First-Line Tiragolumab With Atezolizumab Plus Chemo Improves PFS, OS in Patients With ESCC

Patients with esophageal squamous cell carcinoma (ESCC) saw improved progression-free (PFS) and overall survival (OS) after being treated initially with both PD-1 and TIGIT immunotherapy alongside chemotherapy, compared with chemotherapy alone, according to new findings.

Results for SKYSCRAPER-08 (NCT04540211), were released today ahead of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI). The trial is the first phase 3 study to explore the efficacy and safety of anti-TIGIT tiragolumab in combination with PD-1 inhibitor atezolizumab (Tecentriq) plus chemotherapy vs. chemotherapy alone in patients with advanced esophageal squamous cell carcinoma in the first-line setting. Genentech makes both immunotherapies.

Pamela Kunz, MD | Image: Yale School of Medicine

Pamela Kunz, MD, a medical oncologist specializing in gastrointestinal cancers at Yale School of Medicine, commented, “Esophageal squamous cell carcinoma accounts for most esophageal cancer cases worldwide. This phase 3 trial demonstrates that dual immunotherapy plus chemotherapy with the novel checkpoint inhibitor, tiragolumab, improves progression-free and overall survival without compromising safety.”

ESCC accounts for 80% of cases of esophageal cancer, which ASCO officials said is the 8th most common type of cancer worldwide. Patients such as those in SKYSCRAPER 08, who have locally advanced unresectable or metastatic ESCC typically have very poor outcomes, with 5-year survival rates reported as low as 5%, officials said.

The trial involving 461 patients evaluated efficacy and safety of adding the T-cell immunoglobulin and ITM domain (TIGIT) inhibitor tiragolumab to atezolizumab in combination with paclitaxel or cisplatin chemotherapy, compared with placebo plus chemotherapy as first-line treatment in patients with unresectable locally advanced, unresectable recurrent, or metastatic esophageal squamous cell carcinoma. The primary endpoints were independent review facility-assessed (IRF) PFS and OS.

Results. For this study,229 patients were randomized to receive the immunotherapy combination plus chemotherapy and 232 patients were randomized to receive the placebo plus chemotherapy. Results were as follows:

• After a minimum follow-up of 6.5 months, results the median IRF PFS was 6.2 months in patients who received tiragolumab and atezolizumab plus chemotherapy, compared with 5.4 months in patients who received the placebo plus chemotherapy (HR 0.56; 95% CI, 0.45-0.70; P < .0001).
• After a minimum follow-up of 14.5 months, the median IRF OS was 15.7 months in patients receiving the investigational combination vs 11.1 months in those receiving placebo plus chemotherapy (HR, 0.70; 95% CI, 0.55-0.88; P = .0024).
• Treatment-related adverse events (TRAEs) were seen in 98.2% of patients in both arms; most were related to chemotherapy. AEs of note for the investigational combination arm were immune-related rash (38.6%), immune-mediated hepatitis (35.1%), immune-mediated hypothyroidism (17.5%), infusion-related reaction (17.5%), and immune-related pneumonitis (7.5%). Investigators reported that most AEs of special interest were grade 1 or grade 2 and easily manageable.
• Grade 3/4 TRAEs in were seen in 59.6% of patients receiving the investigational combination and 56.4% of patients taking placebo plus chemotherapy. In the investigational arm, 2.6% of patients died, compared with 0.9% in the placebo plus chemotherapy arm.

There had been speculation whether tiragolumab had achieved its OS end point in SKYSCRAPER 08, following an investor call in April 2023. TIGIT-targeting therapies had not met end points in other trials, including a study involving patients with extensive stage small cell lung cancer.

However, phase 1a/1b results published in JAMA Oncology in September 2023 showed an overall response rate of 28% among 18 patients with esophageal cancer, both squamous and adenocarcinoma, who were treated with tiragolumab and atezolizumab. Authors of that study noted that preclinical models had shown that combined effect of the 2 separate mechanisms would work better than either alone. Inhibiting TIGIT, they wrote, “might potentiate the antitumor immune response of PD-L1 inhibitor atezolizumab in patients with PD-L1–selected tumors and enhance the clinical benefit associated with immune checkpoint blockade.”

SKYSCRAPER 08 focused on Asian patients, as this group has higher than normal rates of esophageal cancer, the study’s lead author said in a statement from ASCO. Patients were enrolled in 67 centers in mainland China, South Korea, Thailand, Taiwan, and Hong Kong. About half the patients with ESCC live in China, ASCO leaders said in a statement.

“Esophageal squamous cell carcinoma has a significant impact on patients’ functioning and quality of life, including symptoms such as trouble sleeping, weight loss, anxiety and depression, pain, and difficulty swallowing,” Chih-Hung Hsu, MD, PhD, from the National Taiwan University said. “Given the demographics of patients with esophageal cancer, the study was intended to focus on the Asian population.”

Reference

Hsu CH, Lu Z, Gao S, et al. SKYSCRAPER-08: A phase III, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (tira) + atezolizumab (atezo) and chemotherapy (CT) in patients (pts) with esophageal squamous cell carcinoma (ESCC). Presented at: ASCO Gastrointestinal Cancers Symposium (ASCO GI), January 18-20, 2024; San Francisco CA. Abstract 245. doi: 10.1200/JCO.2024.42.3_suppl.245