After announcing a phase 3 launch based on positive midstage results, iTeos Therapeutics and GSK are finally sharing the highlights from the phase 2 TIGIT trial, revealing a more than 30% difference in confirmed overall response rates between the investigational treatment versus monotherapy.
The interim data cut assesses belrestotug, an anti-TIGIT antibody, plus dostarlimab, GSK’s anti-PD-1 treatment sold under the name Jemperli. Findings were shared in a late-breaking abstract Sept. 14 at this year’s European Society for Medical Oncology conference in Barcelona.
The midstage trial, dubbed GALAXIES Lung-201, evaluated the combo among patients with previously untreated, unresectable, locally advanced or metastatic PD-L1-high non-small cell lung cancer (NSCLC).
At the June 7 data cutoff, 124 patients were eligible for evaluation. Patients were split into four cohorts. One group of patients didn't receive any TIGIT treatment, while groups A, B and C received belrestotug at 100 mg, 400 mg and 1,000 mg, respectively. All patients received dostarlimab at 500 mg.
Clinically meaningful improvement in the overall response rate (ORR)—the trial’s primary endpoint—was seen across each TIGIT cohort, with a 63.3% ORR reported for group A, a 65.6% ORR seen for arm B and 76.7% for dose C. This compares with the 37.5% ORR observed for dostarlimab alone. The median follow-up time varied by arm, with dostarlimab at seven months, group A and B both at 8.5 months and dose C at 6.7 months.
The confirmed ORR (cORR), defined as a complete or partial response confirmed by repeat imaging at four or more weeks after the response criteria were first met, was about 60% for each dose. This is compared to a 28.1% cORR for dostarlimab as a monotherapy.
The ORR and meaningful difference of 30% compared to dostarlimab by itself separates the TIGIT/PD-1 doublet from others, iTeos President and CEO Michel Detheux, Ph.D., said in a Sept. 14 release.
“The improvement in depth of response in tumor measurement in patients treated with the doublet compared to those treated with PD-1 alone holds promising therapeutic potential for a patient population with limited options,” Detheux said. “Based on these results, we are committed to leveraging our science to impact the lives of people living with cancer and are excited to see progression free survival data in 2025.”
As for safety, the investigational combo was tied to “a higher incidence of manageable immune-related adverse events,” compared to dostarlimab alone, according to the release. The most frequent treatment-related adverse events reported were skin and subcutaneous tissue disorders.
The combo’s safety profile has been “broadly consistent” with the known profile of combination therapy with checkpoint inhibitors, according to iTeos.
On a Monday morning call, iTeos revealed that patients receiving the combo with belrestotug doses of 100 mg and 400 mg had a 19% rate of discontinuation of both study drugs, which was 13 percentage points higher than in the arm studying dostarlimab by itself, according to an analysis by Leerink Partners. The rate is also almost double the discontinuation rates reported for Roche's TIGIT/PD-L1 combo of tiragolumab and Tecentriq in the same setting, Leerink Partners said.
To cut down on unnecessary discontinuations, management said they have changed the protocol for investigators. The study lacked necessary labs to screen for and intervene early to prevent immune-related myocarditis, information that Leerink Partners views as "a double-edged sword"—such oversights are concerning, but also can be fixed to reduce discontinuations.
Investors were less than impressed, with iTeo's stock falling 27% since market open this morning. Leerink believes investors are "overly emphasizing the toxicity signal and dose selection uncertainty and underappreciated the strong efficacy signal" from the trial, writing that they are confident iTeos and GSK can reduce discontinuations in future studies.
Previously, immune-mediated adverse events were cited by Merck & Co. in two failed trials for the company's TIGIT/PD-1 fixed combo of vibostolimab and Keytruda in melanoma and extensive-stage small cell lung cancer.
In May, GSK and iTeos announced that a positive interim analysis had bolstered confidence, prompting the companies to launch a phase 3 study called GALAXIES Lung-301 in the same setting. The companies didn’t reveal any data at the time, just noting that the investigational combo met the predefined criteria for meaningful clinical activity and tumor reductions.
Dosing for GALAXIES Lung-301 started in July, with the trial expected to enroll around 1,000 patients. The study is testing the belrestotug-Jemperli combo against a placebo-Keytruda arm and has a primary completion date slated for 2028, according to ClinicalTrials.gov. The partners will be studying 400 mg of belrestotug in the phase 3 trial.
Analyst group William Blair previously said it would be interested in comparing the findings to those from Roche’s phase 2 CITYSCAPE study in NSCLC. That study saw success combining tiragolumab with Tecentriq, with an objective response in 31.3% of patients versus 16.2% with Tecentriq plus placebo.
However, Roche’s tiragolumab has hit trouble in late-stage trials, failing to hit the primary endpoint in a phase 3 SCLC study dubbed SKYSCRAPER-02. More recently, the Swiss pharma halted the SKYSCRAPER-06 study evaluating the combo plus chemotherapy in front-line nonsquamous NSCLC after the pair was beat by Keytruda and chemotherapy.
Roche still has ongoing tiragolumab-Tecentriq studies—and even pocketed a win for the TIGIT in a phase 3 SKYSCRAPER-08 esophageal study—though the use of an outdated control therapy have left doubts about clinical significance.
However, the earlier flops shook TIGIT players, with GSK and iTeos assessing “how best to proceed with additional clinical development” of their rival asset after a phase 3 Roche flop in 2022.
GSK paid iTeos $625 million upfront for the right to co-develop and co-commercialize belrestotug in 2021, tacking on up to $1.45 billion in milestones. While Roche’s setbacks may have led to some soul-searching, it doesn’t appear to have had too big of an impact—belrestotug is currently being studied in six separate clinical trials.
Editor's note: This story was updated at 4 p.m. ET on Sept. 16 to include analyst commentary.