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FDA Pipeline: Reviews and Designations in Multiple Myeloma, Lymphoma, Prostate Cancer

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Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review for daratumumab in combination with a triplet therapy in multiple myeloma, Breakthrough Therapy designation to copanlisib for marginal zone lymphoma, and Fast Track designation for ARV-110 in metastatic castration-resistant prostate cancer.

Priority Review for Daratumumab in Combination With Bortezomib/Thalidomide/Dexamethasone in Multiple Myeloma

The FDA granted a Priority Review for a supplemental Biologics License Application for the use of daratumumab in combination with bortezomib/thalidomide/dexamethasone as treatment for patients newly diagnosed with multiple myeloma who are candidates for autologous stem cell transplant (ASCT).  The FDA assigned a Prescription Drug User Fee Act target date of September 26, 2019 to make a decision on daratumumab in this indication.

Daratumumab is a human IgG1k monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. 

The supplemental Biologics License Application submission is based on data from the phase III CASSIOPEIA study of daratumumab in combination with bortezomib/thalidomide/dexamethasone as treatment for patients newly diagnosed with multiple myeloma who are candidates for ASCT. Data from the trial was presented at the 2019 ASCO Annual Meeting (Abstract 8003).

CASSIOPEIA is a randomized, open-label, multicenter study including 1,085 newly diagnosed patients with previously untreated symptomatic multiple myeloma who are eligible for high dose chemotherapy and stem cell transplant. In the first part of the study, patients were randomly assigned to receive induction and consolidation treatment with daratumumab combined with bortezomib/thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone alone. The primary endpoint is the proportion of patients that achieve a stringent complete response.

In the second part of the study, patients that achieved a response will undergo a second randomization to either receive maintenance treatment of daratumumab 16 mg/kg every 8 weeks for up to 2 years vs observation. The primary endpoint of this part of the study is progression-free survival.

Breakthrough Therapy Designation for Copanlisib in Marginal Zone Lymphoma

The FDA granted Breakthrough Therapy designation for copanlisib for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies.

Copanlisib is an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with inhibitory activity predominantly against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. 

The Breakthrough Therapy designation was granted based on data from the marginal zone lymphoma subgroup of the phase II CHRONOS-1 study, which is the trial that accelerated the U.S. FDA approval of copanlisib for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

In the phase II study 16439 part B (CHRONOS-1), copanlisib showed preliminary efficacy in patients with indolent non-Hodgkin lymphoma—including 23 patients with relapsed or refractory marginal zone lymphoma—who have received at least two prior therapies. At the primary analysis, the overall response rate of the overall indolent non-Hodgkin lymphoma population (n = 142) was 59.2%, and was 69.6% in the population of patients with marginal zone lymphoma (n = 23). An 18-month follow-up analysis of CHRONOS-1 showed an overall response in the full analysis set population of 60.6%, and 78.3% in the marginal zone lymphoma histology population (n = 23). The most common treatment-emergent adverse events (experienced by greater than or equal to 20% of the marginal zone lymphoma subgroup) were hyperglycemia and fatigue (47.8%), hypertension and diarrhea (43.5%), nausea (26.1%), pyrexia, and cough (21.7%). The most common Grade 3 treatment-emergent adverse events were hypertension (39.1%) and hyperglycemia (34.8%).

Fast Track Designation for ARV-110 in Metastatic Castration-Resistant Prostate Cancer

ARV-110 has been granted Fast Track designation for the treatment of men with metastatic castration-resistant prostate cancer whose disease has progressed after treatment with two or more systemic therapies. ARV-110 is an orally bioavailable proteolysis targeting chimera protein degrader designed to selectively target and degrade the androgen receptor protein. ARV-110 is currently being evaluated in a phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetics of ARV-110 in men with metastatic castration-resistant prostate cancer whose disease has progressed after treatment with standard of care. ARV-110 has demonstrated activity in preclinical models of androgen receptor mutation or overexpression, both common mechanisms of resistance to currently available androgen receptor–targeted therapies.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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