Rigosertib Misses Primary End Point in Phase 3 Study of Higher-Risk Myelodysplastic Syndrome

The primary end point of improved survival in the phase 3 INSPIRE trial was missed, as the overall survival (OS) findings were not significantly different for patients with higher-risk myelodysplastic syndrome (MDS) who were treated with either rigosertib or physician’s choice, announced Onconova Therapeutics, Inc.¹

The study aimed to evaluate the safety and efficacy of intravenous (IV) rigosertib in patients with higher-risk MDS who have previously failed hypomethylating agent (HMA) treatment. Rigosertib is a proprietary small molecule that has been able to block cellular signaling by targeting RAS effector pathways in preclinical model data.

The median OS among patients receiving rigosertib in the intent-to-treat population was 6.4 months compared with 6.3 months with the physician’s choice (P =.33). In the prespecified patient population, the difference between the 2 study arms was not significant. An increase in OS in the physician’s choice arm was unexpected in the post-interim analysis. Additional analyses will be conducted.

The safety of this agent appeared to be generally well tolerated. Reports of adverse events (AEs) were similar to what has been found in prior study of IV rigosertib in this patient population. Serious AEs were not common, and a similar profile for serious (AEs) was observed for both arms of the study.

“Onconova would like to thank the MDS community for its participation in the INSPIRE trial. We report these results with great disappointment, and we remain deeply indebted to every patient, physician, and family member involved in the study,” said Steven M. Fruchtman, MD, president and chief executive officer, Onconova, in a statement. “Onconova is fortunate to have built a product pipeline that includes multiple promising agents, including oral rigosertib and ON 123300. Both compounds target meaningful cancer pathways, and we look forward to further efforts with these programs.”

The INSPIRE trial was a global, multicenter, controlled study that randomized patients to receive best supportive care with either IV rigosertib or physician’s choice of treatment. These patients had to have higher-risk MDS and had previously progressed on, failed to respond to, or relapsed after treatment with an HMA within 9 cycles within 1 year after initiation of the HMA therapy. Patients had to have MDS, at least 1 cytopenia, and an ECOG performance status of 0, 1, or 2. Patients were ineligible for the study if they had previously participated in a rigosertib study, received induction chemotherapy, or was a suitable candidate for allogeneic stem cell transplant.

In this study, rigosertib agent was administered to patients at 1800 mg every 24 hours for 3 days every 2 weeks during the first 8 cycles. It was then administered every 4 weeks thereafter in combination with the best supportive care. The secondary end points of the study were OS of patients with monosomy 7 chromosomal aberrations, OS of patients with trisomy 8 chromosomal aberrations, percentage of patients with response, scores of quality of life questionnaire, percentage of patients with bone marrow blast response rate, and the percentage of patients with hematologic improvement.

“While the INSPIRE data readout in HR-MDS is a disappointment, as a RAS pathway inhibitor oral rigosertib could address a number of oncology settings outside of hematology,” stated Richard C. Woodman, MD, chief medical officer of Onconova. “We plan to take learnings from genomic analyses of the INSPIRE trial to inform the future development of rigosertib. We also look forward to the continued expansion of the investigator-initiated study program with oral rigosertib beyond the ongoing Phase 1/2a study in KRAS+ lung adenocarcinoma into additional solid tumors.”

This agent is under evaluation in the open-label phase 1/2a study (NCT04263090) in combination with nivolumab (Opdivo) as treatment of patients with stage IV lung adenocarcinoma who harbor a KRAS mutation and have previously progressed on standard frontline treatment.

Rigosertib is also under evaluation in patients with coronavirus disease 2019 (COVID-19). According to a press release from July 2020, the company submitted an application with the National Institute of Allergy and Infectious Disease to obtain funding from the National Institutes of Health in order to conduct human studies of rigosertib as treatment of patients with COVID-19.²

_References

_{1. Onconova therapeutics announces topline results from the pivotal phase 3 INSPIRE trial. News release. Onconova Therapeutics. August 24, 2020. Accessed August 24, 2020. https://bit.ly/31ogusH}

_{2. Onconova therapeutics submits application for rigosertib to participate in federally funded human studies in COVID-19 disease. News release. Onconova Therapeutics. July 27, 2020. Accessed August 24, 2020. https://bit.ly/34rInSH}