Accelerated Approval of Glofitamab-Gxbm for Selected Relapsed or Refractory Large B-Cell Lymphomas
The FDA granted accelerated approval to glofitamab-gxbm for relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), or large B-cell lymphoma (LBCL) arising from follicular lymphoma after two or more lines of systemic therapy.
Glofitamab-gxbm, a bispecific CD20-directed CD3 T-cell engager, was studied in trial NP30179 (NCT03075696), an open-label, multicenter, single-arm trial that included 132 patients for the evaluation of efficacy. Eighty percent of patients had relapsed or refractory DLBCL, NOS and 20 percent had LBCL arising from follicular lymphoma. Patients had received at least two prior lines of systemic therapy (median 3, range 2-7). The trial excluded patients with active or previous central nervous system lymphoma or disease.
The main efficacy outcome measures were objective response rate (ORR) and duration of response (DOR), determined by an Independent Review Committee using the 2014 Lugano criteria. The ORR was 56 percent (95% CI: 47, 65) with 43 percent achieving complete responses. With an estimated median follow-up of 11.6 months among responders, the estimated median DOR was 18.4 months (95% CI: 11.4, not estimable). The 9-month Kaplan-Meier estimate for DOR was 68.5 percent (95% CI: 56.7, 80.3). The median time to response was 42 days.
The prescribing information includes a boxed warning for serious or fatal cytokine release syndrome (CRS). Other warnings and precautions include neurologic toxicity including immune effector cell-associated neurotoxicity (ICANS), serious infections, and tumor flare. Among 145 patients with relapsed or refractory LBCL evaluated for safety, CRS occurred in 70 percent (Grade 3 or higher CRS, 4.1%), ICANS in 4.8 percent, serious infections in 16 percent, and tumor flare in 12 percent.
The most common (>= 20%) adverse reactions, excluding laboratory terms, were CRS, musculoskeletal pain, rash, and fatigue. The most common (>= 20%) Grade 3-4 laboratory abnormalities were decreases in lymphocyte counts, phosphate, neutrophil counts, and fibrinogen, as well as increase in uric acid.
Following a single 1,000 mg dose of obinutuzumab on Cycle 1 Day 1 to deplete circulating and lymphoid tissue B cells, glofitamab-gxbm is administered by intravenous infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. The cycle length is 21 days. Refer to the prescribing information for complete dosing information.
Glofitamab-gxbm should only be administered by a health care professional with appropriate medical support to manage severe reactions, including CRS. Because of the CRS risk, patients should be hospitalized during and for 24 hours after the first step-up dose (2.5 mg on Day 8 of Cycle 1), and for the second step-up dose (10 mg on Day 15 of Cycle 1) if any grade CRS occurs with the 2.5 mg dose. For subsequent doses, patients who experience Grade >=2 CRS with their previous infusion should be hospitalized during and for 24 hours after the completion of the next infusion.
Approval of Talazoparib With Enzalutamide for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer
Talazoparib with enzalutamide has been approved for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). Efficacy was evaluated in TALAPRO-2 (NCT03395197), a randomized, double-blind, placebo-controlled, multi-cohort trial enrolling 399 patients with HRR gene-mutated mCRPC.
Patients were randomized (1:1) to receive enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. Patients were required to have a prior orchiectomy and, if not performed, received gonadotropin-releasing hormone (GnRH) analogs. Patients with prior systemic therapy for mCRPC were excluded; however, prior CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) was permitted. Randomization was stratified by previous treatment with a CYP17 inhibitor or docetaxel. HRR genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) were assessed prospectively using tumor tissue and/or circulating tumor DNA (ctDNA)-based next generation sequencing assays.
The major efficacy outcome measure was radiographic progression-free survival (rPFS) per RECIST version 1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone, assessed by blinded independent central review.
A statistically significant improvement in rPFS for talazoparib with enzalutamide compared to placebo with enzalutamide was observed in the HRR gene-mutated population with a median that was not reached versus 13.8 months (HR: 0.45; 95% CI: 0.33, 0.61; p<0.0001). In an exploratory analysis by BRCA mutation status, the hazard ratio for rPFS in patients with BRCA-mutated mCRPC (n=155) was 0.20 (95% CI: 0.11, 0.36) and, in patients with non-BRCAm HRR gene-mutated mCRPC, was 0.72 (0.49, 1.07).
The most common adverse reactions (>=10%), including laboratory abnormalities, were decreased hemoglobin, decreased neutrophils, decreased lymphocytes, fatigue, decreased platelets, decreased calcium, nausea, decreased appetite, decreased sodium, decreased phosphate, fractures, decreased magnesium, dizziness, increased bilirubin, decreased potassium, and dysgeusia. Among all patients with mCRPC treated with talazoparib with enzalutamide on TALAPRO-2 (n=511), 39 percent required a blood transfusion, including 22 percent who required multiple transfusions, and two patients were diagnosed with myelodysplastic syndrome/acute myeloid leukemia.
The recommended talazoparib dose is 0.5 mg taken orally once daily in combination with enzalutamide until disease progression or unacceptable toxicity. The recommended enzalutamide dose is 160 mg taken orally once daily. Patients receiving talazoparib and enzalutamide should also receive a GnRH analog concurrently or should have had bilateral orchiectomy.