ABSTRACT
Immunotherapeutic drugs and target therapies have represented an epochal change in treating cancer patients. They represent an attractive option in oncologists’ armamentarium, particularly if we consider the optimal balance between efficacy and toxicity. As a step forward, immuno- and target-therapies have merged intending to improve efficacy: antibody-drug conjugates ensure the perfect combination. They allow the delivery of large amounts of drugs to the target with a limited ‘off-target’ effect and a low rate of adverse events. These aspects could make immunoconjugates palatable as the first choice for fragile patients, but solid evidence does not exist on the use of these drugs in this population type, especially older people.
Letter to the editor
‘The treatment of cancers cannot be worse than the disease’ is a statement representing the important concept of tolerability. Usually, older patients suffering from cancer express concerns about side effects during the decision-making process for cancer treatments.Citation1 In some cases, patients could choose to start a less active regimen if it appears to be more tolerable.
Immunotherapy development, particularly immune checkpoint inhibitors (ICIs), has revolutionized modern cancer care for patients of all ages, including older patients. On average, ICIs have a favorable toxicity profile compared with cytotoxic chemotherapy; although, with rare but serious immune-related adverse events (irAEs).Citation2 These aspects allow immunotherapy to be a valuable approach for fragile patients, such as older patients.
On the other hand, immunotherapy advances introduce new challenges for the care of older adults with cancer. Older adults remain under-represented in cancer clinical trials,Citation3 and our knowledge of immune system senescence in older patients remains scarce.
Together with immunotherapy, precision oncology could play an important role when treating older adults. The balance between off-target and on-target effects could significantly reduce toxicities usually reported with chemotherapy, enhancing activity against cancer cells.
The frontier of precision oncology should be represented by antibody-drug conjugates (ADCs).
ADCs are monoclonal antibodies (mAb) conjugated to cytotoxic drugs; they use mAb that are specific to tumor cell-surface proteins; thus, have tumor specificity and potency not achievable with traditional drugs.Citation4
In the past decade, a large number of ADCs have resulted in regulatory approval (e.g. ado-trastuzumab emtansine and brentuximab vedotin). During this time, an increased number of ADCs gained authorization in different chemotherapeutic settings: enfortumab vedotin in urothelial cancer, trastuzumab deruxtecan in breast and gastric cancer and sacituzumab govitecan in breast cancer. Despite balancing activity and toxicity, the use of ADCs in older patient populations remains a matter of debate. Older patients, as reported by immunotherapy studies, are under-represented in clinical trials that have investigated ADCs’ efficacy and safety.
In phase(s) I,II, III, and IV of clinical trials investigating ADCs in different tumor types, patients from 48 to 96 years were included and evaluated, usually with a good performance status as assessed with ECOG PS (0–1) or the Karnovsky performance status (70 or more)Citation5–33 ().
Table 1. Characteristics of included studies
Predominantly, ADCs have been studied in breast, gastric and gastroesophageal, urothelial and lung cancer. Older patients have not been excluded a priori but were generally represented in a small portion of the sample size; on the other hand, in a post-marketing off-study setting, older people were well represented, and some concerns occurred during oncologists’ chemotherapy approach choice. Often, older patients are less fit for chemotherapy due to a greater rate of comorbidities, increased use of medications and preexisting frailty or functional loss.
Data on ADCs activity in this population come from a subgroup analysis. In different studies, a subgroup analysis was performed in people above and below 65 years.Citation7–10,Citation14,Citation17,Citation24,Citation30–32 Generally, no differences were observed in terms of outcomes, such as overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Regarding toxicities rate, no growth was observed, and the nature of adverse events remains similar.
Notably, sacituzumab govitecan (SG) is an ADCs consisting of anti-TROP-2 mAb conjugated via a hydrolysable linker to the topoisomerase I inhibitor SN-38. The Food and Drug Administration (FDA) approved SG for the treatment of adults with unresectable locally advanced metastatic triple-negative breast cancer (TNBC) previously treated with ≥2 before system therapy.
SG was investigated in a phase III clinical trial compared to single agent chemotherapy among patients with unresectable locally advanced of metastatic TNBC.Citation10 A subgroup analysis report on SG efficacy and safety vs. single-agent chemotherapy among patients aged <65 vs. >65 years was available.Citation34 SG treatment improved median PFS, OS and ORR in patients ≥65 years. Clinical benefits were also observed in seven patients ≥75. Treatment with SG had similar rates of all grades and grade ≥3 treatment-emergent adverse events (TEAEs). Toxicities leading to treatment discontinuation with SG were low in patients ≥65 years.
This preplanned subgroup analysis in patients ≥65 years treated with SG shows that irrespective of age, patients who received SG had a significant survival benefit with a tolerable safety profile. As usual, proactive AEs monitoring and management must be implemented intending to allow optimal therapeutic exposure to SG and generally to ADCs, in older patients.
We observed similar results in other tumor types, such as gastric and gastroesophageal adenocarcinoma, advanced urothelial carcinoma and metastatic colorectal cancer with the use of drugs, such as ado-trastuzumab emtansine, trastuzumab deruxtecan and enfortumab vedotin.Citation7–9,Citation14,Citation30
ADCs represent a valuable and intriguing option in treating cancer expressing a ‘drugable’ target (e.g. HER2, Nectin-4 or TROP-2). Action specificity may result in an elevated on-target and reduced off-target effect, resulting in a better tolerability profile.
Together with immunotherapy, the era of ADCs has come, not only for younger and fit people but also – and maybe predominantly – for older people suffering from cancer. A favorable tolerability profile and high efficacy should lead to a better understanding of the potential use in older patients; therefore, an ad hoc study could assess the real efficacy of these novel agents in an older patient subgroup population.
Common TEAEs with ADCs are neutropenia – including febrile neutropenia –, fatigue, diarrhea and nausea, with interstitial pneumonia events very common in patients undergoing treatment with SG and trastuzumab deruxtecan. A meticulous evaluation must be performed case-by-case before starting treatment with chemotherapeutic drugs and comprising ADCs, especially in older people. Tight monitoring of toxicities and outcomes must be implemented, but older people could derive an immense benefit from an ADCs-based approach.
ADCs retain important value in treating cancer. Despite strong evidence to support the use in older populations not existing, to the best of our knowledge, we can suggest that the use of ADCs in older people may retain a role in a different disease stage. Close toxicities monitoring is mandatory.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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