Tislelizumab Plus Chemotherapy Elicits Strong Survival Benefit in Esophageal Cancer

Harry Yoon, MD

The combination of tislelizumab (BGB-A317) and chemotherapy demonstrated a superior overall survival (OS) benefit compared with chemotherapy alone in patients with metastatic or unresectable esophageal squamous cell carcinoma (ESCC) providing a new first-line option in this population, according to Harry Yoon, MD.¹

Updated findings from RATIONALE 306 (NCT03783442) presented at the 2022 ESMO World Congress on Gastrointestinal Cancer showed that the median OS was 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1) in favor of the combination. Tislelizumab reduced the risk of death by 34% (HR, 0.66; 95% CI, 0.54-0.80; P < .0001).

Investigators in the phase 3 trial also determined that the combination elicited a significant improvement in OS regardless of PD-L1 expression. In patients with a combined positive score (CPS) of 10% or more, tislelizumab induced a median OS of 16.6 months (95% CI, 15.3-24.4) vs 10.0 months (95% CI, 8.6-13.0) in the control arm (HR, 0.62; 95% CI, 0.44-0.86, P =.0020). In those with CPS less than 10%, the median OS 16.7 months (95% CI, 13.0-20.1) vs 10.4 months (95% CI, 9.1-13.0) in favor of tislelizumab (HR, 0.72; 95% CI, 0.55-0.94).

The survival benefit associated with tislelizumab was consistent across all other subgroups including race, geographical region, and investigator choice of chemotherapy.

“These data [introduce tislelizumab as] a third anti–PD-1 antibody that’s been tested in the global population as a potential frontline option for patients with advanced ESCC,” Yoon said.

In an interview with OncLive^®, Yoon, an associate professor of oncology and a consultant in the Division of Medical Oncology in the Department of Oncology at the Mayo Clinic, discussed background information on the RATIONALE 306 trial and highlighted the importance of this OS data. He also mapped out potential future directions for tislelizumab and other novel therapies in ESCC.

OncLive^®: What was the impetus for combining tislelizumab with chemotherapy in the RATIONALE 306 trial?

Yoon: One of the hypotheses was that when you add a PD-1 blockade to chemotherapy, the 2 can cooperate with each other.

There were a few novelties about this particular trial. It was the first global trial [in advanced ESCC] where there was a real choice in chemotherapy. Prior global trials have looked at cisplatin plus fluoropyrimidine, whereas this global study looked at platinum/fluoropyrimidine as 1 choice and platinum/paclitaxel as another choice. So far, this is the only global study in the frontline setting for ESCC that allowed a choice of chemotherapy backbone.

This is also the only frontline study of ESCC that tested oxaliplatin specifically as a chemotherapy backbone for PD-1 blockade. This trial found that there appeared to be a similar level of benefit when PD-1 blockade, specifically tislelizumab, was added with oxaliplatin-based chemotherapy as compared with cisplatin-based chemotherapy.

What were some key updated efficacy findings from this trial?

The biggest finding was that tislelizumab plus chemotherapy showed a significantly better OS compared with placebo and chemotherapy. Specifically, the OS in the tislelizumab arm was 17.2 months vs 10.6 months in the placebo arm. That survival benefit was evident across different PD-L1 scores, including a PD-L1 score of 10 or higher vs less than 10. This benefit was also seen between geographic regions of Asia vs non-Asia and across investigator choices of chemotherapy.

Other findings showed that the addition of tislelizumab to chemotherapy significantly improved progression-free survival and overall response rates, and [the combination] increased duration of response.

What safety data were seen for the combination vs chemotherapy and placebo?

[The combination has] a reasonable safety profile with no new safety signals and appeared to be well tolerated. The [rate of] grade 3 or higher toxicities in the tislelizumab arm was 67% vs 65% in the chemotherapy alone arm.

What could these data mean for patients with metastatic or unresectable ESCC?

Before this study began, its design was discussed with health-care authorities and regulatory groups, including some in the US. There’s a plan to submit these data to regulatory authorities, and if they are approved by guidelines and committees, then we could potentially offer another PD-1 blockade option in the frontline setting for patients with previously untreated ESCC.

How else could tislelizumab be used in this patient population?

Tislelizumab has already been studied in the second-line setting, and it showed a significant benefit in that situation. This agent is also being tested in a number of other situations, including in nonmetastatic disease and in combination with other promising immunotherapy targets.

What ongoing research in the field of esophageal cancer would you like to highlight?

There are many interesting things going on in this space, particularly with immunotherapy. Some areas that I’ve been interested in are how immunotherapy can cooperate with other therapies, particularly with antiangiogenesis therapies, and how it modulates the tumor microenvironment.

[I’m also interested in] the identification of biomarkers that can dissect out which patients might be able to most benefit [from immunotherapy] and which patients might not be benefiting from immunotherapy given in the current way. There are many other exciting immunotherapy options besides PD-1 blockade. Other immune checkpoints are being tested, and there are other ways of engaging the immune system, such as with CAR T-cell therapy and NK-cell therapies. All of those areas are exciting, and they open up many potential avenues for investigation.

Reference

1. Yoon H, Kato K, Raymond E, et al. RATIONALE-306: randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022; Barcelona, Spain. LBA1.