On June 15, 2023, the FDA accelerated the approval of glofitamab-gxbm (Columvi; Genentech), a bispecific CD20-directed CD3 T-cell engager, for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), or large B-cell lymphoma (LBCL) arising from follicular lymphoma after ≥2 lines of systemic therapy. The FDA granted this application priority review and fast track designation.
The approval was based on results from the phase 1/2 NP30179 study, an open-label, multicenter, single-arm clinical trial of 132 patients with relapsed or refractory DLBCL, NOS (80% of patients), or LBCL arising from follicular lymphoma (20% of patients) who had received ≥2 previous lines of systemic therapy (median, 3; range, 2-7). Patients with active or previous central nervous system lymphoma or disease were excluded from the trial.
Objective response rate (ORR) and duration of response (DOR) were the main efficacy measures. The ORR was 56% (95% confidence interval [CI], 47-65), with 43% having complete responses. Responders had an estimated median follow-up of 11.6 months, with an estimated median DOR of 18.4 months (95% CI, 11.4-not estimable). The 9-month Kaplan-Meier estimate for DOR was 68.5% (95% CI, 56.7-80.3), and the median time to response was 42 days.
The prescribing information for glofitamab has a boxed warning for serious or fatal cytokine release syndrome (CRS); other warnings and precautions include neurologic toxicity including immune effector cell–associated neurotoxicity syndrome (ICANS), serious infections, and tumor flare. Of 145 patients with relapsed or refractory LBCL evaluated for safety, 70% had CRS (grade ≥3 CRS, 4.1%), 4.8% had ICANS, 16% had serious infections, and 12% had tumor flare.
The most common (≥20%) adverse reactions, excluding laboratory abnormalities, were CRS, musculoskeletal pain, rash, and fatigue. The most common (≥20%) grade 3/4 laboratory abnormalities were decreased lymphocytes, phosphate, neutrophils, and fibrinogen, and increased uric acid.
Prior to glofitamab administration, a single 1000-mg dose of obinutuzumab (Gazyva; Genentech) is given on cycle 1 day 1 to deplete circulating and lymphoid-tissue B cells, after which glofitamab is administered via intravenous infusion on 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 is given on day 1 of each subsequent cycle for a maximum of 12 cycles. Each cycle is 21 days.
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On May 19, 2023, the FDA accelerated the approval of epcoritamab-bysp (Epkinly; Genmab US), a bispecific CD20-directed CD3 T-cell engager, for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma after ≥2 lines of systemic therapy. The FDA granted this application priority review.
The approval was based on response rate and durability of response in the phase 1/2 EPCORE NHL-1 study, an open-label, multicohort, multicenter, single-arm clinical trial of patients with relapsed or refractory B-cell lymphoma. The 148 patients in the efficacy population had relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma after ≥2 lines of systemic therapy, including ≥1 anti-CD20 monoclonal antibody–containing therapies.
The main efficacy measure was overall response rate, which was 61% (95% confidence interval [CI], 53-69), with 38% complete responses. Responders had a median follow-up of 9.8 months, with an estimated median duration of response of 15.6 months (95% CI, 9.7-not reached).
The prescribing information for epcoritamab includes a boxed warning for serious or life-threatening cytokine release syndrome (CRS) and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome (ICANS). The warnings and precautions include infections and cytopenias. In 157 patients with relapsed or refractory large B-cell lymphoma who received the recommended dose of epcoritamab, 51% had CRS, 6% had ICANS, and 15% had serious infections. A total of 37% of patients had grade 1 CRS, 17% had grade 2, and 2.5% had grade 3. Grade 1 ICANS occurred in 4.5% of patients, grade 2 in 1.3%, and grade 5 in 0.6%.
The most common (≥20%) adverse reactions were CRS, fatigue, musculoskeletal pain, injection-site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common (≥10%) grade 3/4 laboratory abnormalities were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.
The recommended regimen for epcoritamab is subcutaneous administration in 28-day cycles until disease progression or unacceptable adverse events. The drug’s recommended dose comprises step-up dosing in cycle 1 (0.16 mg on day 1, 0.8 mg on day 8, and 48 mg on days 15 and 22) followed by a fixed dosing of 48 mg weekly during cycles 2 and 3, every other week during cycles 4 through 9, and then every 4 weeks on day 1 of subsequent cycles.
On June 20, 2023, the FDA approved a new indication for talazoparib (Talzenna; Pfizer), a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with enzalutamide (Xtandi; Astellas) for homologous recombination repair (HRR) gene mutation–positive, metastatic castration-resistant prostate cancer (mCRPC). The FDA granted this application priority review.
This is the first PARP inhibitor approved for use with a current standard of care (enzalutamide) for adults with mCRPC and HRR gene mutation.
Talazoparib was initially approved as monotherapy for locally advanced or metastatic HER2-negative breast cancer with deleterious or suspected deleterious germline BRCA mutation.
The new approval was based on the results of the phase 3 TALAPRO-2 study, a randomized, double-blind, placebo-controlled, multicohort clinical trial of patients with mCRPC and HRR gene mutation. Patients were randomized 1:1 to enzalutamide 160 mg daily plus talazoparib 0.5 mg or placebo daily.
The eligibility criteria included having a previous orchiectomy or receiving gonadotropin-releasing hormone analogs. Patients were excluded if they had previous systemic therapy for mCRPC, but previous treatment with cytochrome (CY) P17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer was permitted. The trial stratified randomization by previous treatment with a CYP17 inhibitor or docetaxel.
The study investigators prospectively assessed multiple HRR genes using circulating tumor DNA–based next-generation sequencing assays and/or tumor tissue.
There was a significant improvement in radiographic progression-free survival (PFS), which was the major efficacy measure, for talazoparib plus enzalutamide compared with placebo plus enzalutamide in patients with the HRR mutation (median, not reached vs 13.8 months; hazard ratio, 0.45; 95% confidence interval [CI], 0.33-0.61; P<.0001). According to the results of an exploratory analysis by BRCA mutation status, the hazard ratio for radiographic PFS was 0.20 (95% CI, 0.11-0.36) in patients with mCRPC and the BRCA mutation (n=155) and 0.72 (95% CI, 0.49-1.07) in patients who had HRR-positive mCRPC without the BRCA mutation.
The most common (≥10%) adverse reactions, 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. In TALAPRO-2, 39% (199/511) of the total patients with mCRPC who received talazoparib plus enzalutamide needed a blood transfusion, including 22% who needed multiple transfusions, and 2 patients were diagnosed with myelodysplastic syndrome or acute myeloid leukemia.
On May 31, 2023, the FDA approved a new indication for olaparib (Lynparza; AstraZeneca), a poly (ADP-ribose) polymerase inhibitor, in combination with abiraterone (Zytiga; Janssen Biotech) and prednisone (or prednisolone) for adults with deleterious or suspected deleterious BRCA mutation–positive, metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved test.
Olaparib was previously approved as monotherapy for patients with mCRPC and deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutation–positive mCRPC whose disease progressed after previous treatment. The drug also has received various approvals for the treatment of ovarian, breast, and pancreatic cancers.
“Preventing or delaying radiographic progression or death is an important clinical end point in assessing cancer treatment and is very important to patients, their caregivers, and their families,” said Andrew Armstrong, MD, MSc, Duke Cancer Institute, Durham, NC, and a study investigator. “The PROpel results showed the Lynparza combination demonstrated a notable clinically meaningful benefit that should rapidly be considered as the standard-of-care treatment for patients with BRCA-mutated metastatic castration-resistant prostate cancer.”
The new approval was based on results from the phase 3 PROpel clinical trial of 796 patients with mCRPC. Patients were randomized 1:1 to receive olaparib plus abiraterone or placebo plus abiraterone, and they also received prednisone or prednisolone. To be included in the trial, patients had to have a previous orchiectomy or, if not, had to have received gonadotropin-releasing hormone analogs. Patients were excluded if they had received systemic therapy for mCRPC, but previous treatment with docetaxel for metastatic hormone-sensitive prostate cancer was allowed. Randomization was stratified by previous docetaxel treatment and site of metastases. Retrospective testing for BRCA mutational status, with the FoundationOne CDx and FoundationOne Liquid CDx tests, was performed on all available clinical samples.
The major efficacy measure was investigator-assessed radiologic progression-free survival (PFS), with overall survival (OS) as an additional end point. Patients treated with olaparib plus abiraterone had a significant improvement in radiologic PFS compared with those treated with placebo plus abiraterone in the intent-to-treat (ITT) population. In the 85 patients with a BRCA mutation (11% of the ITT population), an exploratory subgroup analysis revealed a median radiologic PFS that was not reached with olaparib plus abiraterone compared with 8 months (95% confidence interval [CI], 6-15) with placebo plus abiraterone (hazard ratio [HR], 0.24; 95% CI, 0.12-0.45). In this subgroup, the OS HR was 0.3 (95% CI, 0.15-0.59). The subgroup of patients without a BRCA mutation (n=711; 89% of ITT population) had a radiologic PFS HR of 0.77 (95% CI, 0.63-0.96) and an OS HR of 0.92 (95% CI, 0.74-1.14), suggesting that the radiologic PFS improvement in the ITT population was mainly attributable to patients with the BRCA mutation.
The most common (≥10%) adverse reactions with olaparib plus abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). A total of 72 (18%) patients needed ≥1 blood transfusions and 46 (12%) needed several transfusions.
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