FDA Approves Glofitamab in Relapsed/Refractory DLBCL and LBCL

Results from the phase 1/2 NP30179 analyzing glofitamab in patients with relapsed/refractory diffuse large B-cell lymphoma and large B-cell lymphoma are reported to have helped lead to its approval.

Glofitamab-gxbm (Columvi) has been approved by the FDA for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or large B-cell lymphoma (LBCL) arising from follicular lymphoma after 2 or more lines of systemic therapy according to a press release from Genentech.¹

Results from the phase 1/2 NP30179 study (NCT03075696) led to the approval. In the phase 1 portion of the study, 171 patients with LBCL who had obinatuzumab (Gazyva) pretreatment were given glofitamab.² The phase 2 trial enrolled 154 patients with diffuse large B-cell lymphoma (DLBCL) who had pretreatment with obinatuzumab and step-up doses of glofitamab.³

“People with diffuse large B-cell lymphoma who have gone through multiple lines of therapy have a poor prognosis and desperately need additional treatment options,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in the press release. “As an off-the-shelf, fixed-duration treatment providing durable response rates, we believe [glofitamab] could change the way this aggressive lymphoma is treated, reinforcing our dedication to bringing innovative treatment options to people with critical unmet needs.”

Findings From the Phase 1 NP30179 Study

Prior to treatment with glofitamab, 1000 mg ofobinutuzumab pretreatment was given to patients to help lessen peripheral and tissue-based B cells and help with cytokine release syndrome (CRS). Patients received 4-hour intravenous infusions of glofitamab, which were then reduced to 2 hours once patients experienced an infusion without complications.

The trial was broken into 3 parts. Part 1 enrolled 3 patients who were given doses of 0.005 mg, 0.015 mg, and 0.045 mg, with all 3 patients withdrawing because of progressive disease. In part 2, a total of 171 patients were given 0.015 mg of treatment. Part 3 is still ongoing.

The median duration of treatment follow-up was 13.5 months, with clinical significance observed in patients receiving 0.6 mg of treatment.

The median age was 64 years, 62.0% of patients were older than 60, and 48.8% had an ECOG performance status of 1 or 2. Additionally, 42.7% of patients had DLBCL, 17.0% had DLBCL from follicular lymphoma, and 5.8% had Richter’s transformation from chronic lymphocytic leukemia. Patients had received a median of 3 prior lines of therapy. Moreover, 90.6% of patients were refractory to prior therapy, the median time since the last therapy was 2.4 months, and the median time since the last anti-CD20 regimen was 5.8 months.

Investigators created 2 step-up dosing cohorts which were tested and included 2.5 mg during cycle 1, day 1; 10 mg on cycle 1, day 8; and 16 mg or 30 mg on cycle 2, day 1. The recommended phase 2 dose (RP2D) was 30 mg.

In patients who had aggressive B-cell non-Hodgkin lymphoma, the overall response rate (ORR) was 48.0% and the complete response (CR) was 33.1%. This included patients with DLBCL who had an ORR of 41.1% and a CR of 28.8%. For those with transformed follicular lymphoma, the ORR was 55.2% and the CR was 34.5%.

At the 10 mg dose, the ORR was 60.9% and the CR was 49.3%, with rates of 55.3% and 42.1% for DLBCL, respectively, and 64.3% for transformed follicular lymphoma. Patients receiving RP2D had an ORR of 71.4% and a CR of 64.3%.

The median duration of response (DOR) for patients with aggressive non-Hodgkin lymphoma was 5.5 months (95% CI, 4.4-not estimable), and the median duration of CR was not reached. In total, 48.6% of patients with any response and 72.8% with a CR were still responding at 12 months. The median progression-free survival was 2.9 months (95% CI, 2.1-3.9).

Regarding safety, 83.6% of patients had at least 1 adverse effect (AE) that was glofitamab related. CRS was the most common AE in 50.3% of patients, with 2.3% having grade 3 and 1.2% having grade 4 events. Symptoms associated with CRS included pyrexia (46.2%), hypotension (24.6%), tachycardia (15.8%), and chills (12.3%). For patients who experienced CRS, the incidence increased with doses but declined after the first administration.

At the RP2D dose, CRS was observed in 71.4%, with 2.9% having grade 3/4 events. Patients were given tocilizumab (11.4%), steroids (11.4%), or both (8.6%) to treat CRS.

Serious AEs were reported in 58.5% of patients, and 45.0% were glofitamab-related. In 1 patient receiving 25 mg of glofitamab experienced a grade 5 AEs, along with 1 patient in the 0.015 mg cohort; both events were unrelated to treatment.

Grade 3 or higher neutropenia was reported in 25.1% of patients with 79.1% being glofitamab related. Febrile neutropenia occurred in 2.9% of patients. Overall, 51.5% of patients had infections, 17.5% had grade 3 or higher AEs, with the most frequent toxicity being pneumonia.

Highlights From the Phase 2 NP30179 Study

The second phase of the NP30179 trial focused on assessing the RP2D in an expansion cohort of patients with DLBCL who received at least 2 previous lines of therapy. Patients were given 1000 mg of obinatuzumab intravenously 7 days before glofitamab. Glofitamab was then given intravenously at the step-up doses of 2.5 mg on day 8 and 10 mg on day 15 of cycle 1, then 30 mg on day 1 for cycles 2 through 12.

The trial featured 108 patients in the pivotal cohort, 40 in the mandatory dexamethasone cohort, and 7 in the dose-escalation cohort. At the data cutoff, 22% of patients finished treatments, 8% were still on the study treatment, and 70% had discontinued.

In total, 71% of patients had DLBCL, 18% had transformed follicular lymphoma, 7% had high-grade B-cell lymphoma, and 4% had primary mediastinal LBCL. Patients had a median age of 66 years and received 3 prior lines of therapy, with 33% having received previous CAR T-cell therapy.

Patients had a median duration of treatment of 79 days, and the median number of cycles of treatment with glofitamab was 5. Additionally, complete responders were on treatment for a median of 12 cycles.

The median follow-up was 12.6 months, with 39% (95% CI, 32%-48%) of patients having a CR byindependent review committee (IRC); the ORR was 52% (95% CI, 43%-60%). The median time to a CR was 42 days (95% CI, 42-44).

The median follow-up was 9.0 months in the initial cohort and 35% of patients had a CR (95% CI, 26-45).

At the time of data cutoff, 66% of patients had continued ORRs and 80% had continued CRs. The median DOR was 18.4 months (95% CI, 13.7-not reached [NR]). A total of 64% (95% CI, 51%-76%) of patients had an ongoing response at 12 months, and the median duration of complete response was NR (95% CI, 16.8-NR). At 12 months, the CR was ongoing and A total of 78% (95% CI, 64%-91%) of patients had a CR ongoing at 12 months.

The 6-month PFS rate in the intent-to-treat population was 46% (95% CI, 37%-54%) and the 12-month PFS was 37% (95% CI, 28%-46%). The PFS by IRC was 4.9 months (95% CI, 3.4-8.1). The 12-month overall survival rate was 50% (95% CI, 41%-58%).

The supporting cohort had a CR rate of 35%, and the median duration of complete response was 34.2 months (95% CI, 17.9-NR), with 2 relapses and 2 deaths occurring after 17 months.

Grade 3 or higher AEs occurred in 62% of patients, and 5% had grade 5 AEs. The most common grade 3/4 AE was neutropenia (27%). The most common AE was CRS in 63% of patients, which typically occurred during the first 3 glofitamab doses. One patient who experienced CRS discontinued treatment, and 7 were admitted to the intensive care unit. Additionally, 38% of patients experienced infections and 15% had infections that were grade 3 or higher.

References

1. FDA approves Genentech’s Columvi, the first and only bispecific antibody with 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://bit.ly/3X7M5dr
2. Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting T-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
3. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913