Association of Age with Efficacy of Immunotherapy in Metastatic Melanoma

Jain, Varsha; Hwang, Wei Ting; Venigalla, Sriram; Nead, Kevin T.; Lukens, John N.; Mitchell, Tara C.; Shabason, Jacob E.

doi:10.1634/theoncologist.2019-0377

Cited by 42 publications

(40 citation statements)

References 9 publications

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“… 17 In another study of 11,944 patients with metastatic melanoma, older (≥60 years) compared with younger patients derived greater benefit with immunotherapies as evidenced by both multivariable Cox proportional hazards analysis and propensity score-weighted multivariable analysis. 18 A similar difference in immunotherapy benefit based on age was not observed in other studies. 19 20 Elevated LDH is a surrogate marker of high tumor burden and an independent predictor of poor outcome.…”

Section: Discussionsupporting

confidence: 71%

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma

Pokorny

McPherson

Haaland

et al. 2021

J Immunother Cancer

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BackgroundRandomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.MethodsData of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (>6 months and <18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy, had prior exposure to PD-1 therapy, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation, progression-free survival (PFS), and retreatment characteristics was analyzed.ResultsOf 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3–49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7–30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.ConclusionIn this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.

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Section: Discussionsupporting

confidence: 71%

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma

Pokorny

McPherson

Haaland

et al. 2021

J Immunother Cancer

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“…Merging the disparate research on cancer 22 and aging can further distinguish whether age-related changes in non-cancerous tissues are 23 recapitulated within the ITME. At present, ICB immunotherapy is less often used to treat elderly 24 patients, due to concerns about efficacy and toxicity, despite the fact that the limited clinical trial 25 data that exists suggests that they experience no reduced benefit as compared to younger 26 patients (Kugel et al, 2018), (Elias et al, 2018), (Daste et al, 2017), (Jain et al, 2019). Age-1 specific characterization of the ITME is essential to understand these results and move forward 2 with efforts to bring immunotherapy to this large group of cancer patients.…”

Section: Introduction 22mentioning

confidence: 99%

“…The possibility of 13 reduced efficacy has been partially addressed by previous studies. There are somewhat mixed 14 results as to the benefit of ICB for patients of advanced age, though most studies and meta-15 analyses of available clinical trial data suggest patients experience no reduced benefit (Kugel et 16 al., 2018), (Elias et al, 2018), (Daste et al, 2017), (Jain et al, 2019). The observed increases in 17 tumor mutational burden with age may explain these results at least partially, as these additional 18 mutations provide a larger space of antigens for the reduced number of unique TCRs to 19 recognize.…”

mentioning

confidence: 98%

“…Given the results of the aforementioned meta-analyses, this model 26 suggests that increased tumor mutational burden (and the corresponding increase in PDL1 1 expression) is largely able to compensate for the loss of T cell infiltration and TCR diversity such 2 that older patients end up doing roughly as well on ICB immunotherapy as their younger 3 counterparts despite several characteristics that are generally disadvantageous, though 4 unaccounted factors may be at play as well. Currently, ICB is still used less often among elderly 5 patients (Jain et al, 2019), (Hurez et al, 2018) due to concerns about efficacy and safety. Our 6 results indicate that older individuals express increased levels of PDL1, which likely allows for 7 the equal level of response to that of younger patients.…”

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confidence: 99%

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Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

Erbe

Wang

Zaidi

et al. 2020

Preprint

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1Advanced age is strongly correlated with both increased cancer incidence and general immune 2 decline. The immune tumor microenvironment (ITME) has been established as an important 3 prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune 4 decline is an important consideration for the treatment of a large subset of cancer patients. 5Current studies of aging-related immune alterations are predominantly performed on non-6 cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration. 7We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the 8 Genotype-Tissue Expression project to distinguish normal age-related immune alterations from 9 age-related changes in tumor immune infiltration. We demonstrate that while there is overlap 10 between the normal immune aging phenotype and that of the ITME, there are several changes 11 in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and 12Macrophage populations. These results suggest that aged immune cells are more susceptible to 13 tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which 14 creates an unfavorable ITME in older patients in excess of normal immune decline with age and 15 may inform the application of existing and emerging immunotherapies for this large population 16 of patients. We additionally identify that age-related increases in tumor mutational burden are 17 associated with decreased DNA methylation and increased expression of the immune 18 checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic 19 application of immune checkpoint blockade in older patients. 20 21

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“…56,57 Another study associated age with therapeutic outcome; a survival benefit in metastatic melanoma patients who received ICIs was seen in both young and older (>60 years) age groups, but the result was more prominent in older age groups. 58 With increased characterization of the molecular and biological landscape, more and more potential immunerelated biomarkers or biological information will be used to identify vulnerabilities that can be exploited in clinical trials to provide the key to their successful application in the clinical setting. The hope is that ongoing and future clinical trials will eventually solve all the related concerns about ICIs in BTC.…”

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confidence: 99%

Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer

Seesaha¹,

Wang²,

Wang³

et al. 2021

OTT

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Biliary tract cancer (BTC) is an uncommon and aggressive neoplasm, with most patients presenting in an advanced stage. Systemic chemotherapy is the limited treatment available but is unsatisfactory, while targeted therapy is still awaiting validation from clinical trials. Given the potential effect of immune checkpoint inhibitors (ICIs) in the treatment of BTC, this review aims to summarize the evidence-based benefits and predictive biomarkers for using inhibitors of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) ligand, or programmed cell death protein-1 and its ligand (PD-1 and PD-L1) as monotherapy or combined with other anti-tumor therapies, while also pointing out certain pitfalls with the use of ICIs which need to be addressed.

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Association of Age with Efficacy of Immunotherapy in Metastatic Melanoma

Cited by 42 publications

References 9 publications

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer

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