SKYSCRAPER-08 hits mark in ESCC with TIGIT, PD-L1 blockade + doublet chemo

In Asian patients with esophageal squamous cell carcinoma (ESCC), adding the TIGIT inhibitor tiragolumab and PD-L1 inhibitor atezolizumab to chemotherapy improved all outcomes in the phase III SKYSCRAPER-08 trial.

“The study met both primary endpoints … demonstrating statistically significant and clinically meaningful improvements in IRF*-assessed progression-free survival (PFS) and overall survival (OS),” said Dr Chih-Hung Hsu from the National Taiwan University Hospital, Taipei, Taiwan, at ASGO GI 2024. “Combining tiragolumab + atezolizumab with chemo also [improved] objective response rate (ORR) and duration of response (DoR) compared with chemotherapy only.”

Coprimary endpoints: OS, IRF-assessed PFS

After a minimum follow-up of 14.5 months (final OS analysis), there was a significant improvement in OS with the experimental vs the control regimen of placebo + chemo (median 15.7 vs 11.1 months; stratified hazard ratio [HR], 0.70; p=0.0024). [ASCO GI 2024, abstract 245]

OS rates were higher with the experimental vs control regimen at 12 months (60.6 percent vs 46.1 percent) and 18 months (47.2 percent vs 33.8 percent).

The investigational regimen also trumped the control regimen in terms of IRF-assessed PFS (median 6.2 vs 5.4 months; stratified HR, 0.56; p<0.0001) after a minimum follow-up of 6.5 months (primary PFS analysis). The 12-month PFS rate was fourfold higher with the former vs the latter (24.0 percent vs 6.1 percent).

“The OS [and PFS benefits with the experimental regimen] were seen in almost all prespecified subgroups [and] regardless of PD-L1 expression level,” said Hsu.

Key secondary endpoints, safety

With the investigational regimen, ORR was nearly 60 percent (11.5 percent complete response [CR]), almost half had an ongoing response, and median DoR was 7.1 months. In the placebo arm, the corresponding rates were 45.5 percent (3.2 percent CR), 23.8 percent, and 4.3 months.

The incidence of grade 3/4 adverse events (AEs) was slightly higher in the experimental vs control arm (68.0 percent vs 61.2 percent), as were the rates of AEs leading to treatment discontinuation (19.7 percent vs 10.6 percent) and dose modification/interruption (64.0 percent vs 56.4 percent) as well as all-grade AEs of special interest (AESI; 75.9 percent vs 49.8 percent).

The most common grade 3/4 AESI in the experimental arm were immune-mediated hepatitis and laboratory abnormalities (3.5 percent each) and immune-mediated rash and infusion-related reaction (3.1 percent each). “Most AEs were low-grade in nature and were easily manageable,” Hsu said.

“The overall safety profile of [the investigational regimen] was consistent with previous observations of combined tiragolumab-atezolizumab treatment and the known safety profile risks associated with individuals chemotherapies,” he added.

Other therapeutic regimens warranted

“Patients with ESCC when presented with metastasis or unresectable locally advanced disease have a very poor prognosis,” said Hsu. Immunotherapy combinations + chemo have emerged recently as standard of care for first-line (1L) treatment of ESCC. However, survival benefit remains modest. “Additional treatment strategies are thus needed to help improve patient outcomes,” he continued.

TIGIT, a novel checkpoint inhibitor, is implicated in several cancers, including ESCC. [Cancers  (Basel) 2022;14:4896; ESMO Open 2023;8:101184] “Inhibition of TIGIT … may further amplify immune responses by complementing the PD-L1/PD-1 pathway,” Hsu said.

The team sought to evaluate the combination of tiragolumab and atezolizumab on top of chemo in this patient setting. The analysis included 461 individuals (median age 63 years, 88 percent men) from 67 centres across Asia** with histologically confirmed locally advanced unresectable or metastatic ESCC who have not received prior systemic therapy.

Participants were randomized 1:1 to receive IV tiragolumab 600 mg + atezolizumab 1,200 mg + chemo (paclitaxel 175 mg/m² + cisplatin 60–80 mg/m²) or placebo + chemo on day 1 of each 21-day cycle (cycles 1–6). They were to continue their respective regimens (without chemo) during the maintenance phase (cycles ≥7) until unacceptable toxicity or loss of clinical benefit.

The study however did not shed light on how each of the two checkpoint inhibitors contributed to the antitumour efficacy of the combination regimen, Hsu noted.

“Nonetheless, taken together, these data [suggest] that this combination may represent an alternative 1L treatment option to standard anti-PD-1/PD-L1 and chemo treatment for patients with locally advanced, unresectable, or metastatic ESCC,” Hsu concluded.