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Antibody–drug conjugates (ADCs) have rapidly transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), moving from proof-of-concept to standard-of-care within the space of a few years. With multiple agents now in late-phase development and others recently approved, the field is grappling with increasingly complex questions around which ADC to use, in which sequence, and how best to combine them with existing targeted therapies and immunotherapy.

Therapeutic advances in targeting HER2 alterations in NSCLC & remaining challenges

 

The approval of trastuzumab deruxtecan (T-DXd) for HER2-mutant NSCLC in 2022, the first ADC approval in this indication, set a benchmark for the class.¹ In the Phase II DESTINY-Lung02 trial (NCT04644237), T-DXd at 5.4 mg/kg demonstrated a confirmed objective response rate (ORR) of 49.0% (95% CI: 38.5–59.6%) and a median duration of response (DoR) of 8.7 months, establishing the drug-to-antibody ratio-optimised dose as the new standard.²

At ASCO 2024, Nicolas Girard, MD, PhD, Institut Curie, Paris, France, discusses the development of new agents for managing HER2-positive NSCLC.

 

HERTHENA-Lung02: patritumab deruxtecan in pretreated EGFRm-NSCLC

 

 

Building on this success, the anti-HER3 ADC patritumab deruxtecan (HER3-DXd) has attracted considerable attention given the near-universal expression of HER3 across EGFR-mutated NSCLC. In the Phase II HERTHENA-Lung01 trial (NCT04619004), HER3-DXd achieved a confirmed ORR of 29.8% (95% CI: 23.9–36.2%) and a median DoR of 6.4 months in heavily pre-treated patients, irrespective of mechanism of EGFR tyrosine kinase inhibitor (TKI) resistance.³ The subsequent Phase III HERTHENA-Lung02 trial (NCT05338970) compared HER3-DXd to platinum-based chemotherapy in patients with EGFR-mutated NSCLC following third-generation TKI failure, demonstrating a statistically significant improvement in progression-free survival (PFS) with a hazard ratio of 0.74, along with meaningful intracranial activity in patients with brain metastases.⁴

OptiTROP-Lung04: sacituzumab tirumotecan in EGFR-mutated NSCLC

 

TROP2-directed ADCs represent another major axis of development. In the Phase III TROPION-Lung01 trial (NCT04656652), datopotamab deruxtecan (Dato-DXd) demonstrated superiority over docetaxel for PFS in pre-treated advanced NSCLC, while offering a more favourable tolerability profile, particularly with respect to alopecia and neutropenia.⁵ Meanwhile, sacituzumab tirumotecan (sac-TMT), a next-generation TROP2-directed ADC with a higher drug-to-antibody ratio, showed compelling activity in the Phase III OptiTROP-Lung04 trial (NCT05870319), in which it achieved a median PFS of 8.3 months versus 4.3 months with platinum-based chemotherapy in patients with EGFR-mutated NSCLC following TKI progression.⁶

 

Novel strategies targeting c-Met in non-small cell lung cancer

 

 

The MET axis has also come into focus. Telisotuzumab vedotin (Teliso-V), an ADC targeting c-MET, received FDA accelerated approval in May 2024 for EGFR wild-type, non-squamous NSCLC with high c-MET overexpression – representing the first approved ADC directed against this target.⁷ Early-phase data from ABBV-400 (NCT05029882), another c-MET-directed ADC, have reinforced the promise of this approach across EGFR wild-type tumour subtypes.⁸

Rational combinations and sequencing

As individual ADCs demonstrate single-agent activity, attention is turning to whether combinations with established agents can augment response depth and durability, particularly in molecularly defined populations. The TROPION-Lung08 programme is evaluating Dato-DXd in combination with osimertinib in the first-line EGFR-mutated setting, with the hypothesis that targeting both the EGFR pathway and TROP2 simultaneously could delay or overcome resistance. Similarly, combinations of T-DXd with immune checkpoint inhibitors are under active investigation, prompted by preclinical data suggesting that DXd-mediated immunogenic cell death may prime anti-tumour immune responses.

Sequencing decisions present an equally pressing challenge. The predominant use of DXd-based payloads across multiple ADCs, T-DXd, HER3-DXd, Dato-DXd, sac-TMT, and others, raises the important question of cross-resistance and payload overlap. Whether prior exposure to one DXd-containing ADC blunts the activity of a subsequent agent targeting a different antigen remains an open and clinically urgent question. Current expert opinion suggests that antibody target, tumour antigen expression, and bystander effect potential should all inform sequencing strategies in the absence of prospective data.⁹

 

Novel conjugates: beyond the DXd paradigm

While the DXd platform has dominated recent approvals, the broader ADC pipeline is exploring a diverse range of payload classes, linker chemistries, and novel antigenic targets. CEACAM5, expressed in a subset of non-squamous NSCLC, has been explored as a target for tusamitamab ravtansine; whilst the Phase III CARMEN-LC03 trial (NCT04154956) did not meet its primary PFS endpoint versus docetaxel in high CEACAM5-expressing patients, a favourable trend in overall survival and a more tolerable safety profile sustain interest in refining patient selection.10

Bispecific ADCs, which incorporate dual antigen targeting into a single conjugate, represent a next frontier. These constructs aim to improve tumour selectivity, enhance internalisation, and reduce off-target toxicity by exploiting differential antigen co-expression patterns on malignant cells. Early-phase studies are underway across multiple bispecific formats, including those combining EGFRxHER3 and HER2xHER3 targeting, though clinical data in NSCLC remain nascent.

Taken together, the trajectory of the ADC field in NSCLC points toward a richer and increasingly personalised treatment toolkit, but one that demands prospective sequencing studies, robust biomarker strategies, and careful attention to cumulative toxicity as multiple agents move toward earlier lines of therapy.

References

  1. 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):241–51.
  2. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant advanced non-small-cell lung cancer: primary results from the randomized, Phase II DESTINY-Lung02 trial. J Clin Oncol. 2023;41(31):4852–63.
  3. Goto K, Mok TSK, Kato T, et al. Patritumab deruxtecan (HER3-DXd) in patients with advanced NSCLC: results of the HERTHENA-Lung01 Phase II trial. J Clin Oncol. 2023;41(27):4337–50.
  4. Mok TSK, Planchard D, Gainor JF, et al. HERTHENA-Lung02: Phase III study of patritumab deruxtecan (HER3-DXd) versus platinum-based chemotherapy in previously treated EGFR-mutated advanced NSCLC. Presented at: ASCO Annual Meeting; May 2025; Chicago, IL.
  5. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small-cell lung cancer: the randomized, open-label Phase III TROPION-Lung01 study. J Clin Oncol. 2025;43(3):260–72.
  6. Zhang L, Fang WF, Wu L, et al. Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated NSCLC following progression on EGFR-TKIs: results from the randomized, multicentre Phase III OptiTROP-Lung04 study. Ann Oncol. 2025;36:S1728–9.
  7. Camidge DR, Ahn MJ, Ameratunga M, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein-overexpressing advanced EGFR-wildtype non-squamous NSCLC in the Phase II LUMINOSITY trial. J Clin Oncol. 2024;42(29):3403–13.
  8. Brandão M, Papadimitrakopoulou VA, Pérol M, et al. ABBV-400 in patients with advanced EGFR wild-type non-squamous NSCLC: results from a Phase I study (NCT05029882). Presented at: ESMO Congress; September 2024; Barcelona, Spain.
  9. Mountzios G. Evaluating the role of ADCs in oncogenic-addicted NSCLC [interview]. VJOncology. 2025.
  10. Besse B, Lo Russo G, Lena H, et al. OA08.05 Tusamitamab Ravtansine vs Docetaxel in Previously Treated Advanced Nonsquamous NSCLC: Results from Phase 3 CARMEN-LC03 Trial. Journal of Thoracic Oncology, 19, S25-S26
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