FDA Approval of Tislelizumab Plus Chemo Offers a New Option in Advanced Gastric/GEJ Adenocarcinoma

Along with the efficacy data supporting the use of tislelizumab-jsgr (Tevimbra) in combination with chemotherapy for the treatment of patients with PD-L1–positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, quality-of-life findings for the combination also highlight the utility of this regimen in this patient population, according to Marcia Cruz-Correa, MD, PhD, AGAF, FASGE.

On December 27, 2024, the FDA approved tislelizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors express PD-L1 (≥1).1 This approval was supported by data from the phase 3 RATIONALE-305 trial (NCT03777657), which demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) for patients receiving tislelizumab plus chemotherapy compared with placebo plus chemotherapy.

Findings showed that patients treated with tislelizumab plus chemotherapy achieved a median OS of 15.0 months vs 12.9 months for those treated with chemotherapy alone (HR, 0.80; 95% CI, 0.70-0.92; P = .0011).

In January, Cruz-Correa and colleagues also presented findings from an analysis on patient-reported outcomes for those treated during RATIONALE-305. Data presented at the 2025 Gastrointestinal Cancers Symposium showed that the tislelizumab regimen was associated with a significantly lower risk of PFS for all PRO domains.2 Improvements were seen in pain/discomfort, upper gastrointestinal (GI) symptoms, and dietary restrictions with the combination for patients with a PD-L1 expression of at least 1%. For those with a PD-L1 expression of at least 5%, tislelizumab plus chemotherapy was linked with an improvement in health-related QOL and dietary restrictions.

“In the [landscape] of FDA-approved drugs, [tislelizumab] provides an additional agent for us to treat our patients,” Cruz-Correa explained. Cruz-Correa is a professor of medicine, in the Department of Biochemistry & Surgery in the School of Medicine at University of Puerto Rico; an affiliated investigator in the Cancer Biology Division at University of Puerto Rico Comprehensive Cancer Center; and director of the Gastrointestinal Oncology Division at Oncologic Hospital Dr. Isaac González Martínez in San Juan.

In an interview with OncLive®, Cruz-Correa highlighted the unique pharmacologic characteristics of tislelizumab, discussed the significance of the approval of tislelizumab plus chemotherapy for patients with advanced gastric/GEJ adenocarcinoma, and detailed findings from the PRO analysis presented following the approval.

OncLive: What is the significance of the FDA approval of tislelizumab in combination with chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma?

Cruz-Correa: Gastric cancer continues to be a disease that disproportionately affects certain groups of patients, including African Americans, Asian Americans, and Hispanic people both in the United States and abroad, and people from certain socioeconomic [backgrounds] who have had a long-standing history of exposure to things that increase their risk [of gastric cancer].

As a GI oncologist, I have seen patients that have had helicobacter pylori for years. When patients get gastric cancer, by the time we see those patients, usually they have advanced disease. Less than one-third of patients [with gastric cancer] are diagnosed at an early stage [where] we can offer curative surgery. For the rest of [the patients], we have to find therapies. For years, our backbone of therapy [in the advanced setting] was mostly chemotherapy.

RATIONALE-305 evaluated a new type of monoclonal antibody that is directed against the PD-1. There are other anti–PD-1 [agents] in the market that have been tested for patients with advanced gastric cancer; however, tislelizumab has a few unique factors associated with the drug.

As I mentioned, this is a monoclonal antibody against the PD-1, not the PD-L1 like some of the other [agents] available right now. Interestingly, we noticed in the preclinical data [for tislelizumab] that the time of the connection between the antibody and the [PD-1] receptor is much higher compared with other agents. [Theoretically,] one could hypothesize that the stronger duration [of binding] could translate into a stronger efficacy, and that was one of the aspects that the RATIONALE-305 trial was trying to explore.

The other interesting factor about tislelizumab, which could have contributed to the less [severe] adverse [effect] profile and the better efficacy, is that it avoids another receptor located in the macrophage. The receptors in the macrophage normally capture the drug—in this case, the anti–PD-1—and normally, this process causes the destruction of the antibody. The combination of both [increased binding time] plus the fact that it avoids the whole process of being [destroyed] by the macrophages could have been partly responsible for the efficacy that we saw [in RATIONALE-305].

Importantly, [RATIONALE-305] had a large group of patients from Asia. In Asia—and we have our Asian American patients—there is a high prevalence of gastric cancer.

Within the landscape of other anti PD-1 approved agents, why is this approval different, and for which patients specifically would you recommend this agent be used for?

For many years, we had no options [beyond chemotherapy]. We ended up giving chemotherapy, and then studies started looking at the use of anti–PD-L1 and –PD-1 agents.

Based on this data [from RATIONALE-305], patients who do not have the high presence of PD-1 that will be a population to consider. Most of the time when we examine the use of checkpoint inhibitors in patients with gastric cancer, we always look to see whether there's a [high] expression of PD-L1. Based on this data, one group of patients who will benefit is the group without classic high expression of PD-L1 [who still have some expression].

The other patients who we might consider for this agent are those who are very sick. When a [patient has] gastric cancer—[specifically] advanced gastric cancer—one of the biggest concerns that patients have is how to [maintain] their weight. Maintaining your caloric requirement is extremely difficult [for a patient with advanced gastric cancer]. We see a lot of weight loss very quickly, sometimes even before we make the diagnosis.

[At the 2025 Gastrointestinal Cancers Symposium,] we presented long-term follow-up of the patient-reported outcomes [from RATIONALE-305].4 This particular trial had multiple questionnaires and instruments that measure different aspects that are associated with how patients feel. [These questionnaires provided] a lot of information about how active patients felt, and one of the instruments measured different types pain. In every quality-of-life category we measured [for tislelizumab plus chemotherapy vs placebo plus chemotherapy], the tislelizumab [regimen] scored much better. We're talking about an approximate 20% to 30% decrease in symptoms [including] abdominal pain, weakness, [fatigue], and many others. If a patient can eat better because they have less abdominal pain, that will translate into a better QOL.

When [clinicians] think about a drug, [they] have to [consider] the [efficacy] and QOL. Nutrition, especially for gastric cancer patients. We prefer to use the enteral route [to provide nutrition] before the parenteral route, so that’s another way patients could benefit.

Some [prior] studies [of other treatment regimens in gastric cancer] included PRO [data], but not all of them. [Our PRO analysis] and the publications that will be forthcoming in the coming months looked into these PROs. If a drug cannot be tolerated for everyone, this is something treating medical oncologists need to consider.

Looking at the financial aspect is also important. One of the biggest concerns patients have is financial toxicity. My hope is that, eventually, the prices would [become] less expensive, which would impact that financial aspect of care for patients with cancer, including gastric cancer.

How does the cost-effectiveness of combining immunotherapy with chemotherapy vary across different regions, and what impact does this have on treatment accessibility?

When you start thinking about adding immunotherapy to chemotherapy, the [cost] starts to go up. However, there were some studies that looked into the cost analysis and compared how much it cost to add tislelizumab to chemotherapy in Asia vs the United States. Interestingly, in Asia, using the combination of chemotherapy plus tislelizumab was cost effective. The measure, called ‘willingness to pay,’ and the years-adjusted quality of life was good. [Adding] tislelizumab [to chemotherapy] was cost effective in Asia and in China, specifically.

However, in the United States, [willingness to pay] was still above that threshold. We still need to make it more affordable and less [financially] toxic for everyone. If you take away the financial constraints, the study was powered strongly to be able to examine the efficacy of the addition of an anti–PD-1 [agent] in first line for patients with advanced gastric cancer. It demonstrated that the addition of the anti–PD-1 antibody tislelizumab was associated with increased OS and a decreased AE profile.

How would you assess the accessibility delivering tislelizumab in combination with chemotherapy for patients with advanced gastric cancer, particularly in the community setting?

One of the biggest barriers and challenges that we have in the United States and around the world is that not every drug gets approved within different health plans. [For example,] there could be a new drug that works very well, but it could take months [to become accessible]. I practice at the University of Puerto Rico, but we also practice in community hospitals that we work with. Sometimes, it takes a year or more to get a drug [added to the] collective portfolio of approved agents. That is a challenge, but it's still an opportunity. If we work with the community, which we have done for many years with local advocacy groups, community-based organizations, and groups like the American Cancer Society and other organizations, this helps move [health care] policy.

For years, we have been very strongly involved with public action committees where we bring the data [forward]. As scientists, we bring the data to these forums. Once you have FDA approval, you work together with Medicare and other organizations to get drugs included [in coverage].

One aspect that is very important and one of the reasons we participated in this clinical trial when we started is that we didn't have many [treatment] options for our patients [with advanced gastric cancer]. We wanted to participate because it allowed us to provide to 50% of our patients a drug that, hypothetically, should work but was not [yet] available.

One way that community physicians can be involved and advocate for their patients is to [bring] clinical trials to the community setting. We have done it; we have a Community Cancer Research Network, [which allows us to] provide infrastructure and training. The trial gets to patients in the community, and [patients] don't have to fly or drive for 3 hours to come to the metropolitan area [for treatment at an academic center]. They get [treated in the community], and that access is key. It starts with clinical trials.

References

1. Tevimbra approved in U.S. for first-line treatment of gastric and gastroesophageal junction cancers in combination with chemotherapy. News release. BeiGene. December 27, 2024. Accessed January 27, 2024. https://ir.beigene.com/news/tevimbra-approved-in-u-s-for-first-line-treatment-of-gastric-and-gastroesophageal-junction-cancers-in-combination/cedb475b-fcfe-47a4-8afe-8a501d9cf849
2. Xu L, Long Y, Yao L, Wang H, Ge W. Updated cost-effectiveness analysis of tislelizumab in combination with chemotherapy for the first-line treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma. Front Oncol. 2024;14:1477722. Published online December 16, 2024. doi:10.3389/fonc.2024.1477722
3. Cruz-Correa M, Oh D-Y, Xu R-H, et al. Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial. J Clin Oncol. 2025;43(suppl 4):365. doi:10.1200/JCO.2025.43.4_suppl.365