The checkpoint inhibitors are among the most important advances in oncology in recent times. They have changed the natural history of many tumors, particularly melanoma. They have a favorable toxicity profile, which for most patients is manageable and tolerable. However, there are several toxicities that have the potential to be quite severe, including colitis and hepatitis. Because of their efficacy in solid tumors common to older patients, these agents were very quickly utilized in this group. As is often the case, older patients have been underrepresented in clinical trials, so there are less data available to make these important treatment decisions.

“With proper management, older patients can take full advantage of the benefit of checkpoint inhibitor therapy with reasonable toxicity.”

— Stuart M. Lichtman, MD, FACP, FASCO

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Albeit retrospective, the study by Nebhan et al,¹ summarized in this issue of The ASCO Post, provides a large database analysis of patients older than 80 (median = 83 years) treated with single-agent checkpoint inhibitors for various cancers. This huge database of 928 patients demonstrated that when patients older than 85 were compared with younger patients, these agents demonstrated equivalent efficacy, incidence, and range of toxicity. However, the oldest patients (> 90 years) had an increased incidence of treatment discontinuation.

The most common cancers included in the database were non–small cell lung cancer, melanoma, and genitourinary malignancies. The analysis did not specify the evaluation of mutation or microsatellite instability status; this would be particularly important for colorectal and endometrial cancers, where there is a higher incidence of microsatellite instability–high tumors (~13% in colorectal and ~25% in endometrial cancers). MSI-high tumors have an increased response (overall response rates = ~47% in colorectal and ~36% in endometrial cancers). Clearly, response rates, even in those with microsatellite instability–high tumors, vary widely based on diagnosis and stage.

There is a tremendous temptation to use checkpoint inhibitors in older patients, usually for very good reason. They have an increased therapeutic index as compared with chemotherapy due to increased efficacy and lower toxicity. However, although these novel agents are usually well tolerated, there will always be a small subset of patients who have severe and life-threatening toxicity. The risk of significant toxicity in older patients does not appear to be increased, but the effect on older patients will markedly differ from that in younger patients. Due to issues of resilience, comorbidity, poor function, and extensive disease, older patients will have increased mortality. If they do recover, this recovery period is likely to take longer and may preclude further checkpoint inhibitor therapy. These issues are likely to be exacerbated by the need for high-dose steroid therapy and possibly further immunotherapy.

Appropriate Indications in Older Patients

The analysis by Nebhan et al clearly shows that older patients should receive checkpoint inhibitor therapy with the appropriate indications. The therapeutic index may vary by diagnosis, but I believe it is acceptable with all indications. Patients need to be educated about the potential toxicity and instructed to call with any changes. They should be seen often to assess their clinical status. Social support in this area is critically important. Patients need to plan how they will get to the treatment center or hospital if toxicity occurs suddenly. They also need to be instructed to tell any health-care provider they may contact that they are on checkpoint inhibitor therapy, so the appropriate supportive care measures can be instituted.

The study also demonstrates that a large volume of data can be collected and analyzed, thus providing valuable clinical information. It is a credit to the investigators that such a database exists and is published with their thoughtful analysis. Ideally, prospective studies should be performed. But in certain clinical settings, this may not be possible. However, when it is anticipated that older patients will be part of a clinical trial or a large data set, baseline information specific to older patients must be collected. This does not consist of the usual demographics and medical history. Issues such as activities of daily living and instrumental activities of daily living, comorbidity, drug utilization, social supports, functional status, and cognition need to be obtained. It has been amply demonstrated that the collection of such valuable information may take only minutes, but when the final data analysis takes place, it can be correlated with outcome analysis. This will magnify many-fold the value of the study and patient participation. This is not something that can be done retrospectively.

Fortunately, we are in an era of newer and, for the most part, more specific and less toxic therapy. Older patients may benefit from these treatments and should be considered for such treatment. With proper management, they can take full advantage of the benefit with reasonable toxicity. 

Dr. Lichtman is Professor of Medicine, Weill Cornell Medical School; Attending, Memorial Sloan Kettering Cancer Center; Past President, International Society of Geriatric Oncology (2016–2018).

DISCLOSURE: Dr. Lichtman has served as a consultant or advisor to Magellan Health and Remedy One.

REFERENCE

1. Nebhan CA, Cortellini A, Ma W, et al: Clinical outcomes and toxic effects of single-agent immune checkpoint inhibitors among patients aged 80 years or older with cancer: A multicenter international cohort study. JAMA Oncol 7:1856-1861, 2021.

ADDITIONAL READING

1. Lorenzi M, Amonkar M, Zhang J, et al: Epidemiology of microsatellite instability high and deficient mismatch repair in solid tumors: A structured literature review. J Oncol 2020:1-17, 2020.

2. Makker V, Colombo N, Casado Herráez A, et al: Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. January 19, 2022 (early release online).

3. Mohile SG, Dale W, Somerfield MR, et al: Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol 36:2326-2347, 2018.

4. Petrelli F, Ghidini M, Ghidini A, et al: Outcomes following immune checkpoint inhibitor treatment of patients with microsatellite instability-high cancers: A systematic review and meta-analysis. JAMA Oncol 6:1068-1071, 2020.

5. Schneider BJ, Naidoo J, Santomasso BD, et al: Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 39:4073-4126, 2021.

6. Wong SK, Nebhan CA, Johnson DB: Impact of patient age on clinical efficacy and toxicity of checkpoint inhibitor therapy. Front Immunol 12:786046, 2021.