Courtney Flaherty 

Early and late responders with ESCC experienced comparable OS benefits with Tevimbra plus chemo.

Patients with locally advanced, unresectable or metastatic esophageal squamous cell carcinoma (ESCC) who responded to first-line Tevimbra (tislelizumab) plus chemotherapy showed improved overall survival (OS) with deeper responses and a longer time to maximum response, according to data from the phase 3 RATIONALE-306 study presented at the 

2025 ASCO Gastrointestinal Cancers Symposium.

As of November 24, 2023, 68.3% (207 patients) of patients in the intention-to-treat population who received Tevimbra plus chemotherapy achieved a response, with a median time to response of 6.1 weeks. Most responses (64.7%) were achieved within eight weeks of treatment; 22.2% of responses were achieved after eight weeks, up to and including 14 weeks; and 13% of responses were achieved after 14 weeks.

Overall survival: the time from diagnosis or treatment initiation when a patient with cancer is still alive.

Time to maximum response: time it takes for a patient’s tumor to reach the greatest degree of shrinkage or response to treatment.

Intention-to-treat population: a group of patients who were randomly assigned to receive a particular treatment, whether or not they actually received that treatment or adhered to it.

Depth of response rate: how much a tumor shrinks in response to therapy.

ECOG performance status of 0 or 1: a tool used by clinicians to assess a patient’s overall health and ability to perform daily activities. A status of 0 indicates that a patient is fully active and has no restrictions. With a status of 1, a patient is restricted in strenuous physical activity but is able to carry out light housework or sedentary activities.

Overall response rate: the percentage of patients whose cancer shrinks or disappears entirely after treatment.

PD-L1 tumor area positivity score of 10% or greater: at least 10% of the tumor area of covered by PD-L1-positive cells, which are proteins found on some cancer cells that helps cancer cells evade the immune system.

For patients in these three time-to-response groups, the median OS was 21.8 months, 23.1 months and 29 months, respectively. The median OS after first response in these respective groups were 21.3 months, 21.3 months and 23.2 months.

“In the [Tevimbra] plus chemotherapy arm, 64.7% of responders achieved a response within eight weeks, while still 35.2% of responders achieved response at later assessments,” lead study author Dr. Yi Li, of Fifth Medical Center, Chinese PLA General Hospital in Beijing, China, and colleagues wrote in a poster presentation of the data. “[However,] the [OS] benefits were comparable between early responders and late responders.”

The depth of response rate among responders to Tevimbra plus chemotherapy was 62.1%. Over half (50.2%) of responders achieved a depth of response above 50% up to and including 80%; a depth of response above 30% up to and including 50% was observed in 29.8% of responders; and a depth of response greater than 80% up to and including 100% was observed in 20% of responders. Among these three depth-of-response groups, the median OS was 23.7 months, 16.1 months and 34.5 months, respectively.

Among responders, the median time to maximum response was 19 weeks. Maximum response was achieved within 14 weeks, after 14 weeks up to and including 28 weeks, and after 28 weeks in 32.7%, 34.6% and 32.7% of responders, respectively. The median OS for patients in these respective time to maximum response categories was 14.3 months, 17.4 months and 39.9 months. The median OS after maximum response was 12.6 months, 14.3 months and 24.8 months, respectively.

RATIONALE-306 was a trial that enrolled patients at least 18 years of age with unresectable locally advanced or metastatic ESCC, no prior systemic treatment for advanced disease, an ECOG performance status of 0 or 1, and measurable or evaluable disease. Upon enrollment, patients were randomly assigned to receive Tevimbra or placebo intravenously once every three weeks alongside chemotherapy. Treatment continued until disease progression or unacceptable toxicity.

The study’s primary end point was OS in the intention-to-treat patient population. Key secondary end points included progression-free survival, overall response rate, duration of response, OS in patients with a PD-L1 tumor area positivity score of 10% or greater, and safety. Notably, tumor response was assessed every six weeks for the first 48 weeks and every nine weeks thereafter.

Disclosures: Dr Li has no relationships to disclose.

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Response characteristics of tislelizumab (TIS) plus chemotherapy (chemo) in first-line (1L) treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC): a post hoc analysis of RATIONALE-306. Dr Yi Li, et al. 

Articles

Patients with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC) showed improved overall survival (OS) when treated with Tevimbra (tislelizumab) plus chemotherapy, as per the phase 3 RATIONALE-306 study. The study revealed that 68.3% of patients achieved a response, with a median time to response of 6.1 weeks. The depth of response and time to maximum response were significant factors influencing OS. The trial's primary endpoint was OS, with secondary endpoints including progression-free survival and overall response rate.

Early and late responders with esophageal squamous cell carcinoma experienced comparable OS benefits with Tevimbra plus chemo in the RATIONALE-306 trial.

Tevimbra Plus Chemotherapy May Improve Survival in First-Line ESCC

Opdivo and chemo showed long-term survival in advanced gastric, gastroesophageal junction or esophageal cancer.

Chinese patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma demonstrated a clinically meaningful, long-term improvement in overall survival (OS) compared with chemotherapy alone after first-line treatment with Opdivo (nivolumab) plus chemotherapy during the phase 3 CheckMate 649 trial.

 demonstrated that, at a minimum follow-up of 61.2 months for the Chinese population treated during the study, Opdivo plus chemotherapy (99 patients) generated a median OS of 14.3 months compared with 10.3 months for chemotherapy alone (109 patients) The 60-month OS rates were 20% and 7%, respectively.

Among patients with a PD-L1 combined positive score (CPS) of at least 5, those in the Opdivo group (75 patients) achieved a median OS of 15.5 months versus 9.6 months for patients in the chemotherapy group (81 patients). The respective 60-month OS rates were 24% and 8%.

Overall survival (OS): how long patients live after diagnosis.

Progression-free survival (PFS): how long patients live without disease progression.

Objective response rate (ORR): percentage of patients showing tumor shrinkage.

Complete response (CR): tumor is completely gone.

Partial response (PR): tumor shrinks by at least 30%.

Stable disease (SD): tumor neither shrinks nor grows.

Duration of response (DOR): how long a response lasts.

ECOG performance status: a measure of a patient's general health.

PD-L1 combined positive score (CPS): a measure of PD-L1 expression on tumor cells.

Immunologic etiology: immune system-related cause of disease.

The OS benefit with Opdivo plus chemotherapy was consistent across prespecified subgroups in the Chinese population.

In the overall population, the median progression-free survival (PFS) was 8.3 months for the Opdivo group versus 5.6 months for the chemotherapy alone group. In the population with a PD-L1 CPS of at least 5, the median PFS was 8.5 months and 4.3 months for Opdivo plus chemotherapy and chemotherapy alone, respectively.

“These extended follow-up results align with the overall CheckMate 649 trial population, reinforcing Opdivo plus chemotherapy as the standard first-line treatment for Chinese patients with advanced gastric cancer, GEJ cancer, [or] esophageal adenocarcinoma,” lead study author Dr. Lin Shen, and colleagues wrote in a poster presentation of the data.

Shen is vice president of Clinical Oncology at Beijing Cancer Hospital and Peking University, as well as deputy director at Beijing Institute for Cancer Research in China.

In April 2021, the FDA approved Opdivo combined with select types of chemotherapy for the frontline treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, based on prior data from CheckMate 649.

Safety and Additional Efficacy Data for the Chinese Population

No new safety signals with Opdivo plus chemotherapy were reported with longer-term follow-up. Any-grade treatment-related side effects (TRAEs) occurred in 99% of patients in the Opdivo group versus 94% of patients in the control group. The rates of grade 3 (severe) or 4 (life-threatening) TRAEs were 66% and 50%, respectively. Serious any-grade TRAEs were reported in 26% of patients in the experimental group versus 13% of patients in the chemotherapy alone group. The respective rates of grade 3 or 4 serious TRAEs were 19% and 10%.

The most common grade 3 or 4 TRAEs reported in the Opdivo group included decreased neutrophil count (17%), decreased platelet count (7%), thrombocytopenia (7%), decreased white blood cell count (6%), anemia (6%) and neutropenia (6%).

In the chemotherapy alone group, the most frequent grade 3 or 4 TRAEs comprised decreased platelet count (11%), decreased neutrophil count (11%), neutropenia (8%) and vomiting (5%).

TRAEs led to treatment discontinuation in 51% of patients in the Opdivo group versus 26% of patients in the chemotherapy alone group. Four treatment-related deaths (4%) were reported in the experimental group versus 1 treatment-related death (1%) in the control group.

Notably, grade 3 or 4 TRAEs with potential immunologic etiology occurred in no more than 7% of Chinese patients in the Opdivo plus chemotherapy group across organ categories; no grade 5 (death) events occurred in either group.

In the overall population, the ORR was 66% in the Opdivo group versus 45% in the chemotherapy alone group. In the experimental group, the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) rates were 17%, 49%, 25% and 9%, respectively. These respective rates were 8%, 37%, 30% and 14% in the control group.

The median duration of response (DOR) in the overall population was 12.5 months for the Opdivo group versus 5.6 months for the chemotherapy alone group.

In the PD-L1 CPS of at least 5 population, the ORR was 68% in the Opdivo group versus 48% in the chemotherapy alone group. The respective CR, PR, SD and PD in the Opdivo group were 19%, 49%, 23% and 9%. These respective rates were 11%, 37%, 25% and 17% in the control group. The median DOR in this population was 12.5 months and 6.9 months for the experimental and control groups, respectively.

The OS, PFS and ORR benefits with the Opdivo regimen were consistent across different PD-L1 CPS subgroups.

Among all randomly assigned patients in the experimental group, patients who responded to Opdivo plus chemotherapy (49 patients) experienced a median OS of 21.5 months compared with nine months for those who had SD or PD (33 patients). In the chemotherapy group, responders (42 patients) achieved a median OS of 14.5 months versus 9.1 months for non-responders (34 patients).

In the population of patients with a PD-L1 CPS of at least 5, those who responded to Opdivo plus chemotherapy (40 patients) had a median OS of 23.3 months versus 11.5 months for those who did not respond to the experimental regimen (23 patients). In the chemotherapy group, the median OS was 13.1 months for responders (33 patients) versus 9.1 months for non-responders (22 patients).

The randomized, open-label, global phase 3 study enrolled patients with previously untreated, unresectable, advanced or metastatic gastric cancer, GEJ cancer and esophageal adenocarcinoma. Patients were not permitted to have HER2-positive disease, and an ECOG performance status of 0 to 1 was required.

Patients were randomly assigned in a 1:1:1 fashion. In the first experimental group, patients received Opdivo at 360 milligrams (mg) in combination with XELOX (oxaliplatin and capecitabine) once every three weeks; or Opdivo at 240 mg plus FOLFOX (oxaliplatin, leucovorin and fludarabine) once every two weeks. In the control group, patients received chemotherapy alone in the form of XELOX once every three weeks or FOLFOX once every two weeks. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or end of study.

In the Opdivo group, 15% of patients received FOLFOX, and 85% were given XELOX. These rates were 13% and 87%, respectively, in the control group.

The study also included a second experimental group where patients received Opdivo at 1 mg per kilogram (mg/kg) plus Yervoy (ipilimumab) at 3 mg/kg once every three weeks for 4 cycles, followed by Opdivo alone at 240 mg once every two weeks.

Blinded independent central review–assessed PFS and OS in the population of patients with a PD-L1 CPS of at least 5 served as the trial’s dual primary end goal. Secondary end goals included OS and PFS in the overall population, the population of patients with a PD-L1 CPS of at least 1 and the population of patients with a PD-L1 CPS of at least 10; and overall response rate.

“First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up of Chinese pts from CheckMate 649.” By Dr. Shen L et al. 

Opdivo (nivolumab) combined with chemotherapy significantly improved overall survival (OS) in Chinese patients with advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma compared to chemotherapy alone, as shown in the CheckMate 649 trial. The median OS was 14.3 months for the Opdivo group versus 10.3 months for chemotherapy alone. The treatment was effective across various PD-L1 subgroups, with consistent progression-free survival (PFS) and overall response rate (ORR) benefits. Safety profiles were manageable, with no new safety signals, although treatment-related adverse events were more frequent in the Opdivo group.

Opdivo plus chemo showed long-term survival advantages in Chinese patients with advanced gastric, gastroesophageal junction or esophageal cancer.

Opdivo Regimen May Prolong Survival in Chinese Patients With Certain GI Cancers

Patients who received lymphodepletion in the inpatient setting had a 60-day non-relapse mortality rate of 7.1%.

Patients with B-cell acute lymphoblastic leukemia (B-ALL) and mantle cell lymphoma (MCL) experienced similar rates of non-relapse mortality and an acceptable safety profile with outpatient administration of lymphodepletion ahead of receiving Tecartus (brexucabtagene autoleucel) when compared with inpatient administration of lymphodepletion and Tecartus, results from a retrospective study presented at the 

Findings showed that patients administered lymphodepletion in the outpatient setting (28 patients) — irrespective of the setting for Tecartus infusion — experienced a 60-day non-relapse mortality rate of 3.6% versus 7.1% for those given lymphodepletion and Tecartus in the inpatient setting (28 patients). The six-month progression-free survival (PFS) rate was 83.3% for the outpatient group versus 71.1% for the inpatient group.

Lymphodepletion: chemotherapy administered before CAR-T cell therapy.

Non-relapse mortality: death without a recurrence or progression of disease after a stem cell transplant.

Progression-free survival (PFS): the time patients live without their disease spreading or worsening.

ECOG performance status: a system of scoring a patient’s ability to complete daily tasks, with a lower score indicating higher function.

Allogeneic stem cell transplant: the replacement of a patient’s stem cells with cells from a donor.

Autologous stem cell transplant: when a patient receives an infusion of their own healthy stem cells.

Cytokine release syndrome (CRS): a condition sometimes seen after CAR-T cell therapy when there is a large release of cytokines into the blood from immune cells, which may lead to symptoms including nausea, fever, rash, headache, low blood pressure, rapid heartbeat and trouble breathing.

Complete response (CR): the disappearance of cancer.

Immune effector cell-associated neurotoxicity syndrome (ICANS): A neurological condition that may occur from CAR-T cell therapy caused by an immune response from the treatment. Symptoms include difficulty concentrating, confusion, headache, mood changes, seizures, muscle weakness/numbness and vision problems.

“[Tecartus] is safe to administer [in the outpatient setting] with similar efficacy and non-relapse mortality,” lead study author Dr. Tamer Othman of City of Hope in Durante, California, and colleagues wrote in a poster presentation of the data. “Future studies with [a] larger sample size and longer follow-up are needed to confirm our findings.”

Investigators conducted a retrospective study of adult patients with B-ALL or MCL treated with Tecartus at City of Hope between Nov. 1, 2020, and March 31, 2024. Patients were divided into two groups. The first group included patients given lymphodepletion in the outpatient setting, irrespective of the setting of Tecartus infusion. The second group featured patients given lymphodepletion in the inpatient setting.

In the overall population (56 patients), 66% had B-ALL, and 34% had MCL. The median age was 55 years, and most patients were male (77%), were Hispanic White (61%), had an ECOG performance status of 0 to 1 (93%), and had higher disease burden (75%). Patients received a median of four prior lines of therapy; 23% of patients underwent a prior allogeneic stem cell transplant and 7.1% received a prior autologous stem cell transplant.

In the outpatient group, 82% of patients received Tecartus in the outpatient setting; all patients in the inpatient group were infused with CAR-T cell therapy in the inpatient setting. Notably, 86% of patients in the outpatient group were admitted to the hospital after starting lymphodepletion in the outpatient setting at a median of eight days after the start of lymphodepletion. Reasons for admission included Tecartus-related toxicities such as fever because of cytokine release syndrome (CRS) (71%), hypotension due to poor oral intake (4.2%) and dyspnea (4.2%). Other reasons for admission included high-burden disease (13%), fever during lymphodepletion due to leukemia (4.2%) and pain control during lymphodepletion (4.2%). The median time hospitalized during the first 100 days from the start of lymphodepletion was 10 days in the outpatient group versus 27 days in the inpatient group.

Additional data showed that patients with B-ALL in the outpatient group (20 patients) achieved a complete response (CR) rate of 90% versus 88% in the inpatient group (17 patients). In patients with MCL, the CR rates were 75% in the outpatient group (eight patients) versus 73% in the inpatient group (11 patients).

Safety data showed that any grade CRS occurred in 86% of patients in the outpatient group versus 82% in the inpatient group. The rates of grade 3 (severe) or higher CRS were 7.1% and 14%, respectively. The respective median durations of CRS were four days and four days. Any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 54% of patients in the outpatient group versus 61% in the inpatient group. The respective rates of grade 3 or higher ICANS were 29% and 25%. The median duration of ICANS was four days in the outpatient group versus seven days in the inpatient group. Actemra (tocilizumab) was given for toxicity to 79% of patients in the outpatient group versus 75% of patients in the inpatient group. The median number of Actemra doses was two in both groups.

Steroids were given for toxicity to 79% of patients in the outpatient group versus 71% of patients in the inpatient group; the rates of prophylactic dexamethasone administration were 32% and 25%, respectively. Prophylactic anakinra was given to 29% of patients in the outpatient group versus 7.1% of those in the inpatient group. Treatment anakinra was given to 25% and 18% of patients, respectively.

“Outpatient administration of brexucabtagene autoleucel (brexu-cel) for acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL) is safe and feasible” by Dr. Tamer Othman et al., 

Outpatient lymphodepletion followed by Tecartus was found to be safe and effective in treating B-cell acute lymphoblastic leukemia and mantle cell lymphoma.

Tecartus After Outpatient Lymphodepletion Safe, Effective in B-ALL and MCL

Some pediatric patients with B-ALL may benefit from a novel CAR-T cell therapy, according to a presentation at the 2024 ASH Annual Meeting.

Children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) demonstrated high remission rates after treatment with a novel bicistronic CD19/CD22-directed CAR-T cell therapy.

The treatment also generated durable responses and was shown to be safe among these patients, including those with isolated or combined extramedullary relapsed disease, according to updated data from a phase 2 trial presented at the 

At a median follow-up of 13.9 months, the one-year event-free survival (EFS) rate was 75.5%, and the one-year overall survival (OS) rate was 93.5% among patients enrolled and treated with bicistronic CD19/CD22-directed CAR-T cell therapy (343 patients). 

Bicistronic CD19/CD22 CAR-T cell therapy: a specific type of CAR-T cell therapy that targets two proteins on B-cell leukemia cells: CD19 and CD22.

Event-free survival (EFS): the length of time after treatment that a patient lives without the cancer returning or worsening.

Overall survival (OS): the length of time a patient lives after being diagnosed with cancer, regardless of their disease status, until death of any cause.

Cytokine release syndrome (CRS): when the body releases too many cytokines into the bloodstream and overreacts to an infection or injury. This is a serious condition.

Complete remission (CR): when patients fully respond to treatment, meaning they no longer show signs or symptoms of cancer.

Minimal residual disease negativity: minimal residual disease means a small amount of cancer cells may remain in the body after treatment. Negativity refers to having no traces of cancer in the body after treatment.

Following CAR-T cell expansion, the one-year EFS rates among patients who underwent bridging bone marrow transplant (38 patients) versus those who did not (280 patients) were 89.7% versus 76.8%, respectively. The respective one-year OS rates were 95.8% versus 95.2%.

“After CAR-T cell therapy, we have found that the one-year EFS [rate] is higher [with] CAR-T cell treatment plus bone marrow transplant than CAR-T cell treatment alone, [although the] one-year OS [rates were] very similar between these two [populations],” presenting author Dr. Hua Zhang, vice president and chief scientific officer at SPH Biotherapeutics (HK), Limited, stated in an oral presentation of the data during a virtual press briefing.

Most patients developed cytokine release syndrome (CRS); those with lower-grade CRS had better one-year EFS outcomes than those with higher-grade CRS. Among the 172 patients with grade 1 or 2 (mild or moderate) CRS, the one-year EFS rate was 80.9%. The one-year EFS rate for the 145 patients with grade 3 or 4 (severe or life-threatening) CRS was 69.9%.

In the presentation, Zhang added that “in this study, we found the severity of CRS was not related to the study dose range of infused cells, whereas it was highly correlated with disease burden and CAR-T cell viability.”

Complete Responses to CAR-T Cell Therapy in Pediatric B-ALL

Following treatment, complete remission (CR) to treatment was achieved across all patients in the isolated extramedullary relapse cohort. In the refractory, isolated, combined hematologic relapse cohort, all but one patient with isolated bone marrow relapse achieved a CR. This patient died before their evaluation.

A total of 13 and 228 patients in the isolated bone marrow and bone marrow plus testes relapse subgroups, respectively, underwent subsequent transplantation according to protocol criteria. Notably, 25 additional patients in the isolated bone marrow subgroup underwent transplantation according to parental request.

Based on these results, a phase 1 study of the regimen is underway. Investigators on the study plan to enroll 12 to 18 patients in the study.

Previously reported data from this phase 2 trial showed that co-administration of CD19- and CD22-directed CAR-T cell therapy produced relatively durable EFS rates and a high CR rate among 225 children with relapsed or refractory B-ALL or those at a high risk of hematologic or extramedullary relapse. CR was achieved in 99% of patients (194 patients), all of whom achieved minimal residual disease negativity. 

The 12-month EFS rates were 69.2%, 95% and 68.6%for patients treated for hematologic relapse without consolidative allogeneic hematopoietic cell transplantation (allo-HSCT; 116 patients), isolated testicular relapse (two patients) and isolated central nervous system (CNS) relapse (10 patients), respectively.

Accordingly, investigators developed a bicistronic CD19/CD20-directed CAR-T cell therapy to enhance EFS, OS and safety outcomes for patients with relapsed or refractory B-ALL, regardless of prior exposure to consolidative allo-HSCT after CAR-T cell therapy

“Safety and efficacy of bicistronic CD19/CD22 CAR T cell therapy in childhood B cell acute lymphoblastic leukemia” by Dr. X. Wan, et al. Presented at the 2024 ASH Annual Meeting.

A novel bicistronic CD19/CD22-directed CAR-T cell therapy has shown promising results in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), achieving high remission rates and durable responses. The phase 2 trial reported a one-year event-free survival (EFS) rate of 75.5% and an overall survival (OS) rate of 93.5%. The therapy was effective across various relapse types, with cytokine release syndrome (CRS) severity correlating with disease burden. A phase 1 study is underway to further explore this treatment's potential.

Treatment with bicistronic CD19/CD22 CAR-T cell therapy has shown event-free survival improvements in children with relapsed or refractory B-ALL.

Courtney Flaherty

Tevimbra Plus Chemotherapy May Improve Survival in First-Line ESCC

Opdivo Regimen May Prolong Survival in Chinese Patients With Certain GI Cancers

Tecartus After Outpatient Lymphodepletion Safe, Effective in B-ALL and MCL

CAR-T Cell Therapy Shows EFS Benefit in Pediatric Leukemia Subset

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