乌鸦传媒

Most patients with heavily treated relapsed/refractory B-cell lymphomas responded to a bispecific T-cell-engaging antibody following obinutuzumab (Gazyva) pretreatment, according to preliminary clinical data.

Across the range of doses evaluated, 53.8% of patients responded to glofitamab, increasing to 65.7% for patients who received the recommended phase II dose. More than a third of all patients had complete responses, which proved durable in most cases.

The treatment was associated with low rates of severe cytokine release syndrome (CRS) and neurotoxicity-like symptoms, reported Michael J. Dickinson, MBBS, DMedSc, of Peter MacCallum Cancer Center and the University of Melbourne in Australia, and co-authors in the .

"What struck me was that at sub-1-mg doses every couple of weeks, we were beginning to see striking clinical responses in patients with highly refractory B-cell lymphoma," Dickinson told 乌鸦传媒 via email. "As we escalated the doses, the response rates continued to improve to the point we have seen responses -- durable responses -- that suggest that this off-the-shelf drug could compete with complex therapies like CAR-T [chimeric antigen receptor T-cell therapy] in terms of response rates in relapsed aggressive lymphoma. There is also striking activity in indolent lymphoma."

"In the highly refractory patient population treated in the trial, at the recommended phase II dose we observed that 57.1% had a complete remission, and 84% had retained that remission at the data cutoff, many observed for several years. This is remarkable because unlike some of the other agents in this space, it's been developed as a time-limited therapy; only eight or 12 cycles were given," he added.

Despite recent therapeutic advances, relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) remains a poor-prognosis condition. Autologous stem-cell transplantation can cure a fraction of patients, but many others cannot undergo the procedure because of toxicity or inadequate response to second-line chemotherapy, Dickinson and co-authors noted.

Before CAR T-cell therapy, patients who did not respond to chemoimmunotherapy or relapsed within a year had a 7% rate of complete response to subsequent therapy. Though practice changing, CAR T-cell therapy requires careful patient selection and extensive healthcare coordination, has manufacturing-related limitations, and can have potentially life-threatening complications, the authors said.

Bi-specific T-cell engaging therapies represent a potential new option in the setting of relapsed/refractory B-NHL. Distinct from other agents in the class, glofitamab has a longer half-life and a molecular configuration that enables bivalent binding to CD20 and monovalent binding to CD3. The unique configuration was associated with "profound antitumor efficacy" in preclinical models of (DLBCL) pretreated with obinutuzumab.

The authors reported findings from the initial cohorts of a dose-finding study of glofitamab. Enrollment was limited to patients with heavily treated B-NHL. Of the 171 patients included in data analysis, 155 (90.6%) were refractory to their most recent therapy. The study population had a median treatment history of three prior regimens.

All patients received obinutuzumab pretreatment to reduce toxicity, followed 7 days afterward by glofitamab at doses ranging from 0.005-30 mg. The primary endpoints were safety, pharmacokinetics, and maximum tolerated dose of glofitamab.

DLBCL accounted for 74% of the study population, and most of the remaining patients had transformed follicular lymphoma, other aggressive histologies, and relapsed/refractory indolent lymphoma subtypes.

CRS occurred in 86 (50.3%) patients, and reached grade 3/4 severity in 3.5%. Two patients (1.2%) developed grade 3 transient immune-effector cell-associated neurotoxicity syndrome-like symptoms. Five patients (2.9%) withdrew because of adverse events.

The overall response rate (ORR) of 53.8% included complete responses in 36.8% of patients. The treatment resulted in "significant clinical activity" at glofitamab doses as low as 0.6 mg. The recommended phase II dose is 30 mg.

Response rates by disease subtype were 48% for aggressive NHL, 41.4% for DLBCL, 55.2% for transformed follicular lymphoma, and 70.5% for grade 1-3a follicular lymphoma. Among patients who received glofitamab doses ≥10 mg, the ORR for all patients was 63.3% and ranged from 55.3% to 69% across the disease subtypes represented in the trial.

The next phase of clinical evaluation is to study the recommended phase II dose of glofitamab in more patients with the most common disease subtypes, and that work has already begun, said Dickinson.

"Trials are exploring combinations with other attractive novel therapies," he added. "Glofitamab is especially exciting because we know that all this activity we are seeing occurs even in the setting of potentially competing anti-CD20 antibody [in this case, obinutuzumab], which means it can be combined with established rituximab [Rituxan]-containing combinations such as R-CHOP without the rituximab diminishing its activity."

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