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FDA News: September 11, 2023, to October 16, 2023

November 2023 Vol 16, No 6 – Online Only

NEW DRUG

FDA Approves Aphexda, in Combination With Filgrastim, to Mobilize Stem Cells for Transplant in Patients With Multiple Myeloma

On September 11, 2023, the FDA approved motixafortide (Aphexda; BioLineRx) subcutaneous injection, a hematopoietic stem cell (HSC) mobilizer, for use in combination with the granulocyte colony-stimulating factor filgrastim (Neupogen; Amgen), to mobilize HSCs to the peripheral blood for collection and subsequent autologous stem cell transplantation (ASCT) in patients with multiple myeloma. Motixafortide is the first novel stem cell mobilizer in a decade to receive FDA approval for multiple myeloma.

The approval was based on the results of the GENESIS study, a randomized, double-blind, placebo-controlled, phase 3 clinical trial that evaluated the safety and efficacy of motixafortide plus filgrastim versus placebo plus filgrastim for the mobilization of HSCs for ASCT in patients with multiple myeloma.

ASCT is part of the standard of care for patients with multiple myeloma. The success of ASCT in prolonging patient survival depends on the adequate mobilization of the stem cells used. Historically, many patients have had difficulty collecting enough HSCs for ASCT after 1 apheresis session.

“Greater numbers of patients with multiple myeloma are candidates for autologous stem cell therapy; however, achieving target collection goals can be difficult in some patients given modern barriers, including the treatment of older patients and use of contemporary induction regimens,” said John DiPersio, MD, PhD, Director, Center for Gene and Cellular Immunotherapy, and Professor, Medicine, Pathology and Immunology, Washington University School of Medicine, St. Louis, and lead investigator of the GENESIS study, in a press release. “Innovation in this area of medicine has been needed, and today’s approval of Aphexda addresses the demand for new therapies that can meet today’s challenges by delivering more reliability in stem cell mobilization, versus filgrastim alone, with fewer days of apheresis sessions and fewer doses of filgrastim for people living with this cancer,” he added.

The American Society for Transplantation and Cellular Therapy guidelines recommend a stem cell collection target of 3 × 106 to 5 × 106 CD34+ cells/kg, as well as the collection of enough stem cells to perform 2 transplants.

The GENESIS study was divided into 2 parts: a single-center, lead-in, open-label study of 12 patients who received motixafortide plus filgrastim to confirm the appropriate dose of motixafortide, and a double-blind, placebo-controlled, multicenter trial that randomized (2:1) 122 patients to motixafortide plus filgrastim or to placebo plus filgrastim. The CD34+ cells were assessed by central and local laboratories, with the central laboratory results used for the efficacy results and the local laboratory results used for treatment decisions.

Of the patients who received motixafortide plus filgrastim, 67.5% achieved the stem cell collection goal of ≥6 × 106 CD34+ cells/kg in ≤2 apheresis sessions compared with only 9.5% of the patients who received placebo plus filgrastim (measured by central laboratory). In addition, 92.5% of patients achieved the stem cell collection goal in ≤2 apheresis sessions in the motixafortide arm versus 21.4% in the placebo arm (measured by local laboratories). The local laboratory data were used for a sensitivity analysis, and the data are descriptive and were not statistically powered nor prespecified.

Older patient age and previous exposure to lenalidomide (Revlimid; Bristol-Myers Squibb)-containing induction regimens (including 3-4 drug combination regimens) are associated with impaired stem cell mobilization. The GENESIS study included individuals who represented typical patients with multiple myeloma undergoing ASCT, with a median age of 63 years and approximately 70% of the patients in both study arms receiving lenalidomide-containing induction therapy. The patients who received motixafortide plus filgrastim mobilized >4 times the amount of stem cells with a single dose over 24 hours than those who received placebo plus filgrastim. Overall, 1 dose of motixafortide plus filgrastim enabled most of the patients to achieve the collection goal of ≥6 million HSCs.

The safety profile of motixafortide was based on the results of the GENESIS study, which included 92 patients who received at least 1 dose of motixafortide 1.25 mg/kg subcutaneously plus filgrastim and 42 patients who received placebo plus filgrastim. The premedication regimen changed during the study when evidence of hypersensitivity reactions was noted.

Of the 92 patients who received at least 1 dose of motixafortide, 14 received the triple-drug premedication regimen of an H1 antihistamine, an H2 blocker, and a leukotriene inhibitor, and 78 did not receive the premedication regimen or received another regimen. Serious adverse events occurred in 5.4% of patients who received motixafortide plus filgrastim, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia.

The most common (>20%, and ≥2% higher than in the filgrastim plus placebo arm) adverse reactions with motixafortide treatment were injection-site reactions, injection-site pain, injection-site erythema, injection-site pruritus, pruritus, flushing, and back pain. In addition, 1 patient did not receive the fifth dose of filgrastim because of an elevated white blood cell count after receiving motixafortide.

Treatment with motixafortide should be initiated after filgrastim has been administered daily for 4 days. A second dose of motixafortide can be administered 10 to 14 hours before a third apheresis.

The recommended dose of motixafortide is 1.25 mg/kg (actual body weight), by subcutaneous injection, 10 to 14 hours before the initiation of apheresis. More than 1 vial of motixafortide may be needed for a full dose. A second dose of motixafortide can be administered 10 to 14 hours before a third apheresis if necessary.

Because of the risks for anaphylactic shock and hypersensitivity reactions with motixafortide treatment, all patients should receive a 3-drug premedication regimen that includes an H1 antihistamine, an H2 blocker, and a leukotriene inhibitor.

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NEW INDICATIONS

Bosulif Now FDA Approved for Pediatric Patients With Chronic Myelogenous Leukemia

On September 26, 2023, the FDA approved a new indication for bosutinib (Bosulif; Pfizer), a tyrosine kinase inhibitor, for the treatment of chronic-phase, Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia (CML) in pediatric patients aged ≥1 years who are newly diagnosed or who are intolerant of or whose disease is resistant to previous therapy. A new capsule dosage form was also FDA approved, in 50-mg and 100-mg strengths; bosutinib was previously available only in 100-mg, 400-mg, and 500-mg tablet forms. The FDA granted this approval priority review and an orphan drug designation.

This marks the first approved indication of bosutinib for a pediatric population.

Bosutinib was previously approved for this indication only in adults, as well as for adults with accelerated- or blast-phase Ph-positive CML that is resistant to or who are intolerant of previous therapy.

This new approval was based on the results of the phase 1/2 BCHILD study, a multicenter, nonrandomized, open-label clinical trial to identify a recommended dose of bosutinib for pediatric patients with newly diagnosed chronic-phase, Ph-positive CML or with chronic-phase, Ph-positive CML who had treatment-resistant disease or who were intolerant of previous treatment; to estimate the safety, tolerability, and efficacy of bosutinib; and to evaluate bosutinib’s pharmacokinetics in this patient population.

The trial included pediatric patients with chronic-phase, Ph-positive CML that was treatment resistant or who were intolerant of treatment who received bosutinib at 300 mg/m2 to 400 mg/m2 orally once daily (n=28) and pediatric patients with newly diagnosed chronic-phase, Ph-positive CML who received 300 mg/m2 of bosutinib once daily (n=21).

Major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR) were the main efficacy measures. The MCyR and CCyR rates for the pediatric patients with newly diagnosed chronic-phase, Ph-positive CML were 76.2% (95% confidence interval [CI], 52.8-91.8) and 71.4% (95% CI, 47.8-88.7), respectively. The rate of MMR was 28.6% (95% CI, 11.3-52.3), and the median duration of follow-up was 14.2 months (range, 1.1-26.3 months).

For the pediatric patients with chronic-phase, Ph-positive CML that was treatment resistant or who were intolerant of previous treatment, the MCyR rate was 82.1% (95% CI, 63.1-93.9), the CCyR rate was 78.6% (95% CI, 59-91.7), and the MMR rate was 50% (95% CI, 30.6-69.4). Of the 14 patients who reached MMR, 2 lost MMR after 13.6 months and 24.7 months of receiving treatment. The median follow-up was 23.2 months (range, 1-61.5 months).

“The biology of cancer is often different in children, and we need more treatments that are designed specifically for this vulnerable patient population….[W]e are thrilled when a drug receives FDA approval for use in our youngest patients,” said Gwen Nichols, MD, Chief Medical Officer, The Leukemia & Lymphoma Society, in a press release.

The most common (≥20%) adverse reactions in the pediatric patient population were diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation. The most frequent (≥45%) laboratory abnormalities in the pediatric patients that worsened from baseline were increased creatinine, increased alanine aminotransferase or aspartate aminotransferase, decreased white blood cell count, and decreased platelet count. Because serious adverse reactions, such as anaphylaxis, have occurred, bosutinib is contraindicated in patients with a history of hypersensitivity to this agent.

The recommended dose of bosutinib for pediatric patients with newly diagnosed chronic-phase, Ph-positive CML is 300 mg/m2 orally once daily taken with food; for pediatric patients with chronic-phase, Ph-positive CML that is treatment resistant or who are intolerant to previous treatment, the recommended dose is 400 mg/m2 orally once daily taken with food. If a patient cannot swallow the capsules, the contents of the capsules can be mixed with applesauce or yogurt.

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Temodar Receives FDA Approval for New and Updated Indications and Doses Through the Project Renewal Program

On September 14, 2023, the FDA approved new and updated indications for temozolomide (Temodar; Merck) capsules and injection, an alkylating drug, including for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma, and for the treatment of adults with refractory anaplastic astrocytoma. The previously approved indication for the treatment of adults with newly diagnosed glioblastoma, concomitant with radiotherapy, then as maintenance treatment, remains unchanged.

This updated approval includes additional prescribing revisions for temozolomide. Temozolomide has revised dosing regimens and is now administered orally or intravenously for patients newly diagnosed with glioblastoma and for those newly diagnosed with anaplastic astrocytoma or those with refractory anaplastic astrocytoma. For complete dosing details, refer to temozolomide’s complete prescribing information. The Warnings and Precautions section of the prescribing information includes a new warning for temozolomide capsules regarding the risks from exposure to opened capsules, emphasizing that the capsules should not be opened, chewed, or dissolved, but should be swallowed whole with a glass of water. The Patient Counseling Information section and the Patient Information document for temozolomide were also updated. For complete details on the revisions, please refer to temozolomide’s prescribing information.

The efficacy of temozolomide for the adjuvant treatment of patients with newly diagnosed anaplastic astrocytoma was based on published studies involving temozolomide, specifically the randomized, open-label, multicenter CATNON clinical study (NCT00626990), which investigated the use of temozolomide in patients with anaplastic astrocytoma as adjuvant therapy to radiation therapy versus radiation therapy alone, with a major efficacy outcome measure of overall survival (OS).

The efficacy of temozolomide for the treatment of refractory anaplastic astrocytoma was evaluated in the single-arm, multicenter, MK-7365-006 clinical trial. All patients had anaplastic astrocytoma at first relapse and a baseline Karnofsky Performance Scale (KPS) score of ≥70. The patients previously received radiation therapy and could have also received a nitrosourea compound, with or without another chemotherapy. In all, 54 patients had disease progression during previous therapy with a nitrosourea compound and procarbazine, and their disease was refractory to chemotherapy (ie, the population with refractory anaplastic astrocytoma). Temozolomide capsules were administered on days 1 to 5 of each 28-day cycle, at a starting dose of 150 mg/m2 daily. If the absolute neutrophil count was ≥1.5 × 109/L, and the platelet count was ≥100 × 109/L at the nadir and on day 1 of the next cycle, the temozolomide dose was increased to 200 mg/m2 daily.

The main efficacy measure was progression-free survival (PFS) at 6 months; secondary outcomes were OS and overall response rate (ORR). The patients with refractory anaplastic astrocytoma (n=54) had a median age of 42 years (range, 19-76 years), 65% were male, and 72% had a KPS score of >80. At diagnosis, 63% of the patients had surgery (excluding biopsy). Of those patients undergoing surgical resection, 73% had subtotal resection and 27% had gross total resection; 18% of the patients had surgery at the first disease relapse. The median time from initial diagnosis to first relapse was 13.8 months (range, 4.2 months-6.3 years).

In the 54 patients with refractory anaplastic astrocytoma, the ORR (complete response [CR] plus partial response) was 22% (n=12) and the CR rate was 9% (n=5). The median duration of all responses was 50 weeks (range, 16-114 weeks); the median duration of CR was 64 weeks (range, 52-114 weeks). In this population, the 6-month PFS was 45% (95% confidence interval [CI], 31%-58%) and the 12-month PFS was 29% (95% CI, 16%-42%), with a median PFS of 4.4 months. The 6-month OS was 74% (95% CI, 62%-86%) and the 12-month OS was 65% (95% CI, 52%-78%), with a median OS of 15.9 months.

The FDA approved these new and updated indications and additional clinical information under its Project Renewal program, a collaborative initiative of the Oncology Center of Excellence that is aimed at updating the prescribing information for older oncology drugs, to ensure that a drug’s prescribing information is based on up-to-date scientific information that is clinically meaningful. According to the FDA, Project Renewal is limited to older oncology drugs with decades of use, multiple supportive clinical studies, and substantial postmarketing experience. Temozolomide was first approved by the FDA in 1999 for patients newly diagnosed with glioblastoma and is the second drug to receive an update to its prescribing information under this pilot program (the first drug was capecitabine [Xeloda]).

The most common (≥20%) adverse reactions associated with temozolomide treatment include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions; the most common (≥10%) grade 3/4 hematologic laboratory abnormalities in patients with anaplastic astrocytoma include decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes.

Temozolomide is contraindicated in patients with serious hypersensitivity to temozolomide, to any of the other ingredients in Temodar, or to dacarbazine.

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Keytruda Now Approved for Neoadjuvant and Adjuvant Treatment of Resectable NSCLC

On October 16, 2023, the FDA approved a new indication for pembrolizumab (Keytruda; Merck), a PD-1 inhibitor, combined with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent pembrolizumab as postsurgical adjuvant treatment for resectable (tumors ≥4 cm or node positive) non–small cell lung cancer (NSCLC).

Pembrolizumab monotherapy was previously approved for the adjuvant treatment of patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC, after resection and platinum-based chemotherapy as first-line treatment, as well as in patients with NSCLC and PD-L1 expression without ALK or EGFR mutations, and for patients with metastatic NSCLC and PD-L1 expression, after platinum-based chemotherapy. Pembrolizumab also has indications for the treatment of several other cancer types.

This approval of pembrolizumab was supported by results of the KEYNOTE-671 study, a multicenter, randomized, double-blind, placebo-controlled clinical trial of 797 patients with previously untreated and resectable stage II, IIIA, or IIIB (N2) NSCLC by the American Joint Committee on Cancer’s Cancer Staging Manual, 8th Edition. Patients were randomized to pembrolizumab or to placebo, with platinum-based chemotherapy, every 3 weeks for 4 cycles (neoadjuvant treatment) followed by continued single-agent pembrolizumab or placebo every 3 weeks for up to 13 cycles (adjuvant treatment).

The primary efficacy measures were overall survival (OS) and investigator-assessed event-free survival (EFS). The median OS was not reached for patients who received pembrolizumab (95% confidence interval [CI], not estimable-not estimable) and was 52.4 months for patients who received placebo (95% CI, 45.7-not estimable; hazard ratio [HR], 0.72 [95% CI, 0.56-0.93]; P=.0103). The median EFS was not reached in the pembrolizumab arm (95% CI, 34.1-not estimable) and was 17 months in the placebo arm (95% CI, 14.3-22; HR, 0.58 [95% CI, 0.46-0.72]; P<.0001).

The most common (≥20%) adverse events with pembrolizumab treatment in KEYNOTE-671 were nausea, fatigue, neutropenia, anemia, constipation, decreased appetite, a decrease in white blood cell count, musculoskeletal pain, rash, cough, vomiting, diarrhea, and dyspnea. Among patients who received neoadjuvant pembrolizumab, 6% were unable to undergo surgery as a result of adverse reactions compared with 4.3% in the placebo arm. Among patients who received neoadjuvant treatment and surgery in the pembrolizumab arm, 3.1% had delays in surgery as a result of adverse reactions compared with 2.5% in the placebo arm.

The recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks. Pembrolizumab should be administered before chemotherapy when both treatments are administered on the same day.

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Opdivo Now Approved for Adjuvant Treatment of Stage IIB/C Melanoma

On October 13, 2023, the FDA approved a new indication for nivolumab (Opdivo; Bristol-Myers Squibb), a PD-1 inhibitor, for the adjuvant treatment of completely resected stage IIB/C melanoma in patients aged ≥12 years. The FDA granted this application an orphan drug designation.

Nivolumab has been previously approved for the treatment of many cancers, including the adjuvant treatment of melanoma with lymph node involvement or metastatic melanoma in patients who underwent complete resection.

This approval of nivolumab was supported by results of the CheckMate-76K study, a randomized, placebo-controlled, double-blind clinical trial that enrolled 790 patients with stage IIB/C melanoma. Patients were randomized (2:1) to nivolumab 480 mg or to placebo dosed via intravenous infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable adverse events. The patients in this trial underwent complete resection of the primary melanoma with negative margins and a negative sentinel lymph node within 12 weeks before randomization. Randomization was stratified by T category according to the American Joint Committee on Cancer’s Cancer Staging Manual, 8th Edition (T3b vs T4a vs T4b).

The primary efficacy measure was recurrence-free survival (RFS), which was defined as the investigator-assessed time between randomization and first disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first. The median RFS was not reached in the nivolumab arm (95% confidence interval [CI], 28.5-not reached) or in the placebo arm (95% CI, 21.6-not reached; hazard ratio [HR], 0.42; 95% CI, 0.30-0.59; P≤.0001). At 1 year, the RFS rate was 89% (95% CI, 86-92) for nivolumab compared with 79% (95% CI, 74-84) for placebo. In a prespecified exploratory subgroup analysis, the RFS unstratified HR was 0.34 (95% CI, 0.20-0.56) in patients with stage IIB melanoma and 0.51 (95% CI, 0.32-0.81) in patients with stage IIC melanoma.

The most common (≥20%) adverse reactions with nivolumab treatment in CheckMate-76K were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.

The recommended dose of nivolumab for patients weighing ≥40 kg is 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable adverse events for up to 1 year. The recommended dose for pediatric patients weighing <40 kg is 3 mg/kg nivolumab every 2 weeks or 6 mg/kg every 4 weeks until disease progression or unacceptable adverse events for up to 1 year.

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Braftovi Plus Mektovi Now FDA Approved for Treatment of Metastatic NSCLC With BRAF Mutation

On October 11, 2023, the FDA approved a new indication for encorafenib (Braftovi; Array BioPharma) combined with binimetinib (Mektovi; Array BioPharma) for adults with metastatic non–small cell lung cancer (NSCLC) and a BRAFV600E mutation, as detected by an FDA-approved test.

The FDA also approved 2 companion diagnostic tests, FoundationOne CDx (tissue) and FoundationOne Liquid CDx (plasma), for encorafenib plus binimetinib. Tumor tissue should be tested if the BRAFV600E mutation is not detected in plasma.

The FDA granted this application an orphan drug designation.

Encorafenib plus binimetinib was previously approved for the treatment of patients with unresectable or metastatic melanoma and a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. Encorafenib plus cetuximab (Erbitux; Eli Lilly and Company) was previously approved for the treatment of metastatic colorectal cancer in adults who have a BRAFV600E mutation, as detected by an FDA-approved test, and have received previous therapy.

This approval was based on data from the phase 2 PHAROS study, an ongoing open-label, multicenter, single-arm clinical trial evaluating the efficacy of encorafenib and binimetinib in 98 patients with metastatic NSCLC and documented BRAFV600E mutations. Patients were treatment naïve or had disease progression after previous therapy that did not include BRAF or MEK inhibitors. In this trial, treatment with encorafenib and binimetinib continued until disease progression or unacceptable toxicity.

The key efficacy measures included objective response rate (ORR) per RECIST v1.1 and duration of response (DOR) based on independent review committee assessment. Among the 59 treatment-naïve patients with NSCLC who received encorafenib plus binimetinib, the ORR was 75% (95% confidence interval [CI], 62-85). The median DOR was not estimable (95% CI, 23.1-not estimable). Among the 39 patients who received previous treatment, the ORR after receiving encorafenib plus binimetinib was 46% (95% CI, 30-63), with a median DOR of 16.7 months (95% CI, 7.4-not estimable).

The most common (≥25%) adverse events with encorafenib plus binimetinib were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.

For patients with metastatic NSCLC and BRAFV600E mutations, the recommended dose of encorafenib is 450 mg orally once daily. The recommended dose of binimetinib is 45 mg orally twice daily.

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