Melphalan Approved As a Liver-Directed Treatment for Uveal Melanoma
The FDA approved melphalan for injection/hepatic delivery system containing melphalan as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases that affect less than 50 percent of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.
Efficacy was evaluated in the FOCUS study (NCT02678572), a single-arm, multicenter, open-label trial that enrolled 91 patients with uveal melanoma with unresectable hepatic metastases. Limited extrahepatic disease in the bone, subcutaneous sites, lymph nodes, or lung was permitted if the life-threatening component of the uveal melanoma was in the liver and the extrahepatic disease was amenable to resection or radiation. Key exclusion criteria were metastases in >=50 percent of the liver parenchyma, Child-Pugh Class B or C cirrhosis, or hepatitis B or C infection.
The main efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) as assessed by an independent central review committee using RECIST v1.1. ORR was 36.3 percent (95% CI: 26.4, 47) and median DoR was 14 months (95% CI: 8.3, 17.7).
Melphalan is administered via the device constituent part, hepatic delivery system by infusion into the hepatic artery every 6-8 weeks for up to six total infusions. The recommended melphalan dose is 3 mg/kg based on ideal body weight, with a maximum dose of 220 mg during a single treatment.
The prescribing information for the melphalan kit has a boxed warning for severe peri-procedural complications, including hemorrhage, hepatocellular injury, and thromboembolic events. It also has a boxed warning for myelosuppression with resulting severe infection, bleeding, or symptomatic anemia.
Because of the risk of severe peri-procedural complications, including hemorrhage, hepatocellular injury, and thromboembolic events, melphalan kit is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The most common (>=20%) adverse reactions or laboratory abnormalities were thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased blood alkaline phosphatase, and dyspnea.
Melphalan and the melphalan kit are contraindicated in patients with active intracranial metastases or brain lesions with a propensity to bleed; liver failure, portal hypertension, or known varices at risk for bleeding; surgery or medical treatment of the liver in the previous 4 weeks; uncorrectable coagulopathy, inability to safely undergo general anesthesia, including active cardiac conditions, such as unstable coronary syndromes (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease; history of allergies or known hypersensitivity to melphalan; history of allergies or known hypersensitivity to a component or material utilized within the melphalan kit, including history of allergy to natural rubber latex; history of allergy or hypersensitivity to heparin or presence of heparin-induced thrombocytopenia; and history of severe allergic reaction to iodinated contrast not controlled by premedication with antihistamines and steroids.
Enzalutamide Granted Priority Review for Prostate Cancer
The FDA granted Priority Review of a supplemental New Drug Application (sNDA) highlighting enzalutamide for the treatment of patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) with high-risk biochemical recurrence (BCR). The FDA grants Priority Review to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The Prescription Drug User Fee Act date for an anticipated FDA decision is in fourth quarter 2023.
The sNDA is based on results from the Phase III enzalutamide trial, which evaluated patients with nmCSPC with high-risk BCR across three study arms: enzalutamide plus leuprolide (n=355), placebo plus leuprolide (n=358), or enzalutamide monotherapy (n=355). The study met its primary endpoint of metastasis-free survival for the enzalutamide plus leuprolide arm, demonstrating a statistically significant 58 percent reduction in the risk of metastasis or death over placebo plus leuprolide (HR: 0.42; 95% CI: 0.30-0.61; p<0.0001).
The overall safety profile was consistent with the known safety profile of each of the medicines. The most common adverse events in those treated with enzalutamide plus leuprolide were fatigue, hot flush, and arthralgia. Adverse events for patients treated with enzalutamide monotherapy were fatigue, gynecomastia, and arthralgia.
The sNDA for enzalutamide in nmCSPC with high-risk BCR is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, two initiatives of the FDA designed to bring safe and effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines by participating international partners.
The EMBARK data are being discussed with other regulatory authorities around the world to support potential additional license applications for enzalutamide in this indication in 2023 and beyond.
FDA Approves Luspatercept-aamt as First-Line Treatment of Anemia
Luspatercept-aamt has been approved by the FDA for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naive) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions.
This expanded indication to the first-line setting is based on interim results from the pivotal Phase III COMMANDS trial, in which luspatercept-aamt demonstrated superior efficacy of concurrent RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase compared to epoetin alfa, an ESA, regardless of ring sideroblast status. These results underscore luspatercept-aamt's ability to address chronic anemia earlier in the treatment journey in a broader range of patients.
In the Phase III COMMANDS trial, results showed 58.5 percent (n=86) of patients treated with luspatercept-aamt versus 31.2 percent (n=48) of patients treated with epoetin alfa achieved the primary endpoint of RBC-TI of at least 12 weeks with a mean Hb increase of at least 1.5 g/dL within the first 24 weeks (p<0.0001). The most common (>10%) adverse reactions were diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea.
COMMANDS (NCT03682536) is a Phase III, open-label, randomized study evaluating the efficacy and safety of luspatercept-aamt versus epoetin alfa for the treatment of anemia due to very low-, low- or intermediate-risk (IPSS-R) MDS in patients who are red blood cell (RBC) transfusion-dependent and were ESA-naive.
The primary endpoint evaluated in this study is RBC transfusion independence (RBC-TI) for 12 weeks with a mean hemoglobin (Hb) increase >=1.5 g/dL. Key secondary endpoints include erythroid response (HI-E) of at least 8 weeks during weeks 1-24 of the study, RBC-TI >=12 weeks, and RBC-TI for 24 weeks. Eligible patients were >=18 years old with lower-risk MDS who require transfusions. Patients were randomized 1:1 to receive subcutaneous luspatercept-aamt (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg, titration up to 1,050 IU/kg) weekly for >=24 weeks. The majority of study participants (>90%) were outside of the United States and a non-U.S.-licensed epoetin alfa product was used in the control arm for such patients.
At the time of the planned interim analysis (October 31, 2022), 147 evaluable patients received luspatercept-aamt and 154 evaluable patients received epoetin alfa, with median treatment durations of 41.6 and 27 weeks, respectively. Results published in The Lancet showed the following (2023; https://doi.org/10.1016/S0140-6736(23)00874-7):
* 58.5% (n=86) of patients receiving luspatercept-aamt versus 31.2 percent (n=48) of patients receiving epoetin alfa achieved the primary endpoint of RBC-TI of at least 12 weeks with concurrent mean Hb increase of at least 1.5 g/dL within the first 24 weeks (p<0.0001).
* HI-E increase of at least 8 weeks was achieved by 74.1 percent (n=109) of luspatercept-aamt patients versus 51.3 percent (n=79) of epoetin alfa patients (p<0.0001).
* Within the first 24 weeks of treatment, RBC-TI of at least 24 weeks was achieved by 47.6 percent (n=70) of luspatercept-aamt patients versus 29.2 percent (n=45) of epoetin alfa patients (p=0.0012).
* RBC-TI of at least 12 weeks was achieved by 66.7 percent (n=98) of luspatercept-aamt patients versus 46.1 percent (n=71) of epoetin alfa patients (p=0.0003).
* Patients treated with luspatercept-aamt demonstrated durable responses with nearly 2.5 years of median RBC-TI >=12 weeks (126.6 weeks, Week 1 to end of treatment). The most common (>10%) adverse reactions were diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea.