Selinexor maintenance failed to significantly improve PFS vs placebo in TP53 wild-type advanced or recurrent endometrial cancer in the phase 3 XPORT-EC-042 trial.
Selinexor (Xpovio) maintenance therapy did not lead to a statistically significant improvement in progression-free survival (PFS) vs placebo in patients with TP53 wild-type advanced or recurrent endometrial cancer, according to topline findings from the phase 3 XPORT-EC-042 trial (NCT05611931).¹
At the data cutoff, investigators had documented 106 PFS events in the mITT population. In the modified intention-to-treat (mITT) population, median PFS was 12.75 months with selinexor vs 7.43 months with placebo, corresponding to an HR of 0.76 (95% CI, 0.51-1.12; 1-sided P = .0791). Although the 5.32-month numerical difference favored selinexor, the study did not meet its primary end point and therefore did not establish a maintenance benefit in a population for which additional treatment options are needed.
“These results are meaningful for a patient population lacking effective maintenance therapies that can delay disease progression,” Ignace Vergote, MD, gynecologic oncologist at the Catholic University Leuven in Belgium, European Network for Gynaecological Oncological Trial groups and global lead principal investigator, stated in a news release. “The trend for a longer PFS observed in the mITT population of the selinexor arm continues to highlight the potential of XPO1 inhibition in patients with TP53 wild-type/pMMR [mismatch repair–proficient] endometrial cancer.”
“While disappointed by these unexpected results, we believe they advance the scientific understanding of XPO1 inhibition for tens of thousands of endometrial cancer patients worldwide. We are deeply committed to further investigating these data,” Reshma Rangwala, MD, PhD, chief medical officer and head of research at Karyopharm. "I would like to thank all of the patients, their families and the clinical trial investigators and their staff, as well as ENGOT and GOG, for participating in this trial.”
XPORT-EC-042 is a global, phase 3, randomized, double-blind, placebo-controlled trial that enrolled 257 adults with TP53 wild-type advanced or recurrent endometrial cancer following chemotherapy or chemotherapy plus an immune checkpoint inhibitor.1,2 Patients were randomly assigned 1:1 to oral selinexor at 60 mg once weekly or placebo until disease progression.
The primary end point of PFS was tested sequentially in 2 populations. The mITT population comprised 236 patients with TP53 wild-type/pMMR tumors or TP53 wild-type/mismatch repair–deficient tumors who were medically ineligible for checkpoint inhibition. The original intention-to-treat population included all randomly assigned patients with TP53 wild-type tumors, irrespective of mismatch repair status. Overall survival (OS) was a key secondary end point.
The safety and tolerability profile was described as consistent with the established profile of selinexor, with no new safety signals observed.
“Delaying the progression of cancer by five months at the median is a meaningful and encouraging outcome,” Robert Coleman, MD, FACOG, FACS, of Texas Oncology and the Gynecologic Oncology Group and lead principal investigator in the United States, added in the news release. “Although I am disappointed that the PFS improvement was not statistically significant, I look forward to continuing to follow these results over time and presenting the data from this important trial at an upcoming medical meeting. This patient population who have TP53 wild-type/pMMR advanced or recurrent endometrial cancer remains in need of new treatment options.”
Karyopharm Therapeutics plans to complete its analysis of XPORT-EC-042, continue follow-up for longer-term outcomes, and present the findings at a future medical meeting. The company also said it would reduce planned investment in endometrial cancer while prioritizing its myelofibrosis and multiple myeloma programs.
“While the results we are announcing today fell short of our expectations, they do not diminish our confidence in the broader potential of selinexor and benefit of XPO1 inhibition,” Richard Paulson, president and chief executive officer of Karyopharm, added in the news release. “We remain focused on maximizing our opportunity in myelofibrosis and continuing to build on our profitable multiple myeloma business. Looking ahead, we expect several important milestones in our myelofibrosis program over the next year, including the submission of our supplemental new drug application, the potential addition of selinexor to relevant compendia guidelines and topline data from the 60 mg cohort of the phase 2 SENTRY-2 trial [NCT05980806], each anticipated in the second half of 2026.”
