- Sitagliptin, a DPP-4 Inhibitor, Reduces the Incidence of Acute GVHD After Stem-Cell Transplant
- Pembrolizumab Shows Long-Term Benefits in Patients with Metastatic Colorectal Cancer and MSI-H or dMMR
Sitagliptin, a DPP-4 Inhibitor, Reduces the Incidence of Acute GVHD After Stem-Cell Transplant
BACKGROUND: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem-cell transplant (HSCT). The rate of GVHD is between 34% to 51% within 100 days of undergoing transplant. Dipeptidyl peptidase (DPP)-4 acts as a co-stimulatory factor for T-cell activation. In a preclinical model, down-regulation of DDP-4 expression prevented the incidence of acute GVHD and preserved graft-versus-tumor effects. In addition, a previous study of sitagliptin, a selective DPP-4 inhibitor, in core-blood transplants in adults with hematologic malignancies had an acceptable side-effect profile and decreased incidence of acute GVHD.
METHODS: This single-group, open-label, phase 2 clinical trial included 36 patients who underwent HSCT for 1 of several hematologic malignancies. In all, 13 patients had matched related donors, and the remaining 23 had unmatched related donors. All patients received sitagliptin 600 mg every 12 hours beginning the day before the transplant and continuing until day 14 after transplant, along with a standard immunosuppressive regimen of tacrolimus and sirolimus. The primary end point was grade II to IV acute GVHD by day 100. Secondary end points included mortality not related to disease relapse, disease relapse, and the incidence of chronic GVHD.
RESULTS: Of the 36 patients enrolled in the study, 2 patients had acute GVHD by day 100; 1 patient had grade II acute GVHD involving the gut (stage 1), liver (stage 1), and skin (stage 3) on day 81. Yet another patient had grade IV acute GVHD involving the skin (stage 3), gut (stage 4), and liver (stage 4) on day 29. Overall, the incidence of grade II to IV GVHD was 5%, and the incidence of grade III to IV acute GVHD was 3%. A total of 28 patients received 80% or more of the planned 32 doses of sitagliptin. The rate of disease relapse was 0% at 1 year, confirming the safety and tolerability of the drug. After 1 year, the incidence of disease relapse was 26% (95% confidence interval [CI], 13-41), and the incidence of chronic GVHD was 37% (95% CI, 22-53). A total of 46% (95% CI, 29-62) of the patients had GVHD-free, relapse-free survival. No additional side effects were reported beyond those observed in patients undergoing allogeneic HSCT; in particular, no episodes of hyperglycemia were noted. “The incidence of acute GVHD in our trial appears to be lower than in other trials testing other agents,” the researchers observed.
Source: Farag SS, Zaid MA, Schwartz JE, et al. Dipeptidyl peptidase 4 inhibition for prophylaxis of acute graft-versus-host disease. N Engl J Med. 2021;384:11-19.
Pembrolizumab Shows Long-Term Benefits in Patients with Metastatic Colorectal Cancer and MSI-H or dMMR
BACKGROUND: Chemotherapy is currently the standard of care for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC); however, some patients have disease that is refractory to chemotherapy. Programmed-cell death (PD)-1 inhibitors have emerged as a highly effective therapy in this setting.
METHODS: KEYNOTE-177 was a multicenter, international, open-label, phase 3 study that enrolled 307 treatment-naïve patients with metastatic MSI-H or dMMR CRC. Patients were randomized in a 1:1 ratio to pembrolizumab 200 mg every 3 weeks or to chemotherapy with 5-fluorouracil–based therapy (with or without bevacizumab or cetuximab) every 2 weeks. Crossover from chemotherapy to pembrolizumab was allowed after disease progression. The median duration of patients’ exposure to treatment was 11.1 months in the pembrolizumab group and 5.7 months in the chemotherapy group. Pembrolizumab therapy was continued for a maximum of 35 treatments or until disease progression, unacceptable side effects, illness, or withdrawal. The primary end points were progression-free survival (PFS) and overall survival.
RESULTS: After a median follow-up of 32.4 months, PFS was doubled in the pembrolizumab group compared with the chemotherapy group, for a median of 16.5 months versus 8.2 months, respectively (hazard ratio, 0.60; P = .0002). More patients were alive and progression-free at 12 months and at 24 months in the pembrolizumab group (55.3% and 48.3%, respectively) compared with the chemotherapy group (37.3% and 18.6%, respectively). “After an initial crossing of the progression-free survival Kaplan–Meier curves, a pronounced separation of the curves for pembrolizumab and chemotherapy was observed, which indicated a meaningful long-term benefit with pembrolizumab,” the researchers noted. As of the data cutoff date, 56 patients in the pembrolizumab group and 69 patients in the chemotherapy group had died. Data on overall survival were still evolving and remain blinded until the final analysis. The overall (partial or complete) response was 43.8% in the pembrolizumab group versus 33.1% in the chemotherapy group. The overall ongoing response rate at 24 months was also greater in the pembrolizumab group (83%) compared with the chemotherapy group (35%). The incidence of grade 3 or 4 adverse events was lower with pembrolizumab (56%) versus chemotherapy (78%). In addition, patients in the PD-1 inhibitor group had fewer treatment-related adverse events (22%) than in the chemotherapy group (66%), and 1 death was reported in the chemotherapy group. “These data represent another step forward for biomarker-driven studies targeting MSI-H–dMMR colorectal cancers….Pembrolizumab should be considered an option for initial therapy for patients with MSI-H–dMMR metastatic colorectal cancer,” the authors noted.
Source: André T, Shiu KK, Kim TW, et al; for the KEYNOTE-177 investigators. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207-2218.