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Anti-TIGIT Therapy
Anti-TIGIT Therapy: Current Evidence and Key Ongoing Trials

Released: May 03, 2022

Expiration: May 02, 2023

Ani Balmanoukian
Ani Balmanoukian, MD
Jyoti D. Patel
Jyoti D. Patel, MD
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Immune checkpoint inhibition has changed the landscape of how multiple malignancies are treated, particularly non-small-cell lung cancer (NSCLC). In addition to several agents with established roles in advanced or metastatic NSCLC either as monotherapy or in combination with chemotherapy (CT), we now have immune checkpoint inhibitors recently approved in the neoadjuvant (nivolumab) and adjuvant (atezolizumab) settings. Unfortunately, despite these options, the vast majority of patients either maintain minimal benefit with single‑agent immunotherapy or eventually progress despite combination CT and immunotherapy, leaving an unmet need for the development of novel targets and strategies. In this commentary, Ani Balmanoukian, MD, and Jyoti D. Patel, MD, discuss the role of TIGIT and emerging therapies targeting this pathway for the treatment of lung cancer and other solid tumors.

What Is TIGIT?

Ani Balmanoukian, MD:
TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor that is upregulated by immune cells, including activated T‑cells and natural killer cells, as well as regulatory T‑cells in many cancer types. It binds to 2 ligands, CD155 and CD112, which are both expressed by tumor cells, as well as antigen‑presenting cells in the tumor microenvironment. Expression of ligands that bind TIGIT is one of multiple mechanisms by which tumor cells can downregulate T-cell responses and evade immune recognition.

As monotherapy, anti-TIGIT antibodies have been used to a limited degree in the treatment of various malignancies. More recently, anti-TIGIT antibodies such as tiragolumab have been used in combination with other immune checkpoint inhibitors. Initial results of the phase II CITYSCAPE trial were presented at the 2020 American Society of Clinical Oncology Annual Meeting, with a recent update at the 2021 European Society of Medical Oncology (ESMO) Immuno-Oncology Congress, and it certainly led to a lot of excitement.

Jyoti D. Patel, MD:
In this phase II study, patients with locally advanced or metastatic NSCLC and wild-type EGFR/ALK and PD‑L1 expression ≥1% by tumor proportion score (TPS) were randomized to receive either atezolizumab plus tiragolumab or atezolizumab plus placebo administered every 3 weeks. The primary endpoints were overall response rate and progression-free survival (PFS). The initial results from 2020 showed that in the intention-to-treat population (N = 135), the response rate was higher with dual therapy (37%) vs atezolizumab alone (21%). Of interest, in the 58 patients with high PD-L1 expression (TPS ≥50%), whom we would typically treat in standard practice with pembrolizumab monotherapy, there was a response rate of 66% with the combination of atezolizumab plus tiragolumab. Compared with the 24% response rate in the atezolizumab-only arm, there was a significant improvement with dual therapy in this subgroup. 

Patients with low PD-L1 expression (TPS 1%-49%) often are treated with a combination of pembrolizumab and CT, but those who decline CT or otherwise do not get CT often receive nivolumab and ipilimumab. In this group, response rates were similar for the atezolizumab-only (18%) and combination (16%) arms. Thus, most of the observed effect was driven in those patients with high PD‑L1 expression. This provokes the thought: Does this treatment prevent immune escape by the tumor? Is TIGIT another checkpoint that we can target? Certainly, in this phase II trial, it is. It is important to note, however, that the response to atezolizumab alone in patients with high PD-L1 was a bit lower than I would have expected.

In the updated results presented at the 2021 ESMO Immuno-Oncology Congress, the new data on PFS correlated with the response, showing significant separation of the curves for patients with high PD-L1, with a quadrupling of median PFS (16.6 months vs 4.1 months) in the tiragolumab arm. In patients with low PD-L1, there was no significant difference in PFS (4.0 months vs 3.6 months) between groups. In the updated overall survival analysis, the use of atezolizumab plus tiragolumab in patients with high PD-L1 showed a nice improvement, with an HR of 0.23, so this was a very significant benefit.

In the follow-up, there were no new or unexpected safety signals. When we administer dual checkpoint inhibitors, we are interested in knowing whether there is increased toxicity with 1 drug vs 2 drugs. We’ve certainly seen that with CTLA4 inhibition, which shows high rates of drug discontinuation and immune-related adverse events (AEs). In CITYSCAPE, there was a trend toward increased toxicity that, in my opinion, was not significant (serious AEs of any cause: 52.2% with dual therapy vs 41.2% with monotherapy; grade 3/4 immune‑mediated AEs: 19.4% vs 16.2%, respectively). The AE profile looked easy to tolerate and was essentially on par with what we’ve seen with other immunotherapy trials.

PD-L1 and Emerging Markers of Response to Immunotherapy

Jyoti D. Patel, MD:
I think our preference for binary results leads to some discomfort with PD‑L1 as a marker. We like mutations where, if you have it, the likelihood that you’ll respond is quite high, and if you don’t have it, there is no response. PD‑L1 is challenging, because despite the fact that some patients have high expression, approximately 50% of patients in clinic don’t respond. It’s very difficult to select patients for tiragolumab, which doesn’t target PD‑1 or PD-L1, based on a marker that has such problematic prognostication and predictive value.

In CITYSCAPE, as a phase II trial, the PD‑L1–high population was really selected for enhanced outcomes, and the results in this subset of patients are being pursued. An ongoing phase III trial, SKYSCRAPER-01 (NCT04294810), is specifically looking at patients with high PD‑L1 with tiragolumab plus atezolizumab as frontline therapy for NSCLC. That will give us more information, but one of the caveats that is difficult for me to reconcile is why the high PD-L1 population was underperforming with atezolizumab alone. So, although SKYSCRAPER-01 may help, I don’t think it drills down on host environment and tumor microenvironment to the degree that would allow us to predict best response and truly personalize therapies.

Ani Balmanoukian, MD:
Unfortunately, the excitement in recent years about using tumor mutational burden (TMB) as a marker didn’t work out, although I still look at TMB when I receive the next-generation sequencing results on newly diagnosed patients. There is a definite need for emerging markers of response to immunotherapy, especially in clinical practice, but nothing stands out yet for me. We are all waiting to see what the next best marker will be, and many of these trials are looking to see if selection of specific markers based on the pathways being targeted will be effective. 

Jyoti D. Patel, MD:
I agree that I end up paying attention to TMB even though it doesn’t directly influence my treatment recommendations. A higher TMB gives me greater comfort when deciding to take an immunotherapy-alone approach. Now that more providers are getting next-generation sequencing, we see mutations in STK11, for example, that may lead to some assumptions about expected responsiveness to immunotherapy. However, it’s going to take prospectively designed studies to tease out the multitude of influences for many of these therapies.

Ongoing Clinical Trials Targeting TIGIT

Jyoti D. Patel, MD:
There are several ongoing phase II and III trials with anti-TIGIT antibodies. In addition to tiragolumab, there is vibostolimab, which has shown efficacy in lung cancer and other solid tumors. However, it remains to be determined whether these are drugs that we add for a broad patient population or whether we really start selecting patients for this therapy.

SKYSCRAPER‑02 (NCT04256421) is a phase III trial looking at atezolizumab (plus carboplatin and etoposide) with or without tiragolumab in small-cell lung cancer. Immunotherapy is an important part of treatment, even for small-cell lung cancer. We all recognize that the benefits of immunotherapy are confined to a small number of patients; we just don’t know how to pick those patients yet. A recent press release on SKYSCRAPER-02 indicated that the combination of tiragolumab plus atezolizumab did not meet the coprimary endpoint of improved PFS in the overall patient population. We await presentation of the full results of this study. 

Ani Balmanoukian, MD:
Another trial I find interesting is the phase III SKYSCRAPER‑03 trial (NCT04513925), which is using tiragolumab plus atezolizumab vs durvalumab in the adjuvant setting in stage III NSCLC. 

The combination of tiragolumab and atezolizumab also is being used in the phase II SKYSCRAPER‑05 trial (NCT04832854) for locally advanced NSCLC. This trial in the neoadjuvant setting will look at 2 patient groups with different levels of PD-L1: high expression and all-comers. These trials both have an interesting design, and I’m very curious to see how the results turn out.

It’s exciting to see that TIGIT is being targeted in many different ways, but the landscape is still open to interpretation, and we will see where the data take us.

How Do You Choose the Best Combination Therapy?

Jyoti D. Patel, MD:
We have a relative abundance of drugs available for use right now in patients with advanced NSCLC, and there is a long way to go toward expanding these benefits to everyone. However, if you were meeting a patient—perhaps with high PD‑L1, prior smoker, low TMB—and if the phase III SKYSCRAPER-01 results are somewhat positive, how would you decide between pembrolizumab and the tiragolumab/atezolizumab combination therapy?

Ani Balmanoukian, MD:
I also would add ipilimumab/nivolumab to that mix, because I do use that combination, as well. I think eventually it’s going to come down to the overall response rate and the toxicity profile. On the one hand, it’s good to have options, but on the other hand, it’s going to be challenging to know exactly which treatment option is best for an individual patient when we don’t really have any marker other than PD‑L1 to direct us. In this situation, how would you gauge the patient and treatment selection?

Jyoti D. Patel, MD:
It’s going to be driven, as you said, by response and toxicity. The dosing of pembrolizumab every 6 weeks is very convenient for some patients who, after their diagnosis and completion of initial therapy, are excited to spend less time with us. It is possible we may eventually see alternative dosing schedules for antibodies targeting TIGIT, as well. Ultimately, I anticipate a lot of joint decision-making here to optimize outcomes while considering potential toxicity.

Ani Balmanoukian, MD:
We both have experience using drugs that target TIGIT. I have observed 1 case in stage IV melanoma where the patient received nivolumab upon disease recurrence and subsequently nivolumab and ipilimumab, with mixed response. After enrollment on a clinical trial with anti–PD‑1 and anti-TIGIT combination therapy, we have seen a nice response with very minimal AEs documented so far for this patient. We’re seeing these agents work in our patient population, including those with melanoma, and the data available so far with NSCLC seem promising, so we’ll see where else anti-TIGIT therapies are used in the future.

Jyoti D. Patel, MD:
Another emerging issue is how we’re seeing patients who recur soon after adjuvant therapy or after chemoradiation on durvalumab. This is a totally different patient population than de novo metastatic disease, so these anti‑TIGIT therapies might be especially helpful for these patients. It may be that there are immune signatures that can really be leveraged to guide decisions on best therapy options for patients.

Conclusion
Clearly, there remain unmet needs in lung cancer therapy, but we’re making our way with all of these new agents and gaining a better understanding of sequencing of treatments. Predictive biomarkers are certainly going to play a significant role, as well. In the meantime, we await the results of the phase III clinical trials on anti‑TIGIT therapies, and we will follow enrollment very closely, because there is lots of interest in our community about bringing new treatment options to our patients.

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