Selinexor Shows Potential as Maintenance Therapy for TP53 Wild-Type, pMMR Endometrial Cancer

Longer-term progression-free survival (PFS) data from a prespecified subgroup analysis of the phase 3 SIENDO study (NCT03555422), along with manageable safety signals and quality of life (QOL)–adjusted survival benefit, position selinexor (Xpovio) as a potentially valuable maintenance therapy for the subset of patients with TP53 wild-type endometrial cancer pending further confirmatory trial results, according to Debra L. Richardson, MD, FACS, FACOG.

Findings presented at the 2024 International Gynecologic Cancer Society (IGCS) Annual Global Meeting showed that this PFS benefit was particularly pronounced among those with mismatch repair–proficient (pMMR) disease, a patient population with limited effective regimens.¹

“It’s going to be hard to improve on [outcomes] for the mismatch repair–deficient [dMMR] patients [based on data from] the multiple positive trials that we’ve seen, but for our pMMR patients, this drug may have a role as maintenance therapy,” said Richardson, who is an associate professor and chief of the Section of Gynecologic Oncology and Oklahoma TSET Phase I Program, at Stephenson Cancer Center of The University of Oklahoma (OU) College of Medicine, OU Health, in Oklahoma City.

In an interview with OncLive®, Richardson highlighted the long-term PFS benefit with selinexor in the TP53 wild-type subgroup from the SIENDO trial, the potential role of selinexor as maintenance therapy in pMMR endometrial cancer, and the necessity of aggressive adverse effect (AE) management with dual antiemetic therapy to enhance tolerability in this population.

OncLive: What updated safety and efficacy data from the SIENDO trial were presented at the 2024 IGCS Annual Global Meeting?

Richardson: The median follow-up when the data were first presented at ESMO was a little over 10 months. At the 2024 IGCS meeting, the median follow-up was 36.8 months.¹

There weren’t any new safety signals, as selinexor has now been characterized. We know that it causes nausea and vomiting, which can be mitigated with dual antiemetic therapy, and it can also cause some other gastrointestinal toxicities like diarrhea.

As far as efficacy, we found that the long-term median PFS was 28.4 months [95% CI, 13.1-not reached (NR)] in the TP53 wild-type subgroup compared with placebo, which was 5.2 months [95% CI, 2.0-13.1] with a HR of 0.44 [95% CI, 0.27-0.73; one-sided nominal P-value = .0005].

In addition, the data were broken down by pMMR and dMMR subtype. We really see the highest benefit in that TP53 wild-type, pMMR group, where the median PFS in selinexor-exposed patients was 39.5 months [95% CI, 19.3-NR] compared with 4.9 months [95% CI, 2.0-NR] in the placebo group, with 0.36 [95% CI, 0.19-0.71; one-sided nominal P= .0011]. [In comparison], the TP53 wild-type, dMMR group, which [comprised] approximately 25% of the patients [on the study], was 13.1 months [95% CI, 3.6-NR] compared with 3.7 months [95% CI, 1.9-NR] with placebo. [This is] still a positive benefit but is less than what we saw in the pMMR group.

What was reported in terms of preliminary OS?

[Overall survival (OS) data are] still immature, so we can’t conclude a whole lot about it. It’s less than 30% mature, but the HR for the TP53 wild-type, selinexor-exposed group was 0.65 [95% CI, 0.32-1.29; one-sided nominal P = .11]. Of course, the confidence interval is large because there’s been limited events. It crosses one, so we know that’s not significant at this point. If we break it down into the pMMR and dMMR subtypes, the HR was 0.48 [95% CI, 0.22-1.07; one-sided nominal P = .03] for the pMMR subtype and 0.62 [95% CI, 0.06-6.81; one-sided nominal P = .35] for the dMMR group. [Notably], OS began at the randomization of maintenance therapy.

How does selinexor affect PFS after adjusting for quality of life (QOL) and toxicity?

The investigators did an exploratory quality-adjusted time without symptoms or toxicity [QTWIST] analysis of the TP53 wild-type, pMMR subgroup. What they found is that there was still a benefit [with] selinexor [when] adjusting for QOL and toxicity. There was also an improvement of 10.63 months for the selinexor arm compared with the placebo arm [in the TP53 wild-type population]. [In the pMMR population the median QTWIST PFS] was 29.6 months [95% CI, 23.90-35.15] vs 16.9 [95% CI, 9.06-25.54].

How do these findings fit into the currently evolving treatment paradigm in endometrial cancer?

[Although] we can agree that immuno-oncology is a giant step forward for patients with dMMR [endometrial cancer], it’s a less impressive [advancement] for our patients with pMMR [disease]. We have room for improvement. I think about [using selinexor] for my TP53 wild-type, pMMR patients. If for some reason I had a patient with dMMR disease who was ineligible for immunotherapy, then I would think about putting them onto the ongoing [phase 3 ENGOT-EN20/GOG-3083/ XPORT-EC-042 trial (NCT05611931)].

I’ll point out that this trial is [randomly assigning patients to receive] selinexor at 60 mg rather than the 80 mg that was administered in the SIENDO study both for tolerability and because it’s felt to still be efficacious [at that dose] compared with placebo.

Pending selinexor’s approval, what logistical considerations will need to be made by oncologists looking to use this agent?

[It is important] to remember that [patients] will need dual antiemetic therapy. That’s probably the major toxicity that can be bothersome to patients, especially when we’re thinking about a maintenance therapy where patients would otherwise be on nothing, or potentially immunotherapy, which typically has [a] low [incidence of] AEs. It is important to manage any AEs aggressively so the patient can maintain an effective drug and tolerate it. [This is] similar to what we had to do when PARP inhibitors first came out, and there’s a little bit of a learning curve.

At what point do you recommend testing TP53 status in this patient population?

TP53 status does need to be centrally confirmed for this trial. At our center, we have TP53 assessed by immunohistochemistry by our pathologist. However, if we’re going to think about [administering] a maintenance therapy like this, we want to do it earlier, because there’s only an approximately 8-week time frame from when chemotherapy stops until patients can be randomly assigned [to subsequent treatment] and it does take a little while to get the central review. Thinking about [TP53 status] earlier, when we’re starting [a patient on] their chemotherapy, would be beneficial.

Reference

Pérez-Fidalgo A, Vergote I, Hamilton E, et al. Longer-term safety and efficacy of selinexor maintenance therapy for patients with TP53wt advanced or recurrent endometrial cancer: follow-up subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study. Presented at: 2024 IGCS Annual Global Meeting. October 16-18, 2024. Dublin, Ireland.