Tiragolumab-Atezolizumab Combo Shows Preliminary Clinical Activity in Metastatic Esophageal Cancer

The combination regimen was well tolerated with promising preliminary anti-tumor activity in patients with heavily pretreated esophageal cancer, who had not received immunotherapy.

The combination use of tiragolumab plus atezolizumab (Tecentriq) demonstrated preliminary antitumor activity with an acceptable safety profile in heavily pretreated patients with metastatic esophageal cancer who were not previously treated with immunotherapy, according to data from a phase 1b dose-escalation and -expansion study (GO30103; NCT02794571) presented at European Society of Medical Oncology World Congress on Gastrointestinal Cancer 2021.

“Tiragolumab plus atezolizumab is well tolerated in patients with metastatic esophageal cancer, with expected treatment related adverse events [AEs] including immune mediated events that were mainly rash and laboratory abnormalities,” Zev A. Wainberg, MD, professor of medicine at UCLA and co-director of the UCLA GI Oncology Program, said during a presentation at the virtual meeting.

“The combination showed promising preliminary anti-tumor activity in patients with heavily pretreated esophageal cancer, who had not received immunotherapy, and durable responses were seen as a consequence and based in large part on this study. Tiragolumab plus atezolizumab is now being [evaluated in] large randomized phase 3 trials.”

In the phase 1b expansion cohort, AEs occurred in all patients (n = 21), including 67% who were grade 3 to 4 (n = 14). Serious AEs occurred in 71% of patients (n = 15), 8 patients had an AE that led to treatment interruption and 1 patient had to discontinue treatment.

Treatment-related AEs (TRAEs) occurred in 14 patients (67%), with 1 event being grade 3 (5%). In addition, immune-mediated AEs (imAEs) occurred in 12 patients (57%), with 3 events being grade 3 (14%). No Grade 4 or 5 TRAEs or imAEs were observed.

The most common AEs associated with the combination regimen, occurring in 10% or more of patients, were anemia (24%); decreased appetite, cough, aspartate aminotransferase increase, amylase increase (all 19%); as well as dysphagia, pyrexia, pruritis, rash, and alanine aminotransferase increase (all 14%). The most common imAEs were rash (38%), hepatitis (24%), pancreatitis (19%), as well as diabetes, hyperthyroidism, hypophysitis, and hypothyroidism (all 5%).

Of 18 evaluable patients with at least one tumor assessment, the objective response rate (ORR) was 28%, which includes 5 partial responses. The disease control rate was 50%, with 1 patient still in the study at 2-plus years.

“The responses included patients who had both adenocarcinoma and squamous cell histologies, with 1 patient having a complete resolution of all target disease that was squamous cell,” Wainberg said. “However, as you can see, we listed the prior lines of therapy demonstrating the majority of the responders were seen in heavily pretreated patients, and their response rates were present regardless of PD-L1 status in some of the patients who had very low expression of PD-L1 under 5%. Some of the best responses we’re seeing with this combination, but certainly patients who were also PD-L1 greater than 5%, as defined using the Ventana assay, did have some durable responses as well.”

The median progression-free survival (PFS) was 3.5 months (95% CI, 1.2-5.6), whereas the median duration of response was 15.3 months (95% CI, 7.0 to not reached).

Twenty patients have discontinued treatment, with the majority being a result of disease progression (71%), Wainberg noted.

TIGIT, or T-cell Immunoreceptor with Ig and ITIM domains, is a novel inhibitory immune checkpoint present on activated T cells and NK cells in multiple cancers. Moreover, its expression is correlated with PD-1, especially in tumor-infiltrating T cells, Wainberg explained.

Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR.

“Anti-TIGIT antibodies, such as tiragolumab, could restore the anti-tumor response and may amplify the activity of anti–PD-L1/PD-1 antibodies,” Wainberg said.

In the phase 1b portion of the study, tiragolumab in combination with atezolizumab appeared to be tolerable, with clinical activity seen in an expansion cohort of patients with PD-L1-positive non–small cell lung cancer (NSCLC; ORR, 46%).

Patients – who were enrolled across the United States, Europe, and Asia – received tiragolumab 400 mg or 600 mg intravenously (IV) every 3 weeks plus atezolizumab 1200 mg IV every 3 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. The recommended phase 2 dose was tiragolumab 600 mg.

The randomized phase 2 CITYSCAPE trial (NCT03563716), designed to evaluate the combination as the frontline treatment of patients with metastatic, PD-L1-positive NSCLC, improved ORR (37% vs 21%, respectively) and PFS (5.5 months [95% CI, 4.21-10.4] vs 3.88 months [95% CI, 2.73-4.53]; stratified HR, 0.58; 95% CI, 0.38-0.89), compared with placebo plus atezolizumab.

“As it would seem natural, it seems inclined to investigate anti-TIGIT antibodies, in tiragolumab in particular, in other malignancies where PD-1 inhibition has been shown to be clinically validated,” Wainberg said. “This includes esophageal cancer, where the disease often occurs even after patients receive chemotherapy and targeted antibody immunotherapies. And in fact, TIGIT expression has been shown to be co-expressed with PD-1 in samples of esophageal cancer patients.”

Therefore, the researchers conducted a phase 1b expansion cohort. To be eligible, patients had to have metastatic esophageal cancer that had progressed on available therapies, had an ECOG performance score of 0 or 1, and had not been treated previously with cancer immunotherapy.

As of the data cut-off on April 8, 2021, 21 patients with metastatic esophageal cancer were treated with tiragolumab plus atezolizumab. Patients were a median age of 62 years (range, 50-77). In addition, the majority were male (86%) and White (43%). Overall, 76% had an ECOG performance score of 1, 38% of patients has 2 lines of prior therapies, 62% had squamous cell disease, and 24% had a PD-L1 status.

The combination regimen is now being evaluated further in 2 ongoing, randomized phase 3 studies: SKYSCRAPER-07 (NCT04543617) and SKYSCRAPER-08 (NCT04540211).

Reference:

Wainberg Z, Matos I, Delord J, et al. Phase Ib study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in patients with metastatic esophageal cancer. Ann Oncol. 2021;32:3. doi:10.1016/j.annonc.2021.06.012