That was fast. Just three weeks after touting a late-stage clinical trial win, a defeated Karyopharm Therapeutics now says the FDA doesn’t think the data support a label expansion for cancer drug Xpovio.
After a “productive meeting” with the FDA, Karyopharm realized the two parties “had differing views on the study significance and overall clinical benefit” of Xpovio’s phase 3 Siendo study, the company said Tuesday. The drug topped placebo when used as a maintenance therapy for advanced or recurrent endometrial cancer patients who had responded to front-line chemotherapy, the company revealed last month.
Now that the FDA has suggested existing data are “unlikely to support” an approval, Karyopharm is targeting a subgroup of patients with unmutated p53, a key tumor-suppressor protein that’s sometimes altered in cancers. The company plans to start a new controlled study in p53 wild-type patients after the FDA said further testing in this subgroup is warranted, Karyopharm said.
A p53-specific label would significantly limit Xpovio’s market potential in the indication; about 50% of patients with advanced endometrial cancer belong to this group, Karyopharm CEO Richard Paulson told investors on a call in February.
Running another trial will also push out the drug’s regulatory timeline. Karyopharm expects to have top-line data from the new trial two years from now in the first half of 2024.
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When Karyopharm headlined Siendo’s results last month, industry watchers questioned Xpovio’s strength in the overall patient population. There, the oral XPO1 inhibitor cut the risk of disease progression or death by 30% over placebo. But the absolute improvement on the median time patients had lived without progression of just 1.9 months wasn’t very convincing—even though it met the trial’s statistical significance bar.
A prespecified subgroup analysis of the trial returned a substantially larger benefit in the p53 wild-type patients. In that group, Xpovio takers lived a median 13.7 months without progression versus 3.7 months for placebo, translating into a risk reduction of 62%.
During February’s investor call, Karyopharm management highlighted the lack of maintenance treatment for endometrial cancer. Pairing that with a statistical significance in the entire trial population, the company appeared to believe it had a chance at a broader label.
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Based on Karyopharm’s description, the FDA now seems to think the drug doesn’t deserve a nod in p53-mutant patients and that more data are needed to support one in the p53 wild-type group.
“For us and the FDA to fully understand the robustness of the clinical benefit in [wild-type] p53 patients and the strength of correlation, we believe it would be important to know just how many prespecified groups were looked at, and how the drug fared across these groups as well,” RBC Capital Markets analyst Brian Abrahams wrote in a Tuesday note to clients.
Even with broad approval, most use of Xpovio would likely be in the p53 wild-type subgroup, especially as testing of the protein’s status is common, Abrahams said in a previous note when Karyopharm unveiled the Siendo results.
Karyopharm will detail the full Siendo data at the upcoming European Society of Medical Oncology’s virtual plenary session on March 17.