The investigational agent glofitamab produced high responder rates in combination with obinutuzumab in multiple relapsed or refractory follicular lymphoma.
The investigational CD20xCD3 bispecific antibody Glofitamab as monotherapy or in combination with obinutuzumab (Gazyva), induced high response rates in patients with multiple relapsed or refractory follicular lymphoma.
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.