Chih-Hung Hsu, MD, PhD

Frontline treatment with tiragolumab plus atezolizumab (Tecentriq) and chemotherapy led to statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in patients with esophageal squamous cell carcinoma (ESCC), according to findings from the phase 3 SKYSCRAPER-08 trial (NCT04540211) presented during the 2024 Gastrointestinal Cancers Symposium.

At the February 13, 2023, data cutoff, results from the final OS analysis of the trial demonstrated that patients who received tiragolumab plus atezolizumab, cisplatin, and paclitaxel (n = 229) achieved a median OS of 15.7 months (95% CI, 13.3-20.4) compared with 11.1 months (95% CI, 9.6-13.6) among patients who received placebo plus cisplatin and paclitaxel (n = 232; HR, 0.70; 95% CI, 0.55-0.88; P = .0024). The 12-month OS rates were 60.6% vs 46.1%, respectively, and the 18-month OS rates were 47.2% vs 33.8%, respectively.

Additionally, at the June 15, 2022, data cutoff for PFS, patients in the tiragolumab plus atezolizumab arm experienced a median PFS of 6.2 months (95% CI, 5.7-7.2) compared with 5.4 months (95% CI, 4.4-5.5) in the chemotherapy alone arm (HR, 0.56; 95% CI, 0.45-0.70; P < .0001). The 12-month PFS rates were 24.0% vs 6.1%, respectively.

Tiragolumab is a humanized monoclonal antibody directed against TGIT. TGIT is a coinhibitory receptor and immune checkpoint that is expressed on activated T, natural killer, and regulatory T cells that is implicated in multiple cancer types, including esophageal carcinoma.

“Recently, the combination of anti–PD-1 immunotherapy plus chemotherapy has emerged as a new first-line standard therapy [for patients with ESCC], yet treatments with higher efficacy are still needed,” Chih-Hung Hsu, MD, PhD, of the National Taiwan University Hospital, said during the presentation. “In [data from] previous studies, tiragolumab when combined with other immunotherapies, such as [the] anti–PD-L1 [therapy] atezolizumab, has been shown to augment antitumor responses.”

Enrollment Criteria and Baseline Patient Characteristics

SKYSCRAPER-08 was a double-blind, multicenter study that enrolled patients with histologically confirmed, locally advanced unresectable or metastatic ESCC. Patients who had an ECOG performance status of 0 or 1 and had not received prior systemic therapy were enrolled across 67 centers in China, Hong Kong, Taiwan, South Korea, and Thailand. Investigators stratified patients by ECOG performance status (0 vs 1), previous curative treatment (yes vs no), and PD-L1 status (low [tumor area positivity (TAP) < 10%] vs high [TAP ≥ 10%]).

Patients were randomly assigned 1:1 to receive intravenous (IV) tiragolumab, atezolizumab, cisplatin, and paclitaxel, or IV placebo with cisplatin and paclitaxel. During the induction phase (cycles 1-6), patients received tiragolumab 600 mg, atezolizumab 1200 mg, and cisplatin plus paclitaxel, every 3 weeks; during the maintenance phase (cycles ≥ 7), patients received tiragolumab 600 mg and atezolizumab 1200 mg every 3 weeks. During the induction phase in the control arm, patients received placebo in place of tiragolumab and atezolizumab and chemotherapy at the same dosing schedule as the investigational arm; during the maintenance phase, patients received IV placebo every 3 weeks. Treatment in both arms continued until loss of clinical benefit or unacceptable toxicity.

The primary end points were OS and PFS by independent review per RECIST 1.1 criteria. Secondary end points included objective response rate (ORR) and duration of response (DOR) by independent review, as well as safety.

The baseline patient characteristics were well balanced between the 2 arms; the median age in the tiragolumab plus atezolizumab arm was 63 years (range, 40-81) vs 63 years (range, 42-84) in the placebo arm. Most patients in both arms were less than 65 years of age (57.2% vs 55.6%, respectively), male (87.3% vs 88.8%), had an ECOG performance status of 1 (75.1% vs 74.1%), had not received previous curative treatment (64.2% vs 63.8%), had a PD-L1 TAP score of at least 1% (88.2% vs 89.2%), and had 1 or 0 organs with metastases (53.7% vs 52.6%). All patients in both arms were Asian. Further, 23.1% of patients in the tiragolumab plus atezolizumab arm had metastatic liver disease vs 20.3% in the placebo arm.

Key Secondary End Points and Subgroup Analyses

Additional findings from SKYSCRAPER-08 showed that the ORR among response-evaluable patients in the investigational arm (n = 226) was 59.7%, with a complete response (CR) rate of 11.5%. In the placebo arm (n = 222), the ORR was 45.5% including a CR rate of 3.2%. The median DOR was 7.1 months (95% CI, 6.3-9.5) compared with 4.3 months (95% CI, 4.1-5.5), respectively. At the data cutoff, 47.4% and 23.8% of patients had an ongoing response in the investigational and control arms, respectively. Additionally, 19.0% of patients in the investigational arm achieved stable disease compared with 26.1% in the placebo arm; progressive disease rates were 9.3% vs 19.8%, respectively.

Data from subgroup analyses revealed that the OS benefit observed with tiragolumab plus atezolizumab over placebo was present across nearly all subgroups. Patients who were female (HR, 0.56; 95% CI, 0.28-1.11), had an ECOG performance status of 1 (HR, 0.61; 95% CI, 0.47-0.80), and who had not received previous curative treatment (HR, 0.65; 95% CI, 0.49-0.87) derived the most benefit.

In the PFS subgroup analysis, all examined subgroups experienced a benefit with tiragolumab plus atezolizumab compared with placebo. Investigators observed the greatest benefit among patients who were female (HR, 0.36; 95% CI, 0.20-0.67), had not received previous curative treatment (HR, 0.49; 95% CI, 0.37-0.64), and had a baseline PD-L1 TAP score of at least 10% (HR, 0.50; 95% CI, 0.35-0.70).

Examining Safety Data

In terms of safety, any-grade adverse effects (AEs) occurred at rates of 98.7% vs 99.6% in the tiragolumab plus atezolizumab (n = 228) and placebo (n = 227) arms, respectively, with 98.2% being treatment-related AEs in both arms. Patients in both arms experienced grade 3 to 4 AEs (68.0% vs 61.2%, respectively), grade 5 AEs (5.7% vs 4.8%), serious AEs (41.2% vs 39.2%), AEs leading to treatment discontinuation (19.7% vs 10.6%), and AEs leading to dose modification or interruption (64.0% vs 56.4%). The grade 5 treatment-related AEs in the investigative arm were immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal hemorrhage, hepatic failure, and bacterial pneumonia occurring in 1 patient; in the placebo arm gastrointestinal infection and death were cited as the 2 grade 5 AEs that occurred.

Any-grade AEs of special interest occurred at rates of 75.9% vs 49.8% in the investigational and placebo arms, respectively. AEs of special interest of any grade included infusion-related reaction (17.5% vs 7.9%, respectively) and the following immune-mediated effects: rash (38.6% vs 9.7%), hepatitis (35.1% vs 30.0%), hypothyroidism (17.5% vs 11.5%), pneumonitis (7.5% vs 3.5), and hyperthyroidism (7% vs 1.3%).

At the data cutoff, 32 patients were still undergoing treatment in the investigational arm and 196 had discontinued due to disease progression (n = 112), withdrawal (n = 28), AEs (n = 27), death (n = 14), physician decision (n = 12), symptomatic deterioration (n = 1), protocol deviation (n = 1), and being lost to follow-up (n = 1). In the placebo arm, 10 patients were ongoing treatment and 217 had discontinued due to disease progression (n = 149), withdrawal (n = 25), AEs (n = 11), death (n = 11), physician decision (n = 17), symptomatic deterioration (n = 3), and protocol deviation (n = 1).

“The overall safety profile of this combination has been consistent with previous observations and there were no new safety signals,” Hsu said in conclusion. “These data support that this combination may represent an alternative first-line treatment option for patients with unresectable, locally advanced and metastatic ESCC.”

Editor’s Note: Dr Hsu cites receiving honoraria from Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Ono Pharmaceutical, and Roche; research funding from AstraZeneca, BeiGene, Bristol Myers Squibb, Eucure Biopharma, Johnson & Johnson, Merck Serono, MSD, NGM Biopharmaceuticals, NuCana, Ono Pharmaceutical, Roche/Genentech, Surface Oncology, and Taiho Pharmaceutical; and travel, accommodations, and expenses from Daiichi Sankyo. He also has a consulting or advisory role with AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Merck Serono, MSD, Ono Pharmaceutical, and Roche/Genentech.

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). J Clin Oncol. 2024;42(suppl 3):245. doi:10.1200/JCO.2024.42.3_suppl.245