Karyopharm surprised many when its pipeline lead, selinexor, scored in the multiple myeloma Storm study, leading to a controversial approval last year. But the group has not finished yet: US green light for lymphoma followed this year, and now solid tumours are in its sights.
Results just toplined from the phase III part of the Seal study in 277 liposarcoma patients have shown selinexor to confer a statistically significant improvement in progression-free survival. The study, however, has failed to show an overall survival benefit, a fact that could weigh heavy with regulators.
Karyopharm is convinced that it now has enough for approval, and says it will file the drug, now branded Xpovio, for its new use in the first half of next year. The Seal data will be scrutinised fully when they are presented at the Connective Tissue Oncology Society meeting on November 20.
For now the focus is on Seal’s primary endpoint of median progression-free survival, a measure on which Xpovio beat placebo with a 30% reduction in risk of progression or death (p=0.023).
The study recruited patients who had had between two and five lines of prior systemic therapy, but for now the split across its two cohorts, and clues at to which patients drove the benefit, are not known. Moreover, advanced dedifferentiated liposarcoma has no established standard of care, so what background therapy Xpovio and placebo recipients were on should also be scrutinised.
However, the biggest question about Seal will be its lack of overall survival benefit. Karyopharm stresses that the trial had a crossover design, allowing placebo subjects to receive Xpovio on progression, and it seems that this subsequent treatment allowed placebo recipients to catch up, in survival terms, with those on active therapy the whole time.
The company also says Xpovio recipients showed a “trend towards improvement” in median OS versus those who had remained on placebo without crossing over. The CTOS data should show whether there was no real OS benefit, or whether this comparison simply involved too few patients.
But one important question is why liposarcoma patients should be given Xpovio before all other options are exhausted, if they can rely on a real OS benefit from very late-line Xpovio. This is particularly relevant since taking Xpovio would expose them to side effects including thrombocytopenia, neutropenia, and gastrointestinal and neurological toxicities.
|Selected studies of selinexor|
|Multiple myeloma (penta-refractory)||Storm||25% ORR (20 PR, 1 CR)||Accelerated approval 3 Jul 2019|
|Diffuse large B-cell lymphoma (≥3rd line)||Sadal||29% ORR (21 PR, 18 CR)||Accelerated approval 22 Jun 2020|
|Multiple myeloma (2nd-4th line)||Boston (confirmatory trial for Storm)||mPFS HR=0.70 vs control, p=0.0075; mOS immature||Pdufa 19 Mar 2021|
|Liposarcoma (2nd-5th line)||Seal||mPFS HR=0.70 vs control, p=0.023; mOS not stat sig||US filing due H1 2021|
|Diffuse large B-cell lymphoma (2nd-3rd line)||XPORT-DLBCL-030 (confirmatory trial for Sadal)||Primary endpoints: ORR (phase II), PFS (phase III)||Started Sep 2020|
|Source: company reports.|
It was Xpovio’s side-effect profile that had led to a stormy US advisory meeting over its first use, in penta-refractory multiple myeloma, on the basis of the Storm study (Adcom gives Karyopharm a second chance with selinexor, February 27, 2019).
Approval was delayed until the FDA was shown confidential data from the controlled, earlier-line Boston study, which is intended to back approval in its own right. Meanwhile, the Sadal trial supported the green light for late-line lymphoma this year, and like Storm this was given on an accelerated basis, subject to a confirmatory study.
Sellside consensus is for Xpovio to generate 2026 revenue of $994m, of which multiple myeloma, lymphoma and liposarcoma will account for $716m, $200m and $78m respectively, according to EvaluatePharma sales by indication. Full Seal data at the CTOS should determine whether consensus for the last goes up or down.