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Tislelizumab has a potential in the second-line treatment for patients with advanced or metastatic squamous oesophageal cell carcinoma

The phase III RATIONALE-302 study evaluated the novel monoclonal anti-PD-1 antibody tislelizumab in patients with advanced unresectable or metastatic oesophageal squamous cell carcinoma (ESCC) who received prior systemic treatment. The study met its primary endpoint of overall survival (OS) as compared to chemotherapy with a safety profile of tislelizumab that was consistent with its known risks and no new safety concerns.

To date, advanced or metastatic oesophageal squamous cell carcinoma (ESCC) has an estimated five-year survival rate of only 5%. Although single-agent chemotherapy is recommended when ESCC progresses after first-line therapy, it is associated with limited survival and poor tolerability. Second-line use of anti-PD-1/L1 monoclonal antibodies has improved overall survival (OS) vs. chemotherapy. The novel monoclonal anti-PD-1 antibody tislelizumab has high a affinity and specificity for PD-1 and was designed to minimise binding to FcγR on macrophages and as such limit antibody-dependent phagocytosis. The RATIONALE-302 study evaluated the efficacy and safety of second-line tislelizumab in patients with advanced or metastatic ESCC. At the 2021 ESMO World Congress on Gastrointestinal Cancer, data from the overall and Europe/North America (EU/NA) populations were presented.

RATIONALE-302 study design

In the global phase III RATIONALE-302 study, adults with histologically confirmed advanced/unresectable or metastatic ESCC whose disease progressed during or after first-line systemic therapy with ≥1 evaluable lesion per RECIST v1.1 and an Eastern Cooperative Oncology Group performance score (ECOG PS) of ≤1 were included. Patients were randomised (1:1) to receive tislelizumab 200 mg intravenously every 3 weeks or investigator-chosen standard chemotherapy (paclitaxel, docetaxel or irinotecan). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Stratification factors included chemotherapy option, region and ECOG PS. The primary endpoint was overall survival (OS) in the intent-to-treat (ITT) population.

Statistically significant and clinically meaningful improvement in OS

In the overall population, median OS improved from 6.3 months with chemotherapy to 8.6 months with tislelizumab (HR[95%CI]: 0.70[0.57-0.85], p= 0.0001). The six- and twelve-months OS rates were 62.3% vs. 51.8% and 37.4% vs. 23.7% for tislelizumab and chemotherapy, respectively. Survival benefit was consistently observed in the EU/NA subgroup (median OS 11.2 vs. 6.3 months; HR[95%CI]: 0.55[0.35–0.87]). In the overall population, the median PFS was reported at 1.6 months with tislelizumab as compared to 2.1 months with chemotherapy (HR[95%CI]: 0.83[0.67-1.01]). In contrast, in the EU/NA subgroup, there was no meaningful difference in PFS between the two arms (HR[95%CI]: 0.97[0.64-1.47]). Treatment with tislelizumab was associated with improved ORR (20.3% vs. 9.8%) and median DoR (7.1 vs. 4.0 months, HR[95%CI]: 0.42[0.23–0.75]) vs. chemotherapy in the overall population. Five patients in the tislelizumab arm and one patient in the chemotherapy arm obtained a complete response. The probability of patients with response at twelve months was 35.1% vs. 0.0% for the tislelizumab and chemotherapy arms, respectively. Improvement in ORR (20.0% vs. 11.3%) and median DOR (5.1 vs. 2.1 months; HR[95%CI]: 0.42[0.13–1.39]) was also observed in the EU/NA subgroup.

In general, less patients in the tislelizumab arm suffered from grade 3-5 treatment-emergent adverse events (TEAEs) in both the overall population (46.3% vs. 67.9%) and the EU/NA subgroup (55.6% vs. 71.4%). The most common TRAEs in the overall population were anaemia (11.0% vs. 34.6%), decreased appetite (6.3% vs. 31.3%), diarrhoea (5.5% vs. 27.5%), nausea (2.7% vs. 27.5%), decreased white blood cell count (2.0% vs. 40.8%) and decreased neutrophil count (1.2% vs. 39.2%). Also in the EU/NA group, these toxicities were less frequently reported in the tislelizumab arm as compared to the chemotherapy arm.


In the overall population, tislelizumab demonstrated a statistically significant and clinically meaningful improvement in OS versus chemotherapy in patients with advanced or metastatic ESCC whose tumour progressed during or after first-line treatment. The OS benefit of tislelizumab over chemotherapy in the overall population was consistently observed in patients from the EU/NA subgroup. Furthermore, tislelizumab demonstrated a higher and more durable antitumour response compared with chemotherapy. As tislelizumab also demonstrated a tolerable safety profile, tislelizumab represents a potential new second-line treatment option for patients with advanced or metastatic ESCC.


Ajani J, et al. Randomized, Phase 3 study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302) in the overall population and Europe/North America subgroup. Presented at 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract O-15.

Speaker Jaffer Ajani

Jaffer Ajani

Jaffer Ajani, MD, University of Texas MD Anderson Cancer Center, Houston, United States


See: Keyslides

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