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Orphan Drug Designation of NUV-422 for Malignant Gliomas

The FDA has granted Orphan Drug Designation to NUV-422, a cyclin-dependent kinase (CDK) 2/4/6 inhibitor, for the treatment of patients with malignant gliomas.

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Patient enrollment and dosing is ongoing in the Phase I/II study of NUV-422 in adult patients with recurrent or refractory high-grade gliomas, including glioblastoma multiforme. The Phase I dose-escalation part of the study is designed to evaluate safety and tolerability, as well as determine a recommended Phase II dose based on the tolerability profile and pharmacokinetic properties of NUV-422. The Phase II dose expansion part of the study is expected to initially focus on patients with high-grade gliomas, and it is designed to evaluate overall response rate, duration of response, and survival. Data from the Phase I portion of this study is expected in 2022.


NUV-422 is a selective small molecule resulting from a cyclin-dependent kinase (CDK) inhibitor program. CDK4/6 inhibitors are known clinical entities with proven efficacy, but cancer cells can evade these treatments by increasing signaling through CDK2. Inhibition of CDK2 in addition to CDK4/6 cuts off the tumor's natural escape route. NUV-422 is a potent inhibitor of CDK 2, 4, and 6. Preclinical studies have shown that NUV-422 has favorable blood-brain barrier penetration.


The FDA Office of Orphan Drug Development grants Orphan Drug Designation to support drug candidates in development for underserved patient populations or rare disorders that affect fewer than 200,000 people in the U.S. The designation qualifies a candidate for various development incentives, including tax credits for eligible clinical trials, waiver of application fees, and market exclusivity for 7 years upon FDA approval.


Approval of Isatuximab-Irfc for Multiple Myeloma

The FDA approved isatuximab-irfc in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy.


The efficacy and safety of isatuximab-irfc in combination with carfilzomib and dexamethasone was evaluated in IKEMA (NCT03275285), a multicenter, multinational, randomized, open-label, two-arm, Phase III trial in patients with relapsed and/or refractory multiple myeloma who had received 1-3 prior lines of therapy. The trial randomized 302 patients (3:2) to receive isatuximab-irfc with carfilzomib and dexamethasone (Isa-Kd) or carfilzomib and dexamethasone (Kd).


The main efficacy outcome measure was progression-free survival (PFS), assessed by an independent response committee based on central laboratory data for M-protein and central radiologic imaging review using International Myeloma Working Group criteria. Median PFS was not reached in the Isa-Kd arm and was 20.27 months (95% CI: 15.77-NR) in the Kd arm (HR 0.548; 95% CI: 0.366-0.822; p=0.0032), representing a 45 percent reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to those treated with Kd.


The most common adverse reactions (>=20%) in patients receiving isatuximab with carfilzomib and dexamethasone were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. The most common hematology laboratory abnormalities (>=80%) were decreased hemoglobin, decreased lymphocytes, and decreased platelets.


The recommended isatuximab-irfc dose with carfilzomib and dexamethasone is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity.


A New Dosing Regimen for Cetuximab

The FDA approved a new dosage regimen of 500 mg/m2 as a 120-minute intravenous infusion every 2 weeks (Q2W) for cetuximab for patients with KRAS wild-type, EGFR-expressing colorectal cancer (mCRC) or squamous cell carcinoma of the head and neck (SCCHN). This approval provides for a biweekly dosage regimen option in addition to the previously approved weekly dosage regimen for the approved indications when cetuximab is used as a single agent or in combination with chemotherapy.


The approval was based on population pharmacokinetic (PK) modeling analyses that compared the predicted exposures of cetuximab 500 mg Q2W to observed cetuximab exposures in patients who received cetuximab 250 mg weekly. The application was also supported by pooled analyses of overall response rates, progression-free survival, and overall survival (OS) from published literature in patients with CRC and SCCHN, and OS analyses using real-world data in patients with mCRC who received either the weekly cetuximab or Q2W regimens. In these exploratory analyses, the observed efficacy results were consistent across dosage regimens and supported the results of the population PK modeling analyses.


The most common adverse reactions (incidence >=25%) to cetuximab are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.


Approval of Sacituzumab Govitecan for Triple-Negative Breast Cancer

The FDA granted regular approval to sacituzumab govitecan for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.


In April 2020, sacituzumab govitecan received accelerated approval for patients with mTNBC who have received at least two prior therapies for metastatic disease. The following trial was the confirmatory trial for the accelerated approval.


Efficacy and safety were evaluated in a multicenter, open-label, randomized trial (ASCENT; NCT02574455) conducted in 529 patients with unresectable locally advanced or mTNBC who had relapsed after at least two prior chemotherapies, one of which could be in the neoadjuvant or adjuvant setting, if progression occurred within 12 months. Patients were randomized (1:1) to receive sacituzumab govitecan, 10 mg/kg as an intravenous infusion, on days 1 and 8 of a 21-day (n=267) cycle or physician's choice of single-agent chemotherapy (n=262).


The primary efficacy endpoint was progression-free survival (PFS) in patients without brain metastases at baseline as measured by a blinded, independent, centralized review assessed using RECIST 1.1 criteria. Additional efficacy endpoints included PFS for the full population (with and without brain metastases) and overall survival (OS).


Among all randomized patients (with and without brain metastases), median PFS for patients receiving sacituzumab govitecan was 4.8 months (95% CI: 4.1, 5.8) compared with 1.7 months (95% CI: 1.5, 2.5) in those receiving chemotherapy (HR 0.43; 95% CI: 0.35, 0.54; p<0.0001). Median OS was 11.8 months (95% CI: 10.5, 13.8) and 6.9 months (95% CI: 5.9, 7.6), respectively (HR 0.51; 95% CI: 0.41, 0.62; p<0.0001).


Most common adverse reactions (incidence >25%) in patients receiving sacituzumab govitecan were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain.


The recommended sacituzumab govitecan dose is 10 mg/kg once weekly on days 1 and 8 of 21-day treatment cycles until disease progression or unacceptable toxicity.


Breakthrough Therapy Designation to Futibatinib for Advanced Cholangiocarcinoma

The FDA granted Breakthrough Therapy Designation for futibatinib (TAS-120), a covalently binding FGFR inhibitor, for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements, including gene fusions. Futibatinib is an investigational therapy and has not been approved by any regulatory authority for use in patients.


The designation is based on efficacy and safety results from the Phase II FOENIX-CCA2 study. In May 2018, the FDA Office of Orphan Drug Development granted futibatinib orphan drug status for the treatment of cholangiocarcinoma. Futibatinib is an investigational, oral, potent, selective, and irreversible small molecule inhibitor of FGFR1, 2, 3 and 4 being studied as a potential treatment for patients with advanced solid tumors with FGFR1-4 genetic aberrations, including cholangiocarcinoma, who were previously treated with chemotherapy or other therapies. Futibatinib selectively and irreversibly binds to the ATP binding pocket of FGFR1-4, resulting in the inhibition of FGFR-mediated signal transduction pathways, reduced tumor cell proliferation, and increased tumor cell death in tumors with FGFR1-4 genetic aberrations.


Fast Track Designation for Annamycin in the Treatment of Sarcoma Lung Metastases

The FDA approved a Fast Track Designation request for the drug, annamycin, for the treatment of soft tissue sarcoma (STS) lung metastases.


Once metastasized to the lungs, if tumors cannot be surgically removed, the primary chemotherapy regimen is the anthracycline doxorubicin. While 10-30 percent of patients with sarcoma lung metastases may initially respond to doxorubicin, most will relapse leaving the majority of these patients without an alternative chemotherapy. Treatment options are further limited because of the inherent cardiotoxicity of currently approved anthracyclines, including doxorubicin, which limits the amount of anthracycline that can be given to patients.


Annamycin is a next-generation anthracycline that has recently been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, annamycin has also demonstrated a lack of cardiotoxicity in recently conducted human clinical trials for the treatment of acute myeloid leukemia, so researchers believe that the use of annamycin may not face the same usage limitations imposed on doxorubicin.


Eftilagimod Alpha Receives Fast Track Designation for Recurrent/Metastatic Head & Neck Cancer

Eftilagimod alpha (efti or IMP321), a soluble LAG-3 protein, has received FDA Fast Track designation in first-line recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). It has been granted for the development program of efti for first-line treatment of recurrent or metastatic HNSCC due to its potential to address an unmet medical need, as evidenced by encouraging data indicating a positive risk-benefit ratio.


The data package evaluated by the FDA included promising results from Part C of the Phase II TACTI-002 trial evaluating efti in combination with pembrolizumab second-line PD-X naive HNSCC, and its plans for a trial in first-line HNSCC (TACTI-003). Interim clinical data from the study was presented at the Society for Immunotherapy of Cancer (SITC) in November 2020. The overall response rate reported at SITC was approximately 36 percent (approximately 44% in evaluable patients) for 28 patients receiving efti in combination with pembrolizumab.


FDA Grants Clearance for First & Only Artificial Intelligence System for Colonoscopy

The FDA granted de novo clearance for GI Genius intelligent endoscopy module in the U.S., which is the first and only commercially available computer-aided detection (CADe) system using artificial intelligence (AI) to identify colorectal polyps. The module, compatible with any colonoscope video, provides physicians with a powerful new solution in the fight against colorectal cancer-the third most common form of cancer globally.


"More than 19 million screening colonoscopies are performed in the United States each year. A key factor in the prevention of colorectal cancer is the integration of leading-edge technologies into gastroenterology practices to increase detection rates," said James Weber, MD, a gastroenterologist and Chief Executive Officer of the GI Alliance. "Detection of adenomas during colonoscopy is an important quality metric. The addition of AI can increase the quality of colonoscopies, potentially improving diagnosis and outcomes for colon cancer patients."


"Colonoscopies allow highly skilled gastroenterologists to identify polyps and lesions that might develop into cancer. With GI Genius, we can tap into the potential of artificial intelligence approaches to increase detection rates. This important new development helps us in our mission to detect colon cancer early and to improve patient outcomes," said Michael Sapienza, Chief Executive Officer of the Colorectal Cancer Alliance.


The detection system uses advanced AI to highlight the presence of precancerous lesions with a visual marker in real-time-serving as an ever vigilant second observer. It processes images using advanced algorithms that can identify and mark abnormalities consistent with polyps, including small flat polyps that might otherwise go undetected by the human eye. Studies have shown that having a second observer can increase polyp detection rates and every 1 percent increase in adenoma detection rate (ADR) reduces the risk of colorectal cancer by 3 percent. Use of the GI Genius module has demonstrated a 14 percent absolute increase in ADR compared to colonoscopy alone for both flat (42% increase) and polyploid (36% increase) lesions, thus increasing accuracy and reducing the rise of interval cancers which can occur between colonoscopies.