FDA News: June 22, 2022 to July 14, 2022

TON - August 2022 Vol 15, No 4



In the June 2022 issue of the journal, the FDA News section (page 16) had an error. The article titled “Tibsovo Receives a New Indication, in Combination with Onureg, for Newly Diagnosed Patients with AML and IDH1 Mutation” was wrong. The new indication for Tibsovo is in combination with the subcutaneous/intravenous formulations of azacitidine, not the oral formulation (ie, Onureg). We regret this error. This article has been corrected online.


Xalkori Receives New Indication for Treatment of ALK-Positive Inflammatory Myofibroblastic Tumors

On July 14, 2022, the FDA approved the multikinase inhibitor crizotinib (Xalkori; Pfizer) for the treatment of unresectable, recurrent, or refractory inflammatory myofibroblastic tumors with anaplastic lymphoma kinase (ALK) mutation in patients aged ≥1 years. The FDA granted crizotinib an orphan drug designation for this indication.

Crizotinib was previously approved for the treatment of patients with metastatic non–small-cell lung cancer and ALK or ROS1 mutation, and for young patients aged 1 to 21 years with relapsed or refractory systemic anaplastic large-cell lymphoma and ALK mutation.

This new indication was based on the results of 2 multicenter, single-arm, open-label clinical trials—ADVL0912 and A8081013—that enrolled patients with unresectable, recurrent, or refractory ALK-positive inflammatory myofibroblastic tumors.

The ADVL0912 study included 14 pediatric patients, and 12 of these patients had an objective response to crizotinib, with an overall response rate of 86% (95% confidence interval, 57%-98%).

The A8081013 study enrolled 7 patients, 5 of whom had an objective response.

In the pediatric patients, the most common (≥35%) adverse reactions were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. In the adult patients, the most common (≥35%) adverse reactions were vision disorders, nausea, and edema.

The recommended dose of crizotinib is 250 mg/m2 orally twice daily in adults and 280 mg/m2 orally twice daily in pediatric patients until disease progression or unacceptable toxicity.

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Breyanzi Now FDA Approved for Second-Line Treatment of Large B-Cell Lymphoma

On June 24, 2022, the FDA approved the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (Breyanzi; Juno Therapeutics) for the treatment of adults with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and grade 3B follicular lymphoma.

The FDA granted lisocabtagene maraleucel regenerative medicine advanced therapy and breakthrough therapy designations for this indication. This approval includes a Risk Evaluation and Mitigation Strategy program, because of the risk for life-threatening or fatal cytokine release syndrome (CRS) and neurologic adverse events. This CAR T-cell therapy is not approved for primary central nervous system lymphoma.

Lisocabtagene maraleucel was previously approved for various subtypes of relapsed or refractory LBCL after ≥2 lines of systemic therapy.

This new indication was based on the results of the TRANSFORM study, a global, randomized, multicenter, open-label clinical trial in 184 adults with primary refractory LBCL or with relapsed LBCL within 12 months of having a complete response. Patients were randomized in a 1:1 ratio to a single infusion of lisocabtagene maraleucel after lymphodepleting chemotherapy or to second-line therapy with 3 cycles of salvage chemotherapy, followed by high-dose therapy and autologous hematopoietic stem-cell transplant in patients who had a partial or complete response.

The primary efficacy measure was event-free survival (EFS). The results showed a significant improvement in EFS with the CAR T-cell therapy versus the standard of care (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.22-0.52; P <.0001); the 1-year EFS rates were 45% and 24%, respectively. The median EFS was 10.1 months with lisocabtagene maraleucel (95% CI, 6.1-nonevaluable) versus 2.3 months with the standard of care (95% CI, 2.2-4.3).

The median progression-free survival was 14.8 months with lisocabtagene maraleucel and 5.7 months with the standard of care (HR, 0.406; P = .0001).

The majority (86%) of the patients who received lisocabtagene maraleucel achieved a partial or complete response, including 66% complete responses, compared with 48% of patients in the standard-of-care arm achieving partial or complete responses, including 39% complete responses.

Lisocabtagene maraleucel had a manageable safety profile, with 49 patients having any-grade CRS, 1 patient had grade 3 CRS, and no grade 4 or 5 CRS reported. In all, 12% of the patients who received the CAR T-cell therapy had any-grade neurologic events, including 4% grade 3 events.

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Tafinlar plus Mekinist First Tumor Agnostic Treatment for Any Unresectable or Metastatic Solid Tumors with BRAF Mutation

On June 22, 2022, the FDA accelerated the approval of dabrafenib (Tafinlar; Novartis), a BRAF mutation inhibitor, in combination with trametinib (Mekinist; GlaxoSmithKline), a MEK inhibitor, for the treatment of unresectable or metastatic solid tumors and BRAF V600E mutation in adults and pediatric patients aged ≥6 years who have had disease progression after receiving previous treatment.

The combination of dabrafenib and trametinib is currently approved for unresectable or metastatic melanoma and BRAF V600E or V600K mutations, melanoma with BRAF V600E or V600K mutations involving lymph node(s), metastatic non–small-cell lung cancer with BRAF V600E mutation, and locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation.

“The combination of dabrafenib and trametinib demonstrated meaningful efficacy in multiple BRAF-positive tumor types, including in some patients with rare cancers who have no other treatment options available,” said lead investigator Vivek Subbiah, MD, Medical Director of the Clinical Center for Targeted Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. “Physicians should consider a BRAF test as a routine diagnostic step that could enable a new option for treating patients with many solid tumors.”

This approval was based on the results of 3 clinical trials that included 131 adults in the first 2 studies, 36 patients in the pediatric study, and a total of 24 types of solid tumors.

The phase 2 Rare Oncology Agnostic Research (ROAR) study was an open-label, single-arm, multicenter study of patients with BRAF V600E–positive solid tumors, including low- or high-grade gliomas, biliary tract cancer, adenocarcinoma of the small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. The patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily.

The phase 2 National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) was a precision medicine clinical trial that included adults with BRAF V600E–positive solid tumors, excluding melanoma, thyroid cancer, and colorectal cancer.

The third study, Study X2101, included pediatric patients with BRAF V600 refractory or recurrent low- or high-grade glioma to evaluate the clinical benefit and safety of dabrafenib plus trametinib in pediatric patients.

The major efficacy end point of these 3 studies was overall response rate (ORR), which was up to 80% in patients with BRAF V600E solid tumors. The highest overall responses were seen in biliary tract cancer (46%) and low- and high-grade gliomas (50% and 33%, respectively). In the 2 studies with 131 adults, 54 (41%) patients had an objective response. In the 36 pediatric patients, the ORR was 25%, with a duration of response of ≥6 months in 78% of patients, and of ≥24 months in 44% of patients.

The most common (≥20%) adverse reactions with the combination seen in adults were pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. In the pediatric patients, the most common (≥20%) adverse reactions were pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.

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FDA Issues New Warning for Copiktra About Increased Risks for Serious Side Effects and Mortality

On June 30, 2022, the FDA issued a new boxed warning for duvelisib (Copiktra; Secura Bio) about the increased risk for serious side effects and death with this PI3K inhibitor, based on the results of the DUO clinical trial. Duvelisib is approved for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults after at least 2 previous therapies. Prophylaxis for Pneumocystis jirovecii is recommended during treatment with duvelisib.

The DUO trial was a phase 3, randomized, open-label study that compared duvelisib therapy and the monoclonal antibody ofatumumab (Kesimpta) in 319 patients with relapsed or refractory CLL or SLL who received at least 1 previous therapy.

At a median follow-up of 63 months, the results showed an increased mortality risk with duvelisib versus with ofatumumab (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.51). In patients who received ≥2 previous lines of therapy, the HR for mortality was 1.06 (95% CI, 0.71-1.58). The median overall survival was lower with duvelisib than with ofatumumab (52.3 months vs 63.3 months, respectively).

A safety analysis showed more serious adverse reactions (including grade ≥3), increased treatment modifications resulting from adverse reactions, and a higher incidence of death because of adverse reactions with duvelisib than with ofatumumab.

The FDA is continuing to evaluate the safety of duvelisib and is planning a meeting to discuss the clinical trial findings and whether the drug can continue to be prescribed for patients.

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Talquetamab, Bispecific Monoclonal Antibody, Granted Breakthrough Therapy for Relapsed or Refractory Multiple Myeloma

On June 29, 2022, the FDA granted the investigational first-in-class anti-CD3 and anti-GPRC5D bispecific humanized monoclonal antibody talquetamab (Janssen) a breakthrough therapy designation for relapsed or refractory multiple myeloma in patients who have received ≥4 previous lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. In May 2021, the FDA granted talquetamab an orphan drug designation for the treatment of multiple myeloma.

“This breakthrough therapy designation marks an important step in the continued development of talquetamab, a first-in-class bispecific antibody T-cell engager using GPRC5D,” said Sen Zhuang, MD, PhD, Vice President, Clinical Research and Development, Janssen Research and Development, in a press release. “Despite the therapies available for patients with relapsed or refractory multiple myeloma, new targets and treatments are needed because of the heterogeneity of the disease, which can impact a patient’s response to treatment.”

This approval was based on the results of the phase 1/2 MonumenTAL-1 study, a first-in-human dose-escalation clinical trial that enrolled heavily pretreated patients with relapsed or refractory multiple myeloma. Talquetamab is currently being evaluated for the treatment of relapsed or refractory multiple myeloma, as well as in combination with the investigational T-cell redirecting bispecific antibody targeting B-cell maturation antigen teclistamab, for the treatment of relapsed or refractory multiple myeloma.

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