PURPOSEMetastatic mucosal melanoma responds poorly to anti–programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressiv...

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial

Background Tislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Methods The purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1. Results As of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types. Conclusions Tislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors. Trial registration number CTR20160872.

https://jitc.bmj.com/content/jitc/8/1/e000437.full.pdf

Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study.

Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients.

Background:Inhibitors targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have unprecedented effects in cancer treatment. However, the objective response rates (ORRs), pr...

https://journals.sagepub.com/doi/pdf/10.1177/1758835920937612

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials.

Acral and mucosal melanomas are extremely rare in Caucasians; however, they are the predominant melanoma subtypes in Asians and other non-Caucasian populations. Acral and mucosal melanomas share many clinicopathological features, including aggressive phenotypes, similar genetic landscapes, and grim prognoses. In spite of advances in melanoma management, patients with acral and mucosal melanomas show limited benefit from current therapies. The rarity of these subtypes of melanoma is a significant factor contributing to the poor understanding of these pathological subtypes and the lack of effective interventions. Furthermore, the mechanisms contributing to disparities between different types of melanoma remain largely unclear. Herein, we comprehensively review current knowledge on the clinicopathological characteristics and mutational landscapes of acral and mucosal melanomas, as well as providing an overview of current therapies for patients with these aggressive melanoma subtypes, focusing on available immunotherapeutic interventions. We also discuss pathological differences between different melanoma subtypes and summarize current knowledge on melanoma disparities between Asians and Caucasians. Finally, we discuss emerging immunotherapeutic strategies for the treatment of acral and mucosal melanomas, focusing on combination therapies with immune checkpoint inhibitors. Unraveling the unique features of acral and mucosal melanomas is key for their early diagnosis and for the development of effective therapies.

Immunotherapy in Acral and Mucosal Melanoma: Current Status and Future Directions.

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151).

Programmed cell death 1 (PD-1) checkpoint inhibitor therapy leads to immune-related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with the treatment response in Chinese patients with advanced melanoma. In this study, we conducted a retrospective study of advanced melanoma patients who received PD-1 inhibitor therapy in China between August 2014 and March 2018. A total of 93 patients treated with PD-1 inhibitors including pembrolizumab and nivolumab were enrolled. The most frequent irAEs were pruritus, rash, vitiligo, and fatigue. The median time to onset of irAEs was 6.1 weeks. The overall response rate (ORR) and disease control rate (DCR) were higher in patients with irAEs than those without irAEs (P = 0.004 and P = 0.003, respectively), and better in patients who experienced three or more irAEs than those with none (P <0.001 and P <0.001, respectively). The ORR and DCR were significantly better in patients with grade 1 to 2 irAEs when compared with those with none (P = 0.002 and P = 0.003, respectively). In addition, the median progression-free survival and overall survival were longer in patients with irAEs than in those without irAEs (P = 0.007 and P = 0.002, respectively). In conclusion, our data demonstrated that irAEs were associated with a better clinical outcome after treatment with PD-1 inhibitor therapy in Chinese patients with advanced melanoma.

/pdf/association-between-immune-related-adverse-events-and-332gw7gqmt.pdf

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma.

The clinical efficacy of PD-1 inhibitors as an adjuvant treatment for Asian melanoma patients has not yet been determined. This retrospective study analyzed the clinical data of 90 Chinese patients with completely resected, stage III cutaneous or acral melanoma who received either adjuvant PD-1 inhibitor or high-dose interferon α-2b (HDI). Anti-PD-1 treatment resulted in significantly longer RFS and DMFS than HDI in cutaneous melanoma patients, with hazard ratios (HRs) (anti-PD-1 versus HDI) of 0.402 (95% CI, 0.183-0.886) and 0.324 (95%CI, 0.122 to 0.861) for RFS and DMFS, respectively. However, adjuvant anti-PD-1 treatment had no advantage over HDI in acral melanoma patients with HRs (anti-PD-1 versus HDI) of 1.204 (95% CI, 0.521 to 2.781) and 1.968(95% CI, 0.744-5.209) for RFS and DMFS, respectively. Adjuvant anti-PD-1 treatment yielded a significantly better prognosis than HDI in Chinese patients with stage IIIB/C cutaneous melanoma, but a significant difference was not observed in those with acral melanoma.

Adjuvant PD-1 inhibitor versus high-dose interferon α-2b for Chinese patients with cutaneous and acral melanoma: A retrospective cohort analysis

The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3-4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3-4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3-4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.

/pdf/safety-and-tolerability-of-braf-inhibitor-and-braf-inhibitor-14xtlkifgv.pdf

Xizhi Wen

Papers

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151).

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma.

Adjuvant PD-1 inhibitor versus high-dose interferon α-2b for Chinese patients with cutaneous and acral melanoma: A retrospective cohort analysis

Safety and Tolerability of BRAF Inhibitor and BRAF Inhibitor-Based Combination Therapy in Chinese Patients With Advanced Melanoma: A Real World Study.

KEYNOTE-151: A phase Ib study of second-line pembrolizumab (Pembro) for Chinese patients (pts) with advanced or metastatic melanoma