Glofitamab Monotherapy Produces Sustained Responses in Richter Syndrome

Carmelo Carlo-Stella, MD

Administration of glofitamab (Columvi) after pretreatment with obinutuzumab (Gazyva) provided encouraging antitumor activity with high and durable complete response (CR) rates and a manageable safety profile in heavily pretreated patients with Richter syndrome (RS), according to updated data from the dose-escalation portion of a phase 1 trial (NCT03075696) presented at the 17th Annual International Conference on Malignant Lymphoma (ICML).¹

At a median follow-up of 40.8 months (range, 0-54), glofitamab monotherapy elicited an overall response rate (ORR) of 63.6% in the overall population (n = 11), comprised of a 45.5% complete response (CR) rate and a 18.2% partial response (PR) rate; the percentage of patients who experienced stable disease (SD) or progressive disease (PD) was 18.2%, respectively. The median time to CR was 2.5 months (95% CI, 1.4-not evaluable [NE]).

Moreover, the high CR rates seen with this regimen in highly refractory patients were clinically meaningful and were largely sustained after treatment completion. As of the data cutoff date of January 16, 2023, 80% of CRs (n = 5) were ongoing for more than 33 months. The median time on treatment was 5.5 months (range, 0.5-7.6).

Most patients who received glofitamab achieved a 50% or greater reduction in tumor size from baseline. No metabolic response occurred at the 0.6-mg and 2.5/10/16-mg step-up dose levels. An approximated 25% reduction in tumor size was seen in the former group, while an approximated 60% reduction was observed with the latter dose. Partial metabolic responses were seen at the 25-mg intravenous dose and 2.5/10/16 mg step-up doses, with tumor reductions of approximately 40% and 90%, respectively. The remaining intravenous dose levels of 1.8 mg, 10 mg, 1 mg, as well as the step-up doses of 2.5/10/30 mg, resulted in complete metabolic responses. Tumor reductions ranged from 90% to 100% in these groups.

“Glofitamab step-up dosing represents a potential therapy for patients with RS, who still remain a population with high unmet medical need,” first study author Carmelo Carlo-Stella, MD, of the Department of Biomedical Sciences, Humanitas University, and Department of Oncology and Hematology, IRCCS Humanitas Research Hospital in Rozzano MI, Italy, said in a presentation of the data.

Previous data from the phase 1 dose-expansion portion of the trial were published in the Journal of Clinical Oncology and showed that glofitamab continued to have clinical activity and a manageable toxicity profile in patients with B-cell non-Hodgkin lymphoma (NHL).² When administered at the recommended phase 2 dose—which was step-up dosing of 2.5 mg on day 1 cycle 1, 10 mg on day 8 of cycle 1, and 30 mg on day 1 of cycle 2—the agent produced an ORR of 65.7%, with 57.1% of patients achieving a CR. Responses were quickly achieved and were durable, with 84.1% of patients (n = 63) experiencing an ongoing CR with a maximum of 27.4 months of observation.

The median duration of response (DOR) in patients with aggressive NHL (n = 127) was 5.5 months (95% CI, 4.4-NE), median duration of CR (DOCR) was not yet reached, and the median progression-free survival (PFS) was 2.9 months (95% CI, 2.1-3.9). Notably, 72.8% of patients who achieved a CR in this group still experienced a response at 12 months of follow-up.

At the 2023 ASCO Annual Meeting, investigators reported the activity and safety of glofitamab monotherapy following single-dose obinutuzumab pretreatment in a subgroup of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who developed RS.¹

“The prognosis of these patients is very poor, and they have an estimated median survival of 8 to 12 months. This particularly applies to the 80% of [patients with] RS [who have] clonal-relation between diffuse large B-cell lymphoma and CLL.” Carlo-Stella emphasized. “For these patients, there is no standard of care…”

The dose-escalation phase of the first-in-human trial enrolled patients 18 years of age or older with histologically confirmed relapsed/refractory, CD20-expressing B-cell NHL. Patients were required to have progressed on 1 or more prior systemic treatments, including at least 1 anti-CD20 antibody. Other key inclusion criteria included having an ECOG performance status of 0 or 1.^1,2

Patients received intravenous glofitamab on a fixed-dose schedule or step-up dosing schedule in cycle 1. Seven days prior to glofitamab administration, patients were pretreated with 1000 mg of obinutuzumab to mitigate cytokine release syndrome (CRS). In the fixed dosing schedule, the agent was administered at 5 dose levels ranging from 0.6 mg to 25 mg. For step-up dosing, the target dose was 16 mg or 30 mg. Patients received 2.5 mg of glofitamab on day 8 of cycle 1 and 10 mg on day 15 of cycle 1, and then 30 mg on day 1 of cycle 2 until all 12 cycles had been completed; this equated to approximately 8.3 months of treatment. Treatment duration was fixed at a maximum of twelve 21-day cycles in both groups.

The study’s primary end points were safety and tolerability, pharmacokinetics, maximum tolerated dose (MTD), and dose-limiting toxicities.² Key secondary end points included ORR, DOR, DOCR, PFS, pharmacodynamic biomarkers, and incidence of antidrug antibodies.

At the time of the data cutoff,11 patients had enrolled onto the study.¹ Of these, 5 patients were treated with fixed-dose glofitamab, and 6 patients received the step-up dose of the agent. The median age of patients in the overall population was 71 years (range, 48-77), and 36.4% were male. An ECOG performance status of 0 or 1 was seen in 18.2% and 81.8% of patients, respectively.

Moreover, 90.9% of patients had Ann Arbor stage III or IV disease, and 9.1% had stage I or II disease. An International Prognostic Index score of 3 or above was seen in 45.5% of patients. The percentage of patients with bulky disease, defined as being greater than 6 cm, was 63.6%. The cell of origin was germinal center B-cell (GCB) for 18.2% of patients and activated B-cell (ABC) for 9.1% of patients; 45.5% had a non-GCB/ABC origin.

All patients were refractory to their most recent regimen. Over half of patients were also refractory to their first line of therapy (54.5%), and most were refractory to any prior CD20-directed agent (90.9%). The median number of prior lines of therapy received was 3 (range, 1-4), and the median time since last therapy was 1.8 months (range, 1.4-4.6). Most patients had received prior therapy for CLL (90.9%); this included chemotherapy (72.7%), anti-CD20 therapies (90.9%), BTK inhibitors (36.4%), BCL-2 inhibitors (9.1%), and alkylating agents (45.5%). Regarding prior therapy for RS, 90.9% of patients each received chemotherapy and CD20-directed therapy.

Safety analysis showed that the agent had a manageable safety profile. No patients discontinued treatment due to adverse effects (AEs), and no AEs higher than grade 4 were reported. Any-grade AEs occurred in 100% of patients, with 90.9% of events related to glofitamab treatment. Moreover, 72.7% of patients experienced serious AEs, and 63.6% experienced a grade 3/4 event. Moreover, 54.5% of patients experienced a serious treatment-related AE (TRAE), and 45.5% of patients had a grade 3/4 TRAE.

The most common AEs reported in at least 20% of patients were CRS (all AEs, 72.8%; TRAEs, 72.8%), pyrexia (54.6%, 18.2%), fatigue (36.4%; 18.2%), thrombocytopenia (36.4%; 9.1%), headache (27.3%; 0%), and rash (27.3%; 18.2%). Aside from CRS and thrombocytopenia, all AEs were grade 3 or lower in severity.

Further analysis of patients who experienced CRS events (n = 8) showed that 27.3% experienced a grade 1 event, 27.3% reported a grade 2 event, 9.1% had a grade 3 event, and 9.1% had a grade 4 event. The median time to onset from the 2.5-mg dose was 14.58 hours (range, 3.5-36.7). With the fixed-dosing schedule, 60% of patients (n = 5) experienced CRS in cycle 1, and 20% experienced CRS in cycles 2, 3, and 4, respectively. In the step-up dosing group (n = 6), 66.7% of patients experienced CRS during days 8 to 14 of cycle 1, 50% experienced CRS on days 15 to 21 of cycle 1, and 33.3% experienced CRS during cycle 2. Half of patients were given tocilizumab (Actemra) for CRS management, and 37.5% received were treated with corticosteroids.

“Comparing the graphs for patients receiving glofitamab [at] a fixed dose [vs] step-up dosing, [we see a] major finding suggesting the [superiority] of the step-up dosing [strategy] for mitigating CRS,” Carlo-Stella said during the presentation.

Other AEs of interest included infections/infestations (any grade, 54.5%; grade ≥3, 0%), neutropenia (45.5%; 27.3%), tumor flare (9.1%, 0%), neurologic AEs (45.5%; 9.1%), or immune effector cell–associated neurotoxicity syndrome (18.2%; 9.1%).

References

1. Carlo-Stella C, Hutchings M, Offner F, et al. Glofitamab monotherapy induces durable complete remissions and has a manageable safety profile in patients with Richter’s transformation. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 28.
2. Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting cell–engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell Lymphoma: a phase I trial. J Clin Oncol. 2021;39(18):1959-1970. doi:10.1200/JCO.20.03175