Adding Immunotherapy, Anti-TIGIT in First Line Boosts OS in Esophageal Cancer

SAN FRANCISCO — Adding the novel anti-TIGIT monoclonal antibody tiragolumab plus atezolizumab (Tecentriq) to standard first-line chemotherapy significantly improved survival for patients with advanced esophageal squamous cell carcinoma (ESCC), a phase III trial conducted in Asia showed.

Median overall survival (OS) reached 15.7 months with the combination plus chemotherapy compared with 11.1 months in those who received placebo plus chemotherapy (HR 0.70, 95% CI 0.55-0.88, P=0.0024), reported Chih-Hung Hsu, MD, PhD, of the National Taiwan University Hospital in Taipei City, during a presentation at the Gastrointestinal Cancers Symposium.

Progression-free survival (PFS) improved as well, at 6.2 months in the combination arm versus 5.4 months in the placebo arm (HR 0.56, 95% CI 0.45-0.70, P<0.0001).

Results from this double-blind trial, known as SKYSCRAPER-08, suggest that the combination “may represent an alternative first-line treatment option for patients with unresectable, locally advanced, or metastatic ESCC,” Hsu said.

Tiragolumab’s Contribution?

“You can’t argue that this study met its primary endpoint,” said discussant Michael K. Gibson, MD, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee. “I think I agree with ‘an alternative first-line treatment option,’ but I won’t call it the first-line treatment option.”

Gibson noted that since the study did not include an arm that tested tiragolumab plus chemotherapy, “we can’t isolate the effect of the TIGIT inhibitor on the benefit or toxicity of adding TIGIT to chemotherapy.”

Hsu acknowledged that the study did not address the “important question” of the individual contributions of the two checkpoint inhibitors to the anti-tumor efficacy demonstrated with the combination.

He explained that when SKYSCRAPER-08 was initiated in 2020, the standard of care for advanced ESCC was chemotherapy. “But as we know, the first-line standard of care for this disease has changed over past years,” he said. “Now our standard of care is anti-PD-1 plus chemotherapy. So our study does not answer the question of the contribution of the two checkpoint inhibitors.”

However, Hsu pointed to the phase Ib/II MORPHEUS-EC study (which he also co-authored) in which patients with esophageal cancer were randomized to three arms — chemotherapy, atezolizumab plus chemotherapy, and tiragolumab/atezolizumab plus chemotherapy — and showed an incremental increase in response rates and PFS with the checkpoint inhibitor combination.

“At least from the results of the MORPHEUS-EC study, we have the suggestion that both checkpoint inhibitors did contribute to the efficacy of the combination,” Hsu said. “This does need additional study, especially comparative studies to answer [the question].”

Study Details

Conducted in five countries across Asia, SKYSCRAPER-08 included 461 patients (median age 63 years, 87-89% men) with locally advanced, unresectable, or metastatic ESCC who were randomly assigned to receive cisplatin/paclitaxel plus tiragolumab 600 mg and atezolizumab 1,200 mg or placebo, each given intravenously every 3 weeks. Median follow-up was 14.5 months.

After a 6-cycle induction phase, patients received tiragolumab/atezolizumab or placebo every 3 weeks as maintenance therapy.

The objective response rate was 59.7% with the combination (11.5% complete responses) and 45.5% in the placebo arm (3.2% complete responses). Duration of response was 7.1 months and 4.3 months, respectively.

The 12-month OS rate was 60.6% in the combination arm and 46.1% in the placebo arm — a difference that was maintained at 18 months (47.2% vs 33.8%). The 12-month PFS rate was 24% with the combination and 6.1% with placebo.

Treatment-related adverse events (TRAEs) occurred in 98% of patients in both treatment arms, with most related to chemotherapy, while rates of grade 3 and 4 TRAEs were observed in 59.6% and 56.4% of the two arms, respectively.

Adverse events of special interest in the tiragolumab/atezolizumab arm included immune-mediated rash (38.6%), hepatitis (35.1%), hypothyroidism (17.5%), pneumonitis (7.5%), and hyperthyroidism (7%). Infusion-related reactions occurred in 17.5%, and there were three grade 5 adverse events of special interest.

Adverse events led to discontinuation of all treatments in 4.8% of patients in the tiragolumab/atezolizumab arm and 3.5% of patients in the placebo arm, and to discontinuation of tiragolumab/atezolizumab or placebo in 11.4% and 4.8% of patients, respectively.

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