Immune checkpoint inhibitors have transformed the treatment of non-small cell lung cancer (NSCLC), enabling durable responses in patients who previously had limited treatment options. Yet even among patients whose tumors express high levels of PD-LI, a biomarker used to guide immunotherapy, many do not achieve a lasting benefit.
Improving upon established immunotherapy has therefore become a major focus of lung cancer drug development. Researchers are investigating different approaches, from combining immune checkpoint inhibition with additional biological mechanisms to developing therapies directed at specific molecular characteristics of tumors.
At the IACLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, several Phase III trials provided important new evidence about these strategies. Their results were not uniformly positive, but together they offer valuable insights into what it takes to translate a promising therapeutic approach into meaningful clinical benefit.
Beyond a Single Checkpoint: The HARMONi-2 Results
One of the most significant NSCLC developments presented at WLCL 2026 came from HARMONi-2, a randomized Phase III study evaluating ivonescimab against pembrolizumab in previously untreated patients with advanced, PD-L1-positive NSCLC.
Pembrolizumab blocks PD-1, an inhibitory receptor on immune cells that tumors can exploit to suppress antitumor immune responses. Ivonescimab takes a dual-targeting approach, combining PD-1 blockage with inhibition of vascular endothelial growth factor (VEGF) in a single bispecific antibody.
VEGF is best known for its role in promoting the formation of blood vessels that support tumor growth. However, VEGF signaling can also contribute to immune suppression within the tumor microenvironment, making it an attractive complementary target for immunotherapy.
In HARMONi-2, involving 398 patients, ivonescimab significantly improved median overall survival to 30.8 months compared with 22.6 months for pembrolizumab (HR 0.73). The trial had previously demonstrated a significant progression-free survival benefit, with median PFS of 11.1 versus 5.8 months. The overall survival analysis also reported encouraging results in patients with high PD-LI expression, although these subgroup findings were exploratory.
These results provide clinical evidence supporting a therapeutic strategy that addresses both immune checkpoint signaling and VEGF. While they do not establish the individual contribution of each mechanism of the observed benefit, they reinforce the potential of targeting additional biological processes alongside PD-1 inhibition.
Understanding the Different Dimensions of Clinical Benefit: EVOKE-03
Not every approach to improving immunotherapy has produced the same results. At WCLC 2026, the Phase III EVOKE-03/KEYNOTE-D46 study evaluated sacituzumab govitecan, a TROP2-directed antibody-drug conjugate (ADC), alongside pembrolizumab in 620 previously untreated patients with metastatic NSCLC and high PD-L1 expression (≥50%).
Unlike invonescimab, which combines PD-1 and VEGF inhibition in a single bispecific antibody, sacituzumab govitecan uses an antibody to deliver SN-38, a cytotoxic chemotherapy payload that inhibits topoisomerase I, to TROP2-expressing cancer cells. Combining it with pembrolizumab was intended to bring together targeted drug delivery and immune checkpoint inhibition.
The combination achieved a higher objective response rate than pembrolizumab alone (55.6% versus 43.7%) and numerically longer median progression-free survival (11.8 versus 7.7 months). However, the PFS difference did not meet the study’s predefined threshold for statistical significance, and no overall survival benefit had been demonstrated at interim analysis. Grade 3 or higher treatment-related adverse events were also more frequent with the combination (55.7% versus 16.5%).
The EVOKE-03 findings offer a more nuanced picture than the study’s primary endpoint results alone might suggest. Although more patients responded to the combination and median PFS was numerically longer, the median duration of response was nearly identical between the two groups (21.4 versus 21.3 months). These results highlight how tumor response, progression-free survival, and overall survival capture different dimensions of clinical benefit, which do not necessarily evolve in parallel. Each represents a different dimension of clinical benefit, and understanding how they relate is particularly important when evaluating new treatment strategies. The study also contributes valuable evidence on the balance between efficacy and tolerability. While no new safety signals were identified, the greater frequency of severe treatment-related adverse events underscores the importance of considering the potential benefits of combination therapy alongside the additional burden of treatment for patients.
Taken together, the results add to our understanding of ADC-immunotherapy combinations in NSCLC, providing valuable clinical evidence to inform future research into treatment strategies, patient selection, and the relationship between antitumor activity and longer-term outcomes.
Precision Matters: Lessons from DESTINY-Lung04
A third important result from WCLC 2026 highlighted a different therapeutic strategy: using the molecular characteristics of a tumor to guide treatment selection.
DESTINY-Lung04 investigated trastuzumab deruxtecan, a HER2-directed ADC, in patients with advanced NSCLC harboring specific HER2 mutations. HER2 is a cell-surface receptor involved in regulating cell growth and survival, and certain mutations can drive tumor development. Trastuzumab deruxtecan uses an antibody to deliver a cytotoxic topoisomerase I inhibitor payload to HER2-expressing cancer cells.
The randomized Phase III study enrolled 454 previously untreated patients with advanced NSCLC harboring HER2 exon 19 or 20 mutations. Trastuzumab deruxtecan significantly improved median progression-free survival to 14.3 months compared with 8.3 months for pembrolizumab plus chemotherapy (HR 0.63). Objective response rates were also higher (70.0% versus 44.5%), as was median duration of response (13.4 versus 9.7 months).
At the first interim analysis, an overall survival benefit had not been demonstrated, although formal statistical testing was not yet planned at this stage and differences in subsequent treatments complicated interpretation. Safety also remained an important consideration: drug-related interstitial lung disease/pneumonitis was reported more frequently with trastuzumab deruxtecan (20.8% versus 2.3%), with most events classified as mild or moderate but some serious and fatal cases reported.
The findings nevertheless represent an important advance for patients with HER2-mutant NSCLC, demonstrating that a molecularly targeted ADC can significantly delay disease progression compared with an established first-line treatment regimen.
More broadly, DESTINY-Lung04 reinforces the importance of matching therapeutic strategies to tumor biology. In this case, specific HER mutations defined the study population. For other emerging targets, the most relevant biomarkers may instead involve protein expression, target density, or other molecular characteristics. Understanding these distinctions will be essential as more targeted therapies progress through clinical development.
What These Results Tell Us About the Next Generation of NSCLC Treatment
Together, HARMONi-2, EVOKE-03, and DESTINY-Lung04 illustrate three distinct strategies for advancing NSCLC treatment: combining complementary biological mechanisms, adding targeted drug delivery to immunotherapy, and developing treatments for molecularly defined patient populations. Although the trials investigated different patient populations and cannot be compared directly, their findings offer important insights into the evolving treatment landscape.
For immunotherapy in particular, a central challenge remains: why do some patients achieve durable responses to PD-1 inhibition while others derive limited benefit? Blocking PD-1 addresses one mechanism of immune suppression, but the effectiveness of antitumor immune responses can also be influenced by other features of the tumor microenvironment, including vascular signaling and metabolic conditions.
The HARMONi-2 findings provide clinical evidence for the potential of addressing an additional pathway alongside PD-1 inhibition. While this does not establish that targeting other features of the tumor microenvironment will produce similar benefits, it reinforces the scientific interest in investigating complementary mechanisms that may influence immunotherapy response. One such mechanism attracting growing attention is extracellular tumor acidity.
Tumor Acidity: An Additional Therapeutic Opportunity
While the WCLC 2026 trails discussed above did not investigate tumor acidity, research presented at other major scientific conferences and published in peer-reviewed journals this year highlights growing interest in its role in cancer immunotherapy.
An acidic extracellular environment is a characteristic feature of many solid tumors. High metabolic activity generates acidic byproducts, while inadequate blood perfusion limits their removal. The resulting acidity can influence not only cancer cell behavior, but also the immune cells responsible for recognizing and attacking tumors.
Previous research has established that acidic conditions can impair T-cell activation and suppress the production of cytokines involved in antitumor immune responses, while neutralizing tumor acidity enhanced responses to immune checkpoint inhibition in preclinical studies. Building on this evidence, researchers presenting at AACR 2026 reported that extracellular acidity could impair T-cell activation and expansion independently of lactate accumulation. This distinction is important because it suggests that extracellular acidity may be a therapeutic target in its own right, rather than simply a consequence of altered tumor metabolism.
Further insights emerged from a 2026 study published in Bioactive Materials, which identified the proton-sensing receptor GPCR68 as a mediator of acidity-induced T-cell dysfunction. In preclinical models, localised pH neutralization enhanced the antitumor effects of anti-CTLA-4 treatment, providing additional evidence that modifying extracellular acidity may help improve immune responses. Importantly, the study identified a specific molecular pathway through which extracellular acidity suppresses immune function, strengthening the mechanistic rationale for targeting tumor pH alongside immunotherapy.
This growing body of evidence adds to the scientific rationale for therapeutic approaches designed to counteract tumor acidity, such as Helix BioPharma’s L-DOS47. L-DOS47 is an antibody-enzyme conjugate that targets CEACAM6-expressing tumors and uses urease activity to increase extracellular pH in the tumor microenvironment. Preclinical research has demonstrated that L-DOS47 could increase tumor pH and significantly enhance the antitumor effects of PD-1 inhibition, with reported reductions of approximately 70% in tumor volume and 50% in tumor weight versus PD-1 inhibition alone after four weeks.[11] Having previously evaluated L-DOS47 in advanced NSCLC, both as monotherapy and in combination with chemotherapy, Helix reported encouraging early clinical results in a Phase I study with pemetrexed and carboplatin, including partial responses in five of 12 evaluable patients (42%).[11]
Building on this clinical experience, Helix is now preparing LDOS007, a Phase Ib/randomized Phase II study investigating L-DOS47 in combination with pembrolizumab in previously untreated patients with advanced nonsquamous NSCLC, high PD-L1 expression, and qualifying CEACAM expression. The study will investigate whether targeting tumor acidity can improve clinical outcomes with PD-1 inhibition.
Tumor Acidity: An Additional Therapeutic Opportunity
WCLC 2026 highlighted important advances across both NSCLC and small cell lung cancer (SCLC). In NSCLC, HARMONi-2, EVOKE-03, and DESTINY-Lung04 provided new insights into combining therapeutic mechanisms, evaluating ADC-immunotherapy combinations, and matching treatments to molecularly defined patient populations.
Meanwhile, significant progress was also reported in relapsed SCLC, where two Phase III trials, TAISAHN-302 and ARTEMIS-008, demonstrated improved overall survival with B7-H3-directed ADCs compared with topotecan, offering encouraging evidence for a disease with historically limited treatment options.[2]
Alongside these clinical developments, emerging research into the tumor microenvironment is expanding our understanding of additional factors that may influence treatment response, including extracellular acidity. Together, these advances reflect an increasingly sophisticated approach to lung cancer treatment, in which understanding tumor biology, selecting appropriate therapeutic strategies, and demonstrating meaningful clinical benefit remain central to improving patient outcomes.
B7-H3: What the Right Target Can Unlock
Relapsed SCLC remains particularly challenging to treat, with limited therapeutic options and poor outcomes following initial treatment with chemotherapy and immunotherapy. Topotecan, a cytotoxic chemotherapy drug that inhibits topoisomerase I, an enzyme involved in DNA replication, has long been established as a second-line treatment, although its clinical benefit is modest.[2]
B7-H3 (also known as CD276) is a cell-surface protein involved in immune regulation that is frequently overexpressed in SCLC and has been implicated in tumor progression and immune evasion. Its expression on cancer cells makes it an attractive target for antibody-based therapies. At WCLC 2026, two randomized Phase III trials demonstrated significant improvements in overall survival with B7-H3-directed ADCs compared with topotecan.
Notable, both ADCs, tambotatug pelitecan and risvutatug rezetecan, carry topoisomerase I inhibitor payloads, the same class of cytotoxic agents as topotecan. However, rather than administering these agents as conventional chemotherapy, the ADCs use antibodies targeting B7-H3 to direct their payloads toward cancer cells.
In TAISHAN-302, involving 451 patients, tambotatug pelitecan improved median overall survival to 13.3 months compared with 9.4 months for topotecan, with objective response rates of 59.1% versus 9.7%. In ARTEMIS-008, involving 461 patients, risvutatug rezetecan achieved median overall survival of 18.5 months versus 10.3 months, with response rates of 58.3% versus 12.6%.[1][2]
These findings represent an important advance for a patient population with substantial unmet need, providing compelling clinical evidence for the potential of B7-H3-directed ADCs. Further follow-up will help establish the durability of these benefits, while the role of B7-HE expression in predicting treatment response remains to be clarified.[3][4]
Beyond their immediate clinical significance, these results illustrate how combining a suitable cell-surface target with an effective therapeutic design can open new treatment possibilities. They also raise a broader question: what characteristics make a target particularly well suited to one therapeutic approach rather than another?
Different Targets, Different Therapeutic Strategies
The progress of B7-H3-directed ADCs is part of a broader evolution in lung cancer treatment, with researchers exploring different ways to exploit proteins expressed on the surface of cancer cells.
One example is tarlatamab, a bispecific T-cell engager targeting DLL3, a protein expressed on many SCLC cells. Rather than delivering a cytotoxic payload, tarlatamab binds LLE on cancer cells and CD3 on T cells, bringing them into close proximity to stimulate an antitumor immune response. Its approval for previously treated extensive-stage SCLC demonstrates the potential of using cell-surface targets to engage the immune system directly.[4]
Researchers are also investigating combinations of different therapeutic approaches. At WCLC 2026, an early-phase study evaluating B7-H3-directed ADC elfetabart drozuntecan alongside pumitamig, a bispecific antibody targeting PD-L1 and VEGF-A, reported an objective response rate of 70.4% among 71 efficacy-evaluable patients with SCLC. Although these preliminary findings come from a nonrandomized study with limited follow-up, they support further investigation of this combination strategy.[5]
Together, these developments highlight how different therapeutic modalities can exploit distinct properties of cell-surface proteins. The suitability of a target depends not only on its expression, but also on how its biological characteristics align with the intended therapeutic mechanism.
The progress of B7-H3-directed therapies highlights a broader principle: the therapeutic potential of a cell-surface protein depends not only on its expression, but also on how effectively its biological properties can be exploited by different treatment approaches. This provides a useful framework for examining another emerging target in lung cancer, CEACAM6, where recent research is shedding light on the relationship between target biology and therapeutic design.
CEACAM6: A Target Under Investigation
Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a cell-surface protein attached to the membrane through a glycosylphosphatidylinositol (GPI) anchor.[6] In lung adenocarcinoma, CEACAM6 expression is elevated in tumour tissue compared with matched normal lung tissue.[7]
Recent research is exploring CEACAM6 through several therapeutic strategies, each highlighting a different aspect of target suitability.
Internalisation: the delivery question. ADCs must enter cancer cells to deliver their payload effectively. A 2026 study in the Journal of Controlled Release found that CEACAM6-targeting ADC potency varied across antibodies and cell types, despite similar drug loading. Surface expression and binding strength alone did not consistently predict activity. A measure incorporating internalisation efficiency was more closely associated with potency, highlighting the importance of intracellular delivery.[6]
Selectivity: the normal-tissue question. CEACAM6 is also expressed on granulocytes, and preclinical studies reported reversible depletion of these cells following treatment with a CEACAM6-directed ADC in non-human primates.[8] BHB299, a CEACAM6-directed T-cell engager presented at AACR 2026, was designed to favour cells with high target density while limiting binding to myeloid cells expressing moderate levels. Its pH-dependent T-cell-binding arm is intended to support activity in the acidic tumour microenvironment. First-in-human studies were planned for 2026.[9]
Location: the access question. CEACAM6-targeted single-domain antibodies have also been attached to liposomal doxorubicin in preclinical research investigating drug delivery to brain metastases from non-small cell lung cancer (NSCLC), where the blood–brain barrier presents a major challenge.[10]
Biological relevance: the EGFR connection. In EGFR-mutant lung adenocarcinoma models, CEACAM6 helped stabilise EGFR and support downstream signalling. Reducing CEACAM6 levels triggered cancer cell death, providing a rationale for investigating strategies targeting this biological relationship. However, CEACAM6 expression also decreased in cells that developed resistance to EGFR tyrosine kinase inhibitors, highlighting the potential effects of treatment on target availability.[7]
Modality fit: not every approach requires internalisation. L-DOS47 combines CEACAM6-targeting single-domain antibodies with urease, an enzyme intended to modify tumour acidity. Unlike an ADC, this approach acts at the cell surface rather than relying on intracellular payload delivery.[11]
Together, these studies illustrate why CEACAM6 is being investigated through different therapeutic approaches, each with distinct requirements for delivery, selectivity and biological activity.
What Makes a Cell-Surface Target Worth Pursuing?
The B7-H3 clinical results and emerging CEACAM6 research point to several considerations in target selection.
• Expression: Is the target sufficiently present in the relevant tumour population?
• Selectivity: Is expression sufficiently limited in healthy tissues to maintain a manageable safety profile?
• Density: Are enough target molecules present on individual cells to support effective engagement?
• Internalisation: Can the target deliver an ADC into the cell efficiently?
• Biological relevance: Does the target contribute to tumour growth or treatment response?
• Modality fit: Does its biology support the intended therapeutic mechanism?
No single property guarantees success. Clinical benefit depends on the interaction between target biology, therapeutic design and patient selection.
Looking Ahead
WCLC 2026 highlighted the potential of B7-H3-directed ADCs to improve outcomes in relapsed SCLC, a setting with historically limited treatment options.
CEACAM6 research illustrates how target development is also moving beyond expression alone, examining selectivity, internalisation, biological function and compatibility with different therapeutic modalities.
Understanding these factors may help translate promising antigens into meaningful treatment options for patients.
References
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2. The ASCO Post Staff. Two phase III trials explore B7-H3-directed ADCs in relapsed SCLC. The ASCO Post. September 16, 2026. https://ascopost.com/news/september-2026/two-phase-iii-trials-explore-b7-h3-directed-adcs-in-relapsed-sclc
3. Medscape Medical News. New data put ADCs on the map in relapsed SCLC. Medscape. September 16, 2026. https://www.medscape.com/viewarticle/new-data-put-adcs-map-relapsed-sclc-2026a1000ya5
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9. Henrici R, Stephenson K, Sanyal R, et al. Abstract 4051: BHB299: an AI/ML-optimized high avidity/low affinity CEACAM6-directed T cell engager for diverse solid tumors. Cancer Res. 2026;86(7 Suppl):4051. doi:10.1158/1538-7445.AM2026-4051
10. Abstract P91: Development of CEACAM6-targeted single-domain antibody-functionalized liposomal doxorubicin for targeted therapy of lung cancer brain metastases. Cancer Res. 2026;86(13 Suppl). https://aacrjournals.org/cancerres/article/86/13_Supplement/P91/786004/Abstract-P91-Development-of-CEACAM6-Targeted
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