Patient characteristics and treatment details
Of the 43 patients with advanced or recurrent mucosal melanoma, 17 (39.5%) were males, and 26 (60.5%) were females, with a median age of 61 years (25-74 years). The most common primary site was the gastrointestinal tract (n=22, 51.2%), followed by the sinonasal (n=14, 32.6%) and genitourinary tracts (n=6, 14.0%). A total of 32 (74.4%) patients had undergone surgical resection, of whom 18 had radical surgery (surgical resection margins negative on final pathology). Before initiation of Endostar-containing treatment, most patients had metastatic disease (n=31, 72.1%), and 12 (27.9%) had locally advanced disease that was deemed unresectable. The majority of patients (n=33, 76.7%) had normal LDH levels, while 9 (20.9%) patients had elevated LDH levels. KIT, BRAF and NRAS mutation status was available for all but four patients. More than half of the patients (25/39, 64.1%) did not have mutations in these genes. The most commonly observed mutation was NRAS (n=9, 23.1%), followed by BRAF (n=3, 7.7%) and CKIT (n=2, 5.1%). Of the three patients with BRAF mutations, one patient harbored the BRAF V600E mutation, and the other two patients had the BRAF G606E and T599del mutations. The baseline patient characteristics are presented in Table 1.
The 43 patients received either Endostar plus temozolomide and cisplatin (n=24, 55.8%) or Endostar plus dacarbazine and cisplatin (n=19, 44.2%); this was the first-line treatment in most patients (40/43, 93.0%). Three patients had first-line anti-PD-1 treatment, and 11 patients received chemotherapy (paclitaxel or dacarbazine plus platinum) in the adjuvant setting. The median number of Endostar-containing treatment cycles was 4 (range: 1-6 cycles), and seven (16.3%) patients had chemotherapy dose adjustments due to drug-related toxicities. No patient discontinued Endostar during the treatment period.
As of September 30, 2020, the median follow-up interval was 17.6 months (range 1.0-35.6 months). Of the 40 evaluable patients, an objective response was observed in 12 (30.0%) patents, four with CR (10%) and eight with PR (20.0%). Five responders (3 with anorectal primary sites and 2 with nasopharyngeal primary sites) received concurrent or sequential radiotherapy, and two received maintenance anti-PD-1 therapy following Endostar-containing treatment. Overall, disease control was achieved in 31 (77.5%) of the 40 patients. According to the primary site, the ORR was highest in those with disease originating from the sinonasal tract (38.5%, 5/13), followed by the genitourinary tract (28.6%, 2/7) and the gastrointestinal tract (25.0%, 5/20). Of the four patients with a CR, two had primary lesions located in the nasal cavity and paranasal sinuses, and two had primary lesions in the anorectum. All four patients had locally advanced disease and underwent concurrent radiotherapy (the two patients with sinonasal melanoma underwent proton heavy ion radiotherapy).
As of the cutoff date, the median PFS was 4.9 months (95% confidence interval [CI]: 3.6 -10.3 months), and the median OS was 15.3 months (95% CI: 9.0 months - not available) for the entire cohort (Figure 1A and 1B). For the eight patients receiving concurrent/sequential radiotherapy or anti-PD-1 maintenance treatment, the median PFS was 12.1 months (95% CI: 4.0 - 20.0 months).
Univariate and multivariate survival analysis
The NLR and LMR cutoffs were determined using receiver operating characteristic (ROC) curves to predict progression at 4.9 months. Univariate analysis was performed and showed that disease stage (p=0.015), previous surgery (p=0.050), liver metastasis (p=0.013), elevated LDH level (p=0.006), and LMR >3.45 (p=0.001) were associated with patient PFS. LMR >3.45 remained the only factor significantly correlated with longer PFS in the multivariate analysis (p=0.012, hazard ratio [HR] 0.28, 95% CI: 0.10-0.76); metastatic stage was adversely correlated with PFS (p=0.071, HR 2.5, 95% CI: 0.90-0.70), but the correlation was not statistically significant. With respect to OS, LMR >3.45 (p=0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p=0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS.
The most common AEs were hematologic AEs, including white blood cell count decreased (20/43, 46.5%), neutrophil count decreased (17/43, 39.5%), platelet count decreased (17/43, 39.5%) and anemia (7/43, 16.3%), as shown in Table 2. Other common AEs included nausea (14/43, 32.6%), vomiting (12/43, 27.9%), liver injury (3/43, 7.0%), fatigue (3/43, 7.0%) and kidney injury (3/43, 7.0%). Among all grade ≥ 3 AEs, platelet count decreased (8/43, 18.6%), white blood cell count decreased (6/43, 14.0%), and neutrophil count decreased (6/43, 14.0%) were the most frequently observed. Grade 3 hypertension and bleeding were observed (one each, 2.3%). No treatment-related deaths occurred.
As of Sep 30, 2020, 32 patients had experienced disease progression. Among them, 23 were subsequently treated with anti-PD-1/PD-L1 antibody alone or in combination with VEGFR-predominant tyrosine kinase inhibitors (TKIs); four underwent salvage chemotherapy, two patients harboring BRAF mutations were subsequently treated with vemurafenib, and one harboring a KIT mutation was treated with imatinib.