Amit M. Oza, MD, MBBS

The invited discussant of the phase III ­ENGOT-EN5/GOG-3055/SIENDO trial was Amit M. Oza, MD, MBBS, Head of the Division of Medical Oncology & Hematology at University Health Network/Mount Sinai, Director of Clinical Research and Clinical Cancer Research Unit at Princess Margaret Hospital, and Professor of Medicine at the University of Toronto.

“Switch maintenance therapy with selinexor improved progression-free survival in women in complete or partial response postchemotherapy. This was driven by an improvement in endometrioid and TP53 wild-type tumors, and the drug was not of value in serous cancers,” he noted. “[This study] offers proof of principle for sequential switch maintenance therapy and opens up new possibilities.”

Nuclear exportins serve as a transport mechanism that “shuttles” key protein drivers from the nucleus to the cytoplasm. In doing so, they can control the concentration of key cell-cycle regulators within the nucleus, such as p53, which can be modulated such that p53 can be excreted out of the nucleus by malignant cells. If selinexor blocks the export of p53, then the drug’s concentration within the nucleus increases, and it exerts a regulatory effect. This was the mechanism explored in this trial, Dr. Oza said.

‘Impressive’ Benefit in Subgroups

The significant improvement in progression-free survival (hazard ratio [HR] = 0.705; P = .024) in the intent-to-treat population was shown in an audited stratification analysis. This was importantly clarified by Dr. Vergote, who presented the findings, he said.

“In particular, there was a very significant and impressive benefit in progression-free survival in the endometrioid subgroup—which is what you’d expect because of their TP53 mutation status—but no benefit in the serous group,” Dr. Oza said. Of the wild-type TP53 tumors, about 80% were of the endometrioid type, but 10% or less were of the serous group. Patients with endometrioid disease treated with selinexor had a “quite impressive” median progression-free survival of 9.2 months vs 3.8 months with placebo (HR = 0.573).

Dr. Oza continued: “It’s even more impressive when the results are dissected by wild-type TP53, which fits in well with selinexor’s biologic mechanism of action. Patients with wild-type TP53 disease conventionally do poorly with chemotherapy.” Median progression-free survival reached 13.7 months in patients with wild-type TP53 disease treated with selinexor vs 3.7 months in those who received placebo (HR = 0.375).

Tolerability and quality of life are important to examine because this is a maintenance treatment that needs to be tolerated long term, Dr. Oza emphasized. Although more toxicities were observed with selinexor, the drug was “reasonably well tolerated,” he noted. Half the patients, however, required dose reductions and interruptions, and 10.5% stopped selinexor entirely, though quality of life was not particularly compromised, he noted.

Future Directions

Dr. Oza said he would like to see more data on the following:

• The details of the statistical correction, which was conducted before the analysis
• The biologic basis of the drug’s activity
• The role and the relevance of the chemotherapy
• The effectiveness of selinexor given with or after hormonal therapy
• The benefit of the drug according to the grade of endometrioid cancer
• Selinexor’s benefit in mismatch repair–deficient cancers.

This XPO1 inhibitor joins a rapidly changing landscape in endometrial cancer that has expanded to include new approaches. In particular, the changing standard of care with immunotherapy “will necessitate reassessment of our treatment approach with systemic therapy and sequencing,” Dr. Oza predicted. The emerging approach to advanced endometrial cancer could include chemotherapy, hormonal therapy, and immunotherapy, with the integration of nuclear exportin inhibitors and targeted agents, such as palbociclib and the WEE1 inhibitor adavosertib. “We will need to determine what is the right sequence for us to optimally treat our patients,” he said. 

DISCLOSURE: Dr. Oza has uncompensated relationships with multiple pharmaceutical companies and is a lead investigator for trials with AstraZeneca, GSK, and Clovis.