FDA roundup: Recent approvals in lymphoma
During the past year, the FDA approved several novel therapies and expanded indications for previously approved treatments for various lymphomas.
Healio has compiled a list of recent FDA decisions — including approval of the first chimeric antigen receptor T-cell therapy for follicular lymphoma — to highlight the growing treatment armamentarium.
Axicabtagene ciloleucel
On March 8, axicabtagene ciloleucel (Yescarta, Kite Pharma, Gilead) received accelerated approval from the FDA for treatment of adults with relapsed or refractory follicular lymphoma after at least two lines of systemic therapy.
The autologous CAR T-cell therapy that targets the CD19 protein, which was approved in October 2017 for relapsed or refractory B-cell lymphoma, is the first CAR T-cell therapy approved for use in follicular lymphoma.
Results from the single-arm, open-label, phase 2 ZUMA-5 trial formed the basis for the FDA’s decision. The data showed that most patients with relapsed or refractory follicular lymphoma responded to one infusion of axi-cel, with approximately three-quarters remaining in complete remission at 18 months.
Axi-cel includes a boxed warning regarding the risks for cytokine release syndrome (CRS), experienced by 8% of patients in ZUMA-5, and neurotoxicity, experienced by 21% of patients in ZUMA-5, associated with CAR T-cell therapy.
Lisocabtagene maraleucel
In February, the FDA granted accelerated approval to liscocabtagene maraleucel (Breyanzi, Bristol Myers Squibb), a gene edited autologous CAR T-cell therapy that targets the CD19 antigen, for treatment of adults with relapsed or refractory large B-cell lymphoma who have received two or more prior therapies. However, the treatment is not indicated for those with primary central nervous system lymphoma.
The FDA based approval on data from the TRANSCEND-NHL-001 trial that showed 73% of patients had an objective response rate and 53% had a complete response rate after one infusion of liscocabtagene maraleucel.
The treatment also includes a boxed warning about the risks of CRS and neurotoxicity associated with CAR T-cell therapy. The FDA also requires a postmarketing study to comply with its Risk Evaluation and Mitigation Strategy Monitoring.
Umbralisimib
Also in February, umbralisimib (Ukoniq, TG Therapeutics) received accelerated approval from the FDA. The agency approved the dual inhibitor of PI3 kinase-delta and CK1-epsilon for treatment of adults with marginal zone lymphoma who received at least one prior anti-CD20-based regimen and adults with follicular lymphoma who received at least three prior lines of systemic therapy.
Results from two single-arm cohorts of the open-label, multicenter UTX-TGR-205 trial formed the basis for approval. Among patients with marginal zone lymphoma, the overall response rate was 49% and 16% achieved complete response. Among those with follicular lymphoma, the overall response rate was 43% and 3% achieved complete response.
Umbralisimib previously received orphan drug designation for both indications as well as priority review for marginal zone lymphoma.
Crizotinib
In January, the FDA approved crizotinib (Xalkori; Pfizer, EMD Serono) for certain patients with systemic anaplastic large cell lymphoma, including children aged at least 1 year and young adults with relapsed or refractory ALK-positive disease.
In the multicenter, open-label, single-arm ADVL0912 study, which formed the basis for FDA approval, the objective response rate was 88% and the complete remission rate was 81% among 26 patients aged 1 to 21 years with relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma who received at least one systemic treatment.
Crizotinib, which is already approved for treatment of patients with metastatic non-small cell lung cancer and ALK-positive or ROS1-positive tumors, was previously granted priority review for the systemic anaplastic large cell lymphoma indication.
Rituximab-arrx
In December 2020, rituximab-arrx (Riabni, Amgen), which is the third biosimilar to rituximab (Rituxan; Genentech, Biogen), received FDA approval for treatment of specific groups of adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis and microscopic polyangiitis.
In a randomized, double-blind, comparative clinical study, rituximab-arrx appeared clinically equivalent to rituximab, with similar safety, pharmacokinetics, pharmacodynamics and immunogenicity, in patients with grade 1 through grade 3A follicular B-cell non-Hodgkin lymphoma and low tumor burden.
Pembrolizumab
In October 2020, the FDA approved an expanded indication for pembrolizumab (Keytruda, Merck) to be used as monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma after frontline therapy or for treatment of children with refractory disease or disease that relapsed after two or more lines of therapy.
The expanded indication was based on results from the phase 3 KEYNOTE-204 trial that showed a 35% reduction in the risk for disease progression or death among patients assigned pembrolizumab vs. brentuximab vedotin (Adcetris, Seagen).
Tafasitamab-cxix
In August 2020, the FDA granted accelerated approval to tafasitamab-cxix (Monjuvi; MorphoSys, Icyte) in combination with lenalidomide (Revlimid, Celgene) for treatment of adults with pretreated diffuse large B-cell lymphoma, representing the first approval of a second-line therapy for adults with DLBCL who progressed during or after first-line therapy.
The indication specifically applies to patients with relapsed or refractory disease not otherwise specified who are not eligible for autologous stem cell transplant.
The agency based its approval on results from the phase 3 L-MIND study evaluating tafasitamab-cxix plus lenalidomide in patients with relapsed or refractory DLBCL who had received one to three prior lines of therapy and were not eligible for high-dose chemotherapy or refused subsequent autologous stem cell transplant. In the study, overall response rate was 55%, with 37% of patients achieving a complete response and 18% achieving a partial response.
Brexucabtagene autoleucel
In July 2020, brexucabtagene autoleucel (Tecartus; Kite Pharma/Gilead) became the first CAR T-cell therapy to win FDA approval for treatment of adults with relapsed or refractory mantle cell lymphoma.
The accelerated approval was based on results from the ongoing pivotal ZUMA-2 trial, which, at press time, showed that 87% of patients responded to one infusion of therapy, with a 62% complete response rate at a minimum follow-up of 6 months.
As with other CAR T-cell therapies, brexucabtagene autoleucel includes a boxed warning addressing the risks for CRS and neurotoxicity.
Selinexor
Selinexor, which is a first-in-class, oral selective inhibitor of nuclear export compound, was previously approved for treatment of adults with relapsed or refractory multiple myeloma who received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.
Approval for this indication was based on data from the phase 2b SADAL study showing an ORR of 29% — 13% of which were complete responses and 16% of which were partial responses. Fifty-six percent of responders maintained their response at 3 months, 38% maintained their response at 6 months and 15% maintained their response at 12 months.
Tazemetostat
Also in June 2020, the FDA granted accelerated approval to tazemetostat (Tazverik, Epizyme) — an EZH2 inhibitor — for treatment of adults with relapsed or refractory follicular lymphoma who have an EZH2 mutation and have received at least two prior therapies and for adults with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.
The agency also approved the cobas EZH2 Mutation Test (Roche Molecular Systems Inc.) as a companion diagnostic for tazemetostat to detect the EZH2 mutation.
The FDA based its approval on results from the phase 2 E7438-G000-101 study. Among patients with the EZH2 mutation who had received at least two prior therapies, the ORR was 69% and median duration of response was 10.9 months. Among those with EZH2 wild-type who had received at least two prior therapies, the ORR was 34% and a median duration of response of 13 months.
Ibrutinib plus rituximab
In April 2020 the FDA approved ibrutinib (Imbruvica; Janssen, Pharmacyclics) in combination with rituximab to treat patients newly diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma.
Approval was based on the phase 3 E1912 study in which a greater proportion of patients treated with ibrutinib plus rituximab remained progression free after a median follow-up of 37 months than those treated with standard chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab. Median OS had not been reached in the ibrutinib plus rituximab group and was 7% in the FCR group after a median follow-up of 49 months.