ADCs in Lung Cancer | ESMO 2026

Antibody–drug conjugates (ADCs) are moving beyond their traditional role as late-line therapies in lung cancer. By combining antibody-mediated tumor recognition with highly potent cytotoxic payloads, ADCs offer a way to redirect treatment toward a tumor-associated surface antigen rather than relying exclusively on the molecular driver that initially fueled tumor growth. Their clinical role is already established in selected HER2-mutated Non-small Cell Lung Cancer (NSCLC), while targets such as TROP2, HER3, MET, B7-H3, and DLL3 are being investigated across NSCLC and Small-cell Lung Cancer (SCLC).

What is changing is not simply the number of ADCs entering development, but where and how they are being positioned in the treatment pathway. Increasingly, ADCs are being evaluated as alternatives to conventional chemotherapy, partners for immunotherapy, and potentially earlier-line treatment options. The ESMO 2026 lung cancer programme provides a clear snapshot of this transition, with several studies testing whether ADCs can move from a salvage strategy toward a component of the treatment backbone.

From Late-line Rescue to Treatment Redesign

The original proposition behind ADCs was relatively straightforward: selectively deliver a highly potent cytotoxic payload to tumor cells through a tumor-associated surface antigen. In lung cancer, however, the opportunity has become more strategic.

The expanding use of targeted therapies and immunotherapy has prolonged treatment sequences, but it has also created increasingly complex resistance states. Once a targeted therapy stops working, conventional chemotherapy often remains the default option, particularly when no immediately actionable resistance mechanism can be identified.

ADCs offer a potential alternative because their activity does not necessarily require continued dependence on the original oncogenic driver. Instead, they can exploit cell-surface antigen expression as a separate therapeutic vulnerability.

This distinction is particularly relevant in EGFR-mutated NSCLC. EGFR Tyrosine Kinase Inhibitors (TKIs) can provide substantial clinical benefit, but progression remains an important challenge. Resistance may emerge through multiple mechanisms, creating a heterogeneous post-TKI population in which subsequent treatment decisions can be difficult.

This is where the TROP2 ADC strategy becomes particularly interesting. Rather than attempting to restore sensitivity to the original EGFR-driven pathway, an ADC can potentially redirect treatment toward a different biological feature of the tumor.

Sacituzumab Tirumotecan takes TROP2 into two Critical Treatment Settings

At ESMO 2026, sacituzumab tirumotecan (sac-TMT) sits at the centre of this evolving ADC narrative, with Phase III studies addressing two fundamentally different stages of the treatment pathway.

OptiTROP-Lung04 (LBA67) evaluates final overall survival with sac-TMT versus platinum-based chemotherapy in patients with EGFR-mutated NSCLC following progression on an EGFR-TKI. In contrast, OptiTROP-Lung06 (LBA66) evaluates sac-TMT plus pembrolizumab versus chemotherapy plus pembrolizumab as first-line treatment for PD-L1-negative advanced nonsquamous NSCLC.

EGFR-Mutated NSCLC: A Key Proving Ground for ADCs

The post-EGFR-TKI setting may represent one of the most compelling opportunities for ADCs because it exposes a fundamental limitation of sequential targeted therapy: once the original driver-directed treatment loses efficacy, patients may be left with limited broadly applicable options.

OptiTROP-Lung04 directly addresses this treatment gap by comparing sac-TMT with platinum-based chemotherapy after EGFR-TKI progression. The significance of the study extends beyond a conventional head-to-head comparison. The ADC does not need to compete with the EGFR TKI itself; rather, it needs to establish itself as an effective next-line treatment after targeted therapy.

This creates a potentially important new treatment sequence. If a TROP2 ADC can demonstrate meaningful benefit in this setting, the post-TKI treatment paradigm could begin to shift from a chemotherapy-dominated approach toward antigen-directed cytotoxic therapy.

The longer-term opportunity could be even broader. Translational work has explored sac-TMT in combination with osimertinib, pointing toward the possibility that TROP2-directed therapy may eventually be integrated with EGFR inhibition rather than being used exclusively after progression. This raises the prospect of ADCs becoming complementary components of treatment rather than purely sequential therapies.

TROP2: From Validated Target to Competitive Platform

The prominence of sac-TMT also highlights the growing importance of TROP2 as an ADC target in NSCLC.

Unlike molecular alterations such as EGFR or ALK, TROP2 expression is not confined to a narrow genomic subgroup. This creates the potential for a broader addressable population while retaining the fundamental advantage of targeted cytotoxic delivery.

However, the same breadth that makes TROP2 attractive also makes it increasingly competitive. As multiple TROP2 ADCs advance, target validation alone will no longer provide meaningful differentiation.

The competitive landscape is likely to increasingly depend on the design of the ADC itself, including the antibody, linker, payload, drug-to-antibody ratio, dosing schedule and overall safety profile. Consequently, the eventual leaders in TROP2 may not simply be the first agents to demonstrate activity. Differentiation is likely to depend on the ability to combine efficacy, durability, tolerability and treatment-setting flexibility.

In other words, TROP2 is evolving from a validated biological target into a platform-level competitive arena, where the quality of the ADC architecture and its clinical positioning may ultimately determine commercial and clinical leadership.

The ADC Opportunity Is Expanding Beyond TROP2

The ESMO 2026 programme also demonstrates that the ADC opportunity is becoming increasingly diversified.

IBI363 is being evaluated in first-line advanced NSCLC in combination with chemotherapy and in locally advanced or metastatic lung adenocarcinoma without actionable genomic alterations that has become resistant to immunotherapy, where it is being studied in combination with bevacizumab versus docetaxel. These studies illustrate an increasingly important development strategy: novel targeted approaches are being tested against established treatment backbones rather than being reserved exclusively for patients who have exhausted standard options.

The comparison with docetaxel is particularly informative from a treatment-positioning perspective. Rather than establishing activity only in a highly selected or heavily pretreated population, the programme is asking whether an emerging targeted approach can challenge a conventional chemotherapy standard in an immunotherapy-resistant setting.

This represents a broader evolution in ADC development. The central question is no longer simply whether an ADC can produce responses in previously treated disease, but whether it can alter the treatment architecture around which lung cancer care is built.

DLL3 Broadens the Opportunity into SCLC

The ADC landscape at ESMO 2026 also extends into SCLC through zocilurtatug pelitecan (zoci; ZL 1310), a DLL3-directed ADC being evaluated with atezolizumab, with or without carboplatin, in extensive-stage SCLC.

The strategic rationale is particularly relevant in SCLC, where aggressive tumour biology, rapid development of treatment resistance and a relatively limited number of validated molecular targets continue to create substantial unmet need.

The zoci programme also reinforces the broader movement of ADCs toward earlier treatment. Rather than reserving DLL3-directed therapy for patients who have exhausted chemotherapy and immunotherapy, the programme is evaluating whether an ADC can be incorporated into a first-line treatment strategy.

ESMO 2026: ADC studies to watch

 

What ESMO 2026 could mean for the ADC Landscape

The most important message from ESMO 2026 is not simply that more ADCs are entering lung cancer development. It is that the role of ADCs is being reconsidered across the treatment continuum.

Three developments stand out.

First, the post-targeted-therapy setting is becoming an important proving ground. OptiTROP-Lung04 places sac-TMT directly against platinum chemotherapy following EGFR-TKI progression, testing whether antigen-directed cytotoxic delivery can become the preferred next step once targeted therapy fails.

Second, ADCs are moving into treatment combinations and earlier lines. OptiTROP-Lung06 asks whether sac-TMT can substitute for conventional chemotherapy within a first-line pembrolizumab-based regimen, while the zoci programme evaluates DLL3-directed treatment in combination with immunotherapy, with or without carboplatin, in extensive-stage SCLC.

Third, the competitive landscape is becoming more differentiated by target and molecular context. TROP2 is emerging as a broad NSCLC platform, HER3 and integrin β6 are being tested in previously treated disease, DLL3 extends the opportunity into SCLC, and bispecific ADC approaches are being explored in post-EGFR disease.

The implication is that the next phase of ADC development will be defined less by the novelty of the modality itself and more by where each ADC can establish a clinically meaningful advantage over existing treatment.

The Bottom Line

ESMO 2026 positions ADCs at an important inflection point in lung cancer. The field is moving from a model in which ADCs are primarily considered targeted alternatives after standard treatment failure toward one in which they may serve as new cytotoxic backbones, combination partners and earlier-line treatment strategies.

Sac-TMT provides the clearest example of this transition, with development spanning both post-EGFR-TKI disease and first-line immunotherapy combinations. At the same time, sigvotatug vedotin, izalontamab brengitecan, HER3-directed approaches, IBI363 and DLL3-directed zoci demonstrate that the opportunity is becoming increasingly diversified across targets and treatment settings. The critical question for the next stage of the field will therefore not be whether ADCs work in lung cancer. It will be which ADCs can demonstrate enough efficacy, durability, safety and flexibility to displace established treatment backbones and ultimately redefine how therapy is sequenced across the lung cancer journey.