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TROP2 TIGIT Lung Cancer
Exploring TROP2 and TIGIT Therapies in Lung Cancer: Lessons From Recent Trials and Looking Forward to New Horizons

Released: December 23, 2025

Benjamin Levy
Benjamin Levy, MD, FASCO
Alex Spira
Alex Spira, MD, PhD, FACP
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Key Takeaways
  • TROP2 ADCs have shown benefit for patients with previously treated EGFR-mutated advanced NSCLC with experts using the approved ADC datopotamab deruxtecan after progression on the FLAURA2 regimen of chemotherapy and osimertinib if a clinical trial is not an option.
  • TIGIT inhibitors like domvanalimab and rilvegostomig have shown encouraging early activity in PD-L1–high NSCLC.
  • Sacituzumab govitecan has shown early evidence of antitumor activity in ES-SCLC.

Among the most closely watched developments in lung cancer are agents targeting TROP2 and TIGIT, which are being explored across multiple settings in non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). These therapies offer the potential to move beyond traditional chemotherapy and immunotherapy with more precisely targeted treatment approaches. In this commentary, we discuss the emerging clinical trial data and how these agents may reshape the treatment paradigm and expand options for patients with refractory or biomarker-defined lung cancers.

The Role of TROP2-Targeted ADCs in Previously Treated Advanced NSCLC

Benjamin Levy, MD, FASCO:
TROP2 is an attractive therapeutic target because of its common overexpression in NSCLC and its association with a worse prognosis. During the past few years, we have seen rapid development of several TROP2-directed antibody–drug conjugates (ADCs), including datopotamab deruxtecan (Dato-DXd), sacituzumab govitecan (SG), and the newer sacituzumab tirumotecan (sac-TMT). These drugs all bind to TROP2 with high affinity and deliver a TOPO-I payload with cleavable linkers, although each differs slightly in its structural design and toxicity profile.

Despite the promising mechanism of these agents, key phase III trials of Dato-DXd and SG in previously treated advanced NSCLC, TROPION-Lung01 and EVOKE-01, were negative for overall survival (OS) vs docetaxel. Unfortunately, we do not have a great explanation for why these studies were unsuccessful in showing benefit for these ADCs. There were also some encouraging signals of potential benefit in progression-free survival (PFS) and OS in nonsquamous subgroups, but these were not enough for regulatory approval. Unfortunately, docetaxel remains the standard of care in the second-line setting for previously treated advanced NSCLC.

However, a pooled analysis of 2 studies with Dato-DXd, TROPION-Lung01 and phase II TROPION-Lung05, reported evidence of antitumor activity in patients with pretreated, EGFR-mutated advanced NSCLC. In this pooled analysis, the overall response rate (ORR) in patients with prior osimertinib treatment was 45% and median duration of response was 6.9 months. This led to the accelerated FDA approval of Dato-DXd for adults with locally advanced or metastatic EGFR-mutated NSCLC after prior EGFR-directed therapy and platinum-based chemotherapy.

Alex Spira, MD, PhD, FASCO:
At this time, Dato-DXd has a role in the postchemotherapy setting for patients with EGFR-mutated advanced NSCLC, for instance, after progression on the FLAURA2 regimen of chemotherapy and osimertinib, particularly when a clinical trial is not available. However, it is important to keep in mind 3 adverse events of special interest associated with this particular ADC that need to be monitored and appropriately managed: stomatitis, interstitial lung disease, and ocular surface events.

Finally, the newest ADC, sac-TMT, has demonstrated OS benefit vs docetaxel for EGFR-mutant, nonsquamous advanced NSCLC after EGFR-TKI and platinum-based chemotherapy (HR: 0.49; P = .0070) and vs pemetrexed plus platinum-based chemotherapy for EGFR-mutant, nonsquamous NSCLC after EGFR-TKI (HR: 0.60; P = .001). It will be interesting to see if we end up with multiple approved TROP2 ADCs to expand treatment options for this group of patients.

Data for TROP2 ADCs in Treatment-Naive NSCLC

Benjamin Levy, MD, FASCO:
We now also have encouraging data for TROP2 ADCs as frontline treatment for advanced NSCLC. At ASCO 2025, I presented data from the phase Ib/II TROPION-Lung02 study of Dato-DXd combined with pembrolizumab with and without platinum-based chemotherapy for patients with treatment-naive advanced NSCLC. ORRs were >50% for the various combinations and across PD-L1 expression levels. The Dato-DXd combinations were also reasonably well tolerated, although stomatitis, interstitial lung disease, and ocular adverse events were also observed in this study.

The phase II EVOKE-02 study also reported meaningful activity of SG plus pembrolizumab and carboplatin in the frontline setting for advanced NSCLC with ORRs ranging from 33% to 67% depending on PD-L1 expression level. Regarding safety, SG is not associated with stomatitis like Dato-DXd, but it does cause higher rates of neutropenia and diarrhea. I think that we will need additional data to determine if these ADCs can be used as first-line treatment.

TROP2 Normalized Membrane Ratio as a Biomarker in NSCLC

Benjamin Levy, MD, FASCO:
Using TROP2 expression to guide patient selection for treatment could achieve a benefit in the greater NSCLC population. Retrospective analysis of the TROPION-Lung01 and TROPION-Lung02 studies suggests that the ratio of TROP2 membrane expression to cytoplasmic expression could indicate greater internalization of TROP2 ADCs and could predict improved ORRs and PFS with Dato-DXd treatment. For instance, median PFS of Dato-DXd for the TROP2 normalized membrane ratio (NMR)–positive population of TROPION-Lung01 was 6.9 months compared with 2.9 months for the TROP2 NMR-negative population and 4.0-4.1 months for the 2 populations treated with docetaxel. However, further study will be needed to refine methods of calculating TROP2 NMR and adopting it as a biomarker.

TIGIT Inhibitors for Advanced NSCLC

Alex Spira, MD, PhD, FASCO:
There are primarily 4 TIGIT therapies that have been evaluated for NSCLC, including domvanalimab, rilvegostomig, belrestotug, and tiragolumab, the latter two of which have been discontinued from further development in NSCLC. Domvanalimab, a monoclonal antibody (mAb), plus zimberelimab, an anti–PD-1 mAb, demonstrated improved PFS and possibly improved early OS compared with zimberelimab alone as frontline treatment for PD-L1–high, advanced NSCLC in 2 phase II studies. In the ARC-7 trial, domvanalimab plus zimberelimab improved PFS (9.3 vs 5.4 months; HR: 0.67), with hints of OS benefit. ARC-10 is even more intriguing, with a median PFS of 11.5 months for the combination compared with 6.2 months for zimberelimab monotherapy (HR: 0.69).

Rilvegostomig is an anti-TIGIT and anti–PD-1 bispecific antibody that showed a promising ORR of 62% in patients with PD-L1–high, checkpoint inhibitor–naive metastatic NSCLC in the phase I/II ARTEMIDE-01 study. We may see that bispecific antibodies are where the field is heading, and rilvegostomig, compared with domvanalimab, allows us to target TIGIT and PD-1 with simpler treatment and potentially fewer adverse effects. We will need more data to determine the true benefit of these agents. So far, the anti-TROP2 ADC trials have enrolled a large proportion of eligible patients, so it will take time to complete studies for these TIGIT agents. The adverse effect profile of the TIGIT agents seems manageable so far, although diarrhea remains a common adverse event across TROP2 and TIGIT agents.

Early Progress in SCLC

Alex Spira, MD, PhD, FASCO:
These TROP2 and TIGIT agents are also being studied in SCLC. In the phase II TROPiCS-03 trial, SG showed evidence of antitumor activity with a 42% ORR and a median duration of response of 4.7 months in pretreated patients with extensive-stage (ES) SCLC. The randomized phase III  EVOKE-SCLC-04 trial is currently comparing SG with standard-of-care topotecan for previously treated ES-SCLC.

To date, the trial results of TIGIT therapies in SCLC have not been positive. In the randomized phase II AdvanTIG-204 trial, the addition of ociperlimab, a TIGIT mAb, to an anti–PD-L1 agent, plus chemoradiotherapy did not improve PFS or ORR vs the anti–PD-L1 plus chemoradiotherapy in limited-stage SCLC. The randomized phase III SKYSCRAPER-02 study in ES-SCLC failed to show benefit with tiragolumab added to an anti–PD-L1 agent and chemoimmunotherapy. To my knowledge, there are no ongoing studies of TIGIT agents in this setting.

Your Thoughts
Have you referred your patients to clinical trials for TROP2 or TIGIT therapies? Have you used Dato-DXd in your clinical practice? Share your perspectives and experiences below.

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