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Atezolizumab for BRAF V600 Unresectable or Metastatic Melanoma

The FDA approved atezolizumab in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

FDA; oncology resear... - Click to enlarge in new windowFDA; oncology research. FDA; oncology research

Efficacy in combination with cobimetinib and vemurafenib was evaluated in a double-blind, randomized (1:1), placebo-controlled, multicenter trial in 514 patients (IMspire150, NCT02908672). After a 28-day cycle of cobimetinib and vemurafenib, patients received atezolizumab 840 mg intravenous infusion every 2 weeks in combination with cobimetinib 60 mg orally once daily and vemurafenib 720 mg orally twice daily, or placebo in combination with cobimetinib 60 mg orally once daily (21 days on/7 days off) and vemurafenib 960 mg orally twice daily.


The primary efficacy outcome measure was investigator-assessed progression-free survival (PFS) per RECIST 1.1. Median PFS was 15.1 months (95% CI: 11.4, 18.4) in the atezolizumab arm and 10.6 months (95% CI: 9.3, 12.7) in the placebo arm (HR 0.78; 95% CI: 0.63, 0.97; p=0.0249).


The most common adverse reactions (>=20%) with atezolizumab in combination with cobimetinib and vemurafenib in patients with melanoma were rash, musculoskeletal pain, nausea, fatigue, hepatotoxicity, pyrexia, nausea pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction.


The recommended atezolizumab dose, following completion of a 28-day cycle of cobimetinib and vemurafenib, is 840 mg every 2 weeks with cobimetinib 60 mg orally once daily (21 days on/7 days off) and vemurafenib 720 mg orally twice daily.


Accelerated Approval of Tafasitamab-Cxix for Diffuse Large B-Cell Lymphoma

The FDA granted accelerated approval to tafasitamab-cxix, a CD19-directed cytolytic antibody, indicated in combination with lenalidomide for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, and for individuals who are not eligible for autologous stem cell transplant.


The efficacy of tafasitamab-cxix with lenalidomide was evaluated in L-MIND (NCT02399085), an open-label, multicenter, single-arm trial in 81 patients. Patients received tafasitamab-cxix 12 mg/kg intravenously with lenalidomide (25 mg orally on days 1 to 21 of each 28-day cycle) for a maximum of 12 cycles, followed by tafasitamab-cxix as monotherapy.


Efficacy was based on best overall response rate (ORR), defined as complete and partial responders and response duration, as assessed by an independent review committee. The best ORR in 71 patients with a diagnosis of DLBCL confirmed by central pathology was 55 percent (95% CI: 43%, 67%), with complete responses in 37 percent and partial responses in 18 percent of patients. Median response duration was 21.7 months (range: 0, 24).


The most common adverse reactions (>=20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite. The recommended tafasitamab-cxix dose is 12 mg/kg as an intravenous infusion.


Accelerated Approval of Belantamab Mafodotin-Blmf for Multiple Myeloma

The FDA granted accelerated approval to belantamab mafodotin-blmf for adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.


Belantamab mafodotin-blmf was evaluated in DREAMM-2 (NCT03525678), an open-label, multicenter trial. Patients received either belantamab mafodotin-blmf, 2.5 mg/kg or 3.4 mg/kg intravenously, once every 3 weeks until disease progression or unacceptable toxicity.


Efficacy was based on overall response rate (ORR) and response duration, as evaluated by an independent review committee using the International Myeloma Working Group uniform response criteria. The ORR was 31 percent (97.5% CI: 21%, 43%). Seventy-three percent of responders had response durations >=6 months. These results were observed in patients receiving the recommended dose of 2.5 mg/kg.


The prescribing information includes a Boxed Warning stating belantamab mafodotin-blmf causes changes in the corneal epithelium resulting in alterations in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes. Ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms should be conducted.


Because of the risks of ocular toxicity, belantamab mafodotin-blmf is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the BLENREP REMS.


Adverse reactions in >=20 percent patients who received belantamab mafodotin-blmf were keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue.


The recommended belantamab mafodotin-blmf dose is 2.5 mg/kg as an IV infusion over approximately 30 minutes once every 3 weeks.


Breakthrough Therapy Designation for Pevonedistat in Higher-Risk Myelodysplastic Syndromes

The FDA granted breakthrough therapy designation for the investigational drug pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS). Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, could be the first novel treatment for HR-MDS patients in more than a decade, expanding treatment options that have so far been limited to hypomethylating agent monotherapy alone. Even with current treatment options, outcomes for people living with HR-MDS remain poor.


The breakthrough therapy designation is based on the final analysis of the Pevonedistat-2001 phase II study, which evaluated pevonedistat plus azacitidine versus azacitidine alone in patients with rare leukemias, including HR-MDS. The FDA considered a number of endpoints, including overall survival, event-free survival, complete remission, and transfusion independence, as well as the adverse event profile. This designation signals a potential advancement in addressing the needs of people living with HR-MDS, for whom few therapies exist and the benefits are limited.


Pembrolizumab Achieves Two US Regulatory Milestones for Triple-Negative Breast Cancer

The FDA has accepted two new supplemental biologics license applications (sBLAs) for pembrolizumab, an anti-PD-1 therapy. The FDA has accepted and granted priority review for a new sBLA seeking accelerated approval for pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (Combined Positive Score [CPS] >=10), based on the phase III KEYNOTE-355 trial.


The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of Nov. 28, 2020. The FDA also accepted for standard review a new sBLA for pembrolizumab for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as neoadjuvant treatment, and then as a single agent as adjuvant treatment after surgery, based on the phase III KEYNOTE-522 trial. The PDUFA date for this application is March 29, 2021.


The applications are based on data from the KEYNOTE-355 and KEYNOTE-522 trials, respectively. In KEYNOTE-355, pembrolizumab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with chemotherapy alone in patients whose tumors expressed PD-L1 at CPS >=10. Approximately 38 percent of patients enrolled in KEYNOTE-355 had tumors expressing PD-L1 at CPS >=10. These data were presented at the virtual scientific program of the 2020 ASCO Annual Meeting. As previously announced, the trial will continue without changes to evaluate the other dual primary endpoint of overall survival.


In KEYNOTE-522, the first randomized trial of an anti-PD-1 therapy in the neoadjuvant/adjuvant setting for TNBC, neoadjuvant pembrolizumab plus chemotherapy resulted in a statistically significant increase in pathologic complete response in patients with early-stage TNBC, regardless of PD-L1 expression. The pembrolizumab regimen also demonstrated a favorable trend for the other dual primary endpoint of event-free survival.


Data from the KEYNOTE-522 trial were presented at the European Society for Medical Oncology 2019 Congress and the 2019 San Antonio Breast Cancer Symposium. As previously announced, pembrolizumab plus chemotherapy was granted breakthrough therapy designation by the FDA for the neoadjuvant treatment of patients with high-risk early-stage TNBC.


Fast Track Designation of BST-236 for Acute Myeloid Leukemia

The FDA granted Fast Track designation for aspacytarabine for the treatment of acute myeloid leukemia (AML) in adults who are 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Aspacytarabine is a novel antimetabolite designed to provide the benefit of intensive chemotherapy while avoiding much of its toxicity. The phase IIb study is currently enrolling patients, evaluating aspacytarabine as a single-agent first-line AML therapy for patients unfit for standard chemotherapy.


Aspacytarabine is composed of cytarabine covalently bound to asparagine, acting as a pro-drug of cytarabine. Cytarabine serves as the backbone of AML therapy for over 40 years due to its superior efficacy. However, it is associated with severe bone marrow, gastrointestinal, and neurological toxicities, which significantly limit its use, especially in older and medically compromised patients. Due to its unique kinetics and metabolism, aspacytarabine is designed to enable high-dose therapy with lower systemic exposure to free cytarabine and relative sparing of normal tissues. As such, aspacytarabine may serve as a superior therapy for AML and other hematological malignancies and disorders, including for older adults who are unfit for intensive therapy.


Aspacytarabine was granted orphan drug designation from the FDA. A phase IIb study is ongoing to confirm the promising results obtained in a phase I/IIa study of aspacytarabine as a single-agent first-line AML therapy.


Guardant360 CDx First Approved Liquid Biopsy for Comprehensive Tumor Mutation Profiling Across All Solid Cancers

The FDA approved Guardant360 CDx for tumor mutation profiling, also known as comprehensive genomic profiling (CGP), in patients with any solid malignant neoplasm. It is also approved as a companion diagnostic to identify non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) alterations who may benefit from treatment with osimertinib. Guardant360 CDx offers patients and clinicians a simple, faster blood test to help inform personalized treatment options. This FDA approval was based on clinical and analytical validation data from over 5,000 samples.


In a retrospective analysis of data from pivotal phase III clinical trials, FLAURA and AURA3, patients with NSCLC identified for treatment with osimertinib using the Guardant360 CDx demonstrated progression-free survival rates consistent with those identified using traditional biomarker testing. Since being introduced as a laboratory developed test (LDT), the Guardant360 liquid biopsy LDT has become widely accepted for blood-based CGP with more than 150 peer-reviewed publications.