Tislelizumab plus chemotherapy demonstrates superior efficacy compared to placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal cancer

Tislelizumab is a high-affinity anti-PD-1 monoclonal antibody that was previously shown to induce a survival benefit as second-line monotherapy in patients with advanced or metastatic oesophageal squamous cell carcinoma (ESCC). In the phase 3 RATIONALE-306 trial, the combination of tislelizumab and chemotherapy also significantly prolonged the survival of advanced ESCC patients in the first-line setting. As such, these data support the use of tislelizumab + chemotherapy as a standard first first-line therapy option for patients with advanced or metastatic ESCC.

ESCC is the predominant subtype of oesophageal cancer, accounting for ≥85% of all cases worldwide. Platinum-based chemotherapy has been the historical standard  first-line treatment for patients with advanced or metastatic ESCC. However, the median overall survival (OS)with this strategy remains to be poor and does not exceed one year. Recently, the addition of anti-PD-1 antibodies to first-line chemotherapy was shown to improve the OS in patients with advanced or metastatic ESCC. However, to date, global phase 3 trials have only studied these agents in combination with cisplatin plus 5-FU. Tislelizumab, an anti-PD-1 monoclonal antibody, has high affinity and specificity for PD-1 and previously demonstrated a survival benefit as second-line monotherapy in patients with advanced or metastatic ESS. During the 2022 ESMO World Congress on gastrointestinal cancer, interim data of the phase 3 RATIONALE-306 trial were reported. This study evaluates the efficacy and safety of tislelizumab plus chemotherapy vs. placebo plus chemotherapy in patients with advanced or metastatic ESCC in the first-line setting.

Study design

The phase 3 RATIONALE-306 trial is a randomised, double-blind, phase III study including adult patients with unresectable locally advanced or metastatic ESCC. Patients were randomised (1:1) to receive tislelizumab 200 mg (arm A) or placebo (arm B) intravenously once every three weeks, both in combination with investigator-chosen chemotherapy (ICC) until disease progression, intolerable toxicity, or withdrawal for other reasons.  The ICC regimen could consist of a platinum (cisplatin or oxaliplatin) combined with a fluoropyrimidine (capecitabine or 5-FU) (option A) or platinum and paclitaxel (option B). The primary endpoint was OS in the intent-to-treat (ITT) population. Hierarchical sequentially-tested secondary endpoints consisted of PFS, objective response rate (ORR), OS in the PD-L1 score ≥10% subgroup, and health-related quality of life. Other secondary endpoints included duration of response (DoR) and safety.

Results

In total,  649 patients were enrolled, with 74.9% of patients coming from Asia and 25.1% from non-Asian countries (Europe, Oceania, and North America). Patients were randomised 1:1 to arm A (tislelizumab+chemotherapy, n=326) and B (placebo+chemotherapy, n=323). At data cutoff (February 2022), the median follow-up was 16.3 and 9.8 months in arms A and B, respectively. The study met its primary endpoint by demonstrating a statistically significant improvement in OS in arm A vs. arm B (median OS: 17.2 vs. 10.6 months; HR[95%CI]: 0.66[0.54, 0.80]; p<0.0001). This OS improvement was consistently observed across prespecified subgroups, irrespective of the ICC option, geographic region, and PD-L1 expression status. In fact, in patients with a PD-L1 score ≥10%, arm A significantly improved the OS vs. Arm B, with a median OS of 16.6 and 10.0 months, respectively (HR[95% CI]: 0.61[0.44, 0.86]; p=0.0020). The OS was also superior in arm A vs. arm B in patients with PD-L1 score <10% (16.7 vs. 10.4 months; HR[95%]: 0.72[0.55-0.94]). Arm A was also associated with a significantly better PFS compred to Arm B with a median PFS of 7.3 and 5.6 months, respectively (HR[95% CI]: 0.62[0.52, 0.75]; p<0.0001). Tumour responses were also more common and more durable with tislelizumab plus chemotherapy. ORR rates were 63.5 vs. 42.4% in arms A and B, respectively (OR[95%CI]: 2.38[1.73-3.27]; p<0.0001). A complete response was observed in 4.6 vs. 2.5% of the cases, and a partial response in 58.8 vs. 39.9%. Median DoR was 7.1 vs. 5.7 months in arms A and B, respectively. The current percentage of patients with ongoing response is 19.3% and 9.5%.

Overall, similar proportions of patients in Arms A and B had ≥1 treatment-related treatment-emergent adverse event (TRAE, 96.6% vs. 96.3%).  TRAEs greater than grade 3 were observed in 66.7% vs. 64.5% of patients, and TRAEs leading to death in 1.9% vs. 1.2%. Serious TRAEs occurred in 28.7% vs. 19.3%, and treatment-emergent AEs leading to discontinuation occurred in 31.8% vs. 22.4% in Arms A vs. B. No new safety signal for tislelizumab was observed.

Conclusions

Tislelizumab plus chemotherapy as first-line treatment demonstrates a statistically significant and clinically meaningful improvement in OS over placebo plus chemotherapy in patients with advanced or metastatic ESCC, with a manageable safety profile. The OS benefit with tislelizumab plus chemotherapy was accompanied by significant improvements in both PFS and ORR, and responses also proved to be more durable compared to placebo plus chemotherapy. These results of the RATIONALE-306 study support the administration of tislelizumab plus chemotherapy as a standard first-line therapy option for patients with advanced or metastatic ESCC.

Reference

RATIONALE-306: Randomized, global, Phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for locally advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC). Presented at ESMO WCGI 2022; Abstract LBA-1.