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Cemiplimab-Rwlc for Locally Advanced & Metastatic Basal Cell Carcinoma

Cemiplimab-rwlc has been granted regular approval for patients with locally advanced basal cell carcinoma (laBCC) previously treated with a hedgehog pathway inhibitor (HHI) or for whom an HHI is not appropriate. It has also been granted accelerated approval for patients with metastatic BCC (mBCC) previously treated with an HHI or for whom an HHI is not appropriate.

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Efficacy was evaluated in Study 1620 (NCT03132636), an ongoing open-label, multicenter, non-randomized trial in patients with advanced BCC (laBCC or mBCC) who had progressed on HHI therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy. Eligibility required that laBCC patients were not candidates for curative surgery or curative radiation therapy, per multidisciplinary assessment. All patients received cemiplimab-rwlc 350 mg every 3 weeks for up to 93 weeks until disease progression, unacceptable toxicity, or completion of planned treatment.


The main efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) as assessed by independent central review. For patients without externally visible target lesions (mBCC), confirmed ORR was assessed according to RECIST 1.1. A composite response assessment incorporating clinical response criteria using digital medical photography, together with RECIST 1.1, was used for those with externally visible target lesions (laBCC and mBCC).


Among 84 patients with laBCC, the confirmed ORR was 29 percent (95% CI: 19, 40) with a median DOR not reached (range: 2.1-21.4+ months) and 79 percent of responders maintaining their response for at least 6 months. Among 28 patients with mBCC, the confirmed ORR was 21 percent (95% CI: 8, 41) with a median DOR not reached (range: 9-23.0+ months), and all responders maintaining their responses for at least 6 months.


Severe adverse reactions are immune-mediated adverse reactions (e.g. pneumonitis, hepatitis, colitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes mellitus, and nephritis) and infusion reactions. The most common adverse reactions (incidence >= 20%) were fatigue, musculoskeletal pain, diarrhea, rash, and pruritis.


The recommended dosage of cemiplimab-rwlc is 350 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.


Accelerated Approval of Umbralisib for Marginal Zone & Follicular Lymphomas

The FDA granted accelerated approval to umbralisib, a kinase inhibitor including PI3K-delta and casein kinase CK1-epsilon, for the following indications:


* Adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen;


* Adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.



Approval was based on two single-arm cohorts of an open-label, multicenter, multi-cohort trial, UTX-TGR-205 (NCT02793583). The study included 69 patients with MZL who received at least one prior therapy, including an anti-CD20-containing regimen, and in 117 patients with FL after at least two prior systemic therapies. Patients received umbralisib 800 mg orally once daily until disease progression or unacceptable toxicity. Efficacy was based on overall response rate (ORR) and duration of response (DOR) using modified 2007 International Working Group criteria assessed by an independent review committee.


For patients with MZL, the ORR was 49 percent (95% CI: 37.0, 61.6) with 16 percent achieving complete responses. Median DOR was not reached (95% CI: 9.3, NE) in these patients. For patients with FL, the ORR was 43 percent (95% CI: 33.6, 52.2) with 3 percent achieving complete responses. Median DOR was 11.1 months (8.3, 16.4).


The most common (>15%) adverse reactions, including laboratory abnormalities, were increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash. Serious adverse reactions occurred in 18 percent of patients, most often from diarrhea-colitis and infection. Diarrhea-colitis and transaminase elevation were the most common reasons for dose modifications.


The prescribing information provides warnings and precautions for adverse reactions, including infections, neutropenia, diarrhea and non-infectious colitis, hepatotoxicity, and severe cutaneous reactions. The recommended umbralisib dose is 800 mg taken orally once daily with food until disease progression or unacceptable toxicity.


Drug Approved to Reduce Bone Marrow Suppression Caused by Chemotherapy

Trilaciclib was granted approval as the first therapy in its class to reduce the frequency of chemotherapy-induced bone marrow suppression in adults receiving certain types of chemotherapy for extensive-stage small cell lung cancer. Trilaciclib may help protect bone marrow cells from damage caused by chemotherapy by inhibiting the cyclin-dependent kinase 4/6 enzyme.


"For patients with extensive-stage small cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan," said Albert Deisseroth, MD, PhD, Supervisory Medical Officer in the Division of Non-Malignant Hematology in the FDA's Center for Drug Evaluation and Research. "Today's approval of [trilaciclib] will give patients a treatment option that can reduce the occurrence of a common, harmful side effect of chemotherapy."


Chemotherapy drugs are designed to kill cancer cells but can damage normal tissues as well. The bone marrow is particularly susceptible to chemotherapy damage. When this happens, the bone marrow produces fewer of these cells, leading to fatigue, increased risk of infection, and bleeding, among other problems. Trilaciclib may help protect the normal bone marrow cells from the harmful effects of chemotherapy.


The effectiveness of trilaciclib was evaluated in three randomized, double-blind, placebo-controlled studies in patients with extensive-stage small cell lung cancer. Combined, these studies randomly assigned 245 patients to receive either an infusion of trilaciclib in their veins or a placebo before chemotherapy. The studies then compared the two groups for the proportion of patients with severe neutropenia and the duration of severe neutropenia in the first cycle of chemotherapy. In all three studies, patients who received trilaciclib had a lower chance of having severe neutropenia compared to patients who received a placebo. Among those who had severe neutropenia, patients who received trilaciclib, on average, had it for a shorter time than patients who received a placebo.


The most common side effects of trilaciclib include fatigue; low levels of calcium, potassium, and phosphate; increased levels of aspartate aminotransferase; headache; and infection in the lungs. Patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.


Orphan Drug Designation Granted to Iadademstat for AML Treatment

The FDA has granted Orphan Drug Designation to the first-in-class LSD1 inhibitor iadademstat for the treatment of patients with acute myeloid leukemia (AML). Iadademstat is an investigational, oral, small molecule covalent inhibitor of the epigenetic enzyme LSD1, a chromatin remodeler that interacts with a variety of transcription factors involved in leukemia and other cancers.


Iadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (Cancer Cell 2018;33(3):495-511). A first Phase I/IIa clinical trial with iadademstat in refractory and relapsed acute leukemia patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi.


Beyond hematological cancers, the inhibition of LSD1 has been proposed as a valid therapeutic approach in some solid tumors, such as small cell lung cancer (SCLC), neuroendocrine tumors, medulloblastoma, and others. Iadademstat has been tested in four clinical trials (two in monotherapy in SCLC and AML, and two in combination in SCLC and AML) in more than 100 patients. In the combination studies, ALICE (ongoing), a Phase IIa trial in combination with azacitidine in elderly or unfit AML patients, and CLEPSIDRA (finalized), a Phase IIa trial in combination with platinum/etoposide in second-line ED-SCLC patients, preliminary efficacy results have been reported.


The FDA's Office of Orphan Drug Products grants orphan status to support the development of medicines for rare disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides certain benefits, including market exclusivity upon regulatory approval if received, exemption of FDA application fees, and tax credits for qualified clinical trials. Iadademstat was previously granted Orphan Drug Designation by the European Medicines Agency for the treatment of AML.


Orphan Drug Designation for Rivoceranib to Treat Adenoid Cystic Carcinoma

Rivoceranib has been granted orphan drug designation for the treatment of adenoid cystic carcinoma (ACC), a rare form of cancer that most commonly develops in the salivary glands or other regions of the head and neck. Approximately 1,200 new cases of ACC are diagnosed each year in the United States. The FDA's Office of Orphan Drug Products grants orphan status to medicines for underserved patient populations, or rare disorders, that affect fewer than 200,000 people in the U.S.


ACC is considered a slow-growing but relentless cancer characterized by nerve invasion and metastases. Although good local control is usually achieved by resection of the primary tumor and adjuvant radiation therapy, more than half of patients eventually have recurrent and/or metastatic disease. Currently, no curative treatments are available for these patients which underscores the need for effective new therapies.


In November 2020, researchers met the initial 55 patient enrollment target for its Phase II, open-label, multicenter, clinical trial of rivoceranib in patients with recurrent or metastatic ACC 1 year ahead of schedule. They also announced increasing the target size of the trial to approximately 72 patients to further explore the potential clinical benefit of rivoceranib in this patient population.


Rivoceranib is the first small-molecule tyrosine kinase inhibitor (TKI) to be approved in gastric cancer, which occurred in 2014 in China. It has been granted Orphan Drug designation in the U.S., Europe, and South Korea and has been clinically tested in over 1,000 patients worldwide.


Rivoceranib acts by inhibiting angiogenesis, a critical process in cancer growth and proliferation. Specifically, rivoceranib potently and selectively inhibits VEGFR-2, which mediates the primary pathway for tumor-mediated angiogenesis. As a best-in-class therapeutic known for its safety and tolerability, researchers believe this treatment has the potential to significantly improve clinical outcomes in combination with chemotherapeutics and immunotherapy, as well as for maintenance therapy. Researchers are developing rivoceranib for the treatment of patients with gastric cancer, colorectal cancer, hepatocellular carcinoma, and adenoid cystic carcinoma.