ITOS - iTeos: Readouts From TIGIT And Adenosine Pathway Inhibitors Makes This A Must Watch

2024-01-10 08:01:12 ET

Summary

• Data readout from phase 2 GALAXIES Lung-201 study, using belrestotug in combination with dostarlimab to treat patients with 1st-line advanced/metastatic NSCLC, expected 2024.
• The global non-small cell lung cancer market is expected to reach $36.9 billion by 2031.
• Data readout from phase 2 TIGIT-006 study, using belrestotug in combination with dostarlimab for the treatment of patients with head and neck squamous cell carcinoma, expected 2024.
• The global head and neck cancer drugs market size is expected to surpass $3.9 billion by 2030.

iTeos Therapeutics (ITOS) is gearing up to report results from several of its programs in 2024. I believe that investors can benefit here, because there is potential with multiple shots on goal. Especially, with respect to the fact that there are two protein targets which have been validated to do well in targeting patients with cancers. Having said that, this company's pipeline is not solely only built around the targeting of TIGIT protein with Belrestotug [EOS-448] against advanced malignancies. It is also advancing a drug with a different mechanism of action, which is the targeting of the adenosine pathway, known as inupadenant [EOS-850].

The key question is why is it important to look into this biotech if it is targeting two well-known oncology targets, potentially with a lot of competition? That's because each of these drugs are being enhanced in some way to generate next-generation drugs to treat these patients with advanced solid tumor malignancies. In essence, to highly increase their potency against the targets of choice. Two data readouts in in 2024 dealing with the TIGIT pathway, will be from two phase 2 studies using belrestotug + dostarlimab [PD-L1] for the treatment of patients with non-small cell lung cancer [NSCLC] and head and neck squamous cell carcinoma [HNSCC]. With respect to the adenosine pathway, there are also two trial data readouts. These will be inupadenant for the treatment of patients with non-small cell lung cancer [NSCLC] and EOS-984 for advanced malignancies.

A Differentiated Anti-TIGIT Molecule To Possibly Lead The Way

As I stated above, there are two key catalysts for investors to look forward to. This would be the release of results from two phase 2 studies, which are being advanced with the use of the belrestotug + dostarlimab combination. This combination is being explored in studies targeting patients with non-small cell lung cancer [NSCLC] and head and neck squamous cell carcinoma [HNSCC]. Both of these trial readouts, from these mid-stage studies, are expected to be released in 2024. The first phase 2 study, known as GALAXIES Lung-201 using belrestotug in combination with dostarlimab to treat patients with 1st-line advanced/metastatic NSCLC. The global non-small cell lung cancer market is expected to reach $36.9 billion by 2031 . The thing is that this market opportunity might be reduced slightly, because even though it is targeting 1st-line patients, there are two considerations here. The first is that it is targeting advanced/metastatic NSCLC patients. It is said that about 30% to 40% of NSCLC patients present with the metastatic case . Then, you have to consider that the intended goal of this trial is to go after such NSCLC patients who are PD-L1 high. That is, patients who have a tumor proportion score [TPS] percentage of > or = to 50%. Then, there is an ability to branch out to another market, which has enormous potential. This would be with respect to the other phase 2 study, known as TIG-006 , which is using belrestotug in combination with dostarlimab to treat patients with 1st-line PD-L1 positive advanced or metastatic HNSCC. The global head and neck cancer drugs market size is expected to surpass $3.9 billion by 2030 . The goal with this particular study is to assess the belrestotug combination in 1st-line PD-L1 positive patients and those with advanced disease. In terms of PD-L1 positive HNSCC patients, this can be in a range. It is said that in prior studies the reported positivity of PD-L1 expression in such patients ranged from 29.5% to 87%. However, it highly depends upon what CPS score is given on what patients are being treated. What is this CPS score? Well it is a score given on the basis of on the number of PD-L1 staining cells, divided by the total number of viable tumor cells, multiplied by 100. The key here is that the phase 2 TIG-006 expansion study, is assessing belrestotug + dostarlimab for the treatment of 1st-line PD-L1 positive advanced metastatic patients in two different cohorts. They are as follows:

• 40 patients to be recruited have a CPS score of > or = to 20
• 40 patients to be recruited have a CPS score of 1 to 19

The ultimate data to come out of each cohort is going to be compared to historical data of such patients treated with KEYTRUDA [pembrolizumab].

Potential Competitors In The Anti-TIGIT Space

Even though there is great potential to advance belrestotug as an anti-TIGIT drug for the treatment of patients with non-small cell lung cancer [NSCLC], head and neck squamous cell carcinoma [HNSCC] and other advanced solid tumor types, there are potential competitors in the space it may have to deal with. Beigene (BGNE) and Novartis (NVS) are advancing anti-TIGIT ociperlimab, Merck (MRK) is advancing vibostolimab, Arcus Biosciences (RCUS) is advancing domvanalimab, Compugen (CGEN) is advancing COM902, Bristol Myers Squibb (BMY) is advancing BMS-986207, Seagen now part of Pfizer (PFE) advancing SEA-TGT, and Agenus (AGEN) is advancing AGEN307.

AstraZeneca and Bristol-Myers Squibb drugs are bi-specific and may have a limited number of isotopes and possible combinations to explore. Seagen's enhanced FC antibody-based design might mean T-reg depletion causing an increased safety risk in terms of Antibody-dependent cellular cytotoxicity [ADCC]. Arcus and Compugen's drugs lack ADCC and FC gamma receptors to help achieve optimal efficacy and good safety. Merck, Roche and Beigene might provide competition since their anti-TIGITS are optimized with both ADCC and FC gamma receptors. However, Roche with its drug fell into failures with its drug tiragolumab + atezolizumab [TECENTRIQ] when treating patients with 1st-line PD-L1 high, locally advanced or metastatic non-small cell lung cancer [NSCLC]. That is, this tiragolumab combination was not able to beat out TECENTRIQ alone in terms of overall survival, in the phase 3 SKYSCRAPER-01 trial . With this failure in mind, plus several competitors in place, how can iTeos Therapeutics overcome these challenges? It's all about the differentiation in molecule and combination factors.

First, with respect to the molecule it is designed in a different manner. In essence, it has been developed with a unique isotope compared to the other anti-TIGIT antibodies. It has also been developed with a fully human antibody with far better optimal binding, thus putting it in hopes of improving the targeting of TIGIT drugs. It has a unique epitope and binding of FC gamma receptor. The uniqueness of the epitope would be with respect to 7 key residues of TIGIT identified for binding. Thus, with an active FC point, it allows for ADCC and FC gamma receptor engagement, which means depletion of T regulatory cells and T-cell exhaustion in the tumor microenvironment [TME]. This is proven in that belrestotug is the only TIGIT in development to achieve a partial response [PR] as a monotherapy.

The second way to overcome competition would be in terms of better combination/better trial learnings. iTeos can take learnings from the prior failed studies from competitors and incorporate different measures. In addition, the ability to do well in combinations highly depends upon what type of PD-L1 partner is chosen. Roche had used its drug Tirogolumab with TECENTRIQ and didn't perform well. However, it is possible that belrestotug might end up doing better with dostarlimab from partner GlaxoSmithKline ( GSK ). That's because dostarlimab plus chemotherapy was shown to achieve a higher objective response rate [ORR] and showed a numerical improvement in overall-survival compared to KEYTRUDA and chemotherapy in the phase 2 PERLA trial. It remains to be seen if another PD-L1 drug provides a superior outcome, but you also have the addition of a unique epitope with belrestotug, which could potentially mean a superior efficacy outcome when both theories are combined.

Financials

According to the 10-Q SEC Filing , iTeos Therapeutics had cash and cash equivalents of $644.9 million as of September 30th of 2023. It believes that it has enough cash to fund its operations through 2026. This is plenty of cash to fund its pipeline and advance several of its clinical programs. Matter of fact, the cash on hand is going to be enough to initiate multiple phase 3 registrational studies to evaluate the use of the belrestotug + dostarlimab combination for the treatment of multiple types of solid tumor malignancies. Thus, there is plenty of cash on hand for the time being and I don't believe that there is any risk of near-term dilution. Should for whatever reason iTeos Therapeutics need to raise additional funds, it does have a financial instrument already in place. This would be with respect to a Sales Agreement made with Cowen, whereby from time to time it could offer and sell shares of its common stock with an aggregate offering price of $125 million. As of September 30th of 203, it had not sold any shares of common stock under this Sales Agreement.

Risks To Business

There are several risks that investors should be aware of before investing in iTeos Therapeutics. The first risk to consider would be with respect to the two data readouts as part of the anti-TIGIT program, which is using belrestotug for the treatment of patients with NSCLC and HNSCC. First, there is no assurance that the results to be readout will turn out to be positive, nor that the stock market will react appropriately to such clinical data. Secondly, there is the overhang of the past failures that Roche had gone through with its anti-TIGIT drug Tirogolumab for the treatment of patients with advanced malignancies. However, I believe that such a challenge is possible to overcome with the unique isotope iTeos has developed compared to its peers. Plus, the fact that GlaxoSmithKline's dostarlimab might prove to be more useful as a PD-L1 drug compared to TECENTRIQ. The second risk to then consider would be the competition in place.

This is a big risk, because should any other company find a way to establish superior safety or efficacy, then it would create a competitive advantage over iTeos' belrestotug. The third and final risk to consider would be with respect to the other drug in the pipeline, which is inupadenant as an adenosine pathway inhibitor. The goal is to use this drug as an A2A receptor antagonist for the treatment of patients with solid tumors. A good thing about this clinical candidate is that it can be utilized in multiple combinations. Having said that, Inupadenant is being explored as a monotherapy and in combination with KEYTRUDA and chemotherapy. There is no assurance that this drug will perform well against NSCLC or any other solid tumor type alone or in combination regimens.

Conclusion

iTeos Therapeutics has multiple clinical data readouts expected in 2024. These would be two with respect to the anti-TIGIT molecule belrestotug and then another two with respect to the adenosine pathway inhibitor drug Inupadenant. Despite Roche seeing trial failures in the targeting of TIGIT, I believe that there is still a possibility of a comeback. Again, this would be with respect to the advancement of a unique epitope antibody capable of better potency engagement with FC gamma receptor and possibly the combination with a superior PD-L1. This of course remains to be seen, but the fact is that there is a need to make a next generation TIGIT antibody drug that is capable of improving the lives of patients with non-small cell lung cancer [NSCLC] and other solid tumor types. Besides, the pipeline is de-risked a bit in that if the TIGIT molecule doesn't work out, then it is already in the process of advancing another established targeting pathway. This would be the targeting of the adenosine pathway. With a unique approach to targeting TIGIT, plus several catalysts on the way this year, I believe that investors might benefit with any potential gains made.

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