Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy

Nakamura, Yoshio; Kitano, Shigehisa; Takahashi, Akira; Tsutsumida, Arata; Namikawa, Kenjiro; Tanese, Keiji; Abe, Takayuki; Funakoshi, Takeru; Yamamoto, Noboru; Amagai, Masayuki; Yamazaki, Naoya

doi:10.18632/oncotarget.12677

Cited by 145 publications

(142 citation statements)

References 37 publications

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“…Patients whose ECOG performance status exceeded 0 had a 2.2 times higher risk of disease progression, consistent with the study findings by Nakamura et al 30 Intriguingly, patients who were age 73 years or older appeared to show a lower risk of progression compared with patients age 55 years or younger. The neutrophil, platelet, and lymphocyte counts did not appear to differ significantly among the age groups, although the platelet count was significantly higher in patients whose ECOG performance status exceeded 0.…”

Section: Association Of Inflammatory Markers With Disease Progressionsupporting

confidence: 91%

“…Baseline LDH level was found to be associated with overall survival in a separate study. 30 In a Phase 1a trial with the anti-PD-1 ligand antibody atezolizumab in patients with metastatic renal cell carcinoma, the exploration of serum markers showed that low baseline levels of acute serum reactants including α-antitrypsin and fibrinogen and the decrease of ferritin level after treatment were associated with longer overall survival. 31 In our cohort study of a well-described, community-based population, we focused on 3 readily available peripheral blood cell counts and observed that absolute neutrophil count and platelet count were significantly associated with PFS in patients with metastatic melanoma receiving pembrolizumab or nivolumab.…”

Section: Original Research and Contributionsmentioning

confidence: 99%

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Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors

Pan¹,

Alavi²,

Herrinton³

2018

TPJ

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Introduction:We investigated the effect of inflammatory biomarkers (neutrophil, platelet, and lymphocyte counts) on risk of progression in patients with metastatic melanoma treated with an immune checkpoint inhibitor targeting programmed cell death protein-1 (PD-1).Methods: This retrospective cohort study included 108 patients with malignant melanoma treated with an anti-PD-1 checkpoint inhibitor from August 2014 through December 2015. The outcome was disease progression noted on imaging or clinical examination. Follow-up began on the date of initiation of anti-PD-1 therapy and ended on the date of progression, disenrollment, death of causes other than malignant melanoma, or the end of the study in February 2017.Results: The median time from initiating therapy with an anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts were associated with progression. The hazard ratio (HR) for neutrophil counts ≥ 5501/µL vs ≤ 3900/µL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p < 0.05). For platelet counts ≥ 304,000 vs ≤ 215,000/µL, the HR was 2.0 (CI = 1.0-3.9, p < 0.05). For lymphocyte counts ≥ 1716/µL vs ≤ 1120/µL, the HR was 0.5 (CI = 0.2-1.0, p = 0.05).Conclusion: For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet counts, or lower lymphocyte counts, are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.

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Section: Association Of Inflammatory Markers With Disease Progressionsupporting

confidence: 91%

Section: Original Research and Contributionsmentioning

confidence: 99%

Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors

Pan¹,

Alavi²,

Herrinton³

2018

TPJ

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“…While we advocate careful selection of patients to be treated with anti‐PD‐1 antibodies followed by ipilimumab, specific biomarkers for identifying those mostly likely to benefit are as yet lacking. In the past, our institute reported pretreatment performance status (PS) of 1 or more, maximum tumor diameter of 30 mm or more, elevated lactate dehydrogenase (LDH) and elevated C‐reactive protein (CRP) to be significantly associated with poor OS of patients receiving first‐line nivolumab therapy . To determine whether or not such clinical parameters reflect the prognosis of patients treated with anti‐PD‐1 antibodies followed by ipilimumab, we examined these potential biomarkers in the present study.…”

Section: Introductionmentioning

confidence: 99%

Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab

Muto¹,

Kitano

Tsutsumida

et al. 2019

The Journal of Dermatology

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Melanoma is one of the most serious form of skin cancer. Nowadays, ipilimumab is used for advanced melanoma refractory to first‐line anti‐programmed death 1 (PD‐1) antibodies. Thirty patients (male : female ratio, 18:12; median age, 60.5 years) sequentially treated with ipilimumab after anti‐PD‐1 antibody (nivolumab or pembrolizumab), while 58 (male : female ratio, 27:31; median age, 66.5 years) with anti‐PD‐1 antibody only. The kind of therapy and schedules were as follows: nivolumab, 2 mg/kg at 3‐week intervals or at 3 mg/kg every 2 week; pembrolizumab, 2 mg/kg every 3 weeks; ipilimumab, 3 mg/kg at 3‐week intervals for four doses. The sequential therapy was selected for the patients with disease progression and/or recovered from severe (immune‐related [ir]) adverse events (AE) after PD‐1 blockade monotherapy. We evaluated multiple parameters and analyzed their relevance to overall survival (OS). The best objective response rate was 6.7% in sequential ipilimumab treatment. Median OS was 163 days (range, 16–489). Baseline absolute lymphocyte count (ALC) and performance status (PS) before sequential ipilimumab were associated with OS in univariate analyses. Baseline PS and irAE within 6 weeks after ipilimumab administration showed significant differences on multivariate analysis. Prior to first‐line PD‐1 blockade, these parameters were not associated with OS. The other factors (i.e. age, sex, number of doses, absolute neutrophil counts, neutrophil : lymphocyte ratio, lactate dehydrogenase and C‐reactive protein) were not associated with OS. [Correction added on 17 April 2019, after first online publication: ‘not related to OS' has been amended to ‘not associated with OS’.] Ipilimumab as sequential therapy did not appear to improve OS and was associated with more severe irAE than PD‐1 blockade monotherapy. We need to carefully consider treating patients with poor PS and low ALC.

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“…On the other hand, we did not detect any correlations between serum 5‐ S ‐CD at baseline and a favorable response to Nivo in 12 cases because median pretreatment serum 5‐ S ‐CD was in fact higher in PR than in PD patients. Serum LD has been proposed as a biomarker in immune‐checkpoint blockade therapy for advanced melanoma, with patients displaying elevated baseline levels being significantly associated with short overall survival compared with those having normal values following treatment with Nivo or other immune‐checkpoint blockade therapies . Therefore, while serum LD should be considered at baseline, 5‐ S ‐CD may be of clinical use for monitoring the early response to immune‐checkpoint blockade therapies in tandem with LD.…”

Section: Discussionmentioning

confidence: 99%

Serum 5‐S‐cysteinyldopa behavior in the early phase of nivolumab treatment of 12 melanoma patients

Omodaka

Minagawa

Uhara

et al. 2018

The Journal of Dermatology

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Along with the expansion of therapeutic options for metastatic melanoma, the development of useful biomarkers is urgently required to predict and monitor treatment response. Serum 5-S-cysteinyldopa (5-S-CD) has been identified as a diagnostic marker of malignant melanoma, but its utility as a biomarker for emerging therapeutic agents remains unknown. We assessed serum 5-S-CD in 12 metastatic melanoma patients (median age, 76 years; six men and six women) who had been treated with nivolumab (Nivo) at Shinshu University Hospital between 2014 and 2016. Serum 5-S-CD and lactate dehydrogenase levels before and at 3-6 weeks of Nivo treatment were obtained and their changes were compared with clinical responses as defined by the Response Evaluation Criteria in Solid Tumors criteria (version 1.1). A decrease of 10 nmol/L or more of serum 5-S-CD was observed only in partial response patients (2/3 cases, 67%), while an increase of 10 nmol/L or more of serum 5-S-CD was witnessed only in progressive disease patients (4/8 cases, 50%). Serum 5-S-CD changes were within ±10 nmol/L in the remaining six patients (partial response, one; stable disease, one; progressive disease, four). The results of the four moderately affected progressive disease patients were suspected to have been influenced by small-sized metastatic lesions, a mixed response that included diminished and enlarged metastatic lesions, prior therapy to Nivo with BRAF inhibitors or radiation, or the development of brain metastasis. Serum 5-S-CD in the early phase of Nivo treatment may be helpful to predict therapeutic response in metastatic melanoma.

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Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy

Cited by 145 publications

References 37 publications

Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors

Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors

Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab

Serum 5‐S‐cysteinyldopa behavior in the early phase of nivolumab treatment of 12 melanoma patients

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