RATIONALE 302: Tislelizumab Improves Overall Survival as Second-Line Treatment of Esophageal Cancer

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In the phase III RATIONALE 302 trial, the novel anti–PD-1 antibody tislelizumab, being developed in China, improved overall survival vs chemotherapy as second-line therapy for esophageal squamous cell carcinoma, according to Jaffer Ajani, MD, of The University of Houston MD Anderson Cancer Center, who reported the findings at the 2021 ESMO World Congress on Gastrointestinal Cancer.1

Patients randomly assigned to receive tislelizumab had a median overall survival of 8.6 months as compared with 6.3 months for patients who received chemotherapy (hazard ratio [HR] = 0.70; P = .0001). The European Union/North America subgroup experienced an even larger improvement with tislelizumab: 11.2 vs 6.3 months (HR = 0.55; 95% confidence interval [CI] = 0.35–0.87).

“Tislelizumab resulted in significantly longer overall survival compared with chemotherapy, with a very robust tail, which means many patients benefited for a long time,” Dr. Ajani commented. The finding of benefit in European and North American patients, in particular, “is very important,” he added, “because we want this type of drug—which is beneficial irrespective of geography—to be available everywhere…. Tislelizumab also resulted in a better safety profile than chemotherapy and certainly should be a preferred option for eligible patients.”

In the overall population, tislelizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival vs chemotherapy.
— Jaffer Ajani, MD

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Tislelizumab has high affinity and specificity for PD-1 and was designed to minimize binding to the Fcγ receptor on macrophages. This limits antibody-dependent phagocytosis, which, as Dr. Ajani explained, “essentially reduces the killing of T cells, which is what we need to gain advantage over the tumor.”

RATIONALE 302 Details

RATIONALE 302 is one of the largest studies of previously treated patients with esophageal cancer. It evaluated the safety and efficacy of tislelizumab in the overall international population (79% Asian) and, in a prespecified analysis, in the subgroup of patients from the European Union and North America.

The study involved 512 patients with advanced or metastatic esophageal squamous cell carcinoma that progressed during or after first-line systemic therapy. About one-third of the patients had a combined positive score staining ≥ 10% for PD-L1 expression.

Patients were randomly assigned to receive tislelizumab at 200 mg intravenously every 3 weeks or investigator’s choice of chemotherapy (paclitaxel, docetaxel, or irinotecan). The primary endpoint was overall survival in all randomly assigned patients.

Survival Difference ‘Clinically Meaningful’

“In the overall population, tislelizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival vs chemotherapy. This was true also for the European and North American patients,” Dr. Ajani reported.

The 2-month absolute difference in overall survival represented a 30% reduction in the risk of death (95% CI = 0.4–0.85; P = .0001). At 12 months, overall survival rates were 37.4% with tislelizumab and 23.7% with chemotherapy. In the European Union/North America analysis, the larger 5-month absolute difference represented a 45% reduction in the hazard ratio (95% CI = 0.35–0.87), with 42.7% vs 17.6% of patients, respectively, alive at 12 months.

“This statistically significant difference of almost 5 months is very impressive,” Dr. Ajani commented. “If we look at the 12-month survival rate, 42% compared with 17%, there is a tail for tislelizu­mab, meaning many patients continued treatment, whereas there was no long-term treatment for the chemotherapy group.”


  • The phase III RATIONALE 302 trial evaluated the anti–PD-1 compound tislelizumab as second-line therapy for advanced esophageal squamous cell carcinoma.
  • Compared with chemotherapy, treatment with tislelizumab significantly improved median overall survival (8.6 months vs 6.3 months; HR = 0.70; P = .0001). In the prespecified subgroup of patients from the European Union or North America, median overall survival was 11.2 vs 6.3 months (HR = 0.55; 95% CI = 0.35–0.87).
  • As anti–PD-1 agents have been shown to improve overall survival in the first-line setting, the role of these drugs in the second line now appears unclear.

Median progression-free survival did not differ significantly between treatment groups (1.6 with tislelizumab vs 2.1 months with chemotherapy), although the 6-month and 12-month progression-free survival figures favored tislelizumab (21.7% vs 14.9% and 12.7% vs 1.9%). This was true as well for the European Union/North America subgroup (HR = 0.97; 95% CI = 0.64–1.47).

Dr. Ajani noted that the lack of difference in median progression-free survival is not unexpected, considering the way in which checkpoint inhibitors work. In addition, he pointed out, the progression-free survival curves began to separate after about 3 months, favoring tislelizumab. After that point, about one-third of the population seemed to benefit from tislelizumab. “We need to identify this group,” he said.

Objective response rates were 20.3% with the checkpoint inhibitor and 9.8% with chemotherapy (odds ratio [OR] = 2.4), with greater durability of response with tislelizumab. At 6 months, 56% of the tislelizumab arm had persisting responses compared with 36% of the chemotherapy arm; by 12 months, 35% were responding, compared with none of the chemotherapy recipients. The median duration of response was 7.1 months vs 4.0 months, respectively. The European Union/North America subgroup had similar numbers.

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

DISCLOSURE: Dr. Ajani has received honoraria from Acrotech, Aduro Biotech, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, DAVA Pharmaceuticals, Lilly, Merck, OncoTherics, and Zymeworks; has served as a consultant or advisor to the American Cancer Society, BeiGene, Bristol Myers Squibb, Insys Therapeutics, Merck, and Vaccinogen; has received research funding from Amgen, Bristol Myers Squibb, Daiichi Sankyo, Delta-Fly Pharma, Gilead Sciences, Lilly/ImClone, Merck, Novartis, Prolinx, Roche/Genentech, Taiho Pharmaceutical, Takeda, and Zymeworks; has received institutional research funding from Astellas Pharma; and holds intellectual property in Amgen, Bristol Myers Squibb, Genentech, Lilly, MedImmune, Merck, Roche, and Taiho Pharmaceutical.


1. Ajani J, El Hajbi F, Cunningham D, et al: Randomized phase III study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302) in the overall population and the Europe/North American subgroup. 2021 ESMO World Congress on Gastrointestinal Cancer. Abstract O-15. Presented July 3, 2021.


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Expert Point of View: Kei Muro, MD, PhD

The RATIONALE 302 trial1 was discussed by Kei Muro, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan, who found the results promising. However, Dr. Muro questioned the role of PD-1/L1 inhibitors as second-line therapy for advanced esophageal squamous cell carcinoma.

RATIONALE 302 is the...