NEWTON, Mass.—Karyopharm Therapeutics Inc., a clinical-stage pharmaceutical company, in early March announced the results of a planned interim analysis of the Phase 2 SOPRA study evaluating single-agent selinexor in relapsed/refractory acute myeloid leukemia (AML). The company has determined in concert with the study’s independent data safety monitoring board (DSMB) that SOPRA will not reach statistical significance for overall survival (OS), the study’s primary endpoint.
However, since selinexor-treated patients that achieved a complete response (CR) showed a substantial OS benefit as compared with the physician’s choice (PC) arm, Karyopharm and the DSMB agreed that patients would be permitted to continue on the selinexor arm or the PC arm, as applicable, following discussion between the patient and their treating physician. The company plans to continue clinical development of selinexor in AML through investigator-sponsored trials in multiple combination regimens, including with chemotherapy, given encouraging data to date across these settings.
SOPRA is a Phase 2 randomized study of patients 60 years of age or older with relapsed or refractory AML who were ineligible for intensive chemotherapy and/or transplantation. Patients were randomized to either receive single-agent oral selinexor 60mg twice weekly or PC. PC included best supportive care (BSC) alone, or BSC plus either azacitidine (Vidaza), decitabine (Dacogen) or low-dose cytosine arabinoside.
Based on unaudited site data, SOPRA enrolled 176 patients (median of two prior regimens) in the United States, Canada, Europe and Israel. Among patients on the selinexor arm, 13 percent demonstrated a CR with or without full hematologic recovery, compared to 3 percent of patients on the PC control arm. Some patients remained on selinexor for over one year, but this did not result in a statistically superior OS compared to the PC arm. The DSMB found no new clinically significant adverse events in the patients receiving selinexor. Importantly, rates of sepsis and febrile neutropenia (FN) were lower on the selinexor arm (sepsis 4.9 percent, FN 14.7 percent) compared to the PC arm (sepsis 6.1 percent, FN 36.4 percent). As expected, the most common selinexor-related adverse events were nausea, anorexia, fatigue, vomiting and thrombocytopenia.
“SOPRA is a robust, well-conducted trial and the response rates achieved with single-agent selinexor in this heavily pretreated older population have been encouraging,” said Dr. Hagop Kantarjian, chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “Importantly, the safety profile was as expected and the recommended Phase 2 dose was generally well-tolerated. Unfortunately, as is common in AML, the higher response rates observed with single-agent selinexor versus physician’s choice did not translate into extended survival in the overall population of these frail and heavily pretreated patients.”
“After performing an in-depth analysis, we and the DSMB agree that, despite the higher complete response rates observed with selinexor, the Phase 2 SOPRA study evaluating single-agent selinexor in relapsed or refractory AML has not reached statistical significance for overall survival, the primary endpoint of the study,” said Dr. Michael G. Kauffman, CEO of Karyopharm. “While we are disappointed with the overall outcome, we are pleased that 60mg of single-agent selinexor dosed twice per week was well tolerated and carried no increased risk of sepsis or febrile neutropenia. At Karyopharm, our primary focus remains the advancement of selinexor in relapsed or refractory multiple myeloma (MM), where we believe we have a clear path to regulatory approval.”
“Beyond myeloma, we see diffuse large B cell lymphoma (DLBCL) and liposarcoma as high unmet need indications where selinexor has a meaningful opportunity for clinical success and where we are expecting key data readouts during 2017,” Kauffman continued. “We look forward to reporting top-line data from our randomized Phase 2b SADAL study evaluating single-agent selinexor in patients with relapsed or refractory DLBCL in early 2017 and top-line data from the Phase 2 portion of the randomized Phase 2/3 SEAL study evaluating single-agent selinexor in patients with advanced liposarcoma in mid-2017.”
“We continue to believe selinexor has potential in AML, most likely in combination with other agents in front-line and later settings. We continue to explore the use of selinexor in combination with novel and standard agents through investigator-sponsored AML studies,” added Dr. Sharon Shacham, president and chief scientific officer of Karyopharm. “Clinical data recently reported at the 2016 American Society of Hematology annual meeting demonstrated that selinexor in combination with certain standard therapies, including intensive chemotherapy as well as hypomethylating agents, demonstrated encouraging activity in AML in adults, both as an initial therapy and in the relapsed setting. The benefit of selinexor in combination with intensive chemotherapy will be assessed in randomized investigator sponsored trials that we expect will begin in 2017. Furthermore, selinexor in combination with intensive chemotherapy has shown very promising responses in pediatric patients with heavily pretreated AML.”
The news caused Karyopharm’s stock price to fall around 15 percent, erasing most of the gains it had made earlier in the day before the news broke but, interestingly, the study failure doesn’t seem to have bothered market analysts nearly as much as it seems to have investors.
“The monotherapy signals do indicate the drug is active, and given the accumulating clinical and preclinical data showing selinexor synergy in a range of combination therapies, we remain positive on the drug’s potential, particularly in MM in combination with Velcade,” wrote Jefferies analyst Dr. Brian Abrahams in a note to investors. “We do not see any negative read-throughs to MM or other indications and remain positive on the potential for selinexor crossing the goal line as a treatment for later-line MM [patients.]”
Wedbush analyst David M. Nierengarten, for his part, maintained an Outperform rating on the company, with a price target of $14, following the news of the SOPRA failure. He keyed in on the fact that complete remission rates for selinexor was 13 percent, as compared to 3 percent in patients randomized on other supportive care, noting, “The higher response rates with selinexor, however, failed to translate to significant survival improvement; specific OS data was not provided, but we note target OS in control arm going-in was three months.”
Nierengarten also made note of the fact that the risk of sepsis and FN were lower in patients treated with selinexor as compared to the control group—this is important because Karyopharm reduced the dosage in 2015 due to increased risk of sepsis revealed early during the trial. He thinks this will help reduce concerns about sepsis risk for the drug.
Finally, he noted that data from the SADAL trial of selinexor in DLBCL are expected to be shared at the AACR Annual Meeting 2017 on April 4 and added, “The poster title suggests durable responses were observed with selinexor in both GCB- (germinal center B cell) and non-GCB subtypes, which would mirror activity observed in Phase 1.”