For patients with treatment-naive, locally advanced or metastatic esophageal squamous cell carcinoma, the addition of two checkpoint inhibitors to chemotherapy significantly improved not only progression-free survival but also overall survival, in the randomized, phase III SKYSCRAPER-08 trial presented at the 2024 ASCO Gastrointestinal Cancers Symposium.1 The trial involving 461 patients met both primary endpoints, with mortality risk reduced by 30% and risk of disease progression or death reduced by 44%.
SKYSCRAPER-08 evaluated the benefit of adding the novel T-cell immunoglobulin and ITIM domain (TIGIT) inhibitor tiragolumab and the PD-L1 blocker atezolizumab to cisplatin plus paclitaxel as initial treatment of locally advanced, unresectable or metastatic esophageal squamous cell carcinoma. TIGIT is an inhibitory receptor expressed on lymphocytes that has emerged as a target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumor cells to downregulate T-cell and natural killer cell functions, thus impeding antitumor responses.
“This immunotherapy plus chemotherapy combination is highly active…. Combining tiragolumab and atezolizumab with chemotherapy resulted in statistically significant and clinically meaningful improvements in overall survival, and independent review assessment of progression-free survival, objective response rate, and duration of response as compared with chemotherapy…. This combination may represent an alternative first-line treatment option for patients with locally advanced or metastatic esophageal squamous cell carcinoma,” said Chih-Hung Hsu, MD, PhD, of the National Taiwan University Hospital.
Chih-Hung Hsu, MD, PhD
This double-blind, randomized, multicenter trial enrolled 461 patients with previously untreated, locally advanced, unresectable or metastatic esophageal squamous cell carcinoma from 67 centers in Asia. Patients were randomly assigned to receive cisplatin/paclitaxel plus either tiragolumab at 600 mg and atezolizumab at 1,200 mg or placebo, each given intravenously every 3 weeks. After a six-cycle induction phase, patients received tiragolumab and atezolizumab or placebo every 3 weeks as maintenance therapy.
Key Findings and Safety
After a minimum follow-up of 14.5 months, median overall survival improved from 11.1 months with placebo and chemotherapy to 15.7 months with tiragolumab and atezolizumab plus chemotherapy (hazard ratio [HR] = 0.70; P = .0024), and median progression-free survival improved from 5.4 months to 6.2 months, respectively (HR = 0.56; P < .0001). “The overall survival benefit was well maintained at 12 months and 18 months, with approximately a 15% increase in favor of the experimental arm…. The progression-free survival benefit was also reflected in the significantly improved 1-year progression-free survival rate, which increased from 6% to 24%.... Of note, the benefit was seen regardless of PD-L1 status,” he said.
By independent central review, the objective response rates were 59.7% (11.5% complete responses) with tiragolumab and atezolizumab plus chemotherapy and 45.5% (3.2% complete responses) with chemotherapy alone. The median duration of response was 7.1 months and 4.3 months, respectively, and at the time of the analysis, 47.4% vs 23.8%, respectively, had an ongoing response, Dr. Hsu reported.
“The overall safety profile of tiragolumab plus atezolizumab and chemotherapy was consistent with previous observations of this treatment and the known safety risks associated with individual chemotherapies,” he stated. The rate of grade 3 or 4 treatment-related adverse events was 59.6% with tiragolumab and atezolizumab plus chemotherapy vs 56.4% with placebo plus chemotherapy. Toxicities led to discontinuation of all treatments in 4.8% and 3.5% of patients, respectively, and to discontinuation of tiragolumab and atezolizumab or placebo in 11.4% and 4.8% of patients, respectively.
The most common toxicities of special interest (any grade) were immune-mediated rash in 38.6% of those given tiragolumab and atezolizumab plus chemotherapy vs 9.7% of those given chemotherapy alone, and, respectively, immune-mediated hepatitis in 35.1% vs 30.0%, immune-mediated hypothyroidism in 17.5% vs 11.5%, and infusion-related reactions in 17.5% vs 7.9%. Three patients in the experimental arm died of immune-mediated toxicity.
DISCLOSURE: Dr. Hsu reported financial relationships with BeiGene, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Ono Pharmaceutical, Roche, AstraZeneca, Merck Serono, and Roche/Genentech.
REFERENCE
1. Hsu CH, Lu Z, Gao S, et al: SKYSCRAPER-08: A phase III, randomized, double-blind, placebo-controlled study of first-line tiragolumab + atezolizumab and chemotherapy in patients with esophageal squamous cell carcinoma. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 245. Presented January 18, 2024.
EXPERT POINT OF VIEW
Discussant of the SKYSCRAPER-08 trial, Michael K. Gibson, MD, PhD, FACP, welcomed the study’s positive findings, referencing the need for more effective therapies in esophageal cancer. Dr. Gibson is Associate Professor of Medicine and Director of Translational Research for Esophago--Gastric Cancer, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville.
Michael K. Gibson, MD, PhD, FACP
In SKYSCRAPER-08, he noted, the 4.6-month improvement in median overall survival with the addition of the two immunotherapies was more impressive than the approximate 2-month survival improvement reported with the addition of a single checkpoint inhibitor to chemotherapy in other trials in this patient population—nivolumab plus chemotherapy in CheckMate 648 (all patients)1 and pembrolizumab plus chemotherapy for patients with esophageal squamous cell carcinoma in KEYNOTE-590.2
“This is not a surprise. I think, at least in this case, more is better—dual immunotherapy added to chemotherapy,” he said. The additional drug did not seem to make this approach less tolerable, Dr. Gibson added.
However, SKYSCRAPER-08 did not include an arm evaluating atezolizumab plus chemotherapy without tiragolumab. Thus, it did not answer the important question of the relative contributions of the two checkpoint inhibitors. “We can’t isolate the effect of the TIGIT [T-cell immunoglobulin and ITIM domain],” he said.
Insights From Related MORPHEUS-EC Trial
The smaller phase Ib/II MORPHEUS-EC trial, also presented at the 2024 ASCO Gastrointestinal Cancers Symposium,3 did attempt to answer the question of relative benefit, stated Dr. Gibson. -MORPHEUS had three arms: chemotherapy alone, chemotherapy plus tiragolumab/atezolizumab, and chemotherapy plus atezolizumab. For the two checkpoint inhibitors vs chemotherapy with atezolizumb, the study showed clinically meaningful improvements in investigator-assessed objective response rate (14% improvement) and median overall survival (3-month improvement); median progression-free survival was similar (approximately 7 months in each arm). The differences were much larger as compared with chemotherapy alone.
Although MORPHEUS-EC did appear to demonstrate meaningful outcomes for the additional two agents, it is a small, early-phase trial, and confirmation is needed. “I agree with the ‘an alternative’ first-line option, but I won’t call this ‘the’ first-line option,” commented Dr. Gibson.
What Next?
Ongoing research should help to elucidate the role of both tiragolumab and atezolizumab in esophageal squamous cell carcinoma. The phase III SKYSCRAPER-07 trial is evaluating atezolizumab with or without tiragolumab as maintenance therapy after definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. An early-phase trial is evaluating neoadjuvant tiragolumab and atezolizumab plus chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. Additional targets, both immunologic and nonimmunologic, are being studied for this common malignancy, added Dr. Gibson.
DISCLOSURE: Dr. Gibson reported financial relationships with Astellas Pharma, Coherus BioSciences, Daiichi Sankyo/Lilly, Regeneron, AbbVie, and UpToDate.
REFERENCES
1. Doki Y, Ajani JA, Kato K, et al; CheckMate 648 Trial Investigators: Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 386:449-462, 2022.
2. Sun JM, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021.
3. Sun JM, Chao Y, Kim SB, et al: MORPHEUS-EC: A phase Ib/II open-label, randomized study of first-line tiragolumab + atezolizumab + chemotherapy in patients with esophageal cancer. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 324. Presented January 18, 2024.
