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Targeting TIGIT: Commentary
Targeting TIGIT: A Novel Mechanism to Inhibit the Immune Checkpoint Pathway

Released: April 14, 2022

Expiration: April 13, 2023

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Immune checkpoint inhibitors blocking CTLA-4 or PD‑1/PD‑L1 have dramatically altered treatment in numerous settings for various cancers, including lung cancer, with a recent approval in the neoadjuvant setting. Unfortunately, these agents are effective in only approximately 20% to 25% of patients, and broader therapeutic coverage is needed. One of the more promising research avenues is to target T-cell immunoglobulin and ITIM domain (TIGIT), an inhibitory checkpoint receptor expressed on activated T-cells and natural killer cells. This therapeutic strategy has shown potential in preclinical and early clinical studies in various malignancies, including melanoma, lung, and esophageal cancers. Multiple molecules targeting TIGIT are now under investigation, including in late-phase clinical trials. In this commentary, Diwakar Davar, MD, and Jyoti D. Patel, MD, discuss the TIGIT pathway and why TIGIT is such an important target in treating non-small-cell lung cancer (NSCLC) in particular.

Diwakar Davar, MD:
The understanding of checkpoint inhibitors was developed by researching PD‑1 and CTLA-4. However, the TIGIT checkpoint is different in important ways from those foundational molecules. PD‑1 is a cell-surface receptor that interacts with its ligand PD‑L1 on tumor cells or antigen-presenting cells. This interaction engages a negative feedback loop that essentially suppresses tumor antigen–specific T‑cells and thereby modulates tumor‑mediated immune suppression. CTLA-4 functions differently, in that 2 primary signals are required for T-cell activation. Signal 1 is the T-cell receptor recognition of MHC-bound peptide. Signal 2, from the interaction between B7 on antigen-presenting cells and the CD28 receptor on T-cells, is the costimulatory signal, without which activated T-cells enter a state of anergy. CD28 and CTLA-4 are opposing molecules, wherein CD28 is required for T-cell activation but is competitively opposed by CTLA-4, as both CTLA-4 and CD28 compete for B7 interaction. So, where PD‑1 is involved in T‑cell engagement from a distal perspective, CTLA-4 is involved in T‑cell engagement from the very initial priming perspective.

The TIGIT receptor family has far more complex interactions with its ligands than PD-1/PD-L1 or B7-H1/CTLA-4. The TIGIT, CD226, CD96, and CD112R axes involve several different ligands, including CD112 and CD155. Essentially, TIGIT (and CD112R) are negative or coinhibitory receptors, somewhat analogous to both PD‑1 and CTLA-4. By contrast, CD226 (and CD96) are positive or costimulatory receptors. Each receptor, both negative and positive, competes for the same set of ligands, and the differential effects of all receptor/ligand interactions determine the overall signal.

An understanding of the complex nature of this relationship could help determine in which line of therapy TIGIT-targeted agents might be most efficacious or could help identify which cell subsets are important for TIGIT biomarker and pharmacodynamic evaluation (T‑cell or natural killer cell subsets vs other cells).

The initial studies that established TIGIT as an important target for cancer immunotherapies were published back to back in 2015 and clearly demonstrated that TIGIT expression was associated with T‑cell dysfunction. TIGIT appears to mark the most suppressive, most dysfunctional CD8-positive T‑cells and the most suppressive FOXP3‑positive regulatory T-cells. In preclinical research, TIGIT blockade synergized with PD‑1 blockade in rescuing antigen‑specific T‑cells.

The question has been whether to develop a molecule to deplete negative cells—an Fc-active molecule, the primary purpose of which is to engage antibody-dependent cellular cytotoxicity (ADCC), or an Fc-inactive molecule, the primary purpose of which is not to engage ADCC, but rather to compete with the ligand for binding. For example, with CTLA-4, ipilimumab has intact IgG1 activity, whereas most PD‑1 inhibitors have an IgG4 backbone and are Fc inactive. In a 2018 Cancer Cell paper, the activity of both TIGIT and CTLA-4 was shown to be dependent on the Fc structure of the antibody; the Fc-active TIGIT moieties allow and encourage a more effective immune synapse and thereby complement antigen recognition by CD8-positive T‑cells. This led to development of a plethora of TIGIT-targeted molecules, some of which are Fc active (eg, tiragolumab), and other agents with either Fc-inactive structures or undisclosed Fc structures.

Dr Patel, what do you think about the early data on the TIGIT inhibitor tiragolumab in NSCLC?

CITYSCAPE and SKYSCRAPER-01: Tiragolumab in NSCLC

Jyoti D. Patel, MD:
The randomized phase II CITYSCAPE trial evaluated the addition of tiragolumab to first-line atezolizumab in patients with NSCLC who were wild type for both EGFR and ALK and who had a PD‑L1 tumor proportion score (TPS) of ≥1%. In the approximately 40% of patients who had a PD‑L1 TPS >50%, there was a 3-fold higher response rate for the combination. Likewise, progression-free survival was superior in the combination arm in patients with a high PD-L1 TPS. A caveat is that this was a small study with only 135 patients. In my opinion, the comparator arm of atezolizumab alone performed worse than expected. Confirmation of these results will be important; the larger SKYSCRAPER-01 study is evaluating the same combination in NSCLC.

Diwakar Davar, MD:
As you said, exciting data from CITYSCAPE suggest that tiragolumab is additive to currently approved checkpoint inhibitor monotherapy in NSCLC. This resulted in SKYSCRAPER‑01, a randomized, double‑blind, placebo‑controlled phase III trial of tiragolumab plus atezolizumab vs atezolizumab plus placebo in >600 patients with PD‑L1–high NSCLC (NCT04294810). In my opinion, if this trial were to be positive, it would potentially be practice changing—although it would need to be considered in the context of the comparative data from studies of first-line pembrolizumab or nivolumab/ipilimumab with or without 2 cycles of chemotherapy.

Jyoti D. Patel, MD:
That’s a real-world clinical conundrum. Today, many patients with advanced NSCLC receive first-line pembrolizumab monotherapy, and approximately one half will benefit with extended disease control, as per results from the KEYNOTE studies. When selecting immunotherapy agents, an important consideration is the risk of increased toxicity. Even if SKYSCRAPER-01 is a positive study, if there are more discontinuations and immune-related adverse events with combination therapy, how much of a burden is that? In other words, is the survival benefit worth the excess toxicity?

Sequencing Tiragolumab

Diwakar Davar, MD:
One of the interesting things about TIGIT is that it is often expressed in inflamed tumors, including PD‑L1–high tumors. An important question is how to sequence TIGIT-targeted agents across lines of therapy while taking into account the PD‑L1 distribution in earlier lines of therapy and the possibility that drugs may be approved in the neoadjuvant and adjuvant settings that are not necessarily that effective in second and later lines of therapy.

Jyoti D. Patel, MD:
There has been rapid recent change in the neoadjuvant and adjuvant settings, with the phase III CheckMate-816 study showing a substantial event-free survival benefit for nivolumab plus platinum chemotherapy in resectable stage IB-IIIA NSCLC. Likewise, the phase III IMpower010 trial demonstrated a disease-free survival benefit with atezolizumab vs best supportive care after adjuvant chemotherapy in resected PD-L1–positive, stage II-IIIA NSCLC. Despite this, approximately 18% of patients who received treatment with atezolizumab in IMpower010 had to discontinue treatment due to toxicity. In the neoadjuvant setting, it seems that PD-1 inhibitors are particularly useful in PD-L1–positive tumors. However, in the adjuvant setting, T‑cell mobilization is important, and drugs like TIGIT inhibitors may be of more benefit. Also, there can be changes in the tumor microenvironment following chemoradiation, and TIGIT inhibitors are now being evaluated in patients with stage III NSCLC who received this treatment.

Regarding chemotherapy‑free options, if a patient receives single‑agent pembrolizumab and loses response, could we add anti-TIGIT therapy, or will we have better biomarkers to possibly discern between inflamed and cold tumors to guide clinical care?

Diwakar Davar, MD:
That’s a great answer to a very complex and increasingly complicated near-future therapeutic landscape.

These studies highlight the question of how to best use tiragolumab in the context of numerous effective immunotherapies for lung cancer. Patients who have a high PD‑L1 TPS preferentially receive pembrolizumab monotherapy unless they have a high disease burden or are very symptomatic. Patients with lower PD-L1 scores can receive nivolumab plus ipilimumab to target both PD‑1 and CTLA-4.

So, what does tiragolumab add? Should it be used in combination with other checkpoint inhibitors? Will the increased toxicity from combination regimens in phase II studies be confirmed in phase III trials in lung cancer and other tumor types? Stay tuned!

Other TIGIT Inhibitors in Clinical Testing for Lung Cancer

Diwakar Davar, MD:
Beyond tiragolumab, several other promising TIGIT inhibitors are being developed for lung cancer. For example, domvanalimab (AB154) is currently being evaluated in multiple clinical trials across various settings. Also, the TIGIT inhibitor vibostolimab (MK-7684) has had very exciting data presented that suggested responses are seen across patients with NSCLC and any PD-L1 status relative to historic controls.

These studies include:

  • After concurrent chemoradiation stage III NSCLC wherein durvalumab is currently the standard of care
    • Phase III PACIFIC-8 (estimated N = 860): durvalumab plus domvanalimab (PD-L1 inhibitor) vs durvalumab/placebo (NCT05211895)
  • First-line advanced or metastatic NSCLC
    • PD-L1 positive: phase II ARC-7 (estimated N = 150): zimberelimab (PD-1 inhibitor) vs zimberelimab plus domvanalimab vs zimberelimab plus domvanalimab plus etrumadenant (dual adenosine receptor antagonist) (NCT04262856)
    • PD-L1 positive: phase III study (estimated N = 598): pembrolizumab/vibostolimab vs pembrolizumab monotherapy (NCT04738487)
    • PD-L1 positive and PD-L1 negative: phase III KEYVIBE-007 (estimated N = 700): pembrolizumab/vibostolimab plus chemotherapy vs pembrolizumab plus chemotherapy (NCT05226598)
  • Second-line or third-line relapsed/refractory NSCLC following progression on chemoimmunotherapy
    • Phase II study (estimated N = 240): pembrolizumab/vibostolimab with or without docetaxel vs docetaxel alone in metastatic NSCLC (NCT04725188)

Jyoti D. Patel, MD:
This space is rapidly changing, and it’s exciting to have multiple TIGIT-targeted agents in development. I certainly hope that these agents are eventually approved and introduced in routine clinical care for patients with NSCLC.

What questions about emerging TIGIT therapies do you want answered so that you feel prepared to discuss these agents with your patients who are open to participating in clinical trials? Share in the comments box below.

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