Melanoma is a relatively rare disease in China, but the incidence is increasing rapidly (1). Although limited epidemiologic data are available, acral and mucosal melanomas are generally considered the most common subtypes in Chinese patients (2). These tend to arise in regions shielded from solar ultraviolet exposure and are regarded as more aggressive than other types of melanoma (3). An analysis of 522 patients with malignant melanoma at a center in China reported that patients had a poor prognosis, which likely reflects the limited effective treatment options available (2, 4). Data from a real-world analysis conducted at the Beijing Cancer Hospital indicate that dacarbazine-based regimens are likely the most frequently used first-line therapies in China and that paclitaxel-platinum combinations were likely the most commonly used in the second line until the approval of the PD-1 inhibitors pembrolizumab and toripalimab as second-line treatment of melanoma in China in 2018 (5–7). Median overall survival (OS) with the chemotherapy-based regimens is poor, at 10.5 months with first-line therapy and 7.5 months with second-line therapy (5). Although immune checkpoint inhibitors have dramatically improved survival outcomes in White populations and are approved for use in China, there are limited available data regarding the safety and efficacy of immune checkpoint inhibitors in Chinese populations (4).

The phase 1b KEYNOTE-151 study (NCT02821000) evaluated the efficacy and safety of the PD-1 inhibitor pembrolizumab as second-line therapy in Chinese patients with advanced melanoma (8). At median follow-up of 7.9 months, pembrolizumab was shown to be well tolerated and had clinically meaningful and durable antitumor activity, including in patients with acral melanoma and mucosal melanoma. The objective response rate (ORR) among all patients was 16.7% (95% CI, 10.0–25.3), and the duration of response (DOR) was 8.4 months (range, 1.1+ to 11.0+ months) (8). Although these results are promising, the duration of follow-up was limited, and the long-term impact of pembrolizumab in Chinese patients remains unknown. Here, we present 3-year follow-up data for patients in the KEYNOTE-151 study, including subgroup analyses by melanoma subtype and by PD-L1 and BRAF mutation status in patients with acral melanoma.

In this 3-year follow-up of the KEYNOTE-151 study, second-line pembrolizumab had a manageable safety profile and continued to show clinically meaningful antitumor activity, durable responses, and prolonged survival in Chinese patients with advanced melanoma. The ORR of 17.6%, DCR of 38.2%, DOR of 13.8 months, and the 36-month OS rate of 22.3% also suggest that pembrolizumab has durable survival benefit in some patients.

The safety profile of pembrolizumab in the current study was similar to that observed at the earlier analysis of KEYNOTE-151 and was generally consistent with the known safety profile of pembrolizumab in global populations (8, 9). The only notable difference compared with the earlier analysis was a higher incidence of treatment-related alanine aminotransferase increase (23.3% vs 14.6%) and vitiligo (14.6% vs <2%). While the rate of vitiligo was similar to that observed in a global pooled analysis of patients with melanoma receiving pembrolizumab (12.0%), the number of patients reporting elevated alanine aminotransferase in KEYNOTE-151 was comparably much higher (4.4%) (9). Although it is unclear why the incidence of alanine aminotransferase increase was so high in this study, all occurrences were grade 1 or 2, indicating they were mild or moderate in severity. Of note, a high rate of treatment-related alanine aminotransferase increase (31.3%) was also observed in the phase 2 POLARIS-01 study, which investigated the PD-1 inhibitor toripalimab in 128 Chinese patients with advanced melanoma previously treated with systemic therapy (10). Elevated alanine aminotransferase levels may therefore be an AE that occurs more frequently with PD-1 inhibitors in patients of Chinese descent.

The efficacy of immune checkpoint inhibitors has been well established in White patients, but there are limited data available regarding their use in Chinese patients, or even the wider Asian population. To our knowledge, the only other prospective trial of an immune checkpoint inhibitor in Chinese patients with data available is the phase 2 POLARIS-01 study (10). POLARIS-01, which included 50 (39.4%) patients with acral melanoma and 22 (17.3%) patients with mucosal melanoma, reported an ORR of 17.3% (1 CR/21 PR), which was similar to that observed in the current analysis. The DCR was 57.5%, the DOR was NR, and the median PFS and OS were 3.6 months and 22.2 months, respectively. These results are suggestive of a greater magnitude of benefit than those observed in the current analysis; however, differences in study design and baseline characteristics, including a higher proportion of patients with stage IV disease and elevated lactate dehydrogenase levels in KEYNOTE-151, preclude direct comparison between the studies. Two retrospective studies have also been conducted. One study, which included 51 patients with melanoma treated with a regimen containing an anti–PD-1 antibody at a single center in China, reported an ORR of 10.8% and a median OS of 13.0 months in patients receiving PD-1 blockade alone (11). A retrospective case series of 52 Chinese patients with advanced melanoma who received immune checkpoint inhibitor therapy reported an ORR of 25.0% and a median OS of 10.0 months among patients who received pembrolizumab monotherapy (12). Although data regarding the efficacy of PD-1 inhibitors in Chinese patients are limited, several studies have been conducted in Japanese patients, who have comparably high rates of acral and mucosal melanoma (13). In the phase 1b KEYNOTE-041 study, at median follow-up of 10.3 months pembrolizumab was shown to have antitumor activity with an ORR of 24.3%, median DOR was NR, and median OS of NR in Japanese patients with unresectable stage III or advanced melanoma (14). Long-term follow-up of a phase 2 study investigating nivolumab as first-line therapy in Japanese patients with stage III/IV melanoma with a median follow-up of 32.9 months reported an ORR of 34.8% and a median OS of 32.9 months, although this analysis was limited by the small number of patients (n = 10) (15). Both the retrospective analyses of immune checkpoint inhibitors in Chinese patients and the results of the prospective study investigating pembrolizumab in Japanese patients reported outcomes that were generally comparable with those seen in the current analysis (ORR, 17.6%; median OS, 13.2 months), although differences in study design and patient populations preclude direct comparison.

As in the earlier analysis of the KEYNOTE-151 study (8), the efficacy of pembrolizumab was also investigated by melanoma subtype at the 3-year follow-up point. In this study, 37.9% of patients had acral melanoma and 14.6% had mucosal melanoma, which is comparable to the proportions observed in a pivotal study conducted in Chinese patients with melanoma (41.8% acral melanoma; 22.6% mucosal melanoma) (2). Data comparing outcomes with PD-1 inhibitors in Chinese patients with acral and mucosal melanoma are limited. In the POLARIS-01 study, the ORR was 14.0% for patients with acral melanoma and 0% for patients with mucosal melanoma (10). The median PFS was 3.2 months and 1.9 months, and the median OS was 16.9 months and 10.3 months, respectively. In retrospective analyses, ORRs with immune checkpoint inhibitors range from 18.8% to 26.7% for patients with acral melanoma and range from 17.6% to 20.0% for patients with mucosal melanoma (11, 12). In the current analysis, the efficacy of pembrolizumab was similar in acral and nonacral cutaneous melanoma (ORR, 18.4% and 19.5%, respectively; median OS, 14.8 months and 13.5 months, respectively). This differed from the results of the POLARIS-01 study, which reported better efficacy in patients with nonacral versus acral melanoma (ORR, 31.0% vs 14.0%; median OS, NR vs 16.9 months) (10). In the current analysis, patients with mucosal melanoma had relatively worse outcomes than patients with cutaneous melanoma subtypes, with a lower ORR (13.3%) and shorter median OS (7.4 months); note, however, the small number of patients in the mucosal subgroup (n = 15). These results are consistent with reports suggesting that patients with mucosal melanoma have unfavorable outcomes with immune checkpoint inhibitors (16, 17). A post hoc analysis of the KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006 studies conducted in a global population reported an ORR of 19% with pembrolizumab in patients with mucosal melanoma and 33% in patients with nonmucosal melanoma, and median OS of 11.3 months and 23.5 months, respectively (16). A lower mutational burden, lower PD-L1 expression, and differences in tumor microenvironment are thought to contribute to the reduced efficacy of immune checkpoint inhibitors in mucosal melanoma (3). Although efficacy in the current analysis was lower in mucosal melanoma compared with cutaneous melanomas, pembrolizumab showed antitumor activity in both acral and mucosal melanoma.

Further subgroup analysis in patients with acral melanoma by PD-L1 expression and BRAF mutation status within the current analysis showed particularly good response and prolonged survival in patients with PD-L1–positive and BRAF wild-type disease. Although limited patient numbers in these subgroups preclude definitive conclusions, the observation warrants further investigation. Further subgroup analyses by PD-L1 and BRAF mutation status in other melanoma subtypes could not be conducted because of small sample sizes.

Although the current study is limited by the single-arm, open-label design, the results provide important data in a patient population with a significant unmet need for improved treatment options. The results of this post hoc exploratory analysis suggest that pembrolizumab as second-line therapy is well tolerated and provides clinically meaningful long-term antitumor activity in Chinese patients with advanced melanoma. Efficacy was observed across subgroups by PD-L1 expression and BRAF mutation status, with notable benefit in patients with acral melanoma who had PD-L1–positive or BRAF wild-type disease. These results strengthen the evidence showing that pembrolizumab is an appropriate second-line therapy for Chinese patients with advanced melanoma, regardless of subtype.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The study protocol and all amendments were approved by the Ethics Committee of Beijing Cancer Hospital, The First Hospital of Jilin University First Affiliated Hospital of Dalian Medical University Ethics Committee, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University Ethics Committee of Sun Yat-Sen University Cancer Center Ethics Committee of Jiangsu Province Hospital. The trial was conducted in accordance with the protocol and its amendments, Good Clinical Practice guidelines, and the provisions outlined in the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.

LS, SD, JFL, and HD substantially contributed to the conception, design, or planning of the study. LS, XZ, YS, HP, DW, JWL, LM, XZW, YG, LZ, SL, XC, JFL, and JG substantially contributed to acquisition of data. LS and CN substantially contributed to analysis of the data. LS, XW, SD, JFL, and HD substantially contributed to interpretation of the results. LS and HD substantially contributed to drafting the manuscript. LS, XZ, YS, HP, DW, JWL, LM, XW, XZW, YG, LZ, SL, XC, SD, JFL, CN, and JG substantially contributed to critically reviewing or revising the manuscript for important intellectual content. All authors contributed to manuscript revision and approved the submitted version.

This study was funded by Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA. The open access publication fees were also funded by the study sponsor.

We thank the patients and their families and caregivers and all investigators and site personnel. Medical writing and/or editorial assistance was provided by Jemimah Walker, PhD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA.

The study received funding from Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA. The funder had the following involvement with the study: the funder of the study collaborated with academic advisers in designing the study, gathering, analyzing, and interpreting the results, and payment of open access publication fees for the current manuscript. LS reports receiving honoraria from MSD, Roche, Juushi Bio, and Novartis. XW reports receiving grants to their institution from Oriengene. SD reports employment at Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA, and is a shareholder of Merck and Co., Inc., Rahway, NJ, USA. CN reports employment at MSD, China, and receiving honoraria from MSD, China. JFL reports employment at Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA. HD reports employment at MSD, China, and receiving honoraria from MSD, China. JG reports advisory/consultancy roles with MSD, Roche, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences, and Oriengene.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.