Knowledge of Unique ADC-Related Toxicities Is Critical for Safe, Effective Use in NSCLC

At the 26th Annual International Lung Cancer Congress, Corey J. Langer, MD, FACP, discussed the detection and management of antibody-drug conjugate (ADC) toxicity in non–small cell lung cancer (NSCLC), emphasizing the need for early recognition and mitigation.1 This included an outline of the mechanisms of toxicity and current armamentarium of approved ADCs; key efficacy data and safety profiles for prominent ADCs in this space; and management strategies for common toxicities such as interstitial lung disease (ILD), ocular toxicity, and peripheral neuropathy

“[There are] multiple mechanisms of ADC toxicity linked to the target, unstable linker, warhead and the bystander effect. They’re common, often treatment limiting, [and can] equal or exceed those we see typically with conventional chemotherapy,” Langer stated during his presentation. “[Moreover], many of these [toxicities] are unique and outside of our comfort zone. Perhaps with new technology we can reduce some of these toxicities, but at the end of the day, this is chemotherapy 2.0.”

Langer is the director of Thoracic Oncology at Abramson Cancer Center and a professor of medicine at Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

Mechanisms of ADC Toxicity and Key Approvals in Lung Cancer

ADCs primarily serve as delivery systems for cytotoxic chemotherapy agents, offering the potential advantage of targeted drug delivery to increase tumor specificity and minimize systemic toxicity, Langer began. However, several pitfalls may limit their therapeutic benefit, including their toxicity profiles.

ADCs are associated with both traditional chemotherapy-related toxicities and unique adverse effects (AEs), such as hepatotoxicity, keratitis, and pneumonitis. The cytotoxic payloads used in ADCs are typically agents not employed as monotherapy in clinical practice due to their limited efficacy and substantial toxicity profiles, he noted, adding that toxicity may arise from the antibody itself or from a bystander effect.

The mechanisms underlying ADC-associated toxicities are multifactorial, Langer continued, as every component of the agent may affect the extent of ADC-induced toxicities. Although designed to selectively bind tumor antigens, ADCs may also bind to normal tissues expressing the same antigen, leading to on-target, off-site toxicity. Following antigen binding, ADCs are internalized and processed, a process that occurs in both malignant and normal cells. It is estimated that approximately 0.1% of the administered dose reaches tumor cells, with the majority catabolized in non-target tissues, contributing to systemic toxicity, Langer noted. Off-target effects may be influenced by properties of the antibody, the chemical linker, and the payload itself.

The drug-to-antibody ratio (DAR) is particularly important, he stated, adding that, “It is a double-edged sword. Higher DAR may lead to increased efficacy, but also the increased risk of premature release into normal cells and [AEs].”

Within the field of lung cancer, the current ADC arsenal includes fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) which was granted FDA approvalfor HER2-mutant NSCLC in the pretreated setting on August 11, 2022, and more recently for solid tumors with high HER2 immunohistochemistry expression on April 5, 2024. Additional approvals include datopotamab deruxtecan-dlnk (Dato-DXd; Datroway)for EGFR-mutant metastatic NSCLC on June 23, 2025, and telisotuzumab vedotin-tllv (Emrelis) for high cMET–expressing metastatic NSCLC on May 14, 2025.

Toxicity Profiles of Approved ADCs

Langer next reviewed the known toxicity profiles of several ADCs in the NSCLC paradigm.

T-DXd

Findings from the phase 2 DESTINY-Lung01 trial (NCT03505710) showed that, at a median follow-up of 13.1 months (range, 0.7-29.1), the centrally confirmed objective response rate (ORR) with 6.4 mg/kg of T-DXd was 55% (95% CI, 44%-65%).2 The median duration of response was 9.3 months (95% CI, 5.7-14.7), the median progression-free survival (PFS) was 8.2 months (95% CI, 6.0-11.9), and the median overall survival (OS) was 17.8 months (95% CI, 13.8-22.1).

Safety data from the trial showed that the agent’s toxicity profile was generally consistent with that of prior studies. The most common AEs were nausea and fatigue. Grade 3 or higher drug-related AEs occurred in 46% of patients (n = 91), the most common of which was neutropenia (19%). Moreover, adjudicated drug-related ILD occurred in 26% of patients and resulted in death in 2 patients. The median duration of onset of ILD was 141 days (range, 14-462) and 21 patients required corticosteroids.

These data led to the phase 2 DESTINY-Lung02 trial (NCT04644237), which evaluated T-DXd at 5.4 mg/kg (n = 102) and 6.4 mg/kg (n = 50) in an attempt to mitigate the agent’s toxicity while preserving efficacy.3 As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. The study was successful in showing that the reduced dose of T-DXd produced clinically meaningful responses, and had a more favorable safety profile, although toxicity profiles for both doses were deemed acceptable and generally manageable, Langer reported.

“Response rates were comparable,” he detailed. “PFS and OS, at least if we look at the confidence intervals, were also quite similar. The incidence of grade 3 toxicity, dose reduction, discontinuation, and drug interruptions were much lower at the 5.4 mg/kg dose, and the incidence of ILD [went] from 28% [with the 6.4 mg/kg dose] down to 12.9%, with a lower [incidence of] grade 5 [toxicity].”

Dato-DXd

Results from the phase 1 TROPION-PanTumor01 trial (NCT03401385) showed clinical activity for Dato-DXd in patients with advanced or metastatic NSCLC.4 Dato-DXd was tested at 3 different doses: 4 mg/kg, 6 mg/kg, and 8 mg/kg.5 As of the data cutoff of September 4, 2020, the ORR per independent central review among all enrolled patients (n = 159) ranged from 21% to 25%.4

Regarding safety, the agent had a manageable safety profile that was consistent with prior data. The most common grade 3 or greater treatment-emergent AEs (TEAEs) were mucosal inflammation, anaemia, stomatitis and fatigue, with patients treated at the 8 mg/kg dose experiencing higher rates overall. ILD occurred in 8% of patients, the majority of which were observed with the 8 mg/kg cohort, including 3 deaths.

“The results are instructive when it comes to the relative toxicity,” Langer stated.

Overall, the 6 mg/kg dose was determined to be the recommended dose for the registrational phase 3 TROPION-Lung01 trial (NCT04656652). Safety findings from TROPION-Lung01, which were presented at the 2023 ESMO Congress, showed that dry eye was the most frequently reported ocular AE at 6.1%, most of which were no greater than grade 2, followed by increased lacrimation in 5.4% of patients. Infusion-related reactions occurred in 8% of patients in both treatment arms; nearly all were grade 2 or lower, with only 1 grade 3 event reported in the Dato-DXd arm.5 The rate of treatment discontinuation due to stomatitis or oral mucositis was 0.7%. Notably, the occurrence of stomatitis appeared to correlate with improved clinical outcomes, suggesting a potential pharmacodynamic association, Langer stated.

Telisotuzumab Vedotin

In the phase 2 LUMINOSITY study (NCT03539536), which evaluated telisotuzumab vedotin in both EGFR wild-type and -mutated, nonsquamous, c-MET protein–overexpressing NSCLC, the ORR was 28.6% (95% CI, 21.7%-36.2%) in the EGFR wild-type cohort at a data cutoff of September 28, 2023.6 In patients with high c-MET overexpression, the ORR was 34.6% (95% CI, 24.2%-46.2%) vs 22.9% (95% CI, 14.4%-33.4%) in those with intermediate c-MET overexpression.

Regarding safety, any-grade TEAEs occurred in 97.1% of EGFR wild-type patients, with grade 3 or higher TEAEs reported in 56.4%. Any-grade treatment-related AEs (TRAEs) were observed in 81.4% of patients, 27.9% of which were grade 3 or higher. TRAEs led to treatment discontinuation in 21.5% of patients, and 1 treatment-related death occurred. The most common any-grade TRAEs were peripheral sensory neuropathy (30.2%), peripheral edema (16.3%), and fatigue (14.0%). Peripheral sensory neuropathy was the most frequent grade 3 or higher TRAE (7.0%). Adjudicated ILD events were reported in 9.9% of patients, including 9 grade 3 or higher cases and 3 fatal events.

Approaches to ADC Toxicity Management

Lastly, Langer outlined toxicity patterns for ADCs broadly, as well as potential mitigation strategies.

“Most of the phase 1/2 trials [for these agents] have identified recommended doses at which toxicity is unacceptable. The usual approaches [to toxicity mitigation] that we use with chemotherapy apply here, including dose interruptions, dose reductions, and steroid use.”

Myelosuppression is among the most common toxicity patterns, especially with auristatin-based ADCs. This can result in treatment discontinuation and, in some cases, morbidity or mortality. Both on-target effects on CD33-positive myeloid progenitors and off-target effects from prolonged linker circulation contribute. Thrombocytopenia has also been observed. In these settings, chemotherapy-like management strategies, including dose modifications and prophylactic use of growth factors should be employed, Langer advised.

Neutropenia and febrile neutropenia are most frequently seen with HER2-targeting ADCs, Langer continued. He recommended standard antiemetic protocols similar to those used with platinum-based chemotherapy, including corticosteroids and 5-HT3 receptor antagonists.

Cardiotoxicity is also a concern with HER2-targeted ADCs. Langer advised that baseline and periodic echocardiographic monitoring every 3 to 6 months should be performed, and treatment should be interrupted if left ventricular ejection fraction (LVEF) declines by greater than 10% to 20% from baseline, and permanently discontinued if the LVEF is less than 40% or if symptomatic heart failure occurs.

Langer further emphasized that ILD is a unique ADC-related toxicity that warrants a proactive approach. “This is something that we have not typically seen,” he stated. “We do see it with immunotherapy, but not typically with chemotherapy. Interventional pulmonologists are amongst our best friends here.”

For symptomatic patients, evaluation begins with chest CT imaging to assess for ILD and rule out differential diagnoses such as infection or disease progression. Bronchoscopy may be required. In asymptomatic, grade 1 ILD, treatment should be interrupted until resolution, with possible corticosteroid initiation. For grade 2 or higher ILD, permanent discontinuation of the ADC is typically recommended. Corticosteroids are standard, and immunosuppresive agents may be considered for steroid-refractory cases, he outlined.

Ocular toxicities are also notable and usually reversible, Langer said, and baseline and symptom-driven ophthalmologic evaluation is advised. Management includes preservative-free artificial tears 4 or more times daily and avoidance of contact lens use. Eye cooling strategies during infusion may also reduce severity.

“We need to engage our ophthalmologists at baseline and certainly when symptoms appear,” Langer emphasized. “Most of this is fully reversible with dose reduction and supportive care.”

Peripheral neuropathy, which is common with microtubule inhibitor payloads, occurs in up to half of patients treated with an ADC, predominantly as sensory neuropathy. Gabapentin or duloxetine may be used for symptomatic relief, Langer stated, adding that treatment should be held for grade 2 to 3 neuropathy until resolution to grade 1 or lower and permanently discontinued at grade 4.

Other notable ADC-related toxicities include hepatotoxicity, stomatitis, and gastrointestinal AEs, Langer outlined. For stomatitis, preventive oral hygiene, bland rinses, and cryotherapy with ice chips during infusion are recommended. He concluded by stating that early dental referral may help prevent progression and improve quality of life in these cases.

References

1. Langer C. Detection and management of ADC toxicities in lung cancer. Presented at: 26th Annual International Lung Cancer Congress; July 25-26, 2025; Huntington Beach, CA.
2. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431
3. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. 2023;41(31):4852-4863. doi:10.1200/JCO.23.01361
4. Datopotamab deruxtecan and Enhertu show promising early clinical activity in patients with advanced non-small cell lung cancer. News release. AstraZeneca. January 29, 2021. Accessed July 28, 2025. https://www.astrazeneca.com/media-centre/press-releases/2021/datopotamab-deruxtecan-and-enhertu-show-promising-early-clinical-activity-in-patients-with-advanced-non-small-cell-lung-cancer.html#
5. Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01. Ann Oncol. 2023;34(suppl 2):S1305-S1306. doi:10.1016/j.annonc.2023.10.06
6. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein–overexpressing advanced nonsquamous EGFR-wildtype non–small cell lung cancer in the phase II LUMINOSITY trial. J Clin Oncol. 2024;42(25):3000-3011. doi:10.1200/JCO.24.00720