Glofitamab Alone or Combined With Obinutuzumab Produced Strong Responses in Relapsed/Refractory Follicular Lymphoma

The investigational CD20xCD3 bispecific antibody, glofitamab, as a monotherapy or combined with obinutuzumab (Gazyva),produced impressive response rates in patients with multiple relapsed or refractory follicular lymphoma, according to a presentation of data from the 2021 American Society of Hematology Annual Meeting and Exposition.

In an updated analysis of a phase 1/2 study, response rates were found to be as high as 100% in the single-agent and combination arms, reported Franck Morschhauser, MD, PhD, during the 2021 ASH Annual Meeting. Complete metabolic response rates ranged from 7% to 33% in the monotherapy cohorts, and was 74% in the combination arm.

“Complete response rates are pretty high, comparable to what has been observed with CAR-T cells but we cannot further compare because the follow-up is very short and the duration of response cannot be interpreted in this context,” said Morschhauser, a professor of hematology from the University of Lille in Lille, France.

In the study, 3 glofitamab step-up monotherapy regimens and 1 step-up combination regimen with obinutuzumab were investigated in 72 patients with heavily pretreated relapsed/refractory follicular lymphoma.

In the glofitamab-monotherapy cohorts (n = 53), 3 patients were started on 2.5 mg intravenously, escalating to 10 mg and 16 mg. A total of 21 patients also started with 2.5 mg and stepped up to 10 mg and then 30 mg; 29 patients started at 0.5 mg and stepped up to 2.5 mg, 10 mg, and then 30 mg.

In the combination arm (n = 19) glofitamab was administered intravenously at 2.5/5/10/30 mg plus obinutuzumab at 1000 mg from cycle 2, day 1 and onwards. In all patients, obinutuzumab at 1000 mg was given 7 days prior to the first dose of glofitamab.

The median number of prior therapies was 3 (range, 1-12) in the monotherapy arms and 2 (range, 1-5) in the combination arm. A total 30.2% in the monotherapy arms and 36.8% in the combination arm had double-refractory follicular lymphoma. Other high-risk characteristics were disease progression within 24 months of treatment (POD24) in 35.8% and 52.6% of monotherapy- and combination-treated patients, respectively, respectively; PI3K inhibitor–refractory in 13.2% and 10.5%, respectively; and bulky disease (>5 cm) in 18.9% and 26.3%, respectively.

The response rate was 81% overall in the 53 patients in the monotherapy cohorts. Response rates were 79% in the 0.5-/2.5-/10-/30-mg cohort, 100% in the 2.5-/10-/16-mg cohort, and 81% in the 2.5-/10-/30-mg cohort. In the combination arm, the response rate was 100%.

The rate of complete metabolic response were 70% overall in all monotherapy-treated patients at a median follow-up of 4.4 months (95% CI, 3.5-8.6). The median complete response (CR) follow-up was 2.5 months (95% CI, 2.0-5.3), and 32 patients have ongoing CRs.

In the combination arm, the complete metabolic response rate was 74% at a median follow-up of 5.5 months (95% CI, 5.4-6.3). The median CR follow-up was 4.2 months (95% CI, 4.1-4.4) and 11 patients had ongoing CRs.

7% in those treated with 0.5/2.5/10/30 mg, 33% in those treated with 2.5/10/16 mg, and 14% in those treated with 2.5/10/30 mg.

“Importantly, the best response was often achieved as soon as the first restaging, with a median follow-up of 4.4 months, 86% [32/37] had an ongoing complete metabolic response, while in the combination cohort, the median follow-up was slightly longer, 5.5 months, and 78% [11/14] had ongoing complete responses,” said Morschhauser. “In the combination cohort, it is important to notice that patients that did not achieve a complete metabolic response at the first restaging, all quickly had progressive disease.”

Response rates were consistent in the 23 patients with double-refractory disease (69% with monotherapy, 100% with combination therapy) and in the 29 patients with POD24 (68% and 100%, respectively), and was slightly inferior in the 9 patients who were refractory to PI3K inhibition (57% and 100%, respectively) and the 15 with with bulky disease (50% and 100%, respectively). However, the latter cohorts were small and, thus, caution is advised in interpreting these data, he said.

The rates of all-grade adverse events (AE) were similar in the monotherapy and combination cohorts at 94.3% and 100%, respectively. Two patients in the monotherapy arms died, due to 1 case of cardio-respiratory arrest and 1 from COVID-19–related pneumonia; 1 patient died in the combination cohort due to the COVID-19–pneumonia. No glofitamab-related AEs led to treatment discontinuation.

The overall rate of CRS in the monotherapy cohorts was 66%. The rates of cytokine release syndrome (CRS) in the monotherapy cohorts were 79.2% with 2.5-/10-/16-mg cohort that were grade 1 (n = 15), grade 2 (n = 3), and grade 3 (n = 1). This rate was 55.2% in the 0.5-/2.5-/10-/30-mg cohort, with 10 CRS events that were grade 1 and 6 that were grade 2.

The CRS rate was 78.9% in the combination cohort; 10 CRS events were grade 1 and 5 were grade 2.

No clear benefit in CRS mitigation was observed with extended step-up dosing,” Morschhauser said.

Myelosuppression was more common in patients who received glofitamab in combination with obinutuzumab. There were higher rates of neutropenia in the combination arm compared with monotherapy (58% vs 26%, respectively), anemia (37% vs 25%), and thrombocytopenia (32% vs 11%).

Based on these data, a dose-expansion cohort is currently enrolling patients to receive glofitamab monotherapy at the 2.5-/10-/30-mg step-up dosing schedule.

Reference

Morschhauser F, Carlo-Stella C, Dickinson M, et al. Glofitamab as monotherapy and in combination with obinutuzumab induces high complete response rates in patients (pts) with multiple relapsed or refractory (R/R) follicular lymphoma (FL). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 128.