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Table of Contents
EDITORIAL
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 368-369

Immune checkpoint inhibitors in older patients with cancer: A new era in cancer therapy


Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission30-May-2021
Date of Decision01-Jun-2021
Date of Acceptance05-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Lalit Kumar
Department of Medical Oncology, All India Institute of Medical Sciences, Room 234, Second Floor, IRCH Building, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_126_21

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How to cite this article:
Arora S, Kumar L. Immune checkpoint inhibitors in older patients with cancer: A new era in cancer therapy. Cancer Res Stat Treat 2021;4:368-9

How to cite this URL:
Arora S, Kumar L. Immune checkpoint inhibitors in older patients with cancer: A new era in cancer therapy. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 27];4:368-9. Available from: https://www.crstonline.com/text.asp?2021/4/2/368/320178



Recent research on the tumor microenvironment and T-cell-mediated downregulation of anti-tumor immunity has led to the development of antibody-based interventions for targeting the interaction between the programmed cell death protein 1 (PD-1) expressed on the T-cells and its ligand, the programmed death-ligand 1 (PD-L1), expressed on the tumor cells, thus leading to immune checkpoint blockade. Blocking the immune checkpoint pathways with antibodies has led to considerably improved outcomes in patients with advanced cancers. Thus, immune checkpoint blockade therapy is the most exciting development in the field of oncology and immunology. Ipilimumab (anti-CTLA4 antibody), pembrolizumab (anti-PD-1 antibody), nivolumab (anti-PD-1 antibody), atezolizumab (anti-PD-L1 antibody), avelumab (anti-PD-L1), etc., have been shown to be efficacious in metastatic malignant melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma, urothelial malignancies, head-and-neck cancers, Hodgkin's lymphoma, cervical cancer, colon cancer, etc., in the pivotal clinical trials.[1],[2],[3],[4],[5],[6],[7],[8],[9] Currently, a number of such molecules are under evaluation for efficacy against various tumors.[10]

Despite cancer being typically associated with advanced age, the subset of older patients is under-represented in clinical trials. There have been concerns about the efficacy and safety of immune checkpoint inhibitors (ICIs) in older patients with cancer because of immunosenescence and the presence of comorbidities with diminished reserves, respectively. It is plausible that immunosenescence may impact the efficacy of ICIs in older patients with cancer through multiple mechanisms, including reduced tumor antigen release, impaired antigen-presenting cell function, and T-cell activation, and reduced ability of the senescent T-cells to eliminate the cancer cells.[11] In a large meta-analysis of 34 randomized studies including a total of 20511 patients, Huang et al. reported that patients aged >65 years derived similar overall survival (OS) (hazard ratios 0.79 vs. 0.76) and progression-free survival (PFS) (hazard ratios 0.77 vs. 0.69) benefits compared to those of their younger counterparts from immunotherapeutic agents.[12] Patients aged 75 years or more did not derive a definite PFS or OS benefit with ICIs; however, these results may have been confounded by the small number of patients in this age group. Concerns about the enhanced toxicity and poor functional reserves in older patients with cancer have been largely dispelled by multiple analyses, confirming that, at least in the trial setting, the tolerance in older patients is similar to that in young patients.[13] Although some broad conclusions may be drawn from the above studies, there is a scarcity of real-world data addressing these concerns in the aged population. Therefore, decisions in the clinics are made by extrapolation from trials that generally enroll young and fit patients with fewer comorbidities.

In this issue of Cancer Research, Statistics, and Treatment, Abraham et al. have reported the outcomes and toxicity of ICIs in older patients with solid tumors.[14] In this single-center, retrospective analysis, patients aged 60 years or more who received ICIs for various malignancies over 7 years were evaluated. OS was the primary endpoint, and PFS and immune-related adverse events were the secondary endpoints assessed. In this cohort of 150 older patients with a median age of 64 (range, 60–86) years, nivolumab was the most commonly used ICI, and the most common indication was metastatic NSCLC. A large proportion of patients had comorbidities, and over one-third had an Eastern Cooperative Oncology Group performance status of 2 or 3. The objective response rate was 30% (including 8% complete responses), and 52% of the patients showed clinical benefit. At a median follow-up of 14.3 months, the median PFS and OS were 4.2 and 8.6 months, respectively. Male gender, age, and performance status were found to be significant predictors of OS. With respect to toxicity, the adverse effects of ICIs in this older population were in line with the previously reported toxicity profile, with no new safety signals observed. Although some grade 1/2 toxicities may not have been recorded rigorously due to the retrospective nature of the study, serious (grade 3 or worse) adverse events were reassuringly rare, and only 2.7% of the patients had to discontinue the drug because of poor tolerance. These results are similar to the real-world data reported in retrospective series from various other centers.[15],[16] The authors have rightly concluded that the efficacy and safety profile of ICIs in older patients in the real world is comparable to that observed in trials. One limitation of the study was the lack of the use of validated geriatric assessment tools[17],[18] and frailty indices, that may have facilitated better patient selection for immunotherapy. This study has uncovered an under-investigated yet important arena of ICI use, which must be addressed specifically in future trials.

The present findings have mirrored the results of a large multi-center analysis from the United Kingdom that found no appreciable loss of efficacy or increase in toxicity from ICIs in a cohort of 448 patients.[19] The findings of the present and earlier studies suggest that carefully selected older patients with cancer who have a good performance status derive a benefit from ICIs without increased toxicity. Therefore, the participation of older patients in clinical trials should be based on physiological age rather than chronological age. Whether the optimal use of ICIs is as monotherapy, or in combination, and their sequencing in reference to surgery, radiation, and chemotherapy (neoadjuvant vs adjuvant setting) are likely to be answered in future studies.



 
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