Englumafusp alfa/Glofitamab Combo Shows Early Responses in R/R Aggressive non-Hodgkin Lymphoma

Franck Morschhauser, MD, PhD

The combination of englumafusp alfa and glofitamab (Columvi) demonstrated clinical activity and tolerability across all dose levels examined in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL), according to dose-escalation findings of the first-in-human phase 1b BP41072 study (NCT04077723) that were presented during the 2024 EHA Congress.¹

Results showed that, of 83 patients in the second-line and beyond setting, the best overall response (BOR) with the combination was 67.0% and the complete response (CR) rate was 57.0%. In the third-line and beyond setting, these rates were 65.7% and 52.8%, respectively.

“I hope I could convince you that this combination of englumafusp alfa and glofitamab shows promising antitumor activity in patients with relapsed/refractory non-Hodgkin lymphoma with aggressive histology,” lead study author Franck Morschhauser, MD, PhD, professor of hematology at the University of Lille in France, said in an oral presentation during the meeting. “This is the first ‘off-the-shelf treatment that can replace CAR T[-cell therapy] with the same mechanism of action, and with, we hope, a positive benefit-risk profile.”

Glofitamab is an anti-CD20xCD3 T-cell engaging bispecific antibody approved for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or large B-cell lymphoma arising from follicular lymphoma, after at least 2 lines of systemic therapy.²

Englumafusp alfa is a costimulatory bispecific antibody-like fusion protein that targets both CD19 on B cells and 4-1BB on immune cells; the agent has previously shown preclinical synergistic activity.¹

In the open-label, phase 1b BP41072 trial, investigators explored englumafusp alfa in combination with glofitamab in patients with relapsed/refractory B-cell NHL after at least 1 prior therapy. Glofitamab was administered at a step-up dosing schedule of 2.5 mg, 10 mg, and 30 mg in cycles 1 and 2 after a single 100-mg dose of obinutuzumab (Gazyva).

As part of the dose-escalation portion of the trial, englumafusp alfa was given after glofitamab step-up dosing on day 8 of cycle 2 at doses ranging from 0.36 mg to 75 mg; both intravenous agents were given the same day at a fixed treatment duration from day 1 of cycle 3 onwards every 3 weeks for up to 12 cycles. In the dose-expansion portion, investigators will perform a randomized evaluation of englumafusp alfa at 2 dose levels in the second-line setting for patients with large B-cell lymphoma.

To be eligible for enrollment, patients must have been at least 18 years old, have relapsed/refractory B-NHL, at least 1 measurable lesion, previously received at least 1 prior treatment, and have an ECOG performance status of 0 to 1.

The coprimary end points were safety and tolerability, recommended phase 2 dose, and pharmacokinetics. At the 2024 EHA Congress, Morschauser presented on updated efficacy data in the dose-escalation portion of patients with relapsed/refractory aggressive B-NHL (n = 83) and safety findings for the overall study population (n = 134).

As of October 25, 2023, the aggressive subset of patients included those with DLBCL (n = 60), transformed follicular lymphoma (n = 18), transformed other indolent NHL (n = 3), and grade 3B follicular lymphoma (n = 2). Seventy-six of the 83 patients received at least 1 dose of englumafusp alfa.

Also in the aggressive subset, the median age was 63 years (range, 22-86); 59.0% of patients were male, and 47.0% had an ECOG performance status of 1. Approximately half (50.6%) had Ann Arbor stage IV disease, and 65.1% had an International Prognostic Index score of 2/3. The median number of prior lines of therapy was 3 (range, 1-8), and 84.3% of patients had at least 2 prior lines of treatment. A total 38.6% of patients had bulky disease (>6 cm) and 9.6% previously underwent autologous stem cell transplant. There were 72.3% of patients who were refractory to anti-CD20 therapy, 42.2% refractory to CAR T-cell therapy, and 81.9% who were refractory to any prior treatment. A total 19.3% of patients had primary refractory disease.

Regarding safety in the entire population (n = 134), any adverse effect (AE) was reported in most patients (97.8%) and any infections in more than half (58.2%); grade 3 and grade 5 infections were in 16.4% and 5.2% of patients, respectively. Additional AEs included cytokine release syndrome (CRS; 55.2%), anemia (32.1%), COVID-19 (26.9%), neutropenia (25.4%), diarrhea (23.9%), and pyrexia (20.9%). Any serious adverse effects (SAEs) occurred in 61.2% of patients, comprising CRS (23.9%), COVID-19 (8.2%), COVID-19–related pneumonia (6.0%), and pyrexia (5.2%). Any treatment-related AEs (TRAEs) occurred in 89.6% of all patients; 73.1% were related only to glofitamab, 53.0% were related to both agents, and 11.9% were related to englumafusp alfa only. Four patients (3.0%) had any TRAE that led to drug withdrawal, and 3 patients (2.2%) died due to TRAEs, which included 1 dose-limiting toxicity of pneumocystis jirovecii pneumonia.

“As with all bispecific studies, we had to pay a toll to the COVID-19 pandemic with 5 COVID-related deaths,” Morschauser said, adding that the addition of englumafusp alfa did not result in any new or cumulative safety signals compared with glofitamab alone.

The combination had a comparable CRS profile with single-agent glofitamab; CRS was grade 1 (48.5%), grade 2 (13.4%), or grade 3 (0.7%). Further broken down, any TRAE of CRS occurred in 55.2% of patients, with 51.2% related to glofitamab alone, 6.7% related to both drugs, and 5.2% related to englumafusp alfa alone. A total 23.9% of patients had any SAE of CRS and 0 cases led to withdrawal. The median time to CRS onset was 1 day (range, 0-3) and the median duration of CRS was 2 days (range, 1-8).

When evaluated by cycle, glofitamab-related CRS was mostly grade 1 on day 1 of cycle 1 (2.5-mg dose, 30.8%), followed by grade 2 (6.5%); at the 10-mg dose, these rates were 9.3% and 10.3%, with 1 grade 3 CRS 1 day after the glofitamab dose on day 8 of cycle 1. On day 1 of cycle 2, the grade 1 and 2 CRS rates were 14.0% and 1.9%, respectively. Grade 1 CRS occurred in 4.7% of patients on day 8 of cycle 2 after the first englumafusp alfa dose was administered; on day 1 of cycle 3 and beyond, the grade 1 CRS event was 7.5% and was related to both drugs.

Additional efficacy data showed that in those with aggressive disease who received CAR T-cell therapy previously (n = 42), the BOR was 61.9% and the CR rate was 47.6%. In those without prior CAR T-cell therapy in the second-line and beyond setting (n = 41), these rates were 73.2% and 66.0%, respectively; in the third-line and beyond setting, the BOR was 71.4% and the CR rate was 60.7%. In the definitive second-line setting, these rates were 77.0% and 77.0%, respectively. In patients with aggressive disease who harbor TP53 mutations (n = 22), the BOR was 77.0% and the CR rate was 68.0%.

Morschauser added that englumafusp alfa prevents early T-cell exhaustion in responders, and that the expansion reversal of PD1+ CD8+ Temra cells is dose dependent and linked to complete molecular response reversal. Furthermore, the pharmacodynamics effect aligns with the designed mechanism of action of 4-1BB costimulation. The effector memory boost by englumafusp alfa was also found to be more pronounced in patients with complete molecular response and was linked with deep ctDNA response at the end of treatment.

Disclosures: Dr Morschauser cited honoraria from AstraZeneca, Chugai, and Takeda; consulting or advisory roles with AbbVie, Bristol Myers Squibb, Gilead, ModeX Therapeutics, Novartis, and Roche; and expert testimony with Roche.

References

1. Morschauser F, Gritti G, Dickinson M, et al. Englumafusp alfa (CD19/4-1BBL) combined with glofitamab is safe and shows high efficacy in patients with R/R aggressive B-NHL: final results of the dose-escalation part of phase 1 trial BP41072. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S237.
2. FDA approves Genentech’s Columvi, the first and only bispecific antibody with a fixed-duration treatment for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Genentech. June 15, 2023. Accessed June 15, 2023. https://www.gene.com/media/press-releases/14994/2023-06-15/fda-approves-genentechs-columvi-the-firs