Antibody-Drug Conjugates in Lung Cancer: The Tip of the Iceberg

Fact checked by: Chris Ryan, Ron Panarotti

Key Takeaways

Three ADCs are currently FDA-approved for biomarker-defined metastatic NSCLC after prior systemic therapy: trastuzumab deruxtecan for HER2-altered tumors, telisotuzumab vedotin for c-MET–overexpressing tumors, and datopotamab deruxtecan for EGFR-mutated tumors.
HER2-altered: For NSCLC with HER2 mutations, trastuzumab deruxtecan (T-DXd) at 5.4 mg/kg IV once every 3 weeks has demonstrated an ORR of approximately 50% and has notable intracranial activity. T-DXd has also shown an approximately 35% ORR in NSCLC with HER2 overexpression (IHC 3+). ILD/pneumonitis remains the principal discontinuation-limiting toxicity, necessitating vigilant monitoring and early intervention.
High c-Met expression (≥50% IHC 3+), nonsquamous, EGFR wild-type: Telisotuzumab vedotin at 1.9 mg/kg IV every 2 weeks produces an ORR of approximately 35%. Peripheral neuropathy and pneumonitis are the primary drivers of treatment discontinuation.
EGFR-mutated NSCLC: Datopotamab deruxtecan (Dato-DXd) at 6 mg/kg IV every 3 weeks is approved specifically for EGFR-mutant NSCLC following disease progression on or after both an EGFR TKI and platinum-based chemotherapy. In this setting, Dato-DXd demonstrates an approximately 43% ORR. Key toxicities requiring proactive management include mucositis/stomatitis, ocular adverse effects, and rare but serious ILD.
The ADC landscape is rapidly expanding across NSCLC and SCLC, with emerging targets, such as HER3, B7-H3, SEZ6, along with bispecific ADCs and advances in payload and linker technologies that are driving the development of numerous new agents currently being evaluated in clinical trials.

Leah Wells, MD, breaks down the expansion and continued investigation of ADCs in lung cancer management.

Antibody-drug conjugates (ADCs) have become increasingly relevant in cancer care over the past decade, with 2 FDA approvals in 2025 highlighting their growing role in lung cancer.^1-3

ADCs consist of 3 components: an antibody that binds to tumor cell surface antigens; a chemical linker; and a cytotoxic payload. Fundamentally, ADCs are a “targeted” delivery of chemotherapy to cells expressing the tumor-associated antigen, but some payloads can diffuse into adjacent antigen-negative tumor cells, addressing the challenge of intratumoral heterogeneous antigen expression through this bystander effect.¹Unfortunately, such “off-target” as well as “on-target, off-tumor” actions create novel, at times severe, ADC toxicities.⁴

The FDA has approved 3 ADCs for different subpopulations of non–small cell lung cancer (NSCLC).

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) targets HER2, carrying a topoisomerase I inhibitor payload.⁵ T-DXd received FDA accelerated approval in 2022 for use in patients with previously treated, advanced HER2-mutant NSCLC.⁶ The recommended dose for this indication is 5.4 mg/kg intravenously (IV) every 21 days.⁵ In the phase 2 DESTINY-LUNG02 trial (NCT04644237), 102 patients with HER2-mutated advanced NSCLC received T-DXd at this dose and achieved an overall response rate (ORR) of 50% (95% CI, 39.9%-60.1%).⁷ Further analysis suggests a 50% (95% CI, 23%-77%) intracranial response in patients with baseline brain metastases treated at the 5.4-mg/kg dose (n = 14).⁸ The most common grade 3 treatment-related adverse effects were hematologic or gastrointestinal, although these rarely led to treatment discontinuation.⁷ Drug-related interstitial lung disease (ILD) occurred in 14.9% of patients, although grade 3 or higher events were rare (2%). Importantly, pneumonitis and ILD represented the most frequent causes of drug discontinuation at 5.9% and 5% of patients, respectively.

In the phase 2 DESTINY-Lung01 trial (NCT03505710), T-DXd given at 5.4 mg/kg produced an ORR of 34.1% (95% CI, 20.1%-50.6%) in patients with previously treated NSCLC with HER2 high expression (3+) by immunohistochemical (IHC) staining (n = 41).⁹ Although this represented less robust activity compared with NSCLC harboring HER2 mutations, these data contributed to the 2024 FDA pan-approval of T-DXd for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.^5,10 The 5.4-mg/kg dose was also recommended in this approval.⁵

The NCCN guidelines list T-DXd as a preferred subsequent therapy option in both HER2-mutant and HER2-overexpressing (IHC 3+) NSCLC.¹¹ T-DXd is actively being studied as frontline treatment for advanced NSCLC with a HER2 mutation or HER2 overexpression; the phase 3 DESTINY-Lung04 trial (NCT05048797) is evaluating the ADC as monotherapy, and the phase 3 DESTINY-Lung06 study (NCT06899126) is evaluating T-DXd in combination with pembrolizumab (Keytruda) and chemotherapy.^12,13 Evaluation of T-DXd in the neoadjuvant space for both HER2 alterations has also begun in the phase 2 HERCULES trial (NCT07428044).¹⁴

Telisotuzumab vedotin-tllv (Emrelis) targets the c-Met protein and carries a microtubule inhibitor payload.¹⁵ It received accelerated FDA approval in 2025 for adult patients with locally advanced or metastatic nonsquamous NSCLC harboring high c-Met protein overexpression (≥50% of tumor cells with IHC 3+) who have received a prior systemic therapy.³ Dosing is 1.9 mg/kg IV every 2 weeks.¹⁵ In the multicohort phase 2 LUMINOSITY trial (NCT03539536), evaluable patients with nonsquamous, EGFR wild-type, high c-Met–expressing NSCLC (n = 84) experienced an ORR of 35% (95% CI, 24%-46%). Among patients (n = 88) with intermediate c-Met protein expression (≥25% to <50% of tumor cells with IHC 3+), the ORR was 22.9% (95% CI, 14.4%-33.4%).¹⁶

In a safety analysis, peripheral sensory neuropathy was a prevalent adverse effect (AE; 30.2% of patients). Furthermore, neuropathy led to treatment discontinuation in nearly 10% of patients (peripheral sensory neuropathy, 7.0%; peripheral sensorimotor neuropathy, 2.3%). Pulmonary toxicity was less frequent but still notable. Pneumonitis occurred in 10.5% of patients (grade ≥3, 2.9%), and this led to drug discontinuation in 7.6% of patients.

NCCN guidelines list telisotuzumab vedotin as a recommended subsequent therapy option for patients with EGFR wild-type, nonsquamous NSCLC with high c-MET expression.¹¹ The confirmatory phase 3 TeliMET NSCLC-01 trial (NCT04928846) is enrolling patients with intermediate, as well as high, c-MET expression, indicating that a lower c-MET expression threshold remains of interest for future approvals.¹⁷ A dose-optimization phase 2 study (NCT06568939) is ongoing, comparing 1.6 mg/kg vs 1.9 mg/kg.¹⁸

Datopotamab deruxtecan-dlnk (Dato-DXd, Datroway) combines a TROP2-targeted antibody with a topoisomerase I inhibitor payload, and this ADC received accelerated FDA approval in 2025 for the treatment of adult patients with locally advanced or metastatic, EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy.^2,19 Dosing is 6 mg/kg IV every 21 days.¹⁹ The phase 3 TROPION-LUNG01 (NCT04656652) and phase 2 TROPION-Lung05 (NCT04484142) trials evaluated the activity of Dato-DXd in patients with relapsed/refractory NSCLC, and, surprisingly, high TROP2 expression did not meaningfully enrich for responders.^20,21Conversely, a pooled analysis of patients with EGFR-mutated NSCLC (n = 117) showed a promising ORR at 43% (95% CI, 34%-52%).²¹ In this pooled analysis, oral mucositis or stomatitis occurred in 69% of patients (grade ≥3, 9%). Ocular surface AEs were observed in 32% of patients, but grade 3 or higher AEs were rare (3%); none led to drug discontinuation. Drug-related ILD or pneumonitis, although uncommon (any grade, 4%; grade ≥3, <1%), was still the toxicity most frequently leading to drug discontinuation.

Per NCCN guidelines, Dato-DXd is a preferred subsequent therapy for patients with EGFR-mutant adenocarcinoma.¹¹ Ongoing trials are investigating Dato-DXd in combination with osimertinib (Tagrisso) as frontline treatment in the phase 3 TROPION-Lung14 trial (NCT06350097), as well as the addition of Dato-DXd to ongoing osimertinib post progression in the phase 3 TROPION-Lung15 trial (NCT06417814).^22,23 Importantly, there are also frontline trials evaluating Dato-DXd in combination with immune checkpoint inhibitors in patients with EGFR wild-type NSCLC, including the phase 3 TROPION-Lung08 trial (NCT05215340) evaluating Dato-DXd plus pembrolizumab and the phase 3 TROPION-Lung10 trial (NCT06357533) investigating Dato-DXd plus rilvegostomig.^24,25

TROP2-directed ADCs are also being explored in small cell lung cancer (SCLC), with a persistent need to identify a reliable biomarker, because TROP2 expression levels have not been strongly associated with responses to these agents.²⁶ There is also ongoing development of novel ADCs in SCLC, concurrently with the expansion of ADCs in the NSCLC space.^1,26 This ADC revolution depends on the integration of new target antigens and cytotoxic payloads, as well as the ongoing refinement of linker technology and biomarker selection.^1,27

For example, patritumab deruxtecan (HER3-DXd) improved progression-free survival, but not overall survival, compared with platinum-based chemotherapy in patients with EGFR-mutated, tyrosine kinase inhibitor–resistant NSCLC in the phase 3 HERTHENA-Lung02 trial (NCT05338970).²⁸

HER3-DXd, as well as another HER3-targeting ADC with a topoisomerase I inhibitor payload, BNT326 (YL202), are currently being evaluated in early phase clinical trial, which include patients with NSCLC, with or without targetable mutations (NCT06172478; NCT07070232).^29,30A bispecific ADC, izalontamab brengitecan, targets EGFR and HER3, with a topoisomerase 1 inhibitor payload, with intriguing response rates observed thus far in heavily pretreated patients with EGFR-mutated NSCLC.^31,32

B7-H3–targeting agents are being increasingly explored in SCLC.²⁶Ifinatamab deruxtecan (I-DXd) has a topoisomerase I inhibitor payload and demonstrated an ORR of 48% with a central nervous system ORR of 46.2% in previously treated patients with extensive stage SCLC (ES-SCLC), making it the focus of the phase 3 IDeate-Lung02 trial (NCT06203210) in this population.^26,33 Combination trials using I-DXd as frontline treatment for ES-SCLC, as well as the exploration of other B7-H3–targeted ADCs, are ongoing in early-phase studies.²⁶

SEZ6-targeting ADCs are also gaining traction. ²⁶ ABBV-706, with a topoisomerase I inhibitor payload, is being more extensively studied as monotherapy for previously treated patients with ES-SCLC in a phase 3 trial (NCT07365241), as well as in combination with atezolizumab (Tecentriq) in the frontline setting in the phase 2 SEZanne trial (NCT07155174).^34,35

ADCs represent a growing field in lung cancer for which the 2025 approvals are just the tip of the iceberg.

Wells is an assistant professor in the Department of Medicine at the University of Wisconsin (UW) School of Medicine and Public Health, and the UW Carbone Cancer Center in Madison.

References

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FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non–small cell lung cancer. FDA. June 23, 2025. Accessed April 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
FDA grants accelerated approval to telisotuzumab vedotin-tllv for non–small cell lung cancer with high c-Met protein overexpression. FDA. May 14, 2025. Accessed April 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-non-small-cell-lung-cancer-high-c-met-protein-overexpression
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A study to assess disease activity and adverse events of intravenous (IV) telisotuzumab vedotin compared to IV docetaxel in adult participants with previously treated nonsquamous non–small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated April 14, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT04928846
A study to assess adverse events and how intravenously (IV) infused telisotuzumab vedotin (ABBV-399) moves through the body as a monotherapy in adult participants with previously treated nonsquamous non–small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated February 23, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06568939
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Phase III, open-label study of first-line osimertinib with or without datopotamab deruxtecan for EGFRm locally advanced or metastatic non–small cell lung cancer (TROPION-Lung14). ClinicalTrials.gov. Updated November 17, 2025. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06350097
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Phase III, open-label, study of first-line Dato-DXd in combination with rilvegostomig for advanced nonsquamous NSCLC with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations (TROPION-Lung10). ClinicalTrials.gov. Updated March 16, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06357533
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A study of HER3-DXd in subjects with locally advanced or metastatic solid tumors (HERTHENA-PanTumor01). ClinicalTrials.gov. Updated May 15, 2026. Accessed May 20, 2026. https://clinicaltrials.gov/study/NCT06172478
A clinical study to test if an investigational treatment called BNT326 is safe and potentially beneficial when used alone or in combination with other investigational treatments such as BNT327, for people with advanced malignant tumors. ClinicalTrials.gov. Updated March 12, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07070232
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A study of ifinatamab deruxtecan versus treatment of physician's choice in subjects with relapsed small cell lung cancer (IDeate-Lung02). ClinicalTrials.gov. Updated March 2, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06203210
A study to evaluate adverse events and change in disease activity of intravenous ABBV-706 versus standard of care in adult participants with relapsed/refractory small cell lung cancer. ClinicalTrials.gov. Updated January 26, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07365241
A study to evaluate the optimal dose, adverse events and change in disease activity of intravenous ABBV-706 in combination with atezolizumab versus standard of care as first-line treatment in adult participants with previously untreated extensive stage small cell lung cancer (SEZanne). ClinicalTrials.gov. Updated April 14, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07155174