Frontline Belrestotug/Dostarlimab Boosts Responses Vs Dostarlimab Alone in PD-L1–High NSCLC

David R. Spigel, MD

The combination of belrestotug (formerly EOS 448) and dostarlimab-gxly (Jemperli) provided a clinically meaningful improvement in objective response rate (ORR) vs dostarlimab monotherapy in patients with previously untreated, unresectable, locally advanced or metastatic, PD-L1–high non–small cell lung cancer (NSCLC), according to data from the phase 2 GALAXIES-Lung 201 study (NCT05565378).¹

The late-breaking findings, which were presented during the 2024 ESMO Congress, showed that when the anti-TIGIT monoclonal antibody was given at doses of 100 mg (n = 30), 400 mg (n = 32), or 1000 mg (n = 30), and paired with dostarlimab, the regimen led to respective investigator-assessed ORRs of 63.3% (95% CI, 43.9%-80.1%), 65.6% (95% CI, 46.8%-81.4%), and 76.7% (95% CI, 57.7%-90.1%) all by RECIST v1.1 criteria; the ORR achieved with single-agent dostarlimab (n = 32) was 37.5% (95% CI, 21.1%-56.3%). The confirmed ORRs in the 100-mg, 400-mg, and 1000-mg cohorts were 60.0% (95% CI, 40.6%-77.3%), 59.4% (95% CI, 40.6%-76.3%), and 63.3% (95% CI, 43.9%-80.1%).

“GALAXIES-Lung 201 is the largest, prospectively designed, randomized, dose-ranging, phase 2 study in patients with newly diagnosed PD-L1–high NSCLC, looking at a combination of an anti-TIGIT and anti–PD-1 regimen,” David R. Spigel, MD, of the Sarah Cannon Research Institute, in Nashville, Tennessee, said in a presentation of the data. “A clinically meaningful improvement in ORR was seen in all combination cohorts compared with the dostarlimab monotherapy. This combination regimen had an increase in immune-related adverse effects [AEs], but these were largely considered generally manageable. Ongoing recruitment in the reported arms and additional follow-up will better characterize the efficacy and safety of this combination regimen.”

Patients with untreated locally advanced or metastatic NSCLC who have high PD-L1 expression defined as a tumor proportion score (TPS) of at least 50% are typically given single-agent immunotherapy but less than 50% will achieve a response, underscoring the need for additional options, according to Spigel.

“Belrestotug is a novel FCy-receptor TIGIT antibody. It has 2 key mechanisms of action: it modulates the CD226 pathway, and it decreases immunosuppressive regulatory T cells,” he noted. “Belrestotug has demonstrated higher potency relative to other anti-TIGIT monoclonal antibodies; [it also] leads to increases in proliferating CD8-positive T cells and a marked decrease in regulatory T cells in patients.”

In July 2023, dostarlimab plus carboplatin/paclitaxel, followed by single-agent dostarlimab, was approved by the FDA for use in select patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or has microsatellite instability;² in August 2024, the indication expanded to adult patients with primary advanced or recurrent endometrial cancer.³ Dostarlimab monotherapy is also indicated for patients with dMMR recurrent or advanced solid tumors who have progressed on or after prior treatment and who have no satisfactory alternative options.⁴

Spigel also noted that data from the phase 2 PERLA trial (NCT04581824) demonstrated that the combination of dostarlimab and chemotherapy showed comparable clinical activity to that achieved by standard-of-care pembrolizumab (Keytruda) plus chemotherapy, with ORRs of 45% (95% CI, 36.4%-54.8%) and 39% (95% CI, 30.6%-48.6%), respectively.⁵

“Antitumor activity with PD-(L)1 inhibitors may be further amplified through combination with novel anti-TIGIT inhibitory immune checkpoint agents, such as belrestotug,” Spigel said. To this end, the open-label, randomized platform study, GALAXIES Lung-201 was launched.¹

The trial enrolled patients with previously untreated, unresectable, locally advanced or metastatic NSCLC with high PD-L1 expression defined as a TPS of at least 50%; this was determined locally or centrally by DAKO 22C3 or VENTANA SP263 assay. Patients needed to be current or former smokers; they could not have actionable driver mutations. Those with asymptomatic and treated brain metastases were permitted.

Study participants were randomized to one of several arms, and randomization was stratified by histology, Spigel noted. Randomization included pembrolizumab given at 200 mg every 3 weeks; single-agent dostarlimab at 500 mg every 3 weeks; or one of three combination arms with belrestotug at the following dose levels: 100 mg, 400 mg, and 1000 mg. The three belrestotug cohorts represent substudy 1, and data from the interim analysis of that cohort was presented by Dr Spigel at the congress. The analysis comprises 124 patients and has a median follow-up of 7.3 months. The data cutoff date was June 7, 2024.

The primary end point was ORR by RECIST v1.1 criteria and investigator assessment, and key secondary end points included progression-free survival, overall survival, duration of response, safety, pharmacokinetics, and antidrug antibodies.

Regarding baseline demographics, “most of the patients were male, a minority of the patients were Asian, and all patients had good performance status,” Spigel said, adding that “these cohorts were relatively well balanced.” However, he noted that there were more patients with an ECOG performance status of 0 in the dostarlimab arm vs the belrestotug arms. “Recall, all patients had to have PD-L1 expression of greater than 50% that could be local or central, but there was central testing for at least 90% expression, and that was true in approximately 40% of patients across the cohorts,” he said.

Additional data showed that the belrestotug combinations were linked with a larger reduction in tumor size and a greater depth of response vs single-agent dostarlimab. “I think [the waterfall plots] help demonstrate the breadth and depth of those responses across these 4 cohorts,” Spigel noted. “…the spider plots also reflect the depth of that response with the combination.”

Investigators also found a trend of a numerically greater magnitude of decreased circulating tumor DNA (ctDNA) that was linked with belrestotug dosing. “ctDNA is emerging as a potential biomarker to measure molecular response—especially in lung cancer,” he said. “At the 100-mg [belrestotug] dose, the [ctDNA] decrease was 55%, but this was 94% and 97% in the 400- and 1000-mg cohorts, compared with a 65% reduction in the dostarlimab cohort.”

Regarding safety, treatment-emergent adverse effects (TEAEs) were experienced by 91% of those in the dostarlimab arm, and 97%, 97%, and 100% of those who received dostarlimab plus belrestotug at a dose of 100 mg, 400 mg, or 1000 mg, respectively; grade 3 or higher TEAEs occurred in 44%, 63%, 50%, and 53% of patients. Treatment-related adverse effects (TRAEs) occurred in 59%, 80%, 84%, and 97% of patients in the dostarlimab and dostarlimab/belrestotug 100-, 400-, and 1000-mg dosing cohorts; these effects were grade 3 or higher for 16%, 33%, 22%, and 43% of patients, respectively. Serious TRAEs were reported in 9% of those in the dostarlimab arm; these occurred in 33%, 25%, and 37% of patients in the belrestotug 100-, 400-, and 1000-mg cohorts.

TRAEs resulted in discontinuation for 23% of those in the belrestotug 100-mg cohort, 16% of those in the belrestotug 400-mg cohort, and 40% of those in the belrestotug 1000-mg cohort; 6% of those on the dostarlimab monotherapy arm experienced TRAEs that led to discontinued treatment. “The most common TEAEs leading to discontinuation were skin and subcutaneous tissue disorders [6%] and respiratory, thoracic, and mediastinal disorders [6%],” Spigel said. Fatal serious TRAEs included immune-mediated-lung disease (n = 1), immune-mediated hepatitis (n = 1), and immune-mediated myocarditis (n = 1).

“The combination regimen led to an increase in [treatment-related] immune-related adverse effects [TR-irAEs] compared to dostarlimab monotherapy” Spigel noted. These effects were experienced by 67%, 56%, and 73% of those in the belrestotug 100-, 400-, and 1000-mg cohorts vs 19% of those in the dostarlimab cohort; TR-irAEs that were grade 3 or higher were experienced by 30%, 16%, and 37% of patients in the respective belrestotug arms vs 13% of those in the dostarlimab arm.

“The most common TR-irAEs were skin and subcutaneous tissue disorders,” Spigel said. Grade 2 or higher TR-irAes with at least 10% or higher incidence in the dostarlimab, belrestotug 100-mg, belrestotug 400-mg, or belrestotug 1000-mg cohorts included immune-mediated dermatitis (0%, 17%, 0%, 20%), pruritus (0%; 10%; 16%; 13%), rash (0%; 7%; 13%; 7%), immune-mediated hypothyroidism (3%; 3%; 9%; 13%), increased alanine aminotransferase (0%; 10%; 0%; 3%); immune-mediated lung disease (0%; 3%; 3%; 10%) and immune-mediated myocarditis (0%; 3%; 0%; 10%) were most frequent in the dostarlimab/belrestotug 1000-mg cohort.

“The majority of grade 2 [or higher] TR-irAEs were skin and subcutaneous tissue disorders across all combination cohorts and were considered generally manageable with steroids,” according to the investigators. Moreover, adaptations to skin toxicity management are ongoing.

“Data support the ongoing GALAXIES Lung-301 study [NCT06472076] of belrestotug plus dostarlimab in patients with previously treated, unresectable locally advanced or metastatic PD-L1–high NSCLC,” Spigel concluded.

Disclosures: Spigel cited research funding from AbbVie, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus, Arrys Therapeuticss, Ascendis Pharma, Asher Biotherapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BuoNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Ellipses Pharma, EMD Serono, Endeavor, Erasca, Faeth Therapeutic, Foundation Bio, FujiFilm Pharmaceuticals, G1 Therapeutics, Gilead Sciences, GRAIL, GSK, Hutchinson MediPharma, Incyte, Ipsen, Janssen, Janux Therapeutics, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo Oncology, Lyell Immunopharma, MacroGeneics, MedImmune, Merck, Millennium Pharmaceuticals, Moderna, Molecular Template, Monte Rosa Therapeutics, Nektar, Novartis, Novocure, Oncologie, Peloton Therapeutics, Phanes Therapeutics, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Roche/Genetech, SeaGen, Shenzhen Chipscreen Biosciences, Strata Oncology, Stemline Therapeutics, Synthekine Taiho, Takeda Pharmaceuticals, Tango Therapeutics, Tarveda, Tizona Therapeutics, and Verastem, Zai Laboratory; and consulting roles with AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, GSK, Ipsen Biopharmaceuticals, Jazz Pharmaceuticals, Lyell, MedImmune, ModeX Therapeutics, Novartis, Novocure, Roche/Genentech, and Sanofi-Aventis.

References

1. Spigel DR, Korbenfeld E, Hayashi H, et al. Interim analysis of GALAXIES Lung-201: phase 2, randomized, open-label platform study of belrestotug plus dostarlimab in patients with previously untreated locally advanced/metastatic PD-L1 high (TPS ≥50%) non-small cell lung cancer. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA52.
2. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed September 14, 2024. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
3. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed September 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-endometrial-cancer-indication-dostarlimab-gxly-chemotherapy
4. GSK receives FDA accelerated approval for JEMPERLI (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors. News release. GlaxoSmithKline. August 17, 2021. Accessed September 14, 2024. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-fda-accelerated-approval-for-jemperli-dostarlimab-gxly-for-adult-patients-with-mismatch-repair-deficient-dmmr-recurrent-or-advanced-solid-tumours/
5. Lim SM, Peters S, Granados ALO, et al. Dostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial. Nat Commun. 2023;14(1):7301. doi:10.1038/s41467-023-42900-4