TNB-486 demonstrated sustained antitumor activity in all but 1 patient with relapsed/refractory follicular lymphoma, regardless of CD20 status, as well as number and type of prior therapy, according to data from a phase 1 trial (NCT04594642) presented at the 2023 EHA Congress.

Results showed that patients who received target doses of 2.4 mg or greater (n = 11) experienced an objective response rate of 91% per independent radiological review committee assessment. The sole nonresponder experienced progressive disease. All responses were complete responses (CRs) and among the 5 patients with available samples, all were negative for minimal residual disease by next-generation sequencing. Notably, CRs were observed in those with CD20 negativity (n = 2/2), prior CD20 T-cell–engaging therapy (n = 2/2), disease progression within 24 months (POD24; n = 5/5), and receipt of at least 4 prior lines of therapy (n = 3/4).

“Preliminary efficacy data from this ongoing phase 1 trial show that treatment with TNB-486 at target doses 2.4 mg or higher results in a high CR rate in heavily pretreated patients with follicular lymphoma, including [those] with POD24 and those failing prior CD20 T-cell–engaging therapy,” lead study author Ryan Jacobs, MD, a hematologist and medical oncologist at Levine Cancer Institute, Atrium Health in Charlotte, North Carolina, said in a presentation of the data.

Despite the emergence of CAR T-cell therapy and CD20-directed T-cell engagers, patients with follicular lymphoma whose disease progresses on at least 2 lines of therapy have unmet clinical need, with shortened progression-free survival (PFS) with each subsequent line of therapy.

CD20 antigen loss can occur following CD20-directed therapy and leads to poor outcomes.

TNB-486 is a CD19 x CD3 fully human IgG4 T-cell engager designed to deliver high efficacy with reduced toxicity.

Eligible patients included those at least 18 years of age with CD19-positive relapsed/refractory B-cell non-Hodgkin lymphoma following at least 2 prior lines of therapy; an ECOG performance status of 2 or below; at least 1 measurable lesion; and no active central nervous system disease.

In the fixed-dose schedule, TNB-486 was escalated as follows: 0.03 mg, 0.09 mg, 0.27 mg, 0.8 mg, and 2.4 mg. Single step-up dosing was initiated at 0.27 mg/0.8 mg and was followed by 0.27 mg/2.4 mg, 1 mg/7.2 mg, and 1 mg/10 mg. For double step-up dosing, patients received 0.27 mg/1 mg divided by either 2.4 mg or 7.2 mg.

TNB-486 was administered through intravenous infusion every 2 weeks in 28-day cycles for up to 2 years. Patients who achieved CR after cycle 6 could extend their treatment interval to every 4 weeks.

Safety, tolerability, and pharmacokinetics served as the primary end points of the study, with antitumor activity per RECIL 2017 criteria serving as the sole secondary end point.

As of the clinical cutoff date of December 31, 2022, 17 patients had been treated and 12 remained on therapy. Five patients had discontinued due to progressive disease (n = 3), adverse effect (AE; n = 1), and COVID-19–related death (n = 1).

Regarding baseline characteristics, the median patient age was 64 years (range, 33-86) and most had Ann Arbor stage III or IV disease (64.7%). Approximately half of patients had POD24 (52.9%) and 29.4% had CD20-negative disease.

Patients had received a median of 3 prior lines of therapy (range, 2-9), and 70.6% received at least 3 lines of therapy. Prior therapy included an alkylating agent (76.5%), anti-CD20 monoclonal antibody (100%), immunomodulatory drug (47.1%), CD19-directed CAR T-cell therapy (11.8%), CD20-directed T-cell engager (11.8%), and autologous hematopoietic stem cell transplant (5.9%).

With a median follow-up of 8 months (range, 1-25), the 6-month PFS rate was 91%.

Regarding safety, AEs occurring in at least 20% of patients included cytokine release syndrome, lymphocyte count decrease, hypophosphatemia, pyrexia, platelet count decrease, neutrophil count decrease, nausea, hypertension, headache, chills, anemia, white blood cell count decrease, sinus tachycardia, peripheral edema, hypotension, fatigue, diarrhea, lactate dehydrogenase increase, hypokalemia, dyspnea, constipation, COVID-19, back pain, and anxiety.

“The safety profile is predictable and manageable with a low rate of ICANS [immune effector cell–associate neurotoxicity syndrome]/CRS [cytokine release syndrome] limited to cycle 1, fully reversible, and of short duration,” Jacobs said, who also noted that step-up dosing was effective in reducing cytokine release. Most CRS events were grade 1 (52.9%); all other events were grade 2 (11.8%). Median onset was 2 days (range, 0-2), and median duration was 1 day (range, 1-2). Tocilizumab (Actemra) was used in 23.5% of cases.

Serious AEs occurred in 41.2% of patients, 17.6% of which were related to treatment. Grade 3/4 AEs occurred in 70.6% of patients, 64.7% of which were treatment related. Treatment discontinuation owing to AEs was low, at 5.9%.

Dose escalation will continue to identify the recommended phase 2 dose of the agent, and double step-up dosing will be proceed in further study to improve the safety profile of the regimen.

Disclosures: Dr Jacobs reports receiving research funding from AstraZeneca, Pharmacyclics, Teneobio, and LOXO Oncology; he has served on a speaker’s bureau for AstraZeneca, Pharmacyclics, Janssen, AbbVie, SecuraBio, Beigene, and Eli Lilly; he has worked as a consultant or in an advisory role for AstraZeneca, AbbVie, SecuraBio, Genentech, Adaptive, Beigene, Pharmacyclics, and Janssen.