David S. Miller, MD

Despite failing to significantly improve outcomes over placebo among patients with advanced or recurrent endometrial cancer, selinexor (Xpovio) maintenance therapy may still have a role for select patients with TP53 wild-type disease, according to David S. Miller, MD.

Long-term data from a prespecified subgroup analysis of the phase 3 SIENDO study (NCT03555422) were reported at the International Gynecologic Cancer Society (IGCS) 2024 Annual Global Meeting and showed that progression-free survival (PFS) outcomes with selinexor were significantly prolonged among patients with TP53 wild-type, mismatch repair–proficient (pMMR) disease compared with placebo.¹

“With 3-years follow-up in the TP53 wild-type group of patients, there remains an advantage for the patients who receive selinexor [vs placebo],” said Miller, a professor in the Department of Obstetrics and Gynecology, Dallas Foundation Chair in Gynecologic Oncology, Amy and Vernon E. Faulconer Distinguished Chair in Medical Science, Harold C. Simmons Comprehensive Cancer Center, at the University of Texas Southwestern Medical Center in Dallas. “The [survival] advantage, however, was more modest in the mismatch repair–deficient [dMMR] patient population vs [the pMMR population], [the former of] which are the patients we anticipated would respond to immunotherapy.”

In an interview with OncLive®, Miller expanded on the importance of investigating outcomes with selinexor in TP53 wild-type patients with endometrial cancer; reported key efficacy, safety, and quality-adjusted survival data in this patient population from the SIENDO trial; and highlighted the ongoing phase 3 ENGOT-EN20/GOG-3083/XPORT-EC-042 trial (NCT05611931) designed to confirm these findings for potential regulatory approval.

OncLive: What was the rationale for evaluating outcomes with selinexor in TP53 wild-type patients through this exploratory analysis?

We had performed a preplanned subgroup analysis looking at TP53 because selinexor is a selective inhibitor of nuclear export and TP53 is a tumor suppressor gene, so if you keep TP53 in the nucleus, [selinexor] presumably works better. One of the [potential] reasons why selinexor didn’t work in TP53-abnormal patients was because TP53 didn’t work. [Therefore, we] were anticipating a difference in [outcomes with selinexor between] these groups.

What key efficacy data have been reported from the subgroup analysis?

[Data from the] prespecified subgroup analysis [were presented] several months ago at the 2024 ASCO Annual Meeting,² and even longer-term follow-up in this TP53 wild-type group of patients [was presented at the] IGCS 2024 Annual Global Meeting.¹

[After 36.8 months of follow-up] in the TP53 wild-type group of patients, the median PFS was 28.4 months [95% CI, 13.1-not reached (NR)] with selinexor [n =77] compared with 5.2 months [95% CI, 2.0-13.1] with placebo.^1,2 The HR was 0.44, [which translates to a] 56% reduction in the risk of disease progression or death [95% CI, 0.27-0.73; one-sided nominal P-value = .0005].

That was broken down by MMR status into pMMR patients and dMMR patients. [The latter group] is one from The Cancer Genome Atlas analysis of endometrial cancers, which we have subsequently learned has been becoming more and more predictive of potential therapies that we can offer our patients beyond surgery. In the pMMR patients, [after a median follow-up of 38.5 months], we saw an even greater PFS of 39.5 months [95% CI, 19.3-NR] in the 47 patients [treated with] selinexor vs 4.9 months [95% CI, 2.0-NR] in the 23 [patients treated with] placebo.¹ The HR was 0.36 [95% CI, 0.19-0.71; one-sided nominal P= .0011], or a 64% reduction [in the risk of progression or death].

In [the dMMR] group of patients, [following 32.8 months of median follow-up], the 20 patients [treated with] selinexor had a median PFS of 13.1 months [95% CI, 3.6-NR] compared with 3.7 months [95% CI, 1.9-NR] in the 9 patients who received placebo. That HR was 0.49 [95% CI, 0.18-1.34; one-sided nominal P = .0825] but the confidence interval crossed 1, and therefore it was not statistically significant. It certainly suggests there was a more modest advantage.

Some of the survival data, which are immature, were also presented, but they too showed the biggest advantage in survival in the pMMR group of patients.

What should be known about the agent’s safety profile and impact on quality-adjusted survival?

There appeared to be no new safety signals. It’s been pretty much as we’ve experienced so far, overall. Leading toxicities [including] nausea, vomiting, and diarrhea can be better managed now with prophylactic medication. Looking at grade 3 toxicities, we have to pay attention to neutropenia, nausea, and thrombocytopenia. Approximately 80% of patients will need some sort of dose adjustment, and approximately 20% of patients [on the study] had treatment discontinued due to adverse effects.

Interestingly, the study authors also conducted a [analysis of quality-adjusted time] without symptoms or toxicity, or a Q-TWIST analysis. For patients treated with selinexor, the Q-TWIST was 29.60 months [95% CI, 23.90-35.15] and for patients in the placebo group, it was 16.90 months [95% CI, 9.06-25.54], so [there was a 12.70-]month [95% CI, 2.47-22.18] difference in favor of the selinexor [group].

Given that selinexor is not yet FDA approved for use in this patient population, what are the implications of this research?

We are optimistic, but since this was not a primary end point of the study, the FDA, and I imagine the European Medicines Agency will require a confirmatory trial. The ENGOT-EN20/GOG-3083/XPORT-EC-042 trial, which is sponsored by the Gynecologic Oncology Group as well as the European Network for Gynaecological Oncological Trial group, has been underway for several months. It is in that population of patients who have TP53 wild-type advanced recurrent endometrial cancer. [They will receive] chemotherapy with carboplatin and paclitaxel. They can [receive] immunotherapy with the chemotherapy; however, once the time comes for maintenance therapy, those patients will be randomly assigned 1:1 to selinexor at a at a lower dose of 60 mg compared with the prior dose of 80 mg, which other studies have shown appears to be just as good and a bit more tolerable. That confirmative trial, assuming it is positive, will be sufficient for registration both in the United States and European Union.

Will patients be eligible to enroll onto this study regardless of MMR mutation status?

Yes. One of the concerns is that we’re not going to give patients [with TP53 wild-type disease] immunotherapy. David O’Malley MD, of the Ohio State University Comprehensive Cancer Center–James gave a very nice distillation pointing out that when we look at the tails of these curves, what we see with selinexor is very similar to that which we see with immunotherapy. Sometimes we see the so-called ‘banana curve,’ where the arms tend to merge, and we’re not seeing that. We’re seeing that the curve sort of flattens out after about a year or 2. Some people throw around the word cure, and that might be premature, but it was certainly very encouraging [to see these outcomes], particularly if [a patient has] advanced or recurrent endometrial cancer. [However], at the 2023 ESMO Congress, [investigators reported data from] another subgroup analysis from the [phase 3] RUBY trial [NCT03981796], which evaluated, carboplatin and paclitaxel with or without dostarlimab [Jemperli]. When we looked at the TP53 wild-type group of patients [in that study population], the difference seemed more modest [between the dostarlimab and comparator groups]. The follow-up data are not quite as mature as they are in the SIENDO trial. However, if they do cross-trial comparisons, [oncologists] should not be too concerned about putting their patients on the XPORT-EC-042 trial.

What information is necessary to accurately obtain upfront for the identification of patients with endometrial cancer who may benefit from selinexor?

[TP53 mutation status] can be identified with next-generation sequencing [NGS], but your friendly neighborhood pathologist can also perform an immunohistochemistry [IHC] stain for TP53 mutations. In fact, there was another report at the IGCS 2024 Annual Global Meeting which showed that there is very good concordance between IHC staining and NGS. Our pathologists now report estimates of TP53-mutant or wild-type [status] when we send them a patient with endometrial cancer. That’s information we can have up front. [Typically], we’ll counsel the patient that they’ll get chemotherapy, and then if they do well, they get to have maintenance therapy. We’re seeing advantages with maintenance therapy in ovarian cancer and now we’re seeing it in endometrial cancer. [This information] allows us to be a little better prepared and help the patient anticipate what might be ahead for them.

References

1. 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.
2. Karyopharm presents updated exploratory subgroup analyses from SIENDO study in patients with advanced or recurrent TP53 wild-type endometrial cancer during 2024 ASCO Plenary Series: Rapid Abstract Updates. News release. Karyopharm. June 1, 2024. Accessed October 31, 2024. https://investors.karyopharm.com/2024-06-01-Karyopharm-Presents-Updated-Exploratory-Subgroup-Analyses-from-SIENDO-Study-in-Patients-with-Advanced-or-Recurrent-TP53-Wild-Type-Endometrial-Cancer-During-2024-ASCO-Plenary-Series-Rapid-Abstract-Updates