In the phase 2 STORM Part 1 clinical trial, 21% of patients with refractory multiple myeloma had a partial or better response to oral selinexor (Xpovio) plus dexamethasone. Those findings were the basis for the pivotal phase 2 STORM Part 2 study (Chari A, et al. N Engl J Med. 2019;381:727-738).
This study led to the 2019 FDA approval of selinexor, a selective nuclear export inhibitor that blocks exportin 1, which induces accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation.
Part 2 study was a phase 2b, multicenter, open-label clinical trial with 122 patients with multiple myeloma in the United States and Europe; 53% of patients had high-risk cytogenetic abnormalities. Patients received selinexor 80 mg plus dexamethasone 20 mg twice weekly on days 1 and 3 in 4-week cycles until disease progression, treatment discontinuation, or death. Patients had disease refractory to current standard treatment for multiple myeloma.
All patients had previously received ≥3 regimens that included an alkylating agent, bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex). The primary end point was overall response.
A total of 26 had a response to this combination, which translated to an overall response rate of 25.3% (95% confidence interval, 16.4-36), including 2 stringent complete responses, 6 very good partial responses, and 24 partial responses. By contrast, 39% of the patients had stable disease and 21% had progressive disease or unevaluable disease.
The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months. Patients with a minimal response or better had a median overall survival of 15.6 months.
The most common adverse events of grade ≥3 were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%). Overall, 18% of patients discontinued treatment because of adverse events.
The study results were notable for several reasons. The trial was permissive, allowing patients with reduced renal function, thrombocytopenia, and neutropenia to be included. The patients were heavily pretreated, with a median of 7 previous therapeutic regimens, and the patients had rapidly progressing disease, with a 22% increase in disease burden in the 12 days from screening to initial therapy.
“These characteristics are consistent with the growing population of patients who have exhausted available therapies but still desire to continue therapy,” said the investigators.
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The introduction of BRAF- and MEK-targeted therapies and immune checkpoint inhibitors has significantly improved outcomes in patients with metastatic melanoma. However, many patients have drug resistance—acquired or primary—which results in death from underlying disease.
The COMBI-d and COMBI-v studies evaluated the efficacy and safety of the BRAF inhibitor dabrafenib (Tafinlar) plus the MEK inhibitor trametinib (Mekinist) versus BRAF inhibitor monotherapy in patients with unresectable or metastatic melanoma and BRAF V600E or V600K mutation. In a new study, researchers analyzed the 5-year outcomes of patients who received dabrafenib plus trametinib in these 2 clinical trials (Robert C, et al. N Engl J Med. 2019;381:626-636).
The researchers pooled 5-year survival data for 563 patients in COMBI-d (N = 211) or COMBI-v (N = 352). COMBI-d was a randomized, double-blind, phase 3 clinical trial comparing dabrafenib plus trametinib with dabrafenib plus placebo. COMBI-v was an open-label, randomized, phase 3 clinical trial comparing dabrafenib plus trametinib versus vemurafenib (Zelboraf). Both studies stratified patients by their BRAF genotype and baseline lactate dehydrogenase concentration.
The new study evaluated patients with metastatic melanoma and BRAF V600E or V600K mutation who had been randomized to dabrafenib and trametinib. The primary end points were progression-free survival (PFS) and overall survival (OS) in the COMBI-d and COMBI-v studies, respectively. The median follow-up was 22 months.
The PFS rates were 21% at 4 years and 19% at 5 years, and the OS rates were 37% at 4 years and 34% at 5 years. A multivariate analysis identified several baseline factors that were significantly associated with PFS and OS in both studies, including performance status, age, sex, number of metastatic organ sites, and lactate dehydrogenase level.
In all, 68% of patients demonstrated an objective response rate to treatment with dabrafenib plus trametinib. A complete response was observed in 109 (19%) patients and was associated with improved long-term outcomes, with a 5-year OS rate of 71% and a 5-year PFS rate of 49%.
No unexpected adverse events were reported with extended follow-up. Adverse events led to 18% of patients permanently discontinuing the study regimen.
“Having a complete response to the combined treatment appears to be a strong and early predictor of prolonged benefit,” concluded the researchers. “However, no biomarkers are currently available to determine which patients who discontinue therapy are likely to have disease progression.”
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