Abstract
Introduction
Immune checkpoint inhibitors (ICIs) represent a cornerstone for the treatment of many advanced tumors. When 65 is considered as a cut-off age, ICIs are equally effective in younger and older patients. However, the efficacy of ICIs among patients aged ≥ 75 remains uncertain, since those patients were generally under-represented in clinical trials. We performed a pooled analysis of major randomized trials including data of outcome in very older population.
Material and methods
We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials published from the inception of each database to November 22th, 2019. We only included (1) randomized studies comparing ICIs alone or in combinations with no ICIs, (2) studies reporting data of patients older than 75 years, (3) studies for solid tumors, and (4) studies with HR and 95% confidence interval (CI) available for OS based on 75 years as cut-off age. All data were expressed as the combination of HR and 95% CI, and P < 0.05 was considered to be statistically significant.
Results
A total of n = 8 publications for a total of n = 12 randomized studies were aggregated in the quantitative analysis. Overall, the pooled analysis showed a borderline significant OS benefit for ICIs compared to no ICIs arms (HR = 0.84, 95% CI 0.7–1; P = 0.05) in particular in first-line trials with HR = 0.77 (95%CI 0.61–0.96; P = 0.02).
Conclusion
We conclude that ICIs may be offered in patients older than 75 years, providing a complete geriatric and clinical evaluation is performed in all subjects before starting therapy.
Keywords: Elderly, Immunotherapy, Cancer, Survival, Meta-analysis
Introduction
Immune checkpoint inhibitors (ICIs) represent a cornerstone for the treatment of many advanced tumors. Aging-associated immunosenescence leads to a decline in immune system and may potentially affect response to ICIs in the elderly [1]. When 65 is considered as a cut-off age, ICIs are equally effective in younger and older patients [2]. Nevertheless, this age threshold is unlikely to truly segregate two different subpopulations, probably still including very fit individuals among the age group over 65. Due to a general increase in life expectancy, currently breaking the barrier of 80 years in the industrialized countries, even more very older patients are included among the advanced cancer population. However, the efficacy of ICIs among patients aged ≥ 75 remains uncertain, since those patients were generally under-represented in clinical trials. We tried here to explore this topic by pooling studies reporting efficacy of ICIs in patients older than 75 years.
Material and methods
We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials published from the inception of each database to November 22th, 2019. We selected the most complete and updated results of each trial when duplicate publications were identified. Two investigators (FP, MB) independently performed the selection. We used the terms (elderly or older or “75 years”) and (PD-1 or PD-L1 or CTLA-4 inhibitors or “immune checkpoint inhibitors” or nivolumab or pembrolizumab or avelumab or durvalumab or atezolizumab or cemiplimab or ipilimumab or tremelimumab). We only included (1) randomized studies comparing ICIs alone or in combinations with no ICIs in patients with solid tumors, and (2) studies with HR and 95% confidence interval (CI) available for overall survival (OS) based on 75 years as cut-off age. All data were expressed as the combination of HR and 95% CI, and P < 0.05 was considered as statistically significant. The RevMan software v5.3 was used. We assessed the between-study heterogeneity using the I2 test, which estimates the percentage of total variability across all studies. If the test had shown > 50% or P < 0.10, a random‐effects model would have been used. Otherwise, a fixed‐effects model would have been used to pool effect size. The paper did not need ethics approval because it is a literature review.
Results
A total of n = 8 publications for a total of n = 12 randomized studies were aggregated in the quantitative analysis [3–10]; (Table 1). Overall, n = 1568 patients were analyzed. Among the included studies, n = 5 were in patients with non-small cell lung cancer, and n = 1 each were in patients with melanoma, small-cell lung cancer and renal cell carcinoma, respectively. The heterogeneity of the included studies was significant (P = 0.02, I2 = 75.5%).
Table 1.
Characteristics of analysed studies
| Author/year | Type of study | Cancer type | All patients | N° pts > 75 years (%) | Treatment arms | Line of therapy | Median follow up (months) |
|---|---|---|---|---|---|---|---|
| Brahmer 2015 [3] | Phase III | NSCLC | 272 | 29 (11) | NIVO vs. docetaxel | ≥ 2 | > 11 (minimum) |
| Motzer 2015 [9] | Phase III | RCC | 821 | 74 (9) | NIVO vs. everolimus | ≥ 2 | 15 (minimum) |
| Robert 2015 [4] | Phase III | Melanoma | 418 | 67 (16) | NIVO vs. dacarbazine | 1st | 8.9 vs. 6.8 |
| Govindan 2017 [5] | Phase III | NSCLC | 749 | 71 (9.4) | CT + IPI vs. CT + placebo | 1st | 12.5 vs. 11.8 |
| Nosaki 2019 [6] | Phase IIIa | NSCLC | 1579 | 174 (11) | PEMBRO vs. CT | 1st | 11.7 |
| Marur 2018 [7] | Phase IIIb | NSCLC | 1859 | 215 (11.5) | PEMBRO/NIVO/ATEZO vs docetaxel | ≥ 2 | NR |
| Reck 2016 [8] | Phase III | SCLC | 954 | 72 (7.5) | CT + IPI vs. CT + placebo | 1st | 10.5 vs. 10.2 |
| Hellmann 2019 [10] | Phase III | NSCLC | 793 | 81 (10) | NIVO + IPI vs. CT | 1st | > 29.3 |
NR not reported, NIVO + IPI nivolumab + ipilimumab
aPooled analysis of Keynote 024 + 042
bPooled analysis of OAK + POPLAR + CheckMate 010 + 057
Overall, the pooled analysis showed a borderline significant OS benefit for ICIs compared to no ICIs arms (HR = 0.84, 95% CI 0.7–1; P = 0.05; Fig. 1). When considering only first-line trials, a significant OS benefit was observed for ICIs, with HR = 0.77 (95% CI 0.61–0.96; P = 0.02). Among pre-treated patients aged ≥ 75, ICIs did not provide survival benefit compared to standard therapy (HR = 0.96, 95% CI 0.72–1.26; P = 0.39). None of the studies reported safety data according to the patient age, neither comprehensive geriatric assessment (CGA) for the elderly patients included.
Fig.1.
Forest plot for overall survival for immune checkpoints inhibitors in solid tumors
Discussion
The treatment of very elderly patients with advanced cancer is challenging, and the role of immunotherapy in this population is not well defined yet. When pooled together, pivotal trials showed a borderline significant 16% reduction in risk of death for patients aged ≥ 75 receiving ICIs compared no ICIs arms, with a broad 95% CI. The geriatric associations periodically update their statements, and specific guidelines for lung cancer were published in 2014. Recently, renal cancer guidelines have been delivered, stating that nivolumab may be offered to elderly [11, 12]. Considering melanoma, the survival improvement from immunotherapy is indisputable irrespective of age [4].
The main limitations of the present meta-analysis are represented by the limited number of trials in this setting reporting data with the 75-year cut-off, and by the wide heterogeneity, suggesting the cautious interpretation of our results. The lack of statistical significance may reflect the limited sample size included in the pooled analysis, but it can also be due to the prognostic heterogeneity of elderly population.
Another limitation is the lack of safety data, preventing a proper evaluation of the risk–benefit profile of ICIs in the very elderly population. Indeed, the therapeutic indication in this setting may be oriented more on the safety profile than on the efficacy data of the drug.
Moreover, in this population, age and performance status (PS) alone may not be sufficient for a correct prognostic evaluation, while a comprehensive geriatric assessment (CGA) of functional, mental and nutritional parameters may be more accurate and could be used to guide treatment [13]. At this regard, a prospective study recently showed that a geriatric assessment is effective to predict survival of elderly cancer patients treated with ICIs [14]. However, CGA was generally not performed in the pivotal trials with ICIs.
In very elderly cancer patients, accurately selected weighing the risk–benefit ratio on the basis of PS, CGA and adequate life expectancy, our opinion is that immunotherapy should be used early in the disease history, offering ICIs in later lines only when an improvement in terms of toxicity and quality of life was observed in the respective trials.
Author contribution
All authors made substantial contributions to the conception or design of the work; the acquisition, analysis, and interpretation of data.
Compliance with ethical standards
Conflict of interest
Dr. Melissa Bersanelli received research funding by Roche, Pfizer, Seqirus, AstraZeneca, Bristol-Myers Squibb, Novartis and Sanofi; she also received honoraria for advisory role and as speaker at scientific events by Bristol-Myers Squibb, Novartis and Pfizer. None to declare for all the other authors.
Footnotes
Publisher's Note
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