Immune‐related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: A single‐center retrospective study in Japan

Otsuka, Masaki; Sugihara, Satoru; Mori, Sadao; Hamada, Kengo; Sasaki, Yoshi K.; Yoshikawa, Shusuke; Kiyohara, Yoshio

doi:10.1111/1346-8138.15246

Cited by 18 publications

(18 citation statements)

References 48 publications

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“…The onset of irAEs has also been associated with improvements in PFS and OS in other carcinomas (25). However, the onset of irAE may not be a predictor of effectiveness because there is no clear relationship between the onset of irAE and the onset of response in other carcinomas (26,27). In the present study, the timing of onset of irAE was also varied and not clearly associated with the timing of onset of response (Figure 1).…”

Section: Discussioncontrasting

confidence: 50%

A Multicentre Retrospective Study of Nivolumab Plus Ipilimumab for Untreated Metastatic Renal Cell Carcinoma

et al. 2021

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Background/Aim: To evaluate the effectiveness and safety of nivolumab plus ipilimumab for untreated metastatic renal cell carcinoma in real-world clinical practice in Japan based on 1-year follow-up results. Patients and Methods: This multicentre, retrospective study analysed 45 metastatic renal cell carcinoma patients who received nivolumab plus ipilimumab between August 2018 and January 2019 in Japan. Data were extracted from patients' medical records. Subgroup analyses were performed based on baseline demographic data and treatment history. Results: The objective response rate was 42.5% (complete response rate: 10.0%). The 12-month overall survival rate was 81.4% and the progression-free survival rate was 56.1%. Thirty-five patients (77.8%) showed any grade treatment-related adverse events and 17 (37.8%) showed grade ≥3 treatmentrelated adverse events, with no significant difference in safety between subgroups. Conclusion: The effectiveness and safety of nivolumab plus ipilimumab in real-world clinical practice with 1-year follow-up were comparable with those of the CheckMate 214 trial.Based on GLOBOCAN's 2018 data, renal cell carcinoma (RCC) accounts for approximately 2% of global cancer diagnoses (1, 2). In Japan, the crude incidence rates of RCC in men and women were 8.2 and 3.5 per 100,000, respectively (3). Survival of patients with RCC is highly dependent on the stage at diagnosis, with a 5-year relative survival rate of 93% for stage I localised RCC, 72.5% for stage II/III regional RCC and only 12% for stage IV metastatic RCC (mRCC) (2). In the past two decades, treatments targeting vascular endothelial growth factor receptor tyrosine kinase and mammalian target of rapamycin (mTOR) pathways have clearly improved mRCC management (4). In Japan, tyrosine kinase inhibitors (TKIs) were the most common first-line treatment (72.2%) in patients with mRCC, followed by mTOR inhibitors (14.3%) and cytokines (13.5%), from 2012 to 2015 (5). However, TKIs and mTOR inhibitors are associated with inherent resistance and show limited overall survival.Recently, the focus of mRCC treatment research has moved to immuno-oncology, and evaluations of immune checkpoint inhibitors have shifted the treatment paradigm of mRCC (4). A randomised phase III clinical trial, CheckMate 214, has demonstrated that nivolumab plus ipilimumab combination therapy was superior to a TKI, sunitinib, with respect to therapeutic effects in patients with 6199 This article is freely accessible online.

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Section: Discussioncontrasting

confidence: 50%

A Multicentre Retrospective Study of Nivolumab Plus Ipilimumab for Untreated Metastatic Renal Cell Carcinoma

et al. 2021

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“…Nivolumab was independently assessed in 12 studies. 17,29–39 A post-marketing surveillance study is ongoing to evaluate nivolumab (2 mg/kg every 3 weeks) for Japanese patients with melanoma from approximately 100 institutions since the nivolumab approval date (4 July 2014). 30 In the interim analysis, the estimated median OS was 379 days in the overall population, and 340 days for MM.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, seven independent single-center, retrospective studies showed that MM patients treated with nivolumab had an ORR from 9.5% to 50.0% and a median PFS from 2.1 to 10.2 months. 29,[34][35][36][37][38][39] Pembrolizumab was independently assessed in four studies. 26,[40][41][42] 41 Fifteen patients received 2 mg/kg pembrolizumab every 3 weeks for up to 35 cycles (approximately 2 years).…”

Section: Anti-ctla-4 Monoclonal Antibodiesmentioning

confidence: 99%

“…In addition, seven independent single-center, retrospective studies showed that MM patients treated with nivolumab had an ORR from 9.5% to 50.0% and a median PFS from 2.1 to 10.2 months. 29,[34][35][36][37][38][39] Pembrolizumab was independently assessed in four studies. 26,[40][41][42] An exploratory post hoc analysis of three randomized trials (KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006) enrolled almost 1600 patients with stage III or IV melanoma.…”

Section: Anti-ctla-4 Monoclonal Antibodiesmentioning

confidence: 99%

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Immune checkpoint inhibitors in advanced or metastatic mucosal melanoma: a systematic review

Kan

Zhao

et al. 2020

Ther Adv Med Oncol

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Background: Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM. Methods: We searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate. Results: This review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment. Conclusions: Immune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.

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“…In addition, Freeman-Keller reported an epidemiological correlation between the efficacy of nivolumab and irAEs caused by this agent [95]. Several retrospective studies and case reports have also supported this hypothesis [95][96][97][98]. Taken together, these reports suggested correlations between the efficacy of anti-PD1 Abs and several irAEs, and that CD163 + TAMs play a key role in inducing the efficacy of anti-PD1 Abs as well as several irAEs.…”

Section: Roles Of Tams In Immune-related Adverse Events Iraesmentioning

confidence: 84%

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

Fujimura

Aiba

2020

Biomolecules

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Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163+ M2 macrophages, and CD163+ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy.

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Immune‐related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: A single‐center retrospective study in Japan

Cited by 18 publications

References 48 publications

A Multicentre Retrospective Study of Nivolumab Plus Ipilimumab for Untreated Metastatic Renal Cell Carcinoma

A Multicentre Retrospective Study of Nivolumab Plus Ipilimumab for Untreated Metastatic Renal Cell Carcinoma

Immune checkpoint inhibitors in advanced or metastatic mucosal melanoma: a systematic review

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

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