A narrative review of the efficacy and safety FDA-approved antibody-drug conjugates in older patients

Introduction

Background

Chemotherapy has been the backbone of treatment for many advanced cancers over the years with varying but often limited efficacy (1). While most approved chemotherapy improve survival or prevents tumor growth it often produces substantial toxicity. Older patients and those with significant comorbidities in particular often suffer a decline in activities of daily living (ADLs) as a result of treatment toxicity (2,3). Limiting the delivery of chemotherapy to the sites of cancer using antibodies that bring the chemotherapy to sites expressing cancer antigens reduces side effects. Such antibody-chemotherapy constructs are known as antibody-drug conjugates (ADCs). These complexes contain the antibody against a tumor antigen, and a chemical linker covalently bound to a chemotherapy payload (4-6). However, while ADCs are meant to minimize toxicity, systemic chemotherapy exposure still occurs. In this review article, we will look at United States Food and Drug Administration (FDA) approved ADCs with a specific focus towards older patients, relative efficacy, and toxicity, as a key question is whether these agents are safe to use in older patients.

Rationale and knowledge gap

ADCs are an emerging class of drug in cancer treatment often used in elderly patients. In this review article, we explore the impact of these agents in from both an efficacy and a toxicity as compared with younger cohorts.

Objective

The objective of the study was to understand the changes in the risk benefit ratio for ADCs when they are used in older patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-188/rc).

Methods

For this study, we included 13 FDA-approved ADCs and their indications as of August 31, 2023 initially using PubMed and clinicaltrials.gov and extracted data on age-specific cohorts from clinical trials referenced. We then searched for the FDA package insert using the Google search engine associated with the FDA-approved ADC and added in notable information from the “geriatric use” section of the package insert that was not included in pivotal manuscript from the studies published that led to FDA approval. The search was conducted in English and all findings were either published studies found in PubMed or information that was otherwise noted in the FDA package insert (Table 1).

For drugs in development, we looked at clinicaltrials.gov and used the search term “antibody-drug conjugate” in intervention/treatment. We included phase 1–4 studies under study phase and filtered for results. If the drug was not one of the FDA-approved ADCs, we used the name of the drug in a search engine to determine if the ADC’s development had been discontinued by the sponsor. Such drugs were omitted from this review (Table S1). Additionally for drugs in development, we did look up recent findings that had been presented at oncology conferences but had not been published as a manuscript in PubMed in which we used the Google search engine (Table S2).

ADC structure and mechanism

ADCs consist of a monoclonal immunoglobulin G, against the antigen of the tumor cell, a linker, and a cytotoxic chemotherapy payload (4-6). Targeted antigens must have significantly greater expression in cancer cells than in non-cancer cells (5-7). For example, ERBB2, a target that has led to the development of trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (TDM-1), has 100-fold difference in cancer cells in comparison to non-cancer cells (7).

ADCs typically will bind to the antigen at the antibody-antigen complex and are internalize into the tumor cell within endosomes. These later fuse with lysosomes (4-8) where lysosomal interactions cause payload release (Figure 1). Some of the factors involved in internalization into the tumor cell include size of the antibody and affinity between the antibody and surface antigen. A larger size antibody may have problems with penetrating through the blood and into the tumor tissue (9). Too high of an affinity can reduce the penetration and slow down the internalization (4-9). Engineering of the antibody for smaller size can be accomplished by truncation of the Fc fragment so as to better solid tumors (6,10). However, this may affect the half-life of the ADC. Thus, multiple considerations must be made in terms of the antibody-antigen complex with regards to affinity between antibody and antigen and size of the antibody to allow for good internalization and an effective half-life.

Figure 1 Mechanism of action of ADCs and list of targeted antigens, payloads, and linkers of FDA-approved ADCs. FDA, United States Food and Drug Administration; ADC, antibody-drug conjugate; HER2, human epidermal growth factor 2; Trop2, tumor-associated calcium signal transducer 2; BCMA, B cell maturation antigen; Ab, antibody; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin F; PBD, pyrrolobenzodiazepine.

Linkers connect the antibody and the cytotoxic drug in the ADC (11). There are two types of linkers—cleavable and non-cleavable (Figure 1). Cleavable linkers break down and release the payload at the low lysosomal pH (11,12). Payload release can also be achieved by cleavage of a disulfide bond-based linker that is sensitive to reduced glutathione which is abundant inside cancer cells but not in blood (13). In addition, other non-cleavable linkers do not release payload until the antibody is degraded by lysosomal protease or beta-glucuronididases (11,14).

Cancer cell killing is accomplished by the cytotoxic payload (6) (Figure 1). Microtubule stability is a large part of cancer cell growth and many of the payload drugs kill cells via this mechanism. Emtansine, which is used in TDM-1 along with monomethyl auristatin E (MMAE) and F (MMAF) are tubulin inhibitors (15). Topoisomerase inhibitors interfere with DNA replication by causing DNA strand breaks; examples of this include SN-38 carried by sacituzumab govitecan and deruxtecan payload on trastuzumab (16). Additional payload mechanisms include DNA-crosslinking as seen in loncastuximab tesirine, which is used in relapsed and refractory diffuse large B-cell lymphoma (DLBCL) and DNA cleaving agents such as calicheamicin, which is used in gemtuzumab ozogamicin and inotuzumab ozogamicin (17,18). Different ADCs will carry a different number of payload chemotherapy molecules per antibody. This is termed the drug antibody ratio (DAR) and is associated with potency of the drug (19). Earlier ADCs have a DAR of 2–4 while more recently developed ADCs such as T-DXd have a DAR of nearly 8 (19).

ADC drugs

Gemtuzumab ozogamicin

Gemtuzumab ozogamicin is an ADC targeting CD33 with a calicheamicin payload (20). It was originally approved in 2000 for newly diagnosed CD33 specifically for patients aged ≥60 years or not transplant candidates for acute myeloid leukemia (AML) (21) (Table 2). However, due to concerns of increased incidence of veno-occlusive disease, it was withdrawn per FDA request in 2010 (21). The ALFA-0701 trial comparing gemtuzumab ozogamicin with daunorubicin and cytarabine vs. daunorubicin and cytarabine showed equally significant overall survival (OS) benefit in patients aged ≥60 years and those less than age 60 years (22) (Table 3). Notable adverse events included grade 3 or higher infections seen in 77.9% patients and veno-occlusive disease seen in 5 cases (3.8%) (22) (Table 4). These results led to the re-approval of gemtuzumab ozogamicin in 2017 (21,48). It was also later approved for infants greater than 1 month old per results from the AAML0531 Children’s Oncology Group trial showing superior event free survival with gemtuzumab ozogamicin (23). With regards to the elderly population, AML-19 was a study evaluating gemtuzumab ozogamicin monotherapy vs. best supportive care in transplant-ineligible AML patients at least 61 years old and overall showed an improved median OS 4.9 months [95% confidence interval (CI): 4.2–6.8] in the gemtuzumab ozogamicin arm vs. 3.6 months (95% CI: 2.6–4.2) in the best supportive care group arm (46). There was an OS benefit seen in the ages 76–80 years subgroup OS hazard ratio (HR) =0.66 (95% CI: 0.44–0.99) and the age 81 years and older subgroup OS HR =0.55 (95% CI: 0.31–0.98). The most common nonhematologic grade 3 or higher toxicity was infection (35.1%) in the gemtuzumab ozogamicin arm and there was similar percentage of deaths due to adverse events 17.1% in gemtuzumab ozogamicin and 20.2% in the best supportive care arm (46) (Table 4). Gemtuzumab ozogamicin has also been evaluated as a single agent in 27 patients 65 years or older and while there were no differences in effectiveness observed between these patients and younger patients, elderly patients had a higher rate of fevers and severe or greater infections (48).

Brentuximab vedotin

Brentuximab vedotin is an ADC targeting CD30 with a MMAE payload (49). It was approved originally in March 2018 based on results from the ECHELON-1 trial to receive either brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) or bleomycin plus AVD (24) (Table 2). It was then approved for use in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients 2 years of age or older in November 2022 (25). In subgroup analysis for the ECHELON-1 trial, patients aged >60 years did not have significant OS benefit HR =0.83 (95% CI: 0.47–1.47) while patients age <60 years had a significant OS benefit HR =0.51 (95% CI: 0.29–0.89) (24) (Table 3). The major notable toxicity seen in brentuximab vedotin is peripheral neuropathy seen in 66.9% of patients though in 85.6% of patients there was complete resolution after systemic therapy (24) (Table 4). The National Comprehensive Cancer Network (NCCN) guidelines for Stage III/IV Hodgkin’s lymphoma do list brentuximab vedotin as one of the treatment options but state “use in caution in patients aged >60” (50). It is also approved for CD30-expressing peripheral T cell lymphoma per the ECHELON-2 study (26). While there was a similar efficacy among age subgroup analysis, among older patients 74% patients had adverse reactions grade 3 or higher compared to 62% in patients ages 65 years or younger (26,51) (Table 4). Older age was also a risk factor for febrile neutropenia occurring in 29% of patients who were age 65 years or older vs. 14% in patients less than age 65 years (51). It is also approved in patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen per the AETHERA trial and approved in adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy per the ALCANZA study (27,28). In the ALCANZA study, there were no meaningful differences in safety or efficacy observed between these patients and younger patients (51).

TDM-1

TDM-1 is an ADC targeting human epidermal growth factor 2 (HER2) with a DM-1 payload (15). It is approved in HER2-positive metastatic breast cancer patients previously receiving trastuzumab and a taxane separately or in combination in patients who received prior therapy for metastatic breast cancer or developed disease recurrence during or within 6 months of completing adjuvant therapy (29) (Table 2). It is also approved for use in adjuvant disease in HER2-positive breast cancer patients who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. The EMILIA trial compared TDM-1 with capecitabine and lapatinib and OS HR age subgroup analysis showed a significant benefit of TDM-1 in patients ages <65 years while in patients ages 75 years or older though a small sample size of 25 patients, the OS HR was 2.79 (95% CI: 0.99–7.88) (29). In the KATHERINE trial, which evaluated adjuvant TDM-1 therapy in patients who had residual invasive disease after neoadjuvant therapy, TDM-1 had a clear benefit in patients ages <40 years and ages 40–64 years but this benefit was less clear in patients ages ≥65 years OS HR =0.55 (95% CI: 0.22–1.34) (7) (Table 3). Furthermore, there was a smaller absolute 3-year invasive disease-free survival difference in patients ≥65 years: 87.4% vs. 81.1% compared with patients <40 years: 86.5% vs. 74.9%. In terms of toxicity, thrombocytopenia/decreased platelet count was the most common grade 3 or higher toxicity in both trials. Three patients died in the EMILIA trial secondary to TDM-1, one thought to be from metabolic encephalopathy, another from neutropenic sepsis, and a third from AML (29). In the KATHERINE trial, 18.6% of patients had peripheral neuropathy of any grade and there were 19 cases (2.6%) of pneumonitis seen (7) (Table 4). However, despite these noted age subgroup differences, population pharmacokinetic analysis suggests that age does not have a clinically meaningful effect on the pharmacokinetics of TDM-1 (52).

Inotuzumab ozogamicin

Inotuzumab ozogamicin is an ADC targeting CD22 with a calicheamicin payload that is approved in patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (30,47) (Table 2). The INO-VATE trial compared patients to receive either inotuzumab ozogamicin with standard intensive chemotherapy and in subgroup analysis patients aged greater than 55 years did not have a significant OS HR =0.89 (95% CI: 0.57–1.37) with a median OS of 5.6 vs. 5.3 months while patients aged <55 years had a significant OS benefit (8.6 vs. 8.0 months with OS HR =0.67 (95% CI: 0.47–0.95) (30) (Table 3). In terms of notable toxicity, eight patients from the inotuzumab ozogamicin arm died, including five from veno-occlusive disease. Veno-occlusive and febrile neutropenia (both 11.6%) were the most common grade 3 or higher toxicities seen in the trial (47) (Table 4). Based on population pharmacokinetic analysis in 765 patients, no adjustment to starting dose is required based on age (53).

Polatuzumab vedotin

Polatuzumab vedotin is a CD79b targeted ADC with a MMAE payload that has been FDA-approved in relapsed or refractory DLBCL after at least two prior treatments and previously untreated DLBCL who have an international prognostic index (IPI) score of 2 or greater (31,32) (Table 2). In the GO29365 study, polatuzumab vedotin with bendamustine and rituximab (pola-BR) was compared with bendamustine with rituximab (BR) in transplant ineligible patients and there was a significant OS benefit in patients age ≥65 years HR =0.39 (95% CI: 0.19–0.79) (32). Of note, patients aged ≥65 years (64%) had numerically higher incidence of serious adverse events compared to patients aged >65 years (53%) (54). The POLARIX trial compared untreated intermediate or high-risk DLBCL patients receiving polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with rituximab, cyclophosphamide, doxorubicin, and vincristine (R-CHOP) and in older patients aged greater than 60 years, there was a significant OS benefit HR =0.7 (95% CI: 0.5–0.9) but not seen in patients age ≤60 years HR =0.9 (95% CI: 0.6–1.5) (31) (Table 3). The most common grade 3 or higher toxicity seen in both trials was neutropenia, which was seen in 46.2% of patients receiving pola-BR and in 28% of patients receiving pola-R-CHP (31) (Table 4).

T-DXd

T-DXd is an ADC targeting HER2 with a deruxtecan payload (19) (Table 2). It was initially FDA-approved in patients with unresectable or metastatic HER2-positive breast cancer who had received a prior anti-HER2-based regimen in the metastatic or had disease recurrence during or within 6 months of neoadjuvant or adjuvant therapy (33). It was then approved for unresectable or metastatic HER2 low [immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization (FISH)−] breast cancer who had received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of neoadjuvant or adjuvant therapy from results in the DESTINY-Breast04 trial (34). It also has been approved in non-small cell lung cancer (NSCLC) for unresectable or metastatic NSCLC HER2-positive for patients who have received previous systemic therapy from results in the DESTINY-LUNG01 trial (35). In locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma, it is approved in patients who had received a prior trastuzumab-based regimen from results in the DESTINY-Gastric01 trial (36). In the studies comparing subgroups by age, patients age ≥65 years had significant progression-free survival (PFS) benefit in the hormone receptor cohort HR =0.47 (95% CI: 0.29–0.77) while patients age <65 years did not have significant PFS benefit 0.51 (95% CI: 0.39–0.67) in the DESTINY-Breast04 trial while in the DESTINY-Gastric01 trial patients age ≥65 years had a significant overall response rate (ORR) HR =0.44 (95% CI: 0.26–0.76) while patients <65 years had ORR HR of 0.82 (95% CI: 0.44–1.53) (34,36) (Table 3). A pooled analysis of DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast 03 showed a similar PFS and ORR between patients age <65 and those 65 years and older (55). Drug-related interstitial lung disease (ILD) was a notable adverse event—in the DESTINY-Breast04 trial, drug-related ILD was seen in 12.1% cases, in the DESTINY-Breast03 trial, drug-related ILD was seen in 15% of cases, in the DESTINY-Gastric01 trial 10% of cases, and in the DESTINY-LUNG01 trial drug-related ILD was seen in 26% of cases including 6.5% cases with grade 3 or higher (33-36) (Table 4). Other adverse events seen across the trials include neutropenia, anemia, thrombocytopenia, and diarrhea (33-36). Meanwhile, an age-pooled analysis of T-DXd of patients from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03 showed an increased drug discontinuation percentage in patients age ≥65 years of 25.4% compared to 18.7% in patients age <65 years and incidence of adjudicated drug-related ILD to be 17.5% in patients age ≥65 years vs. 11.8% in patients age <65 years (55). Furthermore, of the 883 breast cancer patients treated with T-DXd 5.4 mg/kg in clinical trials, there was a higher incidence of grade 3–4 adverse events observed in patients aged 65 years or older (60%) compared to younger patients (48%) (56). In the DESTINY-LUNG01 trial and the DESTINY-Gastric01 trials, no differences were seen in safety in patients ≥65 years compared to younger patients (56).

Enfortumab vedotin

Enfortumab vedotin is an ADC targeting nectin-4 with a MMAE payload (57). It has been FDA-approved for locally advanced or metastatic urothelial cancer who previously received a programmed death receptor 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum containing chemotherapy (37) (Table 2). The EV-301 trial showed a significant OS benefit in younger patients but not so in patients age ≥75 years old HR =0.91 (95% CI: 0.55–1.51) (37) (Table 3). Treatment-related rash was seen in 43.9% of patients including 14.5% with grade 3 or higher rash. Ocular disorders were seen in 18.6% of patients including 15.9% with dry eye, 4.1% with blurred, and 0.7% with corneal disorders (37). Peripheral neuropathy was seen in 46.3% of patients including 5.1% with grade 3 peripheral neuropathy (37) (Table 4). In previous earlier phase studies for enfortumab vedotin, there were not differences in safety though between patients ages 65 years or older vs. younger patients (58).

Sacituzumab govitecan

Sacituzumab govitecan is an ADC targeting tumor-associated calcium signal transducer 2 (Trop2) with a SN-38 topoisomerase inhibitor payload (59) (Table 2). It was first FDA-approved for unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies based on data from the ASCENT trial; later after results from the TROPicS-2 trial, sacituzumab govitecan was approved for unresectable locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer whose cancer has progressed after CDK4/6 inhibitor, endocrine therapy, or taxane (38,40). It was also approved from results in the TROPHY-U-01 for locally advanced or metastatic urothelial cancer who have previously a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor (39). In the ASCENT trial, patients ages ≥65 years had a significant PFS benefit HR =0.22 (95% CI: 0.12–0.40) with those receiving sacituzumab govitecan having a PFS of 7.1 months (95% CI: 5.8–8.9) compared to 2.4 months (95% CI: 1.4–2.9) in the chemotherapy arm (38). In the TROPicS-02 trial, patients ages ≥65 years had an OS of 14.9 months (95% CI: 12.0–17.5) in the sacituzumab govitecan arm compared to 10.1 months in the chemotherapy arm with HR of 0.80 (95% CI: 0.54–1.19) while similar results were seen in patients ages <65 years 14.1 months (95% CI: 12.7–16.4) vs. 11.5 months (95% CI: 10.3–11.3) HR 0.81 (95% CI: 0.64–1.02) (40). In the TROPHY-U-01 trial, patients ages ≥65 years had an ORR of 23.3% (95% CI: 13.38–36.04%) while those ages 50–64 years had a 33.3% ORR (95% CI: 20–48.5%) (39) (Table 3). Across the three trials, the most common grade 3 or higher adverse events were neutropenia, anemia, and leukopenia. In the TROPicS-02 trial, there was one drug-related fatal event from septic shock caused by neutropenic colitis and in the TROPHY-U-01 trial, one case of treatment-related death because of sepsis due to febrile neutropenia (39,40) (Table 4). In the ASCENT trial, there was a subgroup analysis performed for patients age ≥65 years showed similar rates of dose reduction between sacituzumab govitecan vs. standard of care (35% vs. 33%) though a higher percentage than those <65 years (35% vs. 19%) with febrile neutropenia 14%, fatigue 10%, and diarrhea 6% being the most common culprits of dose reduction (38,60) (Table 4). No significant differences in safety were seen in other trials involving sacituzumab govitecan in elderly compared to younger patients (61).

Loncastuximab tesirine

Loncastuximab tesirine is a CD19-targeted ADC with a pyrrolobenzodiazepine (PBD) dimer payload (17) (Table 2). It is FDA-approved for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including DLBCL, not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma based on findings from the LOTIS-2 trial (41). Duration of response in the LOTIS-2 trial was similar in the age ≥75 years subgroup 13.37 months (95% CI: 5.98–not reached) compared to the 65–74 years subgroup 10.25 months (95% CI: 3.84–not reached), and the age <65 years subgroup 9.63 months (95% CI: 3.22–not reached) (41) (Table 3). The most common grade 3 or higher treatment adverse events were neutropenia (26%), thrombocytopenia (18%), and increased gamma-glutamyl transferase levels (17%) (41). There were eight treatment-emergent adverse events with fatal outcome in 8 (6%) of the 145 patients, but none were thought to be secondary to loncastuximab tesirine (41) (Table 4). Of the 145 patients who have received loncastuximab tesirine in clinical trials, 14% were 75 years or older and there have not reported differences in safety or effectiveness (62).

Tisotumab vedotin

Tisotumab vedotin is an ADC targeting tissue factor, a transmembrane protein whose primary role is to initiate the coagulation cascade, with a MMAE payload (63) (Table 2). It received FDA approval for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy per findings from the innovaTV 204/GOG 3023/ENGOT-cx6 trial (42). The ORR of the study was 24% (95% CI: 16–33%) with 7 (7%) complete responses though no age-related survival data was reported (42) (Table 3). Most common grade 3 or higher toxicities included neutropenia 3%, fatigue 2%, and ulcerative keratitis 2% (42) (Table 4). Among the 101 patients in the innovaTV 204/GOG 3023/ENGOT-cx6 trial, 13% were age ≥65 years and grade ≥3 adverse reactions occurred in 69% patients age ≥65 years and 59% patients age <65 years (64). No patients age ≥65 years experienced a tumor response (64).

Moxetumomab pasudotox

Moxetumomab pasudotox is a CD22 targeted ADC with a pasudotox payload that received FDA approval for relapsed or refractory hairy cell leukemia in patients who had received at least two prior systemic therapies including treatment with a purine nucleoside analog per findings from Study 1053 (43) (Table 2). No age subgroup data was available; the median age of subjects in this study was 60.0 years with a range of 34–84 years including 31% of the patients being 65 years or older and 8% being 75 years or older (43,65). At median follow-up of 24.6 months, the overall complete response rate was 41% with 34% of all patients being minimal residual disease (MRD) negative (43). There were no treatment-related deaths in the study but 2 cases (3%) of capillary leak syndrome and 4 cases (5%) of hemolytic uremic syndrome. Exploratory analysis showed a higher incidence of adverse reactions leading to drug discontinuation in 23% vs. 7% and renal toxicity in 40% vs. 20% in older patients (65) (Table 4). Recently, this medication is being discontinued from future use in the US as of July 2023 due to low clinical uptake since FDA approval (66).

Mirvetuximab soravtansine

Mirvetuximab soravtansine is a folate-receptor alpha directed ADC with a DM4 payload that is FDA-approved for folate receptor alpha, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who have received 1–3 prior systemic treatment regimens per results from the SORAYA trial (44) (Table 2). No age subgroup analysis was available but the median age of patients on the trial was 62 years with a range of 35–85 years with 44% of patients being 65 years or older (44,67). The median duration of response was 6.9 months (95% CI: 5.6–9.7), and ORR was 38.0% (95% CI: 24.7–52.8%) (44) (Table 3). Keratopathy (9%) and blurred vision (6%) were the most common adverse grade 3 or higher events (44) (Table 4). Adverse reactions occurred in 49% of patients age ≥65 years and 51% patients age <65 years (67).

Belantamab mafodotin

Belantamab mafodotin is an ADC targeting BCMA with a MMAF payload (68) (Table 2). It was originally FDA-approved for relapsed or refractory multiple myeloma patients who had received at least four prior therapies include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent from results from the DREAMM-2 trial (45). In this two-arm study, patients age ≥75 years old had an ORR of 7.7% (95% CI: 0.2–36.0%) in the 2.5 mg/kg cohort which was lower than other age groups but a 35.3% (95% CI: 14.2–61.7%) ORR in the 3.4 mg/kg cohort which was similar to other age groups (45) (Table 3). Keratopathy was the most common grade 3 or higher toxicity (27% in the 2.5 mg/kg cohort and 22% in the 3.4 mg/kg cohort); among the patients who received the 2.5 mg/kg dose, keratopathy occurred in 80% of patients aged less than 65 years and 73% of patients aged 65 years and older (45,69). Two deaths were potentially related to treatment (one case of sepsis in the 2.5 mg/kg cohort and one case of hemophagocytic lymphohistiocytosis in the 3.4 mg/kg cohort) (45) (Table 4). Belantamab mafodotin however was withdrawn from use per FDA request on November 22, 2022 following results from the DREAMM-3 study comparing belanatamab mafodotin compared to pomalidomide plus dexamethasone (Pd) in patients with relapse/refractory multiple myeloma in which belanatmab mafodotin did not have superior PFS to Pd (70).

Notable ADCs in development

There are multiple ADCs in development with notable results with a few of the ADCs in further development are in NSCLC (Table 5).

Patritumab deruxtecan

Patritumab deruxtecan is an ADC targeting HER3, which is expressed in over 80% of NSCLC, and an analysis on the metastatic epidermal growth factor receptor (EGFR) mutant NSCLC patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) showed an ORR of 39% (95% CI: 26.0–52.4%) with a median PFS of 8.2 months (95% CI: 4.4–8.3) (71). At the 5.6 mg/kg dosing, the median age was 66.0 years with a range of 40–80 years. The most common grade 3 or higher adverse events were platelet count decrease/thrombocytopenia (30%), neutrophil count decrease/neutropenia (19%), and fatigue (14%). Adjudicated treatment related ILD was seen in 7% of cases (71). More recently, the HERTHENA-Lung01 study, a phase II trial on EGFR mutant NSCLC patients who had progressed on both an EGFR TKI and a platinum-based chemotherapy showed an ORR of 29.8% (95% CI: 23.9–36.2%) with a median PFS of 5.5 months and a median OS of 11.9 months (72).

Datopotomab deruxtecan (Dato-DXd)

Dato-DXd is an ADC targeting Trop2 with a deruxtecan payload. In the phase 1 trial analyzing the NSCLC cohort, the ORR was 26% (95% CI: 14.6–40.3%) with a median PFS of 6.9 months (95% CI: 2.7–8.8) and a median OS of 11.4 months (95% CI: 7.1–20.6) (73). In the TROPION-Lung02 trial looking at Dato-DXd plus pembrolizumab with or without platinum chemotherapy as first-line therapy in metastatic NSCLC without actionable mutations, there was an ORR of 58% in those who received Dato-DXd and pembrolizumab doublet therapy and ORR of 75% in those who received Dato-DXd, pembrolizumab, and platinum chemotherapy triplet therapy (74). Of note, 17% of patients receiving the doublet therapy in this study had ILD, with 3% having grade 3 and higher and 43% of patients receiving triplet therapy having ILD with 6% having grade 3 and higher (74). In addition, 16% patients in the doublet therapy cohort had ocular surface toxicity and 24% patients in the triplet therapy cohort (74).

Telisotuzumab vedotin (Teliso-V)

Teliso-V targets c-Met with a MMAE payload; in the first in human study 18.8% cases of c-Met NSCLC were found to have response to Teliso-V and on a further study focused on c-Met over-expressing advanced NSCLC, ORR was 36.5% (75,76). The most common adverse event in the study was peripheral sensory neuropathy (25%); two deaths in the study were considered possibly related to Teliso-V including pneumonitis in one patient (76).

Another notable ADC that has been studied in gastric and breast cancer is ARX788. ARX788 is an ADC targeting HER2 with a AS269 payload (78). In the Phase 1 dose expansion study of ARX788 monotherapy in HER2-positive gastric and gastroesophageal cancer, there was an ORR of 37.9% (95% CI: 20.7–57.7%) with a median PFS of 4.1 months (95% CI: 1.4–6.4) and an OS of 10.7 months (95% CI: 4.8–not reached) (77). ILD was seen in 16.7% of cases (77).

ADCs in combination with other agents

Another consideration moving forward is the combination of ADC with other agents (Table 6). One notable example is enfortumab vedotin in combination with pembrolizumab in front-line cisplatin-ineligible patients with locally advanced/metastatic urothelial cancer (79). There was an ORR of 73.3% (95% CI: 58.1–85.4%) with 15.6% complete response (79). The most common grade 3 or higher adverse event was increased lipase seen in 17.8% of patients and fatigue and macropapular rash seen in 11.1% of patients each (79). Sacituzumab govitecan and pembrolizumab combination have been recently studied in NSCLC and urothelial cancer with the most common grade 3 or higher toxicities being diarrhea and anemia similar in toxicity profile to sacituzumab govitecan monotherapy (81). Finally, Teliso-V and EGFR TKI combination are being studied with initial analysis showing ORR of 58% in Teliso-V and osimertinib and median PFS of 5.9 months (95% CI: 2.8–not reached) and ORR of 32.1% in EGFR mutated patients in Teliso-V and erlotinib (82,83). Notable grade 3 or higher toxicities seen in these trials were peripheral sensory neuropathy and in the Teliso-V and erlotinib study there was 14% grade 3 or higher pulmonary embolism toxicity (82,83).

Discussion on efficacy and toxicity of ADCs in elderly

In age subgroup analysis, we showed differing efficacy HRs in brentuximab vedotin [OS: age ≥60 years, HR =0.83 (95% CI: 0.47–1.47) vs. age <60 years, HR =0.51 (95% CI: 0.29–0.89) in the ECHELON-1 trial], TDM-1 [OS: age ≥75 years, HR =2.79 (95% CI: 0.99–7.88) vs. age 65–74 years, HR =0.89 (95% CI: 0.56–1.43) vs. age <65 years, HR =0.73 (95% CI: 0.47–0.87) in the EMILIA trial], inotuzumab ozogamicin [OS: age ≥55 years, HR =0.89 (95% CI: 0.57–1.37) vs. age <55 years, HR =0.67 (95% CI: 0.47–0.95) in the INO-VATE trial], enfortumab vedotin [OS: age ≥75 years, HR =0.91 (95% CI: 0.55–1.51) vs. age <75 years, HR =0.69 (95% CI: 0.53–0.89) in the EV-301 trial], polatuzumab vedotin [PFS: age ≥60 years, HR =0.7 (95% CI: 0.5–0.9) vs. age <60 years, HR =0.9 (95% CI: 0.6–1.5) in the POLARIX trial], and T-DXd [PFS: age ≥65 years, HR =0.7 (95% CI: 0.5–0.9) vs. age <65 years, HR =0.9 (95% CI: 0.6–1.5) in the DESTINY-Breast04; and ORR: age ≥65 years, HR =0.44 (95% CI: 0.26–0.76) vs. age <65 years, HR =0.82 (95% CI: 0.44–1.53) in the DESTINY-Gastric01 trial] in older patients compared to younger (24,29-31,34,36,37) (Table 3). On review of toxicity data across trials by age groups, we saw higher rates of febrile neutropenia in older subjects in the ECHELON-2 trial for brentuximab vedotin and in the ASCENT trial for sacitizumab vedotin, higher rates of severe adverse events in the innovaTV 204/GOG 3023/ENGOT-cx6 trial for tistoumab vedotin and POLARIX trial for polatuzumab vedotin (51,54,60,64). We also saw higher incidences of drug discontinuation in moxetumomab pasudotox in older patients and age-pooled analysis of T-DXd trials (55,65). Meanwhile, the most common grade 3 or higher toxicities were predominantly related to hematotoxicity—anemia and neutropenia which can be debilitating to patients from a fatigue standpoint and put them at increased risk for severe infections which did lead to deaths in sacitizumab govitecan, gemtuzumab ozogamicin, and TDM-1 trials (7,22,29,38,39,46,60). Specifically in hematologic malignancies, veno-occlusive disease is a serious and potentially fatal complication. Meanwhile, in solid tumors, ILD is seen in some of the trials particularly ones in NSCLC such as the DESTINY-Lung 01 trial (26%), TROPION-PanTumor01 (14%, including 8% with grade 3 or higher), and the phase 1 patritumab deruxtecan trial (7%) (35,71,73). In addition, ocular toxicities are another notable adverse event; keratopathy was seen in over 20% of patients in the belantamab mafodotin DREAMM-2 study, 16 and 9% of patients in the mirvetuximab soravtansine while 16% of patients in the Dato-DXd TROPION-Lung02 had ocular surface toxicities (44,45,74).

Thus, the combination of worse outcomes in primary efficacy in some of the ADCs, increased toxicity in older patients in multiple trials, and the implications of some of the most common side effects such as anemia, ILD, and ocular toxicities merits closer investigation particularly as ADCs become more potent with higher DAR such as trastsuzumab deruxtecan (19).

The strength of this study was that the investigators for most of these studies did include some sort of survival subgroup analysis and that the FDA package inserts for each approved ADC had a specific section for “geriatric use” which provided important information that would be easily accessible to the healthcare professional. However, the limitation of the study, likely due to either sample size or length of follow up, was that these publications lacked uniform information on age group survival analysis, as studies used OS, PFS, or ORR, and the age cutoffs were not uniform. More importantly, there was not disclosure of adverse events stratified by age unless there was a study specific to the elderly population such as the EORTC-GIMEMA AML-19 trial (46). Thus, disclosure of adverse events stratified by age in ADC studies would be a good start to better inform providers and their patients along with more detailed efficacy and safety data in the “geriatric use” section of the FDA package insert to better inform the provider. This will become even more paramount as new studies incorporate combination regimens which may include other chemotherapies and immune checkpoint inhibitors.

Conclusions

Despite the goal of avoiding traditional chemotherapy effects, ADCs are associated with considerable systemic toxicity related to the chemotherapy payload carried by each. Like traditional chemotherapy these are particularly problematic for elderly patients who also experience less benefit in terms of efficacy relative to younger patients. This reduction in the therapeutic index occurs across all ADCs regardless of payload or linker, though the toxicity profile varies according to these features. Studies on older patients in T-DXd and moxetumomab pasudotox showed increased rates of drug discontinuation while there were higher percentages of adverse events in elderly in trials involving brentuximab vedotin, polatuzumab vedotin, sacituzumab govitecan, and tistoumab vedotin. Overall adverse events of ADCs demonstrate grade 3 or higher toxicities to be most commonly hematotoxicity with notable toxicities of veno-occlusive disease in hematologic malignancies, peripheral neuropathies, ocular toxicities, and ILD. These findings merit further consideration of patient age and comorbidities when counseling patients on the risks and benefits when using these agents.

Acknowledgments

Funding: This study was supported by the USC/Norris Comprehensive Cancer Center from the National Cancer Institute (No. P30CA014089).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-188/rc

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-188/coif). R.H. has received consulting fees from Targeted Oncology and honoraria from DAVA Oncology and The Dedham Group. J.J.N. reports personal fees from AstraZeneca, Naveris, AADi Biosciences, BioAtla, Mindmed, Genentech, ANP Technologies, Sanofi and G1 Therapuetics, research support from Genentech and Merck, intellectual proptery from Cansera, and ownership interests from Cansera, Epic Sciences, Indee Bio, Quantgene, Amgen, Johnson & Johnson, and Novartis. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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