Anlotinib as a third-line or further treatment for recurrent or metastatic nasopharyngeal carcinoma: a single-arm, phase 2 clinical trial

Nasopharyngeal carcinoma (NPC) ranks 23^rd in cancer prevalence globally [1], with new cases arising predominantly in east and southeast Asia. Approximately 10 to 15% of NPC patients have primary metastasis at the time of diagnosis, and 30% will develop local recurrence or distant metastases despite the standard first-line therapeutic regimens [2, 3]. Although cisplatin/gemcitabine (GP)-based regimens have been recommended as the first-line systemic treatment for recurrent or metastatic (RM)-NPC patients [4], patients who are refractory or progress after first-line treatment have few treatment options. Currently, there is no standard therapy in the second or subsequent line setting for RM-NPC. Therefore, a need exists for novel agents or therapeutic modalities for this refractory disease that carries a grave prognosis.

Antiangiogenic therapy hold promise for RM-NPC. NPC is amenable to antiangiogenic therapy as vascular endothelial growth factor (VEGF) is highly expressed in NPC and correlates with survival [5]. However, the addition of anti-VEGF antibody bevacizumab to paclitaxel plus carboplatin as first-line treatment failed to extend the progression-free survival (PFS) and overall survival (OS) of RM-NPC patients [6]. Other antiangiogenic multikinase inhibitors (MKIs) achieved an objective response rate (ORR) between 6.1 and 20% as monotherapy for pretreated RM-NPC [7‐9]. Safety concerns such as hemorrhage have also hampered the use of antiangiogenic therapies for RM-NPC [10‐12]. These observations suggest that the exploration of novel antiangiogenic MKIs for RM-NPC is necessary.

Anlotinib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit [13, 14]. It has been approved as 3rd line treatment for locally advanced or metastatic non-small cell lung cancer and 2nd line treatment for advanced soft-tissue sarcoma in China [15, 16]. Anlotinib has a low half-maximal inhibitory concentration (IC₅₀) (0.2 nM) and has potent inhibitory activities on FGFR [13, 17]. It has been investigated in a variety of advanced tumors [18‐21] but has not been examined in RM-NPC. This trial investigated the efficacy and safety of anlotinib in pretreated RM-NPC patients. An exploratory analysis was also undertaken to identify prognostic factors for antiangiogenic therapy for RM-NPC.

In this trial, RM-NPC patients who received anlotinib monotherapy as third-line or further therapy demonstrated effective disease control and acceptable toxicity profile. Subgroup analysis identified plasma EBV DNA levels and HFS as prognostic factors of treatment response. The findings support further clinical development of anlotinib for RM-NPC patients who have dismal survival outcomes and limited treatment options.

Several antiangiogenic MKIs had been studied in RM-NPC (Additional file 1: Table S1) [7‐9, 11, 23, 24]. Early trials of sorafenib [23] and sunitinib [11] had shown modest efficacy in RM-NPC but significant risk of fatal hemorrhages. Moderate toxicity was observed during pazopanib [7] and axitinib [8] treatment, but the response rate was still poor, with an ORR of 3.7% to 6.1%. Recent study has reported higher efficacy with apatinib [24] and lucitanib [9] treatment, with an ORR of 20% to 36.4% and a DCR of 54.5% to 90%. However, patients enrolled in the trials mentioned above were resistant to traditional chemotherapy, and most of them had not been exposed to targeted therapy or immunotherapy. In this trial, nearly half (48.7%) of the patients had received anti-PD-1 immunotherapy, and over one third had received anti-EGFR antibody. Anlotinib monotherapy demonstrated an ORR of 20.5%, a DCR of 71.8%, and a median PFS of 5.7 months, which was comparable with the efficacy results of apatinib and lucitanib. These results suggested anlotinib as a promising agent for heavily pretreated NPC patients with both high clinical benefit rate and durable disease control in the era of targeted therapy and immunotherapy. Such an efficacy may be attributed to the high affinity and selectivity of anlotinib for targeted kinases [13, 14].

In this study, patients with prior anti-PD-1 immunotherapy tended to have higher therapeutic efficacy to anlotinib treatment, especially for patients who finished anti-PD-1 immunotherapy less than 3 months before anlotinib treatment. This may be because the anti-tumor immunity remains activated in the short term after the end of immunotherapy, while antiangiogenic drugs could further increase the infiltration of immune effector cells in the tumor microenvironment by normalizing immature blood vessels [25]. The synergistic anti-tumor effect of antiangiogenic therapy and immunotherapy has been indicated by preclinical studies [25] and validated by clinical trials in renal carcinoma [26‐28], endometrial carcinoma [29], and hepatocellular carcinoma [30]. Recent phase II study [31] has demonstrated the promising therapeutic efficacy and safety of camrelizumab plus apatinib in patients with recurrent or metastatic NPC who failed first-line therapy, with an ORR of 65.5% and a DCR of 86.2%. The phase II TORAL trial (ClinicalTrials.gov: NCT04996758) evaluating the efficacy and safety of anlotinib in combination with the anti-PD-1 antibody toripalimab in RM-NPC is currently ongoing.

Grade 3/4 HFS and oral mucositis observed in this trial were more common than previously reported for anlotinib monotherapy in patients with advanced non-small cell lung cancer, soft-tissue sarcoma, and medullary thyroid carcinoma [18, 20, 21]. The higher incidence of HFS and oral mucositis in RM-NPC may be attributed to previous exposure to chemotherapeutic agents commonly used in NPC, including 5-fluorouracil, capecitabine, docetaxel, and other multikinase inhibitors, which can also cause reactions involving the hands, feet, and mucosa [32]. Previous radiotherapy may have also contributed to the higher incidence of oral mucositis. HFS is reversible in most cases but may impact quality of life. In this trial, HFS was associated with better outcomes in RM-NPC patients with anlotinib treatment. The prognostic value of HFS had also been reported in patients with other advanced malignancies treated with MKIs including anlotinib [33, 34]. One of the main concerns with antiangiogenic agents is the occurrences of bleeding. In this trial, grade 1/2 bleeding occurred in 34.2% of the patients; however, no patient had grade 3/4 bleeding. Considering the occurrence of fatal hemorrhage reported during sunitinib treatment in RM-NPC patients who had received high-dose radiation [11], bleeding should also be monitored closely during the treatment of anlotinib in patients with previous radiotherapy.

In this trial, high baseline EBV DNA copy number (≥ 1000 IU/mL) and increase from baseline in EBV DNA level were all associated with higher rate of disease progression during the anlotinib treatment. In the pilot study of single-agent apatinib treatment in RM-NPC patients, low baseline EBV DNA level was associated with long-term response, while change of EBV-DNA level after apatinib treatment was not correlated with the duration of response [35]. These findings suggested that antiangiogenic therapies may be more effective in preventing disease progression in patients with low disease burden. However, although the correlation between treatment response and EBV DNA changes has also been reported in bevacizumab treatment for RM-NPC patients [6], this observation may speak to the anti-tumor efficacy of these drugs on overall disease burden. Therefore, change of plasma EBV DNA level may not be a specific biomarker for the efficacy of antiangiogenic therapies but should still be monitored during antiangiogenic treatment in NPC patients.

The study has several limitations. First, this is a single-arm study in the absence of a control group. Second, the results of dynamic monitoring of EBV DNA copy numbers were not available in all enrolled patients. Thirdly, the results of our subgroup analysis may be limited by the small cohort size. Finally, only Han Chinese subjects were included in the trial. The efficacy and safety of anlotinib should be evaluated in NPC patients of diverse ethnicities across countries in the future.

Anlotinib as a third- or later-line treatment is well tolerated and has demonstrated promising anti-tumor activity and disease control in heavily pretreated RM-NPC patients. The efficacy and safety of anlotinib in combination with immune checkpoint inhibitors for the treatment of RM-NPC patients should be further explored.