Xieqiao Yan

Prognostic factors for conjunctival melanoma: a study in ethnic Chinese patients.

Background/objective In patients with conjunctival melanomas, surgery is the first choice of treatment, but no standard adjuvant therapy has been established. In this study, we evaluated prognostic factors for conjunctival melanoma in ethnic Chinese patients. Methods Demographic data, known (published) prognostic factors, BRAF and KIT gene mutations, treatment strategies and outcomes were reviewed in 53 patients with pathologically confirmed conjunctival melanomas. Univariate and multivariate analyses of factors associated with survival were performed by the Kaplan–Meier method and a Cox proportional hazard model, respectively. Results Univariate analyses for 50 patients in whom data were available showed that a higher T stage (p=0.041), greater tumour thickness (p=0.006), local resection (p=0.033) and no adjuvant therapy (p=0.006) were associated with a worse recurrence-free survival (RFS) and metastasis-free survival (MFS). Patients with more involved quadrants also had worse MFS (p=0.039), while a higher T stage (p<0.001), local resection (p=0.008), and no adjuvant therapy (p=0.028) were associated with worse overall survival (OS). However, BRAF or KIT mutations showed no correlations with RFS, MFS or OS. Patients who received high-dose interferon (HDI) adjuvant therapy had a better RFS (p=0.004), MFS (p=0.001) and OS (p=0.005) than those who did not. Multivariate analysis showed that adjuvant therapy and tumour thickness were significant predictive factors for RFS, and the T stage was a significant predictive factor for OS. Conclusions Adjuvant therapy and tumour thickness are significantly associated with RFS and T stage is a significant predictor of OS in Chinese patients with conjunctival melanomas. Patients may benefit from adjuvant therapy with HDI.

Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy

Purpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma. Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated. Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss. Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946–57. ©2017 AACR.

Efficacy and safety of sorafenib versus sunitinib as first-line treatment in patients with metastatic renal cell carcinoma: largest single-center retrospective analysis.

We conducted this largest, single-center, retrospective study to determine the efficacy of sorafenib versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) in Chinese patients to validate the potential data on direct comparison of the efficacy of first-line treatment with sorafenib and sunitinib in the treatment of mRCC. From November 2006 to March 2015, we reviewed medical records from Peking University Cancer Hospital and found 169 patients receiving sorafenib (400 mg orally BID continuously in a 4-week cycle) and 165 patients receiving sunitinib (50 mg orally daily in a 6-week cycle; 4/2 schedule) as the first-line targeted therapy. Median follow-up was 23.0 months. In sorafenib and sunitinib groups, there is no significant difference in progression-free survival (PFS) (9.0 months [95%CI:8.00-12.00] vs 11.0 months [95%CI:9.00-14.00], respectively; P=0.6289) and overall survival (OS) (28.0 months [95%CI:24.00-34.00] vs 28.0 months [95% CI:19.00-33.00], respectively; P=0.979). Subgroup analysis based on Karnofsky performance status (KPS), pathological type, Memorial Sloan Kettering Cancer Center score, and metastasis was also conducted. Multivariate analysis revealed that sorafenib treated patients had superior efficacy in patients with a KPS of <90 and significantly better PFS (hazard ratio: 0.460 [95% CI:0.222-0.954]). Most common adverse events were hand-foot skin reaction and thrombocytopenia which were manageable. Overall, no significant differences were seen between sorafenib and sunitinib in the treatment of advanced renal cancer. However, fewer toxicities associated with sorafenib and superior efficacy in subgroups (non-clear cell carcinoma and KPS <90) indicates sorafenib as an effective first-line treatment agent in patients with mRCC.

MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases

Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population. Experimental Design: A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival. Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors (P = 0.007, other P < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all P < 0.001), whereas in mucosal melanoma, only C-KIT was (P = 0.006). Although correlated with BRAF mutations (P = 0.001 and P < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival (P = 0.406 and 0.256, respectively). Conclusions: The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. Clin Cancer Res; 23(20); 6120–7. ©2017 AACR.

Outcomes and Predictive Factors of Isolated Limb Infusion for Patients with In-transit Melanoma in China

PurposeThis study was designed to evaluate the efficacy of isolated limb infusion (ILI) treatment in Chinese patients with in-transit melanoma and to identify factors predictive of the outcome.MethodsA total of 150 patients with in-transit melanoma who received a single ILI between 2007 and 2016 were identified from a prospectively collected database.ResultsAll patients had AJCC Stages IIIb, IIIc, and IV disease. Acral lentiginous melanoma (ALM) accounted for 79% of patients, and 59% had a high burden of disease (BOD). The complete response (CR) and partial response (PR) rates were 6 and 35%, respectively. Forty-five percent of patients experienced grade III–IV limb toxicities, but no grade V toxicity was observed. Patients with a low BOD, high limb temperature, high peak creatine phosphokinase (CK) level, and grade III–IV limb toxicity achieved higher response rates. Stage IV disease and high BOD were associated with worse infield progression-free survival (PFS) and overall survival (OS), whereas patients with CR or PR to ILI had better infield PFS and OS. Multivariate analyses showed that disease stage, BOD, and a CR were independent predictors of infield PFS, whereas disease stage and a response to ILI were independent predictors of OS.ConclusionsILI is well-tolerated but the response rate in Chinese patients was lower than that reported in US and Australian studies. The prevalence of the ALM histological type, advanced disease stages, and a high BOD may be the main reasons for this. A response to ILI, BOD, and disease stage are prognostic factors for survival.

Safety and Efficacy of Apatinib Combined with Temozolomide in Advanced Melanoma Patients after Conventional Treatment Failure

OBJECTIVE: Asian melanoma patients, predominantly comprised of acral and mucosal subtypes, might not benefit from immunotherapy and targeted therapy as much as Caucasian patients. Novel treatment strategies are demanded after conventional treatment failure. This was a prospective, single-arm, and single-center dose escalation study to investigate the safety and preliminary efficacy of apatinib combined with temozolomide in heavily treated advanced melanoma patients. METHODS: Patients were sequentially admitted to four dose-escalating groups of apatinib and temozolomide (three cases in each group) using a traditional 3 + 3 dose escalation design method. RESULTS: Twelve patients were enrolled between December 2016 and August 2017. Most patients with an acral or mucosal primary origin progressed after immunotherapy or targeted therapy. Dose escalation had been completed without dose-limiting toxicity. Common adverse events included hypertension, hand-foot syndrome, proteinuria, neutropenia, nausea, and fatigue. All adverse events were grade 1 or 2, while the maximum tolerated dose was not reached. Up to January 2018, 1 patient achieved partial response, 9 experienced stable disease, and 2 exhibited progressive disease. The objective response rate and disease control rate were 8.3% and 83%, respectively. CONCLUSIONS: In conclusion, apatinib combined with temozolomide was well tolerated and has demonstrated efficacy in advanced melanoma patients.

BRAF inhibitors: efficacious and tolerable in BRAF-mutant acral and mucosal melanoma.

BRAF inhibitors substantially have impressive clinical efficacy in cutaneous melanoma. However, their role in acral and mucosal melanoma remains unclear. Records were reviewed of patients with metastatic or unresectable BRAF-mutant acral and mucosal melanoma hospitalized and administrated BRAF inhibitors during January 2011 and March 2016. Clinical data were collected to determine PFS, ORR, DCR, OS, and safety. Among 28 acral and 12 mucosal melanoma patients treated with BRAF inhibitors, median PFS were 3.6 (95%CI 3.0-6.4) and 4.4 (95%CI 0.8-12.7) months, median OS were 6.2 (95%CI 6.1-12.1) and 8.2 (95%CI 6.6-19.9) months; ORRs were 38.1% and 20.0%, DCRs were 81.0% and 70.0% in acral and mucosal melanoma, respectively. BRAF inhibitors were well tolerated. The most common adverse effects (AEs) were cutaneous and hematological. Grade 3/4 AEs were relatively rare. In conclusion, BRAF inhibitors have acceptable efficacy and good tolerance in BRAF mutant acral and mucosal melanoma.

Anti-VEGFR, PDGFR, and CSF1R tyrosine kinase inhibitor CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma: a phase 1 clinical trial

Abstract Background CM082 (X-82) is an oral multikinase inhibitor that targets VEGFR, PDGFR, and CSF1R. We aimed to investigate the safety profile of CM082 in combination with everolimus for treatment of metastatic renal cell carcinoma. Methods We did a phase 1 study in Chinese patients aged 18–75 years, with histologically or cytologically confirmed diagnosis of clear cell renal cell carcinoma, which had progressed on at least one VEGFR tyrosine kinase inhibitor therapy in Peking University Cancer Hospital, Beijing, China. 3+3 dose escalation was done from 100 mg to 200 mg to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of oral CM082 daily in combination with oral everolimus 5 mg daily. We further assessed the safety and efficacy of this combination regimen in an expansion cohort. Findings Between Sept 11, 2015, and July 12, 2016, we enrolled 22 patients with clear cell renal cell carcinoma. At the cutoff date (Aug 16, 2017), 15 patients had completed treatment, four patients had discontinued treatment, and three patients were still on treatment. 21 patients (95%) had received at least one VEGFR tyrosine kinase inhibitor therapy. DLT was observed in one (17%) of six patients: grade 4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, and was chosen as the optimal biological dose regimen. CM082 was well tolerated by most patients at a daily dose of 200 mg or less; grade 3–4 adverse events and adverse reactions were reported in 14 (64%) patients. The most common grade 3–4 adverse event (10%) and adverse reaction (14%) were hypertension. 20 patients (91%) were evaluable for tumour response per Response Evaluation Criteria In Solid Tumors version 1.1. Promising antitumour activity of CM082 and everolimus 5 mg in patients with metastatic renal cell carcinoma has been shown. No complete remission was seen. Partial response was observed in six (30%) of 20 patients, and stable disease was achieved in 14 (70%) of 20 patients. The objective response was achieved in 30% and disease control in 100%. At CM082 200 mg plus everolimus 5 mg, five (36%) of 14 patients had partial response and nine (64%) of 14 patients had stable disease with 100% disease control. The median progression-free survival was 7·9 months (95% CI 4·5–17·0). Interpretation CM082 in combination with everolimus 5 mg was well tolerated in patients with advanced renal cell carcinoma who received at least one previous VEGFR tyrosine kinase inhibitor. MTD was not reached at up to CM082 200 mg plus everolimus 5 mg. This dose regimen was chosen as the recommended phase 2 dose for Chinese patients with renal cell carcinoma. Funding AnewPharma.

The expression and clinical significance of PD-L1 in patients with upper tract urothelial carcinoma.

444 Background: Primary upper tract urothelial carcinoma (UTUC) is rare. In China UTUCs are more common than in Western populations and account for 20–30% of all TCCs.An antibody that targets programmed death ligand-1 (PD-L1) pathway has been shown to be active towards various types of cancer including bladder urothelial carcinoma. In this study, we investigated the PD-L1 expression and prognostic significance in UTUC. Methods: Formalin-fixed paraffin-embedded tumor samples from 78 patients with upper tract urothelial carcinoma from Peking University Cancer Hospital and Peking Universiy First Hospital were retrieved. PD-L1 expression was evaluated by immunohistochemistry using rabbit monoclonal anti-PD-L1 antibody. PD-L1 positivity on tumor cell membrane was defined as ≥ 1% of tumor cell membrane staining.The clinical data of patients were retrospective collected. The multivariate analysis was used to assess the association of PD-L1 expressionwith tumor staging, pathological N classification, whether firs...