Russ Conroy

Results from the phase 2 INFINITY trial (NCT04817826), pre-operative the combination of tremelimumab (Imjudo) and durvalumab (Imfinzi) was safe and produced encouraging clinical activity in patients with mismatch repair deficient (dMMR) and microsatellite instability–high (MSI-H) Epstein-Barr virus (EBV)-negative gastric or gastroesophageal (GEJ) junction cancer, according to a presentation at the 2023 Gastrointestinal Cancers Symposium.

In the efficacy evaluable population, the pathological complete response (pCR) rate for patients who were treated with tremelimumab plus durvalumab was 60%, and the rate of major to complete pathological response in those with less than 10% of viable cells was 80%.

“One [patient] had heterogenous proficient and deficient MMR status at surgery, thus highlighting the importance of adequate initial sampling,” presenting author Filippo Pietrantonio, MD, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said in the presentation.

With a median follow-up of 13.4 months (interquartile range [IQR], 9.7-14.2) months, investigators observed progression-free survival (PFS) events in 2 patients and 4 death events, which were attributed to progressive disease (n = 1), late surgical complications (n =2), and secondary brain tumor (n = 1).

Investigators of the phase 2 INFINITY trial evaluated tremelimumab plus durvalumab combination therapy among patients resectable gastric or GEJ cancer. Patients received 300 mg of tremelimumab for 12 weeks with 1500 mg of durvalumab every 4 weeks for 3 cycles followed by surgery.

The primary end point for cohort 1 was pCR and negative circulating tumor DNA status following neoadjuvant therapy. Key secondary end points included health-related quality of life during neoadjuvant treatment, disease-free survival, OS, safety and surgical morbidity, and exploratory and translational analyses.

From May 2021 to February 2022, 18 patients enrolled and began study treatment. Of these patients, 1 withdrew consent after 1 cycle and 2 refused surgery. Fifteen patients were evaluable for the primary end point, 14 of whom underwent radical surgery and 1 had progressive disease and did not receive radical surgery.

Of the total population, the median patient age was 71.5 years (IQR, 65-80). Additionally, most patients were male (67%), had an ECOG performance status of 0 (67%), and had gastric cancer (78%). Most patients had T3 disease (56%), N2 disease (50%), and no bulky tumors (78%).

In an analysis of exploratory end points, the pCR rate was 17% (n = 1/6) for those with T4 disease and 89% (n = 8/9) for those with stage T2 or T3 tumors (

 = 011). Investigators also reported no correlation between pCR and N status. Moreover, PD-1 combined positive score was not associated with outcomes, and tumor mutational burden demonstrated a non-significant trend towards correlation with pCR.

The most common any-grade immune-related adverse effects (AEs) included pruritus (22%), thyroiditis (22%), hepatitis (17%), and skin rash (17%). Investigators observed several events of grade 3 or higher AEs including hepatitis (n = 1), colitis (n = 1), and pneumonitis (n = 1).

“The global quality of life was preserved during the neoadjuvant phase [of treatment],” Petrantonio said regarding findings from the quality-of-life end point.

Pietrantonio F, Raimondi A, Lonardi S, et al. INFINITY: a multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). 

 2023;41(suppl 4):358. doi: 10.1200/JCO.2023.41.3_suppl.358

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New findings from the phase 2 INFINITY trial shows promise for tremelimumab and durvalumab in patients with gastric/GEJ adenocarinoma.

Tremelimumab Plus Durvalumab Shows Promising Activity, Safety in Gastric/GEJ Adenocarcinoma

Encouraging early clinical activity was demonstrated with the combination of teclistamab (Tecvayli) plus daratumumab (Darzalex), lenalidomide (Revlimid), in patients with relapsed or refractory multiple myeloma, according to a presentation on data from the phase 1b MajesTEC-2 trial (NCT04722146) during the 

2022 American Society of Hematology Annual Meeting

In terms of the hematologic safety profile of the combination therapy, the most common grade 3/4 hematologic adverse effects (AE) were neutropenia, which occurred among 78.1% of patients, 15.6% had thrombocytopenia, and12.5% had febrile neutropenia. The majority of non-hematologic AEs were low-grade, with any-grade cytokine release syndrome occurring most frequently among 81.3% (n = 26) of patients and lasted on average for 2 days.

The majority of infections among patients during treatment were low-grade. The most common grade 3/4 infections included pneumonia (15.6%) COVID-19 (12.5%), and sepsis (9.4%). Two fatal AEs occurred among patients, including 1 related to COVID-19 77 days following the last treatment dose, and another involving multiorgan failure due to sepsis.

“The safety profile of [the combination regimen] was consistent with what is known about the individual agents, with no new safety signals identified,” Emma Searle, MD, MRCP, FRCPath presenting author of the MajesTEC-2 trial and honorary senior lecturer at the University of Manchester, said.

In the ongoing, multicohort, phase 1b MajesTEC-2 study, patients received teclistamab at 0.72 mg/kg or 1.5 mg/kg subcutaneously once a week, and may transition to 3 mg/kg of teclistamab taken subcutaneously once every 2 weeks starting on the third cycle. Patients also received 1800 mg of subcutaneous daratumumab once every week during cycles 1 to 2, once every 2 weeks during cycles 3 to 6, and once every 4 weeks during cycles 7 and beyond. Lenalidomide was given at 25 mg by mouth daily for 21 days of a 28-day cycle starting with cycle 2. Additionally, 40 mg of dexamethasone was taken by mouth once every week during cycles 2 to 4.

The primary end points of the study included safety regarding AEs, as well as dose-limiting toxicities of teclistamab, daratumumab, and lenalidomide. Important secondary end points included overall response rate (ORR), very good partial responses (VGPRs) or better, complete responses (CRs) or better, duration of response (DOR), and time to response.

Patients with measurable multiple myeloma following 1 to 3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug were eligible to enroll in the study.

A total of 32 patients were treated with the triplet regimen in the study; 13 received 0.72 mg/kg of teclistamab, and 19 received 1.5 mg/kg of teclistamab. The median age of patients was 65 years in the 0.72 mg/kg group and 60 years in the 1.5 mg/kg group. According to Searle, over one-third of patients had high-risk cytogenetics defined as having at least 1 of the following aberrations: del17p, t(4;14), or t(14;16). Six patients (46.2%) in the 0.72 mg/kg group and 3 patients (15.8%) in the 1.5 mg/kg group were refractory to lenalidomide. Three patients (23.1%) in the 0.72 mg/kg group and 3 (15.8%) in the 1.5 mg/kg group were refractory to an anti-CD38 antibody.

At a median follow-up of 8.4 months, the ORR was 93.5%. The median time to first response among patients was 1 month, and the median time to CR or better was 3 months.

“At data cutoff, [CR] or better was achieved in over 55% of patients in both dosing groups, and VGPR or better was achieved in 90% [of both dosing groups],” Searle said.

In total, 80.6% of patients remained progression-free and were on treatment at the time of data cutoff. Patient responses deepened over time, and the median DOR had not been reached.

According to Searle, the triplet regimen will be prospectively compared vs daratumumab with lenalidomide and dexamethasone in patients with newly-diagnosed multiple myeloma who are transplant-ineligible or in the randomized, open-label phase 3 MajesTEC-7 trial (NCT05552222). This study will be presented as a trial-in-progress in a later poster session during ASH 2022.

Searle E, Quach H, Wong SW, et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: results from one cohort of MajesTEC-2, a phase 1b, multicohort study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 160.

Results from the phase 1b MajesTEC-2 trial showed that teclistamab plus daratumumab and lenalidomide demonstrated potential for deep and durable responses in relapsed or refractory multiple myeloma.

Russ Conroy | Authors

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