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TROP2 TIGIT Lung Cancer

CE / CME

Expert Analysis: Clinical Advances Journal Club on Emerging TROP-2 and TIGIT Therapies in Lung Cancer

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

European Learners: 1.00 EBAC® CE Credit

Released: January 22, 2026

Expiration: July 21, 2026

Benjamin Levy
Benjamin Levy, MD, FASCO
Alex Spira
Alex Spira, MD, PhD, FASCO
CME/CE Information

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TIGIT Axis Inhibits Innate and Adaptive Immunity Through Multiple Mechanisms

Alex Spira, MD, PhD, FASCO:
The TIGIT axis inhibits both innate and adaptive immunity through at least 5 mechanisms, including immunosuppressive dendritic cells, CD226 signaling, Fap2-induced and intrinsic T-cell and natural killer cell inhibition, as well as T-reg stability and suppression.25 There is a multifactorial rationale for why the TIGIT axis is important.

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Select Anti-TIGIT Therapies

Alex Spira, MD, PhD, FASCO:
There are several TIGIT therapies currently in development. The 4 most notable are the anti-TIGIT IgG1 monoclonal antibodies domvanalimab, belrestotug, and tiragolumab and the anti–PD-1/anti-TIGIT bispecific antibody rilvegostomig.26-29 Two of these agents, belrestotug and tiragolumab, have already been discontinued, as I will discuss, but the other 2, domvanalimab and rilvegostomig, are currently under study in phase III trials.

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GALAXIES Lung-201: Efficacy of Dostarlimab ± Belrestotug in Metastatic NSCLC

Alex Spira, MD, PhD, FASCO:
The phase II GALAXIES Lung-201 study examined the anti–PD-L1 agent dostarlimab as monotherapy and in combination with belrestotug for advanced or metastatic NSCLC.29 The interim analysis reported ORRs of the combination arms were promising, ranging from 63.0% to 77.0%, whereas the ORR of dostarlimab monotherapy was 37.9%. However, at a later interim analysis, ORR were still encouraging with the combination arms, but they failed to show clinically meaningful improvement in PFS.30 Additional poor ORR results in the phase II study of belrestotug combinations vs dostarlimab monotherapy in PD-L1–positive head and neck squamous cell carcinoma (GALAXIES H&N-202) led to the discontinuation of belrestotug.

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SKYSCRAPER-06: Tiragolumab + Atezolizumab + CT in Untreated Metastatic NSCLC

Alex Spira, MD, PhD, FASCO:
Tiragolumab was also studied in combination with the anti–PD-L1 agent atezolizumab and other agents in 2 studies. The double-blind phase II/III SKYSCRAPER-06 study evaluated tiragolumab combined with atezolizumab and CT, followed by tiragolumab plus atezolizumab and pemetrexed maintenance therapy vs placebo with pembrolizumab and CT with placebo, pemetrexed, and pembrolizumab maintenance for patients with untreated metastatic NSCLC.31

This was a negative study that did not meet its primary endpoints of PFS (HR: 1.27; P = .99) and OS (HR: 1.33; P = .98).

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SKYSCRAPER-01: Tiragolumab + Atezolizumab in Untreated Metastatic PD-L1-High NSCLC

Alex Spira, MD, PhD, FASCO:
The double-blind phase III SKYSCRAPER-01 trial randomized patients with untreated metastatic NSCLC with high PD-L1 expression to tiragolumab plus atezolizumab or placebo plus atezolizumab.32 This study also failed to meet primary endpoints of PFS (HR: 0.78; P = .02) and OS (HR: 0.873; P = .22). Despite numerical improvements in median PFS and OS, they did not demonstrate statistical significance.

After multiple failed and discontinued trials in various cancer types, tiragolumab was discontinued.

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ARC-7: Domvanalimab + Zimberelimab ± Etrumadenant vs Zimberelimab in 1L Metastatic PD-L1–High NSCLC

Alex Spira, MD, PhD, FASCO:
Now we move on to the anti-TIGIT agents still in development.

The phase II ARC-7 trial randomized patients with metastatic PD-L1–high NSCLC to one of 3 treatment arms: domvanalimab plus zimberelimab (an anti-PD-L1 monoclonal antibody) with or without etrumadenant, or zimberelimab monotherapy in the first-line setting.33 Here we focus on domvanalimab plus zimberelimab vs zimberelimab monotherapy. Median PFS was 9.4 vs 5.4 months (HR: 0.67), with 12-month PFS rate of 41% vs 25%. Unlike the negative studies we have discussed, this anti-TIGIT/anti–PD-L1 combination has promising results, although the sample sizes are limited (n = 50 in each arm). The most common treatment-emergent AEs were nausea, fatigue, and constipation, which are manageable.

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ARC-10: Domvanalimab + Zimberelimab vs Zimberelimab vs CT in 1L PD-L1–High Stage IIIB-IV NSCLC

Alex Spira, MD, PhD, FASCO:
Similarly, the randomized phase II ARC-10 trial tested domvanalimab plus zimberelimab vs zimberelimab alone vs CT in the first-line setting for PD-L1–high advanced NSCLC.34 Again, we look at the 2 major arms: domvanalimab with zimberelimab vs zimberelimab alone. Median OS was not reached vs 24.4 months (HR: 0.69), and median PFS was 11.5 vs 6.2 months (HR: 0.69). This is again a relatively small trial (n = 38 vs 40), but these results are encouraging. 

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ARC-10: Safety of Domvanalimab + Zimberelimab vs Zimberelimab vs CT in 1L PD-L1–High Stage IIIB-IV NSCLC

Alex Spira, MD, PhD, FASCO:
As expected, the addition of domvanalimab to zimberelimab comes with a slight increase in the rate of treatment-related AEs (81.6% vs 57.5%).34 Overall, this combination appears tolerable.

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ARTEMIDE-01: Efficacy of Rilvegostomig in Checkpoint Inhibitor–Naive Metastatic NSCLC

Alex Spira, MD, PhD, FASCO:
Now we look at phase I/II dose-escalation/expansion data for rilvegostomig in checkpoint inhibitor–naive patients with metastatic NSCLC, presented at ESMO 2025.35 ORR in patients with PD-L1 TPS ranging from 1% to 49% and ≥50% was 29.0% and 61.8%, respectively. ORR was higher in patients who were also CT naive: 44.4% in the PD-L1 TPS 1% to 49% group and 97.7% in the PD-L1 TPS ≥50% group. Rilvegostomig was well tolerated with few treatment discontinuations and low rates of treatment-related AEs. This is a small single-arm study, but the results are encouraging.

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Select Ongoing Trials of Anti-TIGIT Therapies in NSCLC

Alex Spira, MD, PhD, FASCO:
Unfortunately, the realm of TIGIT agents has been littered with failures for reasons that are unclear. However, the data we have discussed make me hopeful that in the future we will see positive results in ongoing phase III studies of domvanalimab and rilvegostomig.

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VELOCITY-Lung Substudy-01: SG + Domvanalimab + Zimberelimab in Untreated mNSCLC

Alex Spira, MD, PhD, FASCO:
We are also interested in the prospect of combining the TROP-2 and TIGIT agents for NSCLC. The phase II VELOCITY-Lung study is evaluating several combinations of zimberelimab with other agents in a preliminary stage followed by an expansion stage with primary endpoint of ORR by investigator.36 Data for the preliminary stage of zimberelimab plus domvanalimab and SG in substudy-01 were reported at ESMO 2025.

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VELOCITY-Lung Substudy-01: Efficacy

Alex Spira, MD, PhD, FASCO:
Twenty-five patients received zimberelimab with domvanalimab and SG, with a promising response rate of 44%.36 There are some questions as to whether TROP-2 agents are effective in squamous populations, but similar ORRs were seen across squamous (50%) and nonsquamous disease (41%), as well as across PD-L1 expression levels (TPS <1%: 38%; TPS ≥1%: 50%). These results in a small patient population suggest some activity and warrant further study of the treatment combination.

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VELOCITY-Lung Substudy-01: Safety

Alex Spira, MD, PhD, FASCO:
The safety profile is as expected with AEs of both TROP-2 ADCs and TIGIT agents, such as diarrhea.36

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Which of the following anti-TIGIT therapies has shown promising efficacy in combination with zimberelimab for first-line treatment of PD-L1-high (PD-L1 tumor proportion score [TPS] ≥50%) metastatic NSCLC?

Based on eligibility criteria for the phase II VELOCITY-Lung Substudy-01 evaluating combinations of zimberelimab with domvanalimab, SG, and etrumadenant, which of the following patients with advanced lung cancer could be considered for enrollment on this trial?

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