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Overall survival (OS) in previously treated esophageal cancer improved significantly with the anti-PD-1 drug tislelizumab compared to chemotherapy, a phase III, randomized trial showed.

Patients randomized to tislelizumab had a median OS of 8.6 months as compared with 6.3 months for patients who received chemotherapy alone. A prespecified subgroup analysis of patients from Europe and North America (EU/NA) showed an even larger improvement from adding tislelizumab to chemotherapy (11.2 vs 6.3 months).

Six- and 12-month landmark analyses yielded strong advantages for the tislelizumab arm in the overall and EU/NA populations, reported Jaffer Ajani, MD, of the MD Anderson Cancer Center in Houston, at the virtual World Congress on Gastrointestinal Cancer (WCGC).

"Tislelizumab demonstrated statistically significant and clinically meaningful improvement in overall survival compared to chemotherapy in patients with advanced/metastatic squamous carcinoma in the second-line setting," said Ajani. "This benefit was also true for European and North American patients, and this is a very important finding because we want this type of drug, which has benefit irrespective of geography, available everywhere. Tislelizumab resulted in a better safety profile than chemotherapy and certainly should be a preferred option for eligible patients."

The trial, known as , is the third to demonstrate a survival advantage in the second-line setting for esophageal squamous cell carcinoma, each using a different anti-PD-1 drug, said WCGC invited discussant Kei Muro, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan. The study of nivolumab (Opdivo) and the study of pembrolizumab (Keytruda) also demonstrated statistically significant improvement in OS in previously treated esophageal squamous cell cancer. The drugs showed similar efficacy in the three trials.

However, the role of immune checkpoint inhibitors as second-line therapy remains unclear, as three phase III trials of the agents have already demonstrated a survival benefit in the first-line setting.

"It can be said that esophageal cancer treatment has entered the era or the heyday of immune checkpoint inhibitors," said Muro. "Based on the results of the [three first-line trials], immune checkpoint inhibitors will be administered in the first-line treatment of esophageal cancer, and the position of immune checkpoint inhibitors in second-line treatment is extremely difficult."

Future studies of immune checkpoint inhibitors for esophageal cancer will focus on perioperative treatment, augmenting radiotherapy efficacy, and various combination strategies, he added.

RATIONALE-302 involved 512 patients with advanced/metastatic esophageal squamous cell carcinoma that progressed during or after first-line systemic therapy. Patients were randomized to tislelizumab or investigator's choice of chemotherapy, and treatment continued until disease progression or unacceptable toxicity. The primary endpoint was OS in all randomized patients.

Tislelizumab was developed in China, and 79% of patients in RATIONALE-302 were from Asia. Patients from EU/NA nations were a prespecified subgroup in the OS analysis, said Ajani.

The overall study population had a median age of 62-63, and about 30% of the patients had combined positive staining ≥10% for PD-L1 expression.

The 2-month absolute difference in OS translated into a 30% reduction in the survival hazard in favor of tislelizumab (95% CI 0.4-0.85, P=0.0001). The 6-month OS values were 62.3% for the tislelizumab arm and 51.8% with chemotherapy. At 12 months, OS was 37.4% with tislelizumab and 23.7% with chemotherapy.

In the EU/NA analysis, the 5-month absolute difference represented a 45% reduction in the hazard ratio (95% CI 0.35-0.87). The 6-month and 12-month OS values were 63.6% vs 52.7% and 42.7% vs 17.6%, both in favor of tislelizumab.

"This statistically significant difference of almost five months is very impressive," said Ajani. "If we look at the 12-month survival rate, 42% compared to 17%, there is a tail for tislelizumab, meaning that there were many patients who continued treatment, where there was no long-term treatment for the chemotherapy group."

Median progression-free survival did not differ significantly between treatment groups (1.6 vs 2.1 months, tislelizumab vs chemotherapy). However, the 6-month and 12-month PFS values favored tislelizumab (21.7% vs 14.9%, 12.7% vs 1.9%).

Ajani noted that PFS began to separate in favor of tislelizumab after about 3 months and continued to benefit with longer follow-up, reflecting the higher response rate (20.3% vs 9.8%) and greater durability of response. More than half of responders in the tislelizumab arm had persisting responses at 6 months as compared with 36% of the chemotherapy arm. By 12 months, no patients in the chemotherapy arm had an ongoing response versus 35.1% of the responding patients randomized to tislelizumab.

Treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients in each treatment group, but grade 3-5 TEAEs occurred more often with chemotherapy (67.9% vs 46.3%). TEAEs leading to discontinuation occurred in 26.7% of the chemotherapy arm and 19.2% of the tislelizumab group.

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