Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results

Gambichler, Thilo; Chatzipantazi, Maria; Schröter, Ulrike; Stockfleth, Eggert; Gedik, Cansu

doi:10.1080/2162402x.2019.1677139

Cited by 16 publications

(7 citation statements)

References 23 publications

(64 reference statements)

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“…BRAF mutations rate in MUPs appears similar to MKPs; however, for MUPs the rate for V600K seems higher than the rate for MKPs (24). Melanomas with the V600K mutation are characterized by a lower dependence on the activation of the ERK pathway and greater use of alternative pathways; against these melanomas they have a higher mutational load and respond better to immunotherapy; this would concretely explain the better response to immunotherapy and the worse response to BRAFi/ MEKi of the MUPs (25)(26)(27). The strengths of our study include the diagnosis of MUP based on Das Gupta's criteria (2), the sample size (one of the largest in MUP literature), the evaluation of Balch's staging proposal, and the evaluation of systemic treatments.…”

Section: Discussionmentioning

confidence: 89%

Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study

et al. 2021

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BackgroundMelanoma of unknown primary (MUP), accounts for up to 3% of all melanomas and consists of a histologically confirmed melanoma metastasis to either lymph nodes, (sub)cutaneous tissue, or visceral sites without any evidence of a primary cutaneous, ocular, or mucosal melanoma. This study aimed to investigate the characteristics, treatment strategies, and prognostic factors of MUP patients, in order to shed some light on the clinical behavior of this malignancy.MethodsAll the consecutive patients with a diagnosis of MUP referring to our institutions between 1985 and 2018 were considered in this retrospective cohort study. The records of 173 patients with a suspected diagnosis of MUP were retrospectively evaluated for inclusion in the study. Patient selection was performed according to the Das Gupta criteria, and a total of 127 MUP patients were finally included in the study, representing 2.7% of the patients diagnosed with melanoma skin cancer at our institutions during the same study period. A second cohort of all consecutive 417 MKP patients with AJCC stages IIIB–IV, referring tions in the period considered (1985–2018), was included in the study to compare survival between MUP and MKP patients. All the diagnoses were based on histopathologic, cytologic and immunohistochemical examination of the metastases. All tumors were re-staged according to the 2018 American Joint Committee on Cancer (AJCC) 8th Edition.ResultsMedian follow-up was 32 months (IQR: 15–84). 3-year progression-free survival (PFS) was 54%, while 3-year overall survival (OS) was 62%. Worse OS and PFS were associated with older age (P = 0.0001 for OS; P = 0.008 for PFS), stage IV (P < 0.0001 for OS; P = 0.0001 for PFS) and higher Charlson Comorbidity Index (P < 0.0001 for OS and P = 0.01 for PFS). Patients with lymph node disease showed longer PFS (P = 0.001) and OS (P = 0.0008) than those with (sub)cutis disease. Complete lymph node dissection (CLND) was the most common surgical treatment; a worse OS in these patients was associated with the number of positive lymph nodes (P = 0.01), without significant association with the number of retrieved lymph nodes (P = 0.79). Survival rates were lower in patients undergoing chemotherapy (CT) and target therapy (TT), and higher in those receiving immunotherapy (IT). 417 patients with AJCC stages IIIB–IV of Melanoma Known Primary (MKP) were included for the survival comparison with MUP. 3-year PFS rates were 54 and 58% in MUP and MKP, respectively (P = 0.30); 3-year OS rates were 62 and 70% in MUP and MKP, respectively (P = 0.40).ConclusionsThe most common clinical scenario of our series was a male patient around 59 years with lymph node disease. We report that CLND associated with IT was the best treatment in terms of survival outcome. In the current era of IT and TT for melanoma, new studies have to clarify the impact of novel drugs on MUP.

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Section: Discussionmentioning

confidence: 89%

Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study

et al. 2021

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“…Despite the lack of response in uveal melanoma patients, we noted high response rates in patients diagnosed with melanomas of unknown primary, with four of the five patients (80%) with unknown primaries showing clinical benefit. This is a promising result for this patient cohort as several studies have found conflicting data regarding their responses to ICIs 16,17 . In addition, we noted several responses in difficult to treat metastatic sites, including the adrenal gland 18 .…”

Section: Discussionmentioning

confidence: 68%

Targeting MDSCs using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma

Tobin

Cogswell

Cates³

et al. 2021

Preprint

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Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

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“…The observed lower median survival may be explained by the fact that patients who were not treated with novel therapies (or not treated at all) were also included. Another recent small pilot study showed different results in 41 patients treated with ICI [ 41 ]. The patient population was small and included a relatively high number of patients with MUP (22%) with comparable baseline characteristics as patients with MKP.…”

Section: Resultsmentioning

confidence: 99%

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy

Verver

Grünhagen

Akkooi

et al. 2021

Cancer Immunol Immunother

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Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan–Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 – 44) and 14 months (IQR 5 – not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58–0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies.

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Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results

Cited by 16 publications

References 23 publications

Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study

Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study

Targeting MDSCs using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy

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