Tiragolumab-atezolizumab combination shows preliminary clinical activity in metastatic esophageal cancer
“The combination showed promising preliminary anti-tumor activity in patients with heavily pretreated esophageal cancer, who had not received immunotherapy, and durable responses were considered a consequence and based on much on this study. Tiragolumab in combination with aezolizumab is now [evaluated in] large phase 3 randomized trials.
In the phase 1b extension cohort, AEs occurred in all patients (n = 21), 67% of whom were grade 3 to 4 (n = 14). Serious AEs occurred in 71% of patients (n = 15), 8 patients had an AE which led to treatment discontinuation, and 1 patient had to discontinue treatment.
Treatment-related AEs (TRAs) occurred in 14 patients (67%), with 1 event being grade 3 (5%). In addition, immune-mediated AEIs (ADEIs) occurred in 12 patients (57%), 3 events being grade 3 (14%). No grade 4 or 5 RAE or IMAE was observed.
The most common AEs associated with the combination regimen, occurring in 10% or more of patients, were anemia (24%); decreased appetite, cough, increased aspartate aminotransferase, increased amylase (all 19%); as well as dysphagia, pyrexia, pruritus, rash, and increased alanine aminotransferase (all 14%). The most common ADEs 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 over 2 years of age.
“Responses included patients who had both adenocarcinoma and squamous cell histologies, with 1 patient having complete resolution of all target diseases which were squamous cells,” Wainberg said. “However, as you can see, we have listed previous treatment lines demonstrating that the majority of responders were seen in heavily pretreated patients, and their response rates were present regardless of PD-L1 status in some of the patients. patients who had very low PD-L1 expression less than 5%. Some of the best responses we see with this combination, but certainly patients who were also PD-L1 greater than 5%, as defined using the Ventana test, also had lasting responses. ”
The median progression-free survival (PFS) was 3.5 months (95% CI, 1.2-5.6), while the median duration of response was 15.3 months (95% CI, 7, 0 to not reached).
Twenty patients discontinued treatment, the majority being the result of disease progression (71%), Wainberg noted.
TIGIT, or T cell immunoreceptor with Ig and ITIM domains, is a new inhibitory immune checkpoint present on activated T cells and NK cells in several cancers. In addition, its expression correlates with PD-1, especially in tumor infiltrating T cells, Wainberg explained.
Tiragolumab is a fully human IgG1 / kappa monoclonal antibody that binds to TIGIT to prevent its interaction with its PVR ligand.
“Anti-TIGIT antibodies, such as tiragolumab, could restore the anti-tumor response and enhance the activity of anti-PD-L1 / PD-1 antibodies,” Wainberg said.
In the phase 1b portion of the study, tiragolumab in combination with aitzolizumab appeared to be tolerable, with clinical activity observed in an expanding cohort of patients with non-small cell PD-lung cancer. L1-positive (NSCLC; ORR, 46%).
Patients – who were recruited from 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 progression of disease, intolerable toxicity, or patient / investigator decision to withdraw. The recommended dose for phase 2 was 600 mg tiragolumab.
The CITYSCAPE phase 2 randomized trial (NCT03563716), designed to evaluate the combination as first-line treatment of patients with PD-L1 positive metastatic NSCLC, improved ORR (37% vs. 21%, respectively) and PFS (5.5 months [95% CI, 4.21-10.4] against 3.88 months [95% CI, 2.73-4.53]; HR laminate, 0.58; 95% CI: 0.38-0.89), compared to placebo plus atezolizumab.
“As seems natural, he seems inclined to test for anti-TIGIT antibodies, in tiragolumab in particular, in other malignant tumors where inhibition of PD-1 has been shown to be clinically validated,” Wainberg said. “This includes cancer of the esophagus, where the disease often occurs even after patients have received chemotherapy and targeted antibody immunotherapies. And in fact, TIGIT expression has been shown to be co-expressed with PD-1 in samples from esophageal cancer patients.
Therefore, the researchers conducted a phase 1b expansion cohort. To be eligible, patients had to have metastatic esophageal cancer that has progressed with available therapies, have an ECOG performance score of 0 or 1, and have not previously been treated with cancer immunotherapy.
As of the data cut-off date of April 8, 2021, 21 patients with metastatic esophageal cancer have been treated with tiragolumab plus atezolizumab. Patients had a median age of 62 years (range, 50-77). In addition, the majority were men (86%) and whites (43%). Overall, 76% had an ECOG performance score of 1, 38% of patients had 2 lines of prior therapy, 62% had squamous cell disease, and 24% had PD-L1 status.
The combined treatment regimen is now being evaluated in 2 ongoing randomized phase 3 studies: SKYSCRAPER-07 (NCT04543617) and SKYSCRAPER-08 (NCT04540211).
Wainberg Z, Matos I, Delord J, et al. Phase Ib study of anti-TIGIT tiragolumab in combination with aezolizumab in patients with metastatic esophageal cancer. Anne Oncol. 2021; 32: 3. doi: 10.1016 / j.annonc.2021.06.012