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TROP2 and TIGIT in Lung Cancer
Targeting TROP-2 and TIGIT: Novel Treatment Approaches for Lung Cancer in 2025

Released: September 30, 2025

Benjamin Levy
Benjamin Levy, MD, FASCO
Helena Yu
Helena Yu, MD
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Key Takeaways
  • TROP‑2–targeting ADCs have moved from concept to clinic in NSCLC: Dato‑DXd currently has FDA accelerated approval for patients with EGFR‑mutated NSCLC after prior EGFR-directed therapy and platinum-based chemotherapy.
  • Sacituzumab govitecan (SG) has shown encouraging activity in the phase II EVOKE‑02 trial with SG plus pembrolizumab and platinum chemotherapy and has achieved Breakthrough Designation in second-line ES-SCLC, reinforcing its potential role across lung cancer subtypes.
  • Although some TIGIT-targeted approaches have shown mixed results, the phase II ARC-10 trial of domvanalimab plus zimberelimab (anti–PD-1/Fc‑silent combination) have shown promising overall survival benefit in patients with PD‑L1–high NSCLC, with a phase III confirmatory trial underway.

Introduction
The landscape of lung cancer therapy continues to evolve as advances in antibody–drug conjugates (ADCs) and immunotherapy combinations offer new and targeted approaches for precision treatment. Among recent developments, TROP-2–targeted ADCs and TIGIT checkpoint inhibitors are emerging as frontrunners that may redefine standards of care by addressing unmet needs in both chemotherapy-refractory and immunotherapy-refractory disease. 

Advances in TROP-2 ADCs for Lung Cancer: Clinical Outcomes and Management Considerations 

Helena Yu, MD:
A deeper understanding of TROP‑2 biology and advances in ADCs have led to practice‑level implications. For example, datopotamab deruxtecan (Dato‑DXd) was granted accelerated approval by the FDA for locally advanced or metastatic EGFR‑mutated non-small-cell lung cancer (NSCLC) after EGFR‑directed therapy and platinum-based chemotherapy in June 2025 based on a pooled subgroup from TROPION-Lung01 and TROPION-Lung05. The confirmed overall response rate (ORR) was 45% (95% CI: 35%-54%) and median duration of response was 6.5 months (95% CI: 4.2-8.4).

The approved dose for Dato-DXd is 6 mg/kg IV once every 3 weeks until disease progression or unacceptable toxicity. The most common adverse events (AEs) associated with Dato-DXd therapy are stomatitis/oral mucositis, nausea, alopecia, fatigue, and cytopenias. In addition, the serious but less common AEs of interstitial lung disease (ILD)/pneumonitis and ocular AEs (eg, keratitis and dry eye) have been noted. In clinical practice, these AEs require vigilance and administration of Dato-DXd should be paired with preventive measures, such as initiating a steroid-containing mouthwash for stomatitis before the first dose and arranging a baseline ophthalmologic assessment for ocular AEs. ILD/pneumonitis also requires careful monitoring and immediate workup with treatment interruption if ILD is suspected.

Frontline Dato-DXd Combinations in NSCLC: Balancing Efficacy, Toxicity, and Biomarker Advances

Helena Yu, MD:
At ASCO 2025, investigators presented the results from a cohort of treatment-naive patients enrolled in the phase Ib TROPION‑Lung02 study of Dato‑DXd plus pembrolizumab with or without platinum chemotherapy in advanced/metastatic NSCLC. The confirmed ORR was 55% with the doublet and 56% with the triplet and a median duration of response of approximately 20 months with the doublet and approximately 14 months with the triplet. As expected, stomatitis was commonly observed in both cohorts, but most of these AEs were low grade, and more hematologic toxicity was observed when chemotherapy was added.

Based on a retrospective exploratory analysis in this cohort of the TROPION-Lung02 study, TROP‑2 quantitative continuous scoring/normalized membrane ratio (QCS/NMR)–positive tumors showed a trend toward longer progression-free survival and overall survival (OS) vs QCS/NMR-negative tumors. Multiple presentations over the past year support QCS/NMR as a predictive biomarker for Dato‑DXd in NSCLC, but assays remain investigational and are not yet actionable with a companion diagnostic. 

Sacituzumab Govitecan in NSCLC: Lessons From EVOKE‑01 and Early EVOKE‑02 Data 

Helena Yu, MD:
The open-label phase III EVOKE‑01 study of sacituzumab govitecan (SG) vs docetaxel in patients with previously treated metastatic NSCLC (after platinum-based chemotherapy and immune checkpoint inhibitor therapy along with ≥1 targeted therapy for any actionable alterations) did not meet the primary endpoint of OS at the final analysis (HR: 0.84; 1-sided P = .053) despite a numeric improvement, fueling a stronger emphasis on frontline combinations with SG. In the phase II EVOKE‑02 trial, SG plus pembrolizumab with or without platinum chemotherapy in patients with advanced NSCLC and no previous systemic therapy for advanced disease showed promising activity across PD‑L1 subgroups and histologies in the untreated setting, with multicohort (A/B/C/D) design covering PD‑L1–high, PD‑L1–low, and squamous/nonsquamous populations. Multiple reports have described early efficacy/safety data that underscore the importance of randomized trials with confirmatory outcomes to define incremental benefit over established pembrolizumab‑based standards. 

TROP‑2 in SCLC: Breakthrough for SG 

Benjamin Levy, MD, FASCO:
Although much of the recent excitement about TROP-2–directed ADCs has centered on NSCLC, clinical activity is also being explored in small-cell lung cancer (SCLC), where therapeutic options after chemoimmunotherapy remain especially limited. For extensive‑stage SCLC that progressed after 1 previous line of platinum-based chemotherapy and anti−PD‑1/PD-L1 therapy, updated analyses from the phase II TROPiCS‑03 study of SG reported an investigator-assessed ORR of ~42% and a disease control rate exceeding 80%, with activity in both platinum‑resistant and platinum‑sensitive disease. Based on these results, the FDA granted Breakthrough Therapy Designation in late 2024 to SG for second‑line extensive-stage SCLC, and the global phase III EVOKE‑SCLC‑04 study is recruiting.

Reassessing TIGIT Blockade in Lung Cancer: Lessons Learned and Emerging Opportunities 

Benjamin Levy, MD, FASCO:
Clinical development of TIGIT inhibitors faced several setbacks. Clinical trials of tiragolumab, including the phase III SKYSCRAPER‑01 comparing atezolizumab with or without tiragolumab in PD‑L1–high advanced NSCLC and the phase III SKYSCRAPER‑06 comparing chemo‑IO with or without tiragolumab, failed to meet survival endpoints. Similarly, clinical trials with belrestotug were discontinued in May 2025 after interim results from phase II GALAXIES Lung‑201 did not meet efficacy criteria, tempering expectations for the class. These experiences refined the field’s understanding of trial design and patient selection for anti-TIGIT therapies, setting the stage for more promising next-generation studies.

In the phase II ARC-10 trial, domvanalimab (Fc‑silent anti‑TIGIT) plus zimberelimab (anti–PD‑1) was compared with zimberelimab alone and reported an OS improvement in patients with PD-L1 ≥50% NSCLC (HR: 0.64; 95% CI: 0.32-1.25), with OS not reached with domvanalimab plus zimberelimab vs approximately 24 months for zimberelimab alone. The combination of domvanalimab and zimberelimab plus chemotherapy is now being tested head-to-head vs pembrolizumab plus chemotherapy in the randomized phase III STAR‑121 trial with an all-comers design. Mechanistic distinctions (Fc‑silent design, potential effects on Treg function) and rigorous randomized validations remain prerequisites for any practice change. 

Bridging the Gap: Advancing Equity in Lung Cancer Trials
An ongoing imperative is to broaden clinical trial enrollment and address disparities, particularly among rural, Black, Hispanic/Latino(a), indigenous, and other underserved groups. Despite higher incidence and mortality rates in some of these groups, participation in pivotal studies of ADCs and immunotherapies in lung cancer trials has been disproportionately low. Without intentional efforts by all of us, trial populations will continue to fail to reflect real‑world lung cancer demographics, limiting the practice ability for us to generalize these findings across patient cohorts and impacting the equitable distribution of advances in care.

Strategies to advance equity include expanding trial sites into community and rural oncology practices, reducing logistical and financial barriers to participation, and adopting decentralized trial elements such as telehealth visits and local lab/imaging access. Culturally tailored outreach and patient navigation services can also foster trust and improve enrollment among historically underrepresented populations. 

Your Thoughts
How might the evolving data on TROP-2–targeting ADCs and TIGIT inhibitors in lung cancer influence your approach to treatment selection and patient management over the next few years? Get involved in the discussion by posting a comment below.

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When considering novel treatment options for your patients with lung cancer, which factor(s) most strongly influences your decision to integrate TROP-2 and TIGIT-targeted therapies into your clinical practice once they are approved?

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