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FDA News: April 17, 2023, to June 15, 2023

July 2023 Vol 16, No 4 – Online Only


FDA Approves Columvi for Select Patients With Relapsed or Refractory Large B-Cell Lymphomas

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.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” said Krish Patel, MD, Director, Lymphoma Program, Swedish Cancer Institute, Seattle, WA, and a study investigator. “Experience from clinical trials demonstrates that Columvi can provide patients with relapsed or refractory diffuse large B-cell lymphoma a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

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) 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 are given on day 1 of each subsequent cycle for a maximum of 12 cycles. Each cycle is 21 days.

Continued approval for this indication may be contingent on a confirmatory trial(s) that verifies and describes clinical benefit.

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Epkinly FDA Approved for Treatment of Advanced Diffuse Large B-Cell Lymphoma

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.

“Despite recent advances in treating advanced DLBCL, due to the aggressive nature and complexity of the disease, there remains a need for new options that can provide remission, are tolerable, and can be administered upon relapse. The approval of Epkinly brings a new option—and with it—new hope to patients and the greater lymphoma community,” said Meghan Gutierrez, Chief Executive Officer, Lymphoma Research Foundation.

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 or 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.

This approval may be contingent on confirmatory trials that verify and describe the clinical benefit of epcoritamab. The randomized phase 3 EPCORE DLBCL-1 trial is ongoing to confirm the clinical benefit of epcoritamab and to evaluate the drug versus standard-of-care chemoimmunotherapy regimens in patients with relapsed or refractory DLBCL.

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Omisirge FDA Approved for Patients With Hematologic Malignancies to Reduce Infection Risk Following Stem Cell Transplant

On April 17, 2023, the FDA approved omidubicel-onlv (Omisirge; Gamida Cell), a substantially modified allogeneic cord blood–based cell therapy, to quicken the recovery of neutrophils in the body and reduce the risk for infection in adults and pediatric patients aged ≥12 years with hematologic malignancies who have a planned umbilical cord blood transplant after a myeloablative conditioning regimen, such as radiation or chemotherapy. The FDA granted this approval priority review and breakthrough and orphan drug designations.

“The approval of Omisirge is a significant development in hematopoietic stem cell transplantation,” said Steven M. Devine, MD, Chief Medical Officer, National Marrow Donor Program/Be The Match. “Adding Omisirge as a new donor source may help increase access to stem-cell transplant for patients from racially or ethnically diverse backgrounds who struggle to find a fully matched donor in the registry.”

The approval was based on data from the P0501 study, an open-label, multicenter, international, randomized, phase 3 clinical trial of 125 patients aged 12 to 65 years with hematologic malignancies who received omidubicel or standard unmanipulated cord blood (UCB) unit transplantation after myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil (CellCept) for graft-versus-host disease (GVHD).

In all, 62 of the study participants were randomized to receive omidubicel and 63 were randomized to receive UCB. A total of 52 patients in the omidubicel arm were transplanted and received a median CD34+ cell dose of 9.0 × 106 cells/kg (range, 2.1-47.6 × 106 cells/kg). A total of 56 patients in the UCB arm were transplanted with 1 or 2 cord units (66% received 2 cord units). In the 42 patients with reported postthaw cell dose, the median CD34+ cell dose was 0.2 × 106 cells/kg (range, 0.0-0.8 × 106 cells/kg). Total body irradiation–based and chemotherapy-based regimens were among the many conditioning regimens used in the study.

The major efficacy measures included time to neutrophil recovery after transplant and the incidence of grade 2 or 3 bacterial infections or grade 3 fungal infections through 100 days after transplant. The median time to neutrophil recovery was 12 days in the omidubicel arm (95% confidence interval [CI], 10-15 days) and 22 days in the UCB arm (95% CI, 19-25 days). In the omidubicel and UCB arms, 87% and 83% of patients, respectively, achieved neutrophil recovery. The incidence of grade 2 or 3 bacterial infections or grade 3 fungal infections through 100 days after transplant was 39% in the omidubicel arm and 60% in the UCB arm.

The prescribing information for omidubicel has a boxed warning for fatal or life-threatening infusion reactions, GVHD, engraftment syndrome, and graft failure. In 117 study participants who received omidubicel for the treatment of any disease, 47% had infusion reactions, 58% had acute GVHD, 35% had chronic GVHD, and 3% had graft failure.

The most common grade 3 to 5 adverse reactions in patients with hematologic malignancies were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).

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FDA Approves Lynparza Plus Zytiga and Prednisone (or Prednisolone) for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer

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) 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 (GnRH) 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 events 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 multiple transfusions.

The recommended dose of olaparib is 300 mg taken orally twice daily, with or without food. The recommended dose of abiraterone is 1000 mg taken orally once daily. Abiraterone should be administered with prednisone or prednisolone 5 mg of orally twice daily. Patients should also receive a GnRH analog concurrently or should have had a bilateral orchiectomy.

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FDA Approves Polivy Plus R-CHP for Previously Untreated Diffuse Large B-Cell Lymphoma

On April 19, 2023, the FDA approved polatuzumab vedotin (Polivy; Genentech), a CD79b-directed antibody–drug conjugate, in combination with rituximab (Rituxan or a biosimilar; Genentech), cyclophosphamide, doxorubicin, and prednisone (R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified, or high-grade B-cell lymphoma and who have an International Prognostic Index (IPI) score of ≥2.

The FDA granted polatuzumab vedotin accelerated approval in June 2019 for use in combination with bendamustine (Bendeka, Treanda) plus rituximab for the treatment of patients with relapsed or refractory DLBCL after ≥2 previous therapies. The FDA decision in April 2023 converts that accelerated approval to a regular approval.

“It has been nearly 20 years since a new treatment option has become available to people newly diagnosed with diffuse large B-cell lymphoma,” Levi Garraway, MD, PhD, Chief Medical Officer and Head of Global Product Development, Roche, stated in a news release. “Today’s decision from the FDA to approve Polivy in combination with R-CHP in this setting brings a much-needed new treatment option which may improve outcomes and bring other benefits to many patients with this aggressive lymphoma.”

The new approval was based on data from the POLARIX study, a randomized, double-blind, placebo-controlled clinical trial of 879 patients with previously untreated large B-cell lymphoma and an IPI score of 2 to 5. Patients were randomized (1:1) to receive polatuzumab vedotin plus R-CHP or rituximab, cyclophosphamide, doxorubicin, vincristine, plus prednisone (R-CHOP) for six 21-day cycles, followed by 2 additional cycles of rituximab alone in both arms.

The primary end point was investigator- assessed progression-free survival (PFS). Key secondary end points included event-free survival, end-of-treatment positron emission tomography–computed tomography, complete response rate, disease-free survival, overall survival, and safety.

Treatment with polatuzumab vedotin plus R-CHP significantly lowered the risk for disease progression or death compared with R-CHOP (stratified hazard ratio, 0.73; 95% confidence interval, 0.57-0.95; P=.02). At a median follow-up of 28.2 months, the PFS rate was 24.3% in the polatuzumab vedotin plus R-CHP arm versus 30.5% in the R-CHOP arm.

The most common any-grade adverse reactions in the polatuzumab vedotin plus R-CHP and R-CHOP arms were peripheral neuropathy (52.9% vs 53.9%, respectively), nausea (41.6% vs 36.8%, respectively), neutropenia (30.8% vs 32.6%, respectively), and diarrhea (30.8% vs 20.1%, respectively).

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