September 2019 Edition Vol.11, Issue 9

The Arduous Route to Approval for a First-in-Class Multiple Myeloma Drug

by Megan Garlapow, PhD

Karyopharm Therapeutics’ decades-long charge to develop a novel first-in-class drug directed against nuclear transport targets has paid off. Selinexor [Xpovio]—in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM)—is the company’s first-in-class oral Selective Inhibition of Nuclear Export (SINE) compound to receive the approval of the U.S. Food and Drug Administration. The approval is testament to the company’s commitment to meet the unmet need of some of the sickest patients with multiple myeloma (MM), an incurable disease.

Around 32,000 new cases of MM will be diagnosed in the United States in 2019, with nearly 13,000 deaths. Approximately 130,000 people are living with the disease.1 Population growth and increased life expectancy both contribute to increases in the number of patients with relapsed/refractory disease. Many patients with MM are actively receiving fourth-line therapy or greater, and new treatment options expand the number of patients surviving to later lines of therapy. Each subsequent line of treatment after the frontline, however, offers diminishing hope and benefit.

Unique Therapeutic Approach

Karyopharm’s SINE technology provides a unique mechanism of action. The SINE approach inhibits the overexpression of Exportin 1 (XPO1), a chaperone protein that, when overexpressed in tumors, removes tumor suppressors from the nucleus of a cell. Removal of tumor suppression enables evasion of the body’s immune system. By inhibiting excessive XPO1, SINE technology restores tumor suppressors to the nucleus, allowing them to detect DNA damage characteristic of tumor cells.2-4

Selinexor’s Regulatory Journey

In February 2019, the Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5 against accelerated approval of the New Drug Application for selinexor. The vote was based on concerns over toxicities in the single-arm phase 2b STORM trial. Patients in this trial were heavily pretreated, having received at least three prior lines of therapy, but the single-arm design of the trial did not allow comparison with a control of whether frequent serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and TEAEs resulting in death were due to the heavily pretreated nature of the patients or due to the therapeutic regimen itself.

As a result, ODAC recommended the FDA await results from the open-label phase 3 BOSTON trial, which compares selinexor plus bortezomib and dexamethasone with bortezomib plus dexamethasone in pretreated patients. The trial readout is expected by late 2019 or early 2020.

Still, on July 3, 2019, the FDA granted accelerated approval to selinexor in combination with dexamethasone for the treatment of adult patients with RRMM who have received at least four prior lines of therapy and with disease resistance to other forms of therapy, including an anti-CD38 monoclonal antibody, at least two proteasome inhibitors, and at least two immunomodulatory drugs.5

Then, on July 23, 2019, a class-action lawsuit was filed based on ODAC’s briefing document filed in February on safety concerns, claiming the company misrepresented the safety and efficacy data for selinexor and that the toxicity profile of the drug is problematic. Selinexor’s adverse event profile, however, could also be due to the heavily pretreated, very-ill nature of the patients who received selinexor, a possibility that the ODAC suggested would be better elucidated with the BOSTON readout.

With a median of seven prior lines of therapy, patients in STORM—and those receiving fourth-line or greater lines of therapy—are in dire need of therapeutic options. “It is important to understand how sick these patients are: they had to be exposed to the five most important agents in myeloma, and they were triple-class refractory,” explained Ajai Chari, MD, Director of Clinical Research in the Multiple Myeloma Program at The Tisch Cancer Institute at Mount Sinai.

He continued, “Such patients have no approved options, and their disease markers increased by approximately 25% over a median of 12 days from screening to the start of treatment. In other words, many of these patients with rapidly progressive disease might very well have ended up in hospice.”

Dr. Chari explained that toxicities were managed with supportive care and almost no patients came off treatment because of them. Once disease control was attained, “patients were able to stay on a completely oral regimen,” he said.

The FDA’s decision to approve selinexor was based on clinical trial results from a subgroup of 83 patients from STORM. The overall response rate was 25.3% with a median time to first response of 4 weeks (range, 1-10) and a median duration of response of 3.8 months.5

STORM Updates

STORM updates include 122 patients in the modified intention-to-treat study population and 123 patients in the safety population. Patients received a median of seven prior lines of treatment, and over half of all patients (53%) harbored high-risk cytogenetics. Even with heavy pretreatment, 26% of patients experienced a partial response or better (95% confidence interval [CI], 19-35), which included two stringent complete responses, six very good partial responses, and 24 partial responses. Median time to partial response was 4.1 weeks (range, 1-14). A total of 39% of patients experienced a minimal response or better.6

Notably, these response rates are on par with what is observed with other therapies in earlier lines of treatment.

The median duration of response was 4.4 months, median progression-free survival was 3.7 months (95% CI, 3.0-5.3), and median overall survival was 8.6 months (Figure 1). In patients who achieved minimal response or better, the overall survival was 15.6 months.6

Common adverse events of fatigue, nausea, and decreased appetite were frequently grade 1 or 2, with grade 3 events in up to 25% of patients and no grade 4 events. All-grade fatigue occurred in 73% of patients, all-grade nausea in 72%, and all-grade anemia in 67%. All-grade thrombocytopenia occurred in 73% of patients and was grade 3 in 25% of patients and grade 4 in 33% of patients. Bleeding events of grade 3 or higher occurred in six patients, due to thrombocytopenia.6

SAEs in 63% of patients most commonly included pneumonia (11%) and sepsis (9%). Dose modifications or interruptions due to adverse events occurred in 80%, with most of these occurring within the first two treatment cycles. Of 28 patient deaths during the study, 16 were due to progressed disease, and 12 were due to adverse events, with two of these events considered by investigators as treatment related.5

For patients who have exhausted available MM therapies, selinexor plus dexamethasone (sel+dex) could provide a much-needed last line of therapy. ODAC noted that “There is no evidence of clinically substantial cumulative toxicity in patients treated long-term with selinexor. Moreover, sel+dex has not been associated with significant major organ toxicities. The longest duration of treatment with selinexor has been >2 years.”5

Karyopharm’s Pipeline

Selinexor was granted an FDA Fast Track designation in November 2018 for the treatment of patients with RR diffuse large B-cell lymphoma (DLBCL) who have received at least two prior lines of therapy and are ineligible for high-dose chemotherapy with stem cell rescue or CAR T-cell therapy.

Ongoing phase 2 and 3 clinical trials are evaluating selinexor in RRMM and in front-line MM, RRDLBCL, liposarcoma, endometrial cancer, and glioblastoma.

Eltanexor (KPT-8602), Karyopharm’s second-generation XPO1 inhibitor, is being investigated in a phase 1/2 trial in myelodysplastic syndrome, colorectal cancer, and prostate cancer, and their oral, first-in-class PAK4 and NAMPT inhibitor KPT-9274 is in a phase 1 trial in solid tumors and non-Hodgkin’s lymphoma.

As clinical development of selinexor continues, manageable safety profiles across tumor types are anticipated. Readouts from clinical trials will be needed. Nonetheless, they are already seeing a different toxicity profile. Myeloma patients, for example, are typically older and have much more cancer involvement of their bone marrow than lymphoma or solid tumor patients. “Therefore, there is likely to be less hematologic toxicities in non-myleoma populations,” said Dr. Chari.

An additional avenue for development of selinexor includes assessing combinations for improving both efficacy and safety.

“Relapsed/refractory myeloma is genomically very complex, and selinexor’s likely use in the future, as with all other agents in this setting, will be combination therapy to attain maximal benefit. Moreover, combination regimens, which are already under investigation, benefit from drug synergy allowing lower doses of each agent to be used, which if used with the appropriate partner drugs, will also result in less toxicities,” Dr. Chari suggested.

 

References

  1. National Cancer Institiute. SEER cancer stat facts: non-Hodgkin lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed September 3, 2019.
  2. Gupta A, Saltarski JM, White MA, Scaglioni PP, Gerber DE. Therapeutic targeting of nuclear export inhibition in lung cancer. J Thorac Oncol. 2017;12(9):1446-1450.
  3. Sun Q, Chen X, Zhou Q, Burstein E, Yang S, Jia D. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther. 2016;1:16010.
  4. Mor A, White MA, Fontoura BM. Nuclear trafficking in health and disease. Curr Opin Cell Biol. 2014;28:28-35.
  5. gov. FDA approves new treatment for refractory multiple myeloma. July 30, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-refractory-multiple-myeloma. Accessed September 3, 2019.
  6. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738.

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