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Targeting TROP2 and TIGIT in Lung Cancer
Harnessing TROP-2 and TIGIT: Emerging Strategies to Enhance Outcomes in Lung Cancer Care 

Released: July 11, 2025

Expiration: January 10, 2026

Lyudmila Bazhenova
Lyudmila Bazhenova, MD
Jyoti D. Patel
Jyoti D. Patel, MD, FASCO
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Key Takeaways
  • TROP-2–directed antibody–drug conjugates, particularly datopotamab deruxtecan and sacituzumab govitecan, show significant efficacy in difficult-to-treat subsets of non-small-cell lung cancer (NSCLC) and small-cell lung cancer, emphasizing the importance of careful dose management when balancing efficacy and toxicity. 
  • Domvanalimab, a TIGIT inhibitor with FC-silencing properties, combined with zimberelimab significantly improves progression-free survival and overall survival vs single-agent zimberelimab in patients with PD-L1–high NSCLC, highlighting antibody characteristics and patient selection as crucial factors associated with clinical benefit. 
  • Continued focus on equitable clinical trial enrollment remains essential to accurately reflect and benefit all patients with lung cancer. 

Understanding the Role and Clinical Potential of TROP-2
Trophoblast cell-surface antigen 2 (TROP-2) is a transmembrane glycoprotein that is overexpressed across various solid tumors, including non-small-cell lung cancer (NSCLC). Its functions are diverse, ranging from promoting cell regeneration to regulating tumor growth and survival. Because of its broad expression and critical roles in tumor biology, TROP-2 has emerged as a compelling target for antibody–drug conjugates (ADCs), a class of therapies combining the specificity of antibodies with potent cytotoxic payloads. 

One ADC targeting TROP-2, datopotamab deruxtecan (Dato-DXd), recently received FDA approval for the treatment of adults with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy. Several other TROP-2–targeting ADCs, including sacituzumab govitecan and sacituzumab tirumotecan, are currently in clinical trials, each demonstrating unique pharmacological properties. Differences in antibody structure, linker stability, payload, and dosing regimens significantly influence their clinical efficacy and safety, emphasizing the importance of precision care in patient selection and management strategies. 

Clinical Pearls From Trials of ADCs Targeting TROP-2 in NSCLC
In June 2025, Dato-DXd was approved by the FDA for patients with NSCLC harboring EGFR mutations after prior EGFR-directed therapy and platinum-based chemotherapy. Data from combined analyses of the phase III TROPION-Lung01 and phase II TROPION-Lung05 trials showed a strong overall response rate (ORR) of 43%, a median progression-free survival (PFS) of nearly 6 months, and a median overall survival (OS) of approximately 16 months. Although its toxicity profile includes concerns requiring healthcare professional (HCP) vigilance (eg, stomatitis, ocular surface events, and interstitial lung disease), Dato-DXd is the first TROP-2–directed therapy available for a certain population of patients living with lung cancer—a population with limited treatment alternatives. 

Sacituzumab govitecan has also shown significant efficacy in patients with NSCLC. Recent results from the phase II EVOKE-02 trial in cohorts C and D (with any PD-L1 expression level) highlighted the clinical promise of sacituzumab govitecan in combination with pembrolizumab and carboplatin for patients with previously untreated metastatic NSCLC and no actionable mutations. The ORRs were 45.1% in patients with nonsquamous histology and 39% in patients with squamous histology, with a median PFS of approximately 8 months in each cohort. Patients demonstrated substantial responses regardless of PD-L1 tumor proportion score expression, indicating the potential to broaden therapeutic benefits beyond current immunotherapy options. 

A key practice insight from this study was the importance of managing dosing to balance efficacy and toxicity. Initially dosed at 10 mg/kg, patients experienced notable toxicities, including neutropenia, diarrhea, and stomatitis. However, a dose reduction to 7.5 mg/kg improved tolerability without compromising efficacy, underscoring a practical clinical pearl: Careful dosing adjustments can optimize patient comfort and adherence, ultimately improving outcomes. 

The phase III EVOKE-01 trial evaluated sacituzumab govitecan vs standard-of-care docetaxel in patients with metastatic NSCLC previously treated with platinum-based chemotherapy and immunotherapy (and ≥1 targeted therapy if actionable genomic alterations were present). The primary endpoint of this study, median OS, was not statistically significant in the ITT population (median: 11.1 months with sacituzumab govitecan vs 9.8 months with docetaxel; HR = 0.84; 1-sided P = .0534), but a meaningful difference was noted for patients with metastatic NSCLC that was nonresponsive to prior anti–PD1/PD-L1 regimen. A subsequent analysis also suggested potential OS benefits in difficult-to-treat populations such as patients with actionable genetic alterations and those with brain metastases. Longer follow-up results recently presented at the 2025 ASCO Annual Meeting showed a preserved numerical improvement in OS and a minimal increase in rates of adverse events (AEs) with sacituzumab govitecan vs docetaxel. Based on these data, sacituzumab govitecan also demonstrates potential as a second-line or beyond therapy, particularly for complex patient scenarios often encountered in clinical practice. 

Sacituzumab tirumotecan received FDA breakthrough designation due to promising early-phase results, notably in patients with advanced or metastatic NSCLC with EGFR mutations (exon19 deletion or exon 21 L858R) with disease progression on or after tyrosine kinase inhibitors and platinum-based chemotherapy. HCPs should closely watch the ongoing development of these therapies, as they represent valuable new options for difficult-to-treat subsets of patients with lung cancer. 

Evaluating TIGIT: Insights and Opportunities
The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) axis is thought to be a critical checkpoint inhibiting both the innate and adaptive immune responses. Several anti-TIGIT antibodies, including domvanalimab, rilvegostomig, tiragolumab, and belrestotug, have undergone and/or are currently under clinical testing. Among these, domvanalimab, an FC-silent monoclonal antibody targeting TIGIT, has demonstrated promise, particularly when combined with zimberelimab (an anti–PD-L1 antibody) in patients with PD-L1–high advanced NSCLC. 

The phase II ARC-7 trial evaluated domvanalimab plus zimberelimab vs zimberelimab monotherapy in patients with previously untreated, PD-L1–high metastatic NSCLC. The results were encouraging, showing a significant increase in PFS. Patients treated with domvanalimab and zimberelimab achieved a median PFS of 9.3 months vs 5.4 months with zimberelimab alone. Of importance, domvanalimab and zimberelimab were not associated with a substantial amount of serious AEs, though mild-to-moderate side effects such as nausea, fatigue, and dyspnea were common. 

Further supporting these promising findings, the phase III ARC-10 trial enrolled patients with NSCLC and PD-L1 TC ≥50%. In Part 1 of the ARC-10 trial, domvanalimab plus zimberelimab demonstrated a meaningful improvement in OS compared with zimberelimab alone (median OS: not yet reached vs 24.4 months, respectively). Additionally, the combination significantly extended median PFS to 11.5 months vs 6.2 months with zimberelimab alone. Importantly, the majority of AEs were mild to moderate, underscoring a favorable risk–benefit balance that enhances the clinical appeal of this combination. 

Although results from other TIGIT-targeted therapies have been mixed, these supportive findings from domvanalimab-based studies highlight how antibody selection (FC-silencing) and patient population (PD-L1–high NSCLC) can critically influence outcomes. These data position domvanalimab as a potentially valuable addition to first-line immunotherapy combinations, underscoring the importance of continued exploration of FC-silent TIGIT inhibitors in carefully selected patient populations. 

Targeting TROP-2 and TIGIT in SCLC: Emerging Opportunities
For patients with small-cell lung cancer (SCLC), targeting TROP-2 shows encouraging results, especially in the second-line setting. In the phase II TROPiCS-03 trial, sacituzumab govitecan reported an ORR, or 41.9%, following progression after 1 line of platinum-based chemotherapy and immunotherapy in patients with extensive-stage SCLC. Although less active in patients with platinum-refractory disease (ORR = 35.0%), these outcomes are promising and represent meaningful clinical advances, highlighting the potential for TROP-2–targeted therapies to address critical unmet needs in SCLC. 

Conversely, TIGIT targeting in SCLC has been challenging with trials like the phase III SKYSCRAPER-02 with tiragolumab yielding limited success. Nevertheless, ongoing trials and evolving combination strategies may offer future insights, reinforcing the importance of continuing to explore novel therapeutic approaches for patients with SCLC. 

Clinical Trials and Equitable Access: A Call to Action
When discussing any new advances in patient care, it is critically important to consider equitable patient access to novel therapies and clinical trials. Despite promising advancements, we remain challenged by underrepresentation of minority, rural, and economically disadvantaged populations. Recognizing barriers including costs, logistical challenges, and patient hesitancy is the first step. However, proactive HCP advocacy and patient-centered strategies remain essential to improving equity in access to novel therapies and increasing diversity in clinical trial participation, ensuring findings reflect and benefit all patients. 

Looking Ahead: Integrating New Therapies into Clinical Practice
As we continue to explore and integrate therapies targeting TROP-2 and TIGIT for our patients with lung cancers, it is clear that these novel approaches hold significant promise. Practical clinical considerations, such as managing toxicity through dose adjustments and identifying the most suitable candidates based on molecular or immunologic profiles, will shape clinical strategies. With ongoing research, increased awareness, and improved access to clinical trials, I believe we are well-positioned to deliver enhanced care and meaningful improvements to patients battling lung cancer. 

Your Thoughts
As new ADCs targeting TROP-2 and TIGIT enter clinical practice, what factors most influence your decision-making when selecting among these agents for patients with advanced NSCLC or SCLC? Tell us your thoughts in the comments 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 these therapies in your clinical practice once they are approved?

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