Topline Summary and Update
iTeos Therapeutics (NASDAQ:ITOS) is an immunotherapy-focused biotech working on a molecule targeting TIGIT, an elusive checkpoint with a checkered past in cancer clinical research. In my last writeup of the company, I indicated growing optimism for the ITOS approach, particularly in lung cancer. I expected that we might see a data readout at this year’s ESMO meeting.
And here we are, ESMO 2024, and we have some more findings to chew on. Let’s revisit the ITOS story to see if there are legs to this idea that they can improve immunotherapy in some tough malignancies.
Pipeline Updates
Belrestotug
The most advanced product candidate being worked on by ITOS is belrestotug, an anti-TIGIT antibody that the company hopes will enhance antitumor immunity, particularly when paired with an anti-PD-1 antibody. For ITOS, that partner is dostarlimab, marketed as Jemperli by GSK (GSK).
Now, arguably the biggest news of the year for ITOS, and an item I covered in my last article, was the official initiation of a randomized, phase 3 trial called GALAXIES-Lung-301, which is comparing belrestotug versus placebo in combination with pembrolizumab (Merck’s Keytruda) in patients with advanced, PD-L1-high non-small cell lung cancer (NSCLC). In this case, the cutoff for “high” is tumor proportion score 50% or higher, the current minimum cutoff for giving patients pembrolizumab alone as a standard of care approach. For patients with lower PD-L1 scoring (and arguably, even for patients between 50% and 89%, according to some), pembrolizumab plus chemotherapy would be favored.
But coming out of ESMO 2024, ITOS presented findings giving a solid first look at this combination. GALAXIES Lung-02 enrolled patients with PD-L1-high, advanced NSCLC to receive pembrolizumab alone, dostarlimab alone, or one of multiple dosing regimens of dostarlimab plus belrestotug. The main objective of this study was to assess response rates of the different treatment approaches.
Results from substudy 1 included data from 124 patients across the 4 dostarlimab-containing arms. Dostarlimab alone led to a clinical response in 37.5% of patients (12/32), whereas the 3 arms combining dostarlimab and belrestotug had response rates ranging from 63.3% to 76.7%. The “confirmed” response rates were 28.1% and 59.4%-63.3%, respectively.
For reference, the KEYNOTE-042 trial, which first established pembrolizumab alone as the standard of care, demonstrated a response rate of 44.8% compared with 27.8% for chemotherapy in this setting, indicating that dostarlimab alone is generally consistent in terms of activity compared with pembrolizumab, and adding belrestotug appears to be adding onto that activity as well. There’s very little we can say about these comparisons, due to different trial populations, but the picture is an interesting one.
According to Dr. Spigel, who presented the findings, the phase 3 dose of belrestotug in GALAXIES Lung-301 is 400 mg, which had a 59.4% response rate in this study. Also, important was the toxicity, with a pretty large jump in the rate of treatment-related adverse events (59% vs 84% for dostarlimab and belrestotug 400 mg plus dostarlimab, respectively) and serious AEs. One patient of 32 in the 400 mg arm died from a treatment-related AE.
ITOS is also exploring the use of belrestotug in other disease settings, most notably in first-line head and neck squamous cell carcinoma.
Financial Overview
As of their most recent quarterly filing, ITOS held $251.1 million in cash and equivalents, with another $320.2 million in short-term investments.
The company recognized $35 million in collaboration revenue related to a milestone payment for initiating the phase 3 trial for belrestotug. Operating expenses reached $49.2 million. After consider other forms of income, the quarter’s net loss reached $7.1 million.
Considering the milestone payment was a one-off, the actual cash burn rate is closer to $42.1 million moving forward, which implies a cash runway for the company of between 14 and 15 quarters.
Strengths and Risks
Strength – Cash sufficient to reach critical milestones
With over 3 years of cash runway, ITOS currently is sitting on a cash pile that should get them all the way through the most important data readouts that they would need to pursue approval. This, in combination with their potential for collaboration revenue, paints a very positive picture for the company’s financials, provided they don’t hit any major roadblocks.
Strength – Strong indicators of clinical activity
The TIGIT story has been beset by failure over the past 3 years, with too many high-profile trial failures in the lung cancer space driving the market’s sentiment on these stocks quite low. The ESMO data that ITOS is presenting here gives an important signal that there’s really something to the TIGIT story in lung cancer, with rather convincing response rates, at least by my reckoning.
Risk – Response rates are a troubling surrogate, and safety is also concerning
That said, we need to be careful against over-interpreting GALAXIES Lung-02. Yes, it looks like response rates were improved, but the study is relatively small, and that apparent improvement in activity can evaporate as you add more patients.
More importantly, response rate is not really the endpoint that’s going to potentially drive this to an approval. Tiragolumab showed evidence that it was improving response rates in studies like SKYSCRAPER-02, but survival was not improved, and tiragolumab has languished ever since.
So looking forward from these data is a risky proposition, with a lot of potential built in. But these response rates could end up meaning nothing to the patients in the end.
Moreover, that increase in high-grade toxicities is something to keep a very close eye on. Any risk of death due to treatment-related AEs will give clinicians a lot of pause, and it could even scuttle an eventual approval application altogether, even if the treatment is effective.
Risk – Limited patient population
And even if it’s successful, this trial population of PD-L1 50% or higher is far from the majority of patients with advanced NSCLC. In KEYNOTE-042, 1653 patients had evaluable samples, and of these only 30.2% had a PD-L1 score meeting the criteria for enrollment.
It’s not small beans by any stretch, but it would definitely be going too far to imply that belrestotug is going to revolutionize all of the lung cancer management, and they still have a lot of proving to do in this PD-L1-high cohort and other treatment settings.
Bottom-Line Summary
ITOS has put forward a very important set of data at ESMO 2024. Clinical activity of add-on anti-TIGIT therapy looks about as convincing as you ever see from a phase 2 trial. While there are substantial risks to the thesis, when you consider that ITOS is trading at a market cap of around $600 million as I write this, there is a lot of upside potential if they can gain a strong foothold with their immunotherapy.
Yes, these are preliminary findings, and yes, there are some safety concerns. But this is yet another data point in recent studies indicating that you can improve on anti-PD-1 therapy for these patients, similar in principle to Summit’s recent success in NSCLC, and one clinical trial for Summit’s Chinese partner (my concerns notwithstanding) has sent their stock to above $20 billion in market cap.
For that reason, and given the advanced stage of their pipeline, I continue to consider ITOS a company worthy of further exploration as an investment thesis. The upside is very real despite the risks, and ESMO 2024 gives us a few signals that they really have something in their hands.
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