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Fast Track Designation Granted to Selinexor for Multiple Myeloma

The FDA has granted Fast Track designation to selinexor, a first-in-class, oral selective inhibitor of nuclear export compound, for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy.

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The FDA's statement, consistent with the design of the phase IIb STORM study, noted that the three prior lines of therapy include regimens comprised of an alkylating agent, a glucocorticoid, bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. In addition, the patient's disease must be refractory to at least one proteasome inhibitor (bortezomib or carfilzomib), one immunomodulatory agent (lenalidomide or pomalidomide), glucocorticoids, and daratumumab, as well as to the most recent therapy.


In the multi-center, single-arm phase IIb STORM (Selinexor Treat-ment of Refractory Myeloma) study, approximately 122 patients with heavily pretreated, penta-refractory myeloma receive 80 mg oral selinexor twice weekly in combination with 20 mg low-dose dexamethasone, also dosed orally twice weekly. Patients with penta-refractory disease are those who have previously received an alkylating agent, a glucocorticoid, two immunomodulatory drugs (IMiDs) (lenalidomide and pomalidomide), two proteasome inhibitors (PIs) (bortezomib and carfilzomib), and the anti-CD38 monoclonal antibody daratumumab, and their disease is refractory to at least one PI, at least one IMiD, daratumumab, glucocorticoids, and their most recent anti-myeloma therapy. Overall response rate is the primary endpoint of the study, with duration of response and clinical benefit rate being secondary endpoints.


The FDA's Fast Track program facilitates the development of drugs intended to treat serious conditions and that have the potential to address unmet medical needs. A drug program with Fast Track status is afforded greater access to the FDA for the purpose of expediting the drug's development, review, and potential approval. In addition, it allows for eligibility for Accelerated Approval and Priority Review, if relevant criteria are met, as well as for Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.


Nivolumab Plus Ipilimumab Approved for Renal Cell Carcinoma

The FDA granted approvals to nivolumab and ipilimumab in combination for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).


The approvals were based on CheckMate 214, a randomized, open-label trial. Patients with previously untreated advanced RCC received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for 4 doses, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks or sunitinib 50 mg daily for 4 weeks, followed by 2 weeks off every cycle.


"Physicians treating advanced RCC have had few options to help achieve the goal of improved survival," said Robert J. Motzer, MD, the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, New York City. "Data from the CheckMate 214 trial demonstrated superior overall survival with nivolumab + ipilimumab, showing the potential for the combination to become a new standard of care for patients with intermediate- and poor-risk advanced RCC. What's more, the combination resulted in fewer overall grade 3/4 adverse reactions compared to sunitinib. Because of these encouraging results, we now have a new treatment option for newly diagnosed advanced RCC patients across PD-L1 expression levels."


Efficacy was evaluated in intermediate or poor-risk patients (n=847). The trial demonstrated statistically significant improvements in overall survival (OS) and objective response rate (ORR) for patients receiving the combination (n=425) compared with those receiving sunitinib (n=422). Estimated median OS was not estimable in the combination arm compared with 25.9 months in the sunitinib arm (HR 0.63, 95% CI: 0.44, 0.89; p<0.0001). The ORR was 41.6 percent (95% CI: 36.9, 46.5) for the combination versus 26.5 percent (95% CI: 22.4, 31) in the sunitinib arm (p<0.0001). The efficacy of the combination in patients with previously untreated RCC with favorable-risk disease was not established.


The most common adverse reactions (reported in at least 20% of patients treated with the combination) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite.


The recommended schedule and dose for this combination is nivolumab (3 mg/kg) followed by ipilimumab (1 mg/kg) on the same day every 3 weeks for 4 doses, then nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks.


The FDA granted these applications Priority Review and Breakthrough Therapy Designation.