Carfilzomib & Daratumumab With Dexamethasone for Multiple Myeloma
The FDA approved carfilzomib and daratumumab in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received 1-3 lines of therapy. The efficacy of carfilzomib and daratumumab with deaxamethasone was evaluated in two clinical trials, CANDOR and EQUULEUS.
CANDOR (NCT03158688) was a randomized, open-label, multicenter trial evaluating the combination of carfilzomib (20/56 mg/m2 twice weekly regimen) with intravenous daratumumab and dexamethasone (DKd) versus carfilzomib (20/56 mg/m2 twice weekly regimen) and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy. A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm.
Efficacy was assessed by an independent review committee (IRC) evaluation of progression-free survival (PFS) using International Myeloma Working Group (IMWG) response criteria. Median PFS was not reached for the DKd arm and was 15.8 months (95% CI: 12.1, NE) for the Kd arm (HR 0.63; 95% CI: 0.46, 0.85; 1-sided p-value 0.0014).
EQUULEUS (NCT01998971) was an open-label, multi-cohort trial evaluating the combination of carfilzomib (20/70 mg/m2 once weekly regimen) with IV DKd. Efficacy was based on overall response rate (ORR) as assessed by IRC using IMWG response criteria. Of the 85 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy enrolled in the DKd cohort, the ORR was 81 percent (95% CI: 71, 89) with a duration of response of 27.5 months (20.5, not estimable).
The most common adverse reactions occurring in at least 20 percent of patients treated with carfilzomib and daratumumab in the combination therapy trials were infusion-related reactions, anemia, diarrhea, fatigue, hypertension, pyrexia, respiratory tract infection, thrombocytopenia, neutropenia, lymphopenia, cough, dyspnea, insomnia, headache, and back pain.
The recommended dosage regimens of carfilzomib, when administered in combination with intravenous daratumumab and dexamethasone, are the following:
* once weekly 20/70 mg/m2 regimen: administer carfilzomib intravenously as a 30-minute infusion on days 1, 8, and 15 of each 28-day cycle at a dose of 20 mg/m2 on cycle 1 day 1 and, if tolerated, increased to 70 mg/m2 on cycle 1 day 8 and thereafter, or
* twice weekly 20/56 mg/m2 regimen: administer carfilzomib intravenously as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle at a dose of 20 mg/m2 on days 1 and 2 of cycle 1 and, if tolerated, increased to 56 mg/m2 on cycle 1 day 8 and thereafter.
The recommended dosage regimen of IV daratumumab, when administered in combination with carfilzomib and dexamethasone, is 16 mg/kg actual body weight administered as split dosing of 8 mg/kg on days 1 and 2 of cycle 1, followed by standard dosing of 16 mg/kg for subsequent doses administered weekly from weeks 2-8, every 2 weeks from weeks 9-24, and every 4 weeks from week 25 and thereafter.
New Drug Application for Trilaciclib in Patients With Small Cell Lung Cancer
The FDA has accepted a New Drug Application (NDA) for trilaciclib for small cell lung cancer (SCLC) patients being treated with chemotherapy and also granted Priority Review with a Prescription Drug User Fee Act (PDUFA) action date of February 15, 2021. Trilaciclib is a first-in-class investigational therapy designed to preserve bone marrow and immune system function during chemotherapy and improve patient outcomes.
The trilaciclib NDA was supported by compelling myelopreservation data from three randomized, double-blind, placebo-controlled clinical trials in which trilaciclib was administered prior to chemotherapy treatment in patients with SCLC. Trilaciclib has been granted Breakthrough Therapy Designation by the FDA. In the NDA acceptance letter, the FDA also stated that it is currently not planning to hold an advisory committee meeting to discuss this application.
"While undergoing chemotherapy, many patients experience significant myelosuppression, become fatigued and susceptible to infection, and often require transfusions and growth factor administrations," said Jared Weiss, MD, from the Lineberger Comprehensive Cancer Center at the University of North Carolina Chapel Hill. "Preventing bone marrow damage proactively is an opportunity to improve the quality of life of patients receiving chemotherapy for small cell lung cancer and reduce costly rescue interventions."
Myelosuppression is the result of damage to bone marrow stem cells and is one of the most common side effects of chemotherapy. Myelosuppression can lead to serious conditions such as anemia, neutropenia or thrombocytopenia, which have broad-ranging clinical, patient experience, and economic impacts on ongoing cancer treatment and overall outcomes. In clinical trials, trilaciclib significantly reduced chemotherapy-induced myelosuppression, and patients receiving trilaciclib experienced fewer dose delays/reductions, infections, hospitalizations, and need for rescue therapies compared to patients receiving chemotherapy alone.
In a randomized trial of women with metastatic triple-negative breast cancer, preliminary data showed that trilaciclib improved overall survival when administered in combination with chemotherapy compared with chemotherapy alone. Trilaciclib is being evaluated in neoadjuvant breast cancer as part of the I-SPY 2 Trial, with a phase II trial in patients treated with chemotherapy for colorectal cancer expected to be initiated in the fourth quarter of 2020.
Efineptakin Alfa & Tisagenlecleucel in R/R Large B-Cell Lymphoma
The FDA cleared an investigational new drug (IND) application for the combination of its lead drug candidate, efineptakin alfa, a novel long-acting human interleukin-7 (IL-7), and tisagenlecleucel, a CD19 CAR T-cell therapy, for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This IND clearance will allow the initiation of a multicenter, phase Ib study evaluating the safety, tolerability, and preliminary anti-tumor activity of efineptakin alfa administration following standard-of-care tisagenlecleucel CAR T-cell therapy.
"In multiple animal models, the addition of [efineptakin alfa] to CAR T cells substantially increased CAR T-cell proliferation, persistence, and target-specific tumor killing, resulting in significantly prolonged survival of the treated animals," noted John DiPersio, MD, PhD, Director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine and Barnes-Jewish Hospital. "In the clinic, treatment with [efineptakin alfa] has shown to increase T-cell counts in the blood and is well-tolerated. Administration of [efineptakin alfa] following [tisagenlecleucel] may increase the expansion and persistence of [tisagenlecleucel] and facilitate the reconstitution of patients' own immune system to fight cancer."
In addition to establishing the safety, tolerability, and assessing the preliminary anti-tumor activity of efineptakin alfa following tisagenlecleucel, this phase Ib study will determine the recommended phase II dose to be used for further clinical development of the combination.
Efineptakin alfa is the only clinical-stage, long-acting human IL-7 and is being developed for oncologic and immunologic indications, in which T-cell amplification and increased functionality may provide clinical benefit. IL-7 is a fundamental cytokine for naive and memory T-cell development and for sustaining immune response to chronic antigens or foreign antigens. Efineptakin alfa exhibits favorable PK/PD and safety profiles, making it an ideal combination partner. Efineptakin alfa is being studied in multiple clinical trials in solid tumors and as a vaccine adjuvant. Studies are being planned for testing in hematologic malignancies, additional solid tumors, and other immunology-focused indications.