Navigating Ambiguity: Karyopharm’s Selinexor Seeks to Build on Early Triumphs in an Evolving Landscape

Karyopharm Therapeutics: Navigating a Complex Path to Expansion for Selinexor

Since Karyopharm Therapeutics secured accelerated FDA approval for selinexor in combination with dexamethasone for relapsed or refractory multiple myeloma (RRMM), the company has been on a mission to expand its footprint in the competitive oncology arena. However, this journey has been far from straightforward, with several challenges looming large.

When selinexor received its initial green light in July 2019 for RRMM, it faced a slew of clinical trial hurdles that initially limited its adoption, even within the multiple myeloma landscape. While the Phase IIb STORM trial’s 8.6-month median overall survival (OS) rate played a pivotal role in securing FDA approval, it fell slightly short when compared to the roughly 9-month OS rates achieved by existing RRMM treatments. This posed a significant hurdle to uninterrupted market success.

The drug’s original approval was limited to adults with RRMM who had exhausted at least four prior therapies and had disease that resisted at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody. This essentially left Karyopharm with a smaller pool of eligible patients compared to first-line multiple myeloma treatments.

Back in 2019, the United States already had nine approved drugs for RRMM, some of which, as revealed in a 2018 meta-analysis, demonstrated better efficacy in terms of median OS than selinexor. For instance, in the POLLUX trial, Janssen and Genmab’s daratumumab combined with Bristol Myers Squibb’s lenalidomide and dexamethasone delivered a staggering median OS rate of 67.6 months, surpassing the 51.8-month median OS achieved with lenalidomide and dexamethasone alone in patients with previous therapy.

In 2020, Karyopharm gained further approvals for selinexor in multiple myeloma (in combination with bortezomib and dexamethasone) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The company is actively exploring alternative selinexor regimens for these indications while also investigating its potential in other disease areas like endometrial cancer and myelofibrosis.

Among these four cancers, endometrial cancer boasts the most promising patient pool in terms of incidence rates alone, with 35.7 cases per 100,000 people. This far outpaces the other three indications, with RRMM affecting 4.4 per 100,000 people in 2016, DLBCL impacting 4.68 people per 100,000 in 2021, and myelofibrosis at 0.47 per 100,000 in 2014. However, the challenge lies in the fact that endometrial cancer is a solid tumor, uncharted territory for selinexor, which has primarily demonstrated its efficacy in hematologic malignancies. Most of Karyopharm’s trials have been centered around hematologic cancers.

While Karyopharm’s SIENDO trial for endometrial cancer didn’t yield the anticipated results, the company hinted in its Q2, 2023 financial report that a subgroup of patients with TP53 wild-type cancer might show more significant benefits. Nevertheless, this trial update could further limit selinexor’s reach and market share.

Despite Karyopharm’s noteworthy achievements with selinexor, the road ahead is intricate and fraught with challenges. The final results of the endometrial cancer trial will be a pivotal determinant of Karyopharm’s trajectory over the next few years.

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