VHIO-led study shows promising antitumor activity of first-in-class XPO1 inhibitor selinexor in patients with advanced gastrointestinal stromal tumor

Dr. César Serrano
  • After an initial response to approved tyrosine kinase inhibitors, principally imatinib, most patients with GIST will develop acquired cancer drug resistance, with few other treatment options available.
  • Selinexor is a first-in-class selective inhibitor of nuclear export antagonist XPO1 that has previously been approved for the treatment of multiple myeloma and diffuse large B-cell lymphoma.
  • Aimed at overcoming resistance to therapy and improving outcomes for patients with advanced GIST, the phase Ib/II SeliGIST/GEIS-41 clinical trial led by VHIO’s César Serrano was designed to evaluate the optimal dosing, safety, and preliminary antitumor activity of selinexor as a single agent and in combination with imatinib.
  • Presented on the ground by first author César Serrano at this week’s ESMO Congress 2022, data show clinical activity and manageable toxicity for both regimens, particularly in patients who received selinexor plus imatinib.

Gastrointestinal stromal tumor (GIST) is a rare type of cancer that begins in the digestive system. Most frequently occurring in the stomach and small intestine, GISTs originate from nerve cells in the walls of the digestive organs that play a role in the process that moves food through the body. Accounting for less than 1% of all gastrointestinal cancers GISTs are the most frequent of all sarcomas.

Over recent years, outcomes for patients with GIST have significantly improved thanks to the advent of tyrosine kinase inhibitors (TKIs), imatinib in particular, that suppress the oncogenic activation of the KIT or PDGFRA genes. Around 80% of GISTs harbor activating KIT or PDGFRA mutations that are drivers of disease progression. While initial responses to these targeted treatments are good, almost all patients ultimately develop acquired resistance and have very few other therapeutic options.

“The approval of the first TKI, imatinib, ushered in a new era of targeted drug development in oncology. While TKIs have undoubtedly improved outcomes for patients with GIST, the clinical benefit after imatinib progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival,” says César Serrano, Principal Investigator of VHIO’s Sarcoma Translational Research Group and a Medical Oncologist at the Vall d’Hebron University Hospital’s Medical Oncology Department headed by VHIO’s Director, Josep Tabernero (Vall d’Hebron Barcelona Hospital Campus).

Aimed at identifying alternative and more effective treatment strategies, the phase Ib/II SeliGIST/GEIS-41 clinical trial was designed to evaluate the appropriate dosing, safety, and preliminary antitumor activity of selinexor, a selective inhibitor of XPOI-meditated nuclear export, as a single agent and in combination with imatinib in patients with advanced GIST.

Spearheaded by the Spanish Group of Sarcoma Research (GEIS), latest findings from this study* were presented by first author César Serrano as a Mini Oral Presentation at this week’s Annual Congress of the European Society for Medical Oncology (ESMO), 09 – 13 September 2022, Paris, France.

A new point of targeted attack

Data from several preclinical studies have evidenced the therapeutic promise of selinexor in GIST as monotherapy and as combinatorial therapy with imatinib. This novel contender selectively blocks the transport of certain tumor suppressor proteins and tumor growth regulators by inhibiting XPO1-dependent nuclear export, leading to the suppression of tumor proliferation and increased death of cancer cells. Administered orally, selinexor is already approved for the treatment of multiple myeloma and diffuse large B-cell lymphoma.

“This agent has a new mechanism of action that has not been previously explored in GIST. We hypothesized that selinexor could open a potential new treatment avenue for heavily pretreated patients who have developed resistance to currently approved therapies”, adds Serrano.

This present study enrolled a total of 30 advanced GIST patients who were treated in two sequential cohorts. The first arm included 12 patients who received imatinib plus selinexor, and the second enrolled 18 patients who received selinexor monotherapy.

While all patients had previously developed cancer drug resistance to imatinib, the investigators observed better results in those patients treated with the combination, reporting that up to 42% showed clinical benefit with responsive and stable disease at 16 weeks versus 28% in the single agent arm. Also of note, two partial responses were observed in the first cohort. In those patients receiving the combination, progression-free survival was 3.3 months versus 2.9 months in the selinexor monotherapy arm.

 Our findings show that imatinib plus selinexor is generally well tolerated, with encouraging clinical activity in heavily pretreated GIST patients. Based on our data, we will seek to expand this first cohort to obtain more data and further evaluate the efficacy of this novel combination in this population,” concludes César Serrano.

Reference:

1. Serrano C, Valverde Morales CM, Cruz Jurado J, Martinez Trufero J, Martinez-Garcia J, Roche S, Redondo Sanchez A, Giuppi M, Suarez B, Romagosa C, Martinez V. A phase Ib/II study of selinexor as single agent and in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial. Annals of Oncology (2022) 33 (suppl_7): S681-S700. https://doi.org/10.1016/annonc/annonc1073

ESMO Congress 2022 session details

Mini Oral session: Sarcoma

Date: Monday, 12th de septiembre
Time: 14:45 – 16:15
1489MO – A phase Ib/II study of selinexor as single agent and in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial
Speaker: César Serrano (Barcelona, España)
Lecture Time: 14:50 – 14:55

 

 

 

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