Validation of the American Joint Committee on Cancer Eighth Edition Staging of Patients With Metastatic Cutaneous Melanoma Treated With Immune Checkpoint Inhibitors

Waninger, Jessica; Vincent, Tiffaney L.; Journey, Sara N.; Skvarce, Jeremy; Chopra, Zoey; Tezel, Alangoya; Bryant, Alex K.; Mayo, Charles S.; Sun, Yilun; Sankar, K. Nathan; Ramnath, Nithya; Sussman, Jeremy B.; Fecher, Leslie A.; Alva, Ajjai; Green, Michael D.

doi:10.1001/jamanetworkopen.2021.0980

Cited by 17 publications

(13 citation statements)

References 31 publications

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“…In this study, patients with liver metastases had an inferior overall response rate (ORR, 0.33; P = .02), progression-free survival (PFS, HR, 4.03; P < .01), and overall survival (OS, HR, 3.17; P = .01) compared to those without liver metastasis. A larger recently published study (36), examined the effect of liver metastases on 1009 patients with advanced melanoma. Here, liver metastasis was associated with a hazard ratio of 2.22 for death ( 95% CI, 1.48-3.33; P < .001) and 2.0 for progression (95% CI 2.00 (1.36-2.79; P<0.001) in a Cox proportional hazard model.…”

Section: Clinical Data With Liver Metastasis Treated With Icimentioning

confidence: 99%

The Liver–Immunity Nexus and Cancer Immunotherapy

Lee

Green

Huppert

et al. 2022

Clinical Cancer Research

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The impact of liver metastases on immune checkpoint inhibitor effectiveness in patients with solid tumor malignancies has been the focus of several recent clinical and translational studies.We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and NSCLC patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with PD-1 and PDL-1 inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a 2 site MC38 model appear to delete CD8+ T cells in a FasL dependent manner. In addition, Treg activation was observed and contributed to the distal immunosuppression. Finally, we discuss the some of the interventions reported to address liver immune suppression such as radiation therapy, combination checkpoint blockade and Treg depletion.Research.

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Section: Clinical Data With Liver Metastasis Treated With Icimentioning

confidence: 99%

The Liver–Immunity Nexus and Cancer Immunotherapy

Lee

Green

Huppert

et al. 2022

Clinical Cancer Research

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“…We observed a 32.5% [95% CI: 26.1–38.9] CR rate, which is above figures obtained in melanoma patients receiving anti-PD-1 monotherapy [ 2 , 3 , 4 , 5 , 6 ] or combined ipilimumab + nivolumab [ 26 ], despite numerous patients with active intracranial metastasis and/or non-treatment-naïve status being included. The high percentage of AJCC M1c and M1d patients, with high LDH serum levels, ECOG performance status >1, or liver metastasis, which all represent poor prognostic factors [ 27 ], also highlights real-life patients’ severity. Benefits of RT were observed particularly in patients failing anti-PD-1 blockade.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Large Use of Combined Hypofractionated Radiotherapy in a Cohort of Anti-PD-1 Monotherapy-Treated Melanoma Patients

Saïag

Molinier

Roger

et al. 2022

Cancers

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To assess the role of radiotherapy in anti-PD-1-treated melanoma patients, we studied retrospectively a cohort of 206 consecutive anti-PD-1 monotherapy-treated advanced melanoma patients (59% M1c/d, 50% ≥ 3 metastasis sites, 33% ECOG PS ≥ 1, 33% > 1st line, 32% elevated serum LDH) having widely (49%) received concurrent radiotherapy, with RECIST 1.1 evaluation of radiated and non-radiated lesions. Overall (OS) and progression-free (PFS) survivals were calculated using Kaplan–Meier. Radiotherapy was performed early (39 patients) or after 3 months (61 patients with confirmed anti-PD-1 failure). The first radiotherapy was hypofractionated extracranial radiotherapy to 1–2 targets (26 Gy-4 weekly sessions, 68 patients), intracranial radiosurgery (25 patients), or palliative. Globally, 67 (32.5% [95% CI: 26.1–38.9]) patients achieved complete response (CR), with 25 CR patients having been radiated. In patients failing anti-PD-1, PFS and OS from anti-PD-1 initiation were 16.8 [13.4–26.6] and 37.0 months [24.6–NA], respectively, in radiated patients, and 2.2 [1.5–2.6] and 4.3 months [2.6–7.1], respectively, in non-radiated patients (p < 0.001). Abscopal response was observed in 31.5% of evaluable patients who radiated late. No factors associated with response in radiated patients were found. No unusual adverse event was seen. High-dose radiotherapy may enhance CR rate above the 6–25% reported in anti-PD-1 monotherapy or ipilimumab + nivolumab combo studies in melanoma patients.

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“…Liver metastases are common in advanced melanoma and are associated with poor response to immunotherapy [ 23 ]. Specifically, in a retrospective analysis of 357 patients with metastatic cutaneous melanoma receiving single or double agent immunotherapy, those with liver metastases and elevated serum LDH had a median OS of 4.2 months [ 24 ]. As such, it is possible that patients presenting with symptomatic liver metastases began immunotherapy treatment soon after diagnosis yet still experienced poor survival outcomes.…”

Section: Discussionmentioning

confidence: 99%

Time to Treatment With Nivolumab or Pembrolizumab for Patients With Advanced Melanoma in Everyday Practice

Ksienski¹,

Truong²,

Croteau³

et al. 2021

Cureus

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Background The anti-programmed cell death one antibodies (Anti-PD-1 Ab) pembrolizumab or nivolumab are commonly prescribed to patients with advanced melanoma. The purpose of the current study is to identify baseline clinical characteristics associated with time to treatment initiation (TTI) of pembrolizumab or nivolumab for advanced melanoma and whether treatment delays are associated with differences in survival outcomes. Methods All patients receiving Anti-PD-1 Ab as a first-line treatment for advanced melanoma outside of clinical trials at British Columbia Cancer Agency between 10/2015 and 10/2019 were identified retrospectively. TTI was defined as the interval from pathologic diagnosis of advanced melanoma to first Anti-PD-1 Ab treatment. To determine the association between TTI and baseline characteristics, multivariable Cox proportional hazard regression analyses provided an estimate of the instantaneous relative risk of starting treatment at any time point (hazard ratio [HR] >1 indicates shorter TTI). To describe changes in overall survival (OS) observed for each four-week delay in treatment initiation, multivariable cox proportional hazard regression modelling was also performed. Results In a cohort of 302 patients, the median TTI was 52 days (interquartile range 30.2-99.0). Pulmonary metastases (M1b)/non-central nervous system visceral metastases (M1c) vs. metastases to skin or non-regional lymph nodes (M1a)(HR=1.50, 95% CI=1.12-2.02; p=0.007) and pre-treatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1 (vs 0/1, HR=1.50, 95% CI= 1.11-2.01; p=0.008) were associated with earlier TTI. An association between treatment delay and improved OS was observed. Conclusion Patients having visceral metastases and poor baseline ECOG PS were more likely to initiate Anti-PD-1 Ab sooner. The association of shorter TTI with worse OS likely represents confounding by indication (urgent treatment offered to patients with aggressive disease).

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Validation of the American Joint Committee on Cancer Eighth Edition Staging of Patients With Metastatic Cutaneous Melanoma Treated With Immune Checkpoint Inhibitors

Cited by 17 publications

References 31 publications

The Liver–Immunity Nexus and Cancer Immunotherapy

The Liver–Immunity Nexus and Cancer Immunotherapy

Efficacy of Large Use of Combined Hypofractionated Radiotherapy in a Cohort of Anti-PD-1 Monotherapy-Treated Melanoma Patients

Time to Treatment With Nivolumab or Pembrolizumab for Patients With Advanced Melanoma in Everyday Practice

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