Age favoured overall survival in a large population-based Danish patient cohort treated with anti-PD1 immune checkpoint inhibitor for metastatic melanoma

Bastholt, Lars; Schmidt, Henrik; Bjerregaard, Jon Kroll; Herrstedt, Jørn; Svane, Inge Marie

doi:10.1016/j.ejca.2019.06.022

Cited by 33 publications

(25 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, emerging evidence suggests that older age might contribute to clinical benefits for patients treated with immune checkpoint inhibitors [41,42]. The association of age with improved response to anti-PD1 therapy has recently been observed in a large cohort of Danish metastatic melanoma patients; patients between ages 70-80 years had significantly longer OS and PFS compared with younger patients [43]. Furthermore, Perier-Muzet et al indicated that old age may improve the anti-PD1 response without increasing the risk for severe adverse events [44].…”

Section: Discussionmentioning

confidence: 99%

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

Kasanen

Hernberg

Mäkelä

et al. 2020

Cancer Immunol Immunother

View full text Add to dashboard Cite

Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8 + T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK-and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

Kasanen

Hernberg

Mäkelä

et al. 2020

Cancer Immunol Immunother

View full text Add to dashboard Cite

show abstract

“…Enhanced programmed cell death ligand 1 (PD-L1) expression in the tumor melanoma, non-small cell lung cancer (NSCLC), renal-cell carcinoma, prostate cancer, colorectal cancer [5][6][7][8] Presence of CD8+tumor-infiltrating lymphocytes melanoma, NSCLC, renal-cell carcinoma, colorectal cancer [5][6][7]9,10] High tumor mutational burden or neoantigen burden melanoma, NSCLC, colorectal cancer, urothelial carcinoma [5,11,12] Presence of intratumoral major histocompatibility complex (MHC) class II expression melanoma [5,13] Presence of intratumoral interferon-γ-immune gene signature melanoma, head and neck cancer [5,14] Low interleukin (IL)-6 expression in the tumor colorectal cancer [15] Peripheral blood count: low absolute neutrophils, low absolute monocytes, low myeloid-derived suppressor cells, high FoxP3+ regulatory T cells, high lymphocytes, high eosinophils, high CD19−HLA-DR+ myeloid cells, high CD14+CD16b−HLA-DRhi monocytes melanoma, NSCLC [5,[16][17][18] Low level of c-reactive protein (CRP) in the serum, low relative eosinophil count uveal melanoma [19] Serum proteome analysis: BDX008 melanoma [20] An alternative approach to the search of predictive biomarkers sensu stricto is the identification of predictive biomarkers which are determined under checkpoint inhibitor therapy but before evidence by radiologic imaging of response to therapy [18,21,22]. Table 2 provides an overview of treatment response monitoring biomarkers.…”

Section: Biomarker Cancer Entity Referencementioning

confidence: 99%

“…Especially combined checkpoint inhibition targeting CTLA4 as well as PD-1 is associated not only with the best therapeutic response but also with a significantly increased rate of severe immune-related adverse events (irAEs) [4]. Hence, research has focused on predictive biomarkers in order to determine prior to therapy which patients and tumors might respond to checkpoint inhibitors and which patients might develop severe side effects [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Table 1 provides an overview of predictive biomarkers in the strict sense that these biomarkers have been determined prior to the start of therapy.…”

Section: Introductionmentioning

confidence: 99%

Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma—An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer

Wahl

Leijs

Araujo

et al. 2020

IJMS

View full text Add to dashboard Cite

We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles.

show abstract

“…What could be the consequences for the daily management of elderly patients according to primary tumors? For melanoma patients, Checkmate 066 study and additional cohort studies of patients aged over 80 have confirmed the benefit of ICIs (23,24). The only issue is to consider or not the addition of an anti-CTLA-4 agent according to the geriatric assessment.…”

Section: Discussionmentioning

confidence: 99%

Timing of immune checkpoint inhibitors for metastatic patients over 75 years of age: the earlier the better

Landre¹,

Guetz²,

Chouahnia³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background The impact of ageing on Immune Checkpoint Inhibitors (ICIs) effectiveness remains controversial. However, data from clinical studies do not show any difference between patients over 65 years and those under 65 years. We focused our study on patients over 75 and looked at the potential impact of timing in the use of ICIs. Methods We performed a meta-analysis of published randomized control trials (RCTs) concerning ICIs versus standard therapy in patients with advanced solid tumors. Overall Survival (OS) among the older (≥75 years) was compared with that of younger patients (< 75 years). Hazard ratios (HRs) with their 95% confidence interval (CI) were collected and pooled. Results Fifteen phase III studies evaluating anti-PD-1(nivolumab or pembrolizumab), anti-PD-L1 (atezolizumab or avelumab) or anti-CTLA-4 (ipilimumab) were included. Patients were enrolled for Non-Small-Cell-Lung-Cancer, Renal-Cell-Carcinoma, Melanoma, Head-and-Neck-Squamous-Cell-Carcinoma or Gastric Cancer. Eight studies assessed treatment in first-line setting and seven in the second line. The median age was 64 years, with 906 patients over 75 years of age and 5233 youngers. In first-line setting, HRs for death were 0.78 (95% CI: 0.61-0.99) in patients ≥75 years versus 0.84 (95% CI: 0.71-1.00) in younger. In second line setting, HRs for death were 1.02 (95% CI: 0.77-1.36) in patients ≥75 years versus 0.68 (95% CI: 0.61-0.75) in younger with a statistically significant difference observed between subgroups (p interaction = 0.009). Conclusions ICIs appears to be effective in patients over 75 years of age. However, the survival benefit is mainly observed in first-line treatment.

show abstract

Age favoured overall survival in a large population-based Danish patient cohort treated with anti-PD1 immune checkpoint inhibitor for metastatic melanoma

Cited by 33 publications

References 27 publications

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma—An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer

Timing of immune checkpoint inhibitors for metastatic patients over 75 years of age: the earlier the better

Contact Info

Product

Resources

About