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FDA Updates Impacting Treatment Approaches in Oncology

doi: 10.1097/01.COT.0000547484.14886.69
FDA Updates
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New Treatment for Hairy Cell Leukemia Approved



The FDA recently approved moxetumomab pasudotox-tdfk injection for IV use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox-tdfk is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“[Moxetumomab pasudotox-tdfk] fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the NCI that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

The efficacy of moxetumomab pasudotox-tdfk was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate was 75 percent.

Common side effects of moxetumomab pasudotox-tdfk include infusion-related reactions, swelling caused by edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea.

The prescribing information for moxetumomab pasudotox-tdfk includes a boxed warning to advise health care professionals and patients about the risk of developing capillary leak syndrome. Symptoms of this include difficulty breathing, weight gain, hypotension, or swelling of arms, legs, and/or face. The warning also notes the risk of hemolytic uremic syndrome. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include decreased renal function, infusion-related reactions, and electrolyte abnormalities. Women who are breastfeeding should not be given moxetumomab pasudotox-tdfk.

The FDA granted this application Fast Track and Priority Review designations. Moxetumomab pasudotox-tdfk also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

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Fast Track Designation Granted to AVB-S6-500 for Ovarian Cancer

The FDA has granted Fast Track Designation to AVB-S6-500 as a potential treatment for platinum-resistant recurrent ovarian cancer.

AVB-S6-500 is a novel high-affinity, soluble Fc-fusion protein designed to block the activation of the GAS6-AXL signaling pathway by intercepting the binding of GAS6 to its receptor AXL. Research has shown GAS6-AXL signaling to be a key molecular pathway that promotes tumor growth and metastases, as well as immune evasion and resistance to other anticancer agents. AXL and GAS6 expression correlate with poor prognosis in cancer.

Results of a phase I study of AVB-S6-500 in healthy volunteers showed a favorable safety profile, with no reported serious or dose-limiting adverse events. Moreover, results of that trial showed a dose-related reduction of circulating free GAS6, a measurement that could be highly useful as a biomarker to better monitor the therapeutic responses and potentially better select responder patient populations. A reduction in this biomarker has correlated to anti-tumor activity in preclinical animal studies.

In preclinical studies, GAS6-AXL inhibition has shown activity, whether achieved by a single agent (including AVB-S6-500) or through combinations of a variety of anticancer therapies, including radiation therapy, immuno-oncology agents, and drugs that affect DNA replication and repair. GAS6/AXL inhibition has also shown potential as a strategy for the treatment of certain fibrotic diseases.

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Fast Track Designation Granted to CX-01 for Acute Myeloid Leukemia

The FDA has granted Fast Track Designation for CX-01 for the treatment of patients over age 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML). Earlier this year, the FDA had also granted Orphan Drug Designation to CX-01 for the treatment of AML.

CX-01 is currently in clinical development for newly diagnosed AML, and refractory myelodysplastic syndrome. It is designed to block the activity of chemokines that support the resistance of blood cancers to treatment and that contribute to the delay of bone marrow recovery after chemotherapy. Among these chemokines are CXCR4 and CXCL12, which are critical to the attachment of blood cancer cells to the protective bone marrow environment, and platelet factor 4, which slows bone marrow recovery after chemotherapy.

Fast Track Designation is intended to facilitate development and expedite review of drugs to treat serious and life-threatening conditions. A drug that qualifies for this designation must demonstrate the potential to treat a serious condition for which there is an unmet medical need for improved treatment.

The Orphan Drug Designation program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S. The designation provides important incentives, including 7-year marketing exclusivity upon FDA approval, tax credits for qualified clinical testing, and prescription drug user fee exemption.

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Elotuzumab Combination Granted Priority Review for Multiple Myeloma

The FDA recently accepted the supplemental Biologics License Application for elotuzumab in combination with pomalidomide and low-dose dexamethasone (EPd) for the treatment of patients with relapsed/refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The FDA granted the application priority review with an action date of Dec. 27, 2018.

Elotuzumab is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. And it also is expressed on natural killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Elotuzumab has a dual mechanism-of-action. It directly activates the immune system through natural killer cells via the SLAMF7 pathway. It also targets SLAMF7 on myeloma cells, tagging these malignant cells for natural killer cell-mediated destruction via antibody-dependent cellular toxicity.

The application is based on data from ELOQUENT-3, a randomized phase II study evaluating the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. Data from this study were presented at the 23rd Congress of the European Hematology Association in June.

The trial randomized 117 patients with relapsed/refractory multiple myeloma who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a PI. Patients were randomized 1:1 to receive either EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity. Patients in both the EPd and Pd arms received 4 mg of pomalidomide for days 1-21 of each cycle, and the weekly equivalent of 40 mg or 20 mg dexamethasone for patients ≤75 years or >75 years, respectively. In the EPd arm, elotuzumab was administered at the dose of 10 mg/kg IV weekly for the first 2 cycles and 20 mg/kg monthly starting from cycle 3.

Patients randomized to EPd experienced a 46-percent reduction in risk of disease progression (HR 0.54; 95% CI: 0.34-0.86, p=0.0078) compared with patients randomized to Pd alone, with median PFS, the study's primary endpoint, of 10.3 months (95% CI: 5.6 to not estimable) compared with 4.7 months (95% CI: 2.8-7.2) in Pd patients. The PFS benefit experienced among patients randomized to EPd was consistent among patients who had received 2-3 prior lines of therapy (HR 0.55; 95% CI: 0.31-0.98) and four or more prior lines of therapy (HR 0.51; CI 95%: 0.24-1.08). The safety profile for EPd was consistent with prior findings for elotuzumab and pomalidomide regimens.

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Cobas EGFR Mutation Test Approved for Use With Gefitinib in Lung Cancer

The FDA has approved the cobas EGFR Mutation Test v2 as a companion diagnostic test (CDx) with gefitinib in the first-line treatment of patients with non-small cell lung cancer (NSCLC).

The test is currently the only FDA-approved diagnostic test for NSCLC using liquid biopsy. EGFR testing in plasma offers a non-invasive option for patients using a simple blood draw for those who are not eligible for a tissue biopsy.

Gefitinib is a targeted monotherapy for the treatment of patients with advanced or metastatic EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC. It acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus inhibiting the transmission of signals involved in the growth and spread of tumors.

The cobas EGFR Mutation Test v2 is a real-time polymerase chain reaction (PCR) test for the qualitative detection of 42 defined mutations of the EGFR gene in exons 18-21, including L858R, exon 19 deletions, and T790M mutations. This in-vitro diagnostic test is the first and currently the only FDA-approved EGFR test to include both tissue and liquid biopsy as patient sample types for testing.

A number of well-published clinical studies such as AURA, AURA2, FLAURA, ENSURE, EURTAC, and FASTACT2 have now demonstrated that the test is a robust and reliable diagnostic test for the detection of defined mutations of the EGFR gene from a tumor tissue biopsy or from plasma and is able to identify those patients most likely to respond to EGFR tyrosine kinase inhibitor therapies. The test is performed on the cobas 4800 System, which offers high-performance PCR amplification and detection coupled with software that automates result interpretation and reporting.

Wolters Kluwer Health, Inc. All rights reserved.
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