):5851–9.

    Article  CAS  PubMed  Google Scholar 

  13. Crombet T, Torres L, Neninger E, Catalá M, Solano ME, Perera A, Torres O, Iznaga N, Torres F, Pérez R, et al. Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer. J Immunother. 2003;26(2):139–48.

    Article  CAS  PubMed  Google Scholar 

  14. Qu L, Wang JH, Du JX, Kang P, Niu XQ, Yin LZ. Use of nimotuzumab combined with cisplatin in treatment of nasopharyngeal carcinoma and its effect on expressions of VEGF and MMP-2. Clin Transl Oncol. 2021;23(7):1342–9.

    Article  CAS  PubMed  Google Scholar 

  15. Zhu Y, Yang S, Zhou S, Yang J, Qin Y, Gui L, Shi Y, He X. Nimotuzumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone in patients with recurrent or metastatic nasopharyngeal carcinoma. Ther Adv Med Oncol. 2020;12:1758835920953738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao C, Miao J, Shen G, Li J, Shi M, Zhang N, Hu G, Chen X, Hu X, Wu S, et al. Anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with cisplatin and 5-fluorouracil in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: a multicentre, open-label, phase II clinical trial. Ann Oncol. 2019;30(4):637–43.

    Article  CAS  PubMed  Google Scholar 

  17. Ueda Y, Enokida T, Okano S, Fujisawa T, Ito K, Tahara M. Combination treatment with paclitaxel, carboplatin, and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic nasopharyngeal carcinoma. Front Oncol. 2020;10:571304.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang M, Huang H, Li X, Huang Y, Chen C, Fang X, Wang Z, Guo C, Lam S, Fu X, et al. Long-term survival of patients with chemotherapy-naïve metastatic nasopharyngeal carcinoma receiving cetuximab plus docetaxel and cisplatin regimen. Front Oncol. 2020;10:1011.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  20. Shao JY, Li YH, Gao HY, Wu QL, Cui NJ, Zhang L, Cheng G, Hu LF, Ernberg I, Zeng YX. Comparison of plasma Epstein-Barr virus (EBV) DNA levels and serum EBV immunoglobulin A/virus capsid antigen antibody titers in patients with nasopharyngeal carcinoma. Cancer. 2004;100(6):1162–70.

    Article  CAS  PubMed  Google Scholar 

  21. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  22. Guigay J, Fayette J, Dillies AF, Sire C, Kerger JN, Tennevet I, Machiels JP, Zanetta S, Pointreau Y, Bozec Le Moal L, et al. Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study. Ann Oncol. 2015;26(9):1941–7.

    Article  CAS  PubMed  Google Scholar 

  23. You R, Liu YP, Lin M, Huang PY, Tang LQ, Zhang YN, Pan Y, Liu WL, Guo WB, Zou X, et al. Relationship of circulating tumor cells and Epstein-Barr virus DNA to progression-free survival and overall survival in metastatic nasopharyngeal carcinoma patients. Int J Cancer. 2019;145(10):2873–83.

    Article  CAS  PubMed  Google Scholar 

  24. Wang FH, Wei XL, Feng J, Li Q, Xu N, Hu XC, Liao W, Jiang Y, Lin XY, Zhang QY, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02). J Clin Oncol. 2021;39(7):704–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ngan RK, Yiu HH, Lau WH, Yau S, Cheung FY, Chan TM, Kwok CH, Chiu CY, Au SK, Foo W, et al. Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann Oncol. 2002;13(8):1252–8.

    Article  CAS  PubMed  Google Scholar 

  26. Hsieh JC, Hsu CL, Ng SH, Wang CH, Lee KD, Lu CH, Chang YF, Hsieh RK, Yeh KH, Hsiao CH, et al. Gemcitabine plus cisplatin for patients with recurrent or metastatic nasopharyngeal carcinoma in Taiwan: a multicenter prospective phase II trial. Jpn J Clin Oncol. 2015;45(9):819–27.

    Article  PubMed  Google Scholar 

  27. Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, Li J, Shi Y, Jin F, Xu R, et al. Toripalimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: the JUPITER-02 randomized clinical trial. JAMA. 2023;330(20):1961–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang Y, Pan J, Wang H, Zhao Y, Qu S, Chen N, Chen X, Sun Y, He X, Hu C, et al. Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: a multicenter phase 3 trial (RATIONALE-309). Cancer Cell. 2023;41(6):1061-72.e4.

    Article  CAS  PubMed  Google Scholar 

  29. Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, et al. Antitumor activity of nivolumab in recurrent and metastatic nasopharyngeal carcinoma: an international, multicenter study of the mayo clinic phase 2 consortium (NCI-9742). J Clin Oncol. 2018;36(14):1412–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang Y, Zhou T, Chen X, Li J, Pan J, He X, Lin L, Shi YR, Feng W, Xiong J, et al. Efficacy, safety, and biomarker analysis of camrelizumab in previously treated recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN study). J Immunother Cancer. 2021;9(12):e003790.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lu N, Jiang YF, Xia WX, Huang Y, Xie CM, Xu C, Ye YF, Liu GY, Bei WX, Ke LR, et al. Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: an open-label phase 2 study. EClinicalMedicine. 2023;62:102136.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ding X, Zhang WJ, You R, Zou X, Wang ZQ, Ouyang YF, Peng L, Liu YP, Duan CY, Yang Q, et al. Camrelizumab plus apatinib in patients with recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II study. J Clin Oncol. 2023;41(14):2571–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yuan L, Jia GD, Lv XF, Xie SY, Guo SS, Lin DF, Liu LT, Luo DH, Li YF, Deng SW, et al. Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial. Nat Commun. 2023;14(1):4893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang Y, Zou Q, Zhao B, Su N, Li Z, Wang X, Liu P, Tian X, Fang X, Cai J, et al. Toripalimab plus anlotinib in patients with recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm phase 2 trial (TORAL). Cell Rep Med. 2024;5(12):101833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Takeda M, Okamoto I, Nishimura Y, Nakagawa K. Nimotuzumab, a novel monoclonal antibody to the epidermal growth factor receptor, in the treatment of non-small cell lung cancer. Lung Cancer (Auckl). 2011;2:59–67.

    CAS  PubMed  Google Scholar 

  36. Tsao SW, Tsang CM, Lo KW. Epstein-Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond B Biol Sci. 2017;372(1732):20160270.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350(24):2461–70.

    Article  CAS  PubMed  Google Scholar 

  38. Tan R, Phua SKA, Soong YL, Oon LLE, Chan KS, Lucky SS, Mong J, Tan MH, Lim CM. Clinical utility of Epstein-Barr virus DNA and other liquid biopsy markers in nasopharyngeal carcinoma. Cancer Commun (Lond). 2020;40(11):564–85.

    Article  PubMed  Google Scholar 

  39. Chan KCA, Woo JKS, King A, Zee BCY, Lam WKJ, Chan SL, Chu SWI, Mak C, Tse IOL, Leung SYM, et al. Analysis of plasma Epstein-Barr virus DNA to screen for nasopharyngeal cancer. N Engl J Med. 2017;377(6):513–22.

    Article  CAS  PubMed  Google Scholar 

  40. Xu JY, Wei XL, Ren C, Zhang Y, Hu YF, Li JY, Chen JL, Wang YQ, Han F, Wang FH. Association of plasma Epstein-Barr virus DNA with outcomes for patients with recurrent or metastatic nasopharyngeal carcinoma receiving anti-programmed cell death 1 immunotherapy. JAMA Netw Open. 2022;5(3):e220587.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhu L, Ouyang T, Xiong Y, Ba L, Li Q, Qiu M, Zou Z, Peng G. Prognostic value of plasma Epstein-Barr virus DNA levels pre- and post-neoadjuvant chemotherapy in patients with nasopharyngeal carcinoma. Front Oncol. 2021;11:714433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors gratefully thank the patients and their families for participating in this study. Nimotuzumab was provided by Biotech pharmaceutical co., Ltd. The authors thank Home for researchers editorial team (www.home-for-researchers.com) for their help with language editing service, and Dr. Kehong Zhang from the Ivy Medical Editing for editing the manuscript during the revision.

Funding

This work was supported by grants from National Natural Science Foundation of China (No. 81672686 to Prof. Qingqing Cai).

Author information

Author notes

  1. Qihua Zou, Yi Cao and Yulin Lai contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Qihua Zou, Yi Cao, Yulin Lai, Yuchen Zhang, Panpan Liu, Lixia Lu, Xiaopeng Tian, Lirong Li, Yingxian Liu, Qingqing Cai & Yi Xia

  2. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Qihua Zou, Yi Cao, Yulin Lai, Yuchen Zhang, Panpan Liu, Xiaopeng Tian, Lirong Li, Yingxian Liu, Qingqing Cai & Yi Xia

  3. Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Lixia Lu

  4. Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China

    Yu Fang & Zhihua Li

  5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, 510120, People’s Republic of China

    Yu Fang & Zhihua Li

  6. Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Hao Wu

  7. Department of Medical Oncology, Huizhou Municipal Central Hospital, Huizhou, 516000, People’s Republic of China

    Tianying Huang

  8. Department of Oncology, Guangzhou Chest Hospital, Guangzhou, 510095, People’s Republic of China

    Ning Su

  9. Department of Oncology, The First Affiliated Hospital/The First Clinical Medicine School of Guangdong Pharmaceutical University, Guangzhou, 510699, People’s Republic of China

    Xicheng Wang

Authors
  1. Qihua Zou
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  2. Yi Cao
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Contributions

Study conceptualization and design: QQC, YX, TYH, QHZ; Study execution: QQC, YX, PPL, LXL, NS, ZHL, XCW, XPT; Data curation: QHZ, YCZ, LRL, YXL; Formal analysis, Methodology, Visualization, Validation: QHZ, YC, YLL, YF; Roles/Writing-original draft: QHZ, YC, YLL, HW; Investigation, Resources writing-review & editing: All authors; Supervision: QQC, YX. Funding acquisition: QQC. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qingqing Cai or Yi Xia.

Ethics declarations

Ethics approval and consent to participate

This trial was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center (B2018-097). All participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Supplementary Information

Additional file 1: Study protocol.

Additional file 2: Table S1. Regimens of the second-line treatment (n=27).

12916_2025_4103_MOESM3_ESM.pdf

Additional file 3: Figures S1-S3. Fig. S1- [Stacked bar plots showing the treatment response in different subgroups of the intention-to-treat population]. Fig. S2- [Forest plot showing subgroup analyses of ORR in the intention-to-treat population]. Fig. S3- [Kaplan-Meier survival curves. (A) PFS2 of patients received the second-line treatment. (B) PFS2 of patients who received ICI plus anlotinib versus those who received ICI plus other regimens. (C) PFS2 of patients who received ICI plus anlotinib as the second-line treatment. (D) OS of patients who received TPN followed by ICI plus anlotinib].

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Zou, Q., Cao, Y., Lai, Y. et al. Nimotuzumab combined with docetaxel and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: a multicenter, phase 2 trial. BMC Med 23, 264 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-025-04103-0

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Keywords

BMC Medicine

ISSN: 1741-7015

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