Limited Clinical Activity Attributed to Second-Line Treatment With Linagliptin Plus Atezolizumab in Gastric/GEJ Carcinoma

Findings from the phase 1b/2 MORPHEUS study indicated that patients with gastric and gastroesophageal junction cancer experienced limited responses to second-line linagliptin plus atezlolizumab.

Second-line treatment with linagliptin (Tradjenta) plus atezolizumab (Tecentriq) for patients with locally or advanced metastatic gastric and gastroesophageal junction cancers resulted in limited clinical activity, according to a presentation on the phase 1b/2 MORPHEUS platform (MORPHEUS; NCT03281369) at the 2021 European Society of Medical Oncology Congress.

Among 14 patients who received atezolizumab plus linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, only 3 exhibited responses, leading to a confirmed investigator-assessed objective response rate (ORR) of 21.4% (95% CI, 4.7%-50.1%).

Among the 12 patients in the active comparator arm who received ramucirumab (Cyramza) plus paclitaxel, there were 2 responses and the investigator-assessed ORR was 16.7% (95% CI, 2.1%-48.4%), Jeeyun Lee, MD, associate professor of hematology/oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, in Seoul, Republic of Korea, and coinvestigators reported in a poster presentation delivered during the meeting.

The authors hypothesized that adding linagliptin, an approved medication to treat patients with diabetes, to atezolizumab could stimulate antitumor immune responses “given the role of DPP-4 in the regulation of several proinflammatory chemokines and intratumoral T-cell recruitment,” they wrote in their poster.

Trials under the MORPHEUS platform are assessing the importance of simultaneously targeting multiple mechanisms of immune escape through immune cell priming and activation, tumor infiltration and/or recognition of tumor cells for elimination.

Patients in the gastric cancer arm of MORPHEUS had histologically or cytologically confirmed locally advanced, unresectable, or metastatic gastric cancer or GEJ adenocarcinoma who had progressed during or following first-line platinum- or fluoropyrimidine- containing chemotherapy. Patients were randomized to atezolizumab at 1200 mg intravenously (IV) every 3 weeks on day 1 of every 21-day cycle plus linagliptin at 5 mg/day orally on day 1 of every 21-day cycle, or ramucirumab at 8 mg/kg IV on days 1 and 15 of every 28-day cycle plus paclitaxel at 80 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle.

The percentage of participants with investigator-assessed objective response, as determined by RECIST v1.1 criteria, was the primary end point. Secondary end points were investigator-assessed progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR), as well as overall survival, safety, pharmacokinetics, and exploratory biomarker analyses.

A total 14.3% of patients in the atezolizumab/linagliptin arm were at least 65 years old compared with 50.0% in the ramucirumab/paclitaxel arm. All 13 patients in the atezolizumab/linagliptin arm for whom baseline lactate dehydrogenase (LDH) levels were available had an LDH level less than 1.5 times the upper limit of normal compared with 58.3% (n = 7/12) in the active comparator arm.

Additional findings showed that the 3 responders in the atezolizumab plus linagliptin arm, 1 had a complete response (CR; 7.1%) and 2 had a partial response (PR; 14.3%). Two patients (14.3%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). The median duration of response (DOR) in this arm was 20.0 months (range, 3.5-31.3), the DCR was 21.4%, and 13 patients (92.9%) had a progressive event or died.

In the active comparator arm with the 16.7% ORR, there were with 0 CRs and 2 (16.7%) PRs. Eight (66.7%) patients had SD as a best response and 2 (16.7%) had PD. The median DOR was 3.3 months (range, 2.9-3.7), and the DCR was 66.7%.

Results also showed that the median progression-free survival (PFS) in the atezolizumab/linagliptin arm was 2.0 months and the median overall survival (OS) was 8.6 months. There were 10 (71.4%) deaths in this arm. In the ramucirumab/paclitaxel arm, the median PFS was 6.1 months, the median OS was 8.3 months, and all 12 patients died.

Regarding safety, all patients in both arms had at least 1 adverse event (AE); the rates of grade 3/4 AEs were 50.0% in the atezolizumab/linagliptin arm vs 75.0% in the active comparator arm. Treatment-related AEs that led to dose modifications or interruptions occurred in 7.1% and 75.0%, respectively, and AEs that led to withdrawal from treatment occurred in 0% and 8.3%, respectively.

Biomarker analyses did not identify trends related to clinical activity. One patient randomized to atezolizumab/linagliptin who achieved a CR had microsatellite instability–high status, an inflamed tumor phenotype, and had moderate PD-L1 immunohistochemical staining.

Of the 2 in this arm with a PR, 1 had an inflamed tumor phenotype and PD-L1–high (immune cell; 15%) expression and the other had a desert tumor phenotype and low PD-L1 expression. All patients treated with atezolizumab plus linagliptin had a 50% to 90% reduction in DPP-4 activity at cycle 1 day 15 compared with baseline; a reduction that was generally maintained.

Reference

Lee J, Ajani JA, Kang Y-K, et al. Phase Ib/II open-label, randomised evaluation of second-line atezolizumab (atezo) + linagliptin (lina) vs ramucirumab (ram) + paclitaxel (pac) in MORPHEUS-gastric cancer. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1382P.