Rigosertib Plus Nivolumab Shows Encouraging Early Results in KRAS-Mutant NSCLC

In patients with KRAS-mutant non–small cell lung cancer, treatment with rigosertib in combination with nivolumab showed promising signals of efficacy and safety.

The combination of rigosertib and nivolumab (Opdivo) appears to be well-tolerated in patients with advanced KRAS-mutated non–small cell lung cancer (NSCLC), according to data from the phase 1/2 clinical trial announced in a press release by Onconova Therapeutics, Inc.1

The positive safety data were from 12 patients who failed at least 1 prior line of therapy with a PD-1 inhibitor, 8 of whom failed at least 2 prior lines of therapy. The findings were presented during the 3rd Annual RAS Targeted Drug Development Summit

“This safety and early efficacy signal highlights the combination of rigosertib and nivolumab’s ability to target KRAS mutated NSCLCs and potentially overcome immune checkpoint inhibitor resistance mechanisms. Importantly, responses were seen with different KRAS-positive variants, addressing a critical unmet need,” said Rajwanth Veluswamy, MD, assistant professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai and Principal Investigator of the trial, in the press release.

Key end points being explored in the ongoing phase 1/2a study (NCT04263090) include finding the maximum tolerated dose (MTD) of rigosertib and the overall response rate (ORR) of rigosertib plus nivolumab. The secondary end points of the study are progression-free survival and overall survival. Overall, the study aims to enroll 30 patients with KRAS-mutant NSCLC.2

The study will follow a 3 + 3 design in which treatment with rigosertib will be tested at starting dose of 280 mg twice daily and escalated to dose level (D) 2 of 560 mg every morning and 280 mg every night, then 560 mg twice daily at D3. Nivolumab will be given in combination with rigosertib at a fixed dose of 240 mg administered once every 2 weeks.

Out of 7 evaluable patients, partial responses were achieved in 29%, notably in patients with either KRAS G12C- or KRAS G12V-mutated tumors. Stable disease was observed in 43% of the evaluable patients, while 57% had progressive disease.1

To date, the MTD of rigosertib has not been reached. The majority of the treatment-related adverse events (TRAEs) that occurred in patients were mild. Two grade 3 TRAEs also occurred. Treatment was discontinued by 3 patients in the study due to 2 cases of grade 2 genitourinary toxicity, and 1 case of grade 3 hyponatremia. Overall, there were no unexpected AEs observed in the study.

Patients with KRAS-mutant NSCLC are actively being recruiting at the Icahn School of Medicine at Mount Sinai in New York, New York. Eligible patients are those ages 18 years or older with histologically or cytologically confirmed disease, who progressed or are intolerant to the standard of care. Patients are also required to have measurable disease per RECIST v1.1, a life expectancy of at least 3 months, an ECOG performance status of 0 to 2, and adequate organ function.2

In order for investigators to carry out their efficacy and safety analyses, patients must be able to provide blood samples, receive core needle biopsies, and take contraception.

Patients are not eligible for enrollment if they are receiving other investigational agents, have EGFR or ALK alterations, or have certain comorbidities that may interfere with study treatment.

“The data…support the potential applicability of rigosertib’s mechanism of action against multiple KRAS mutations and its synergy with immuno-oncology therapeutics. Radiographic responses were seen across multiple KRAS variants, which potentially differentiates rigosertib from other RAS pathway modulators that target particular KRAS mutations. These responses were observed at the primary tumor site as well as metastatic sites such as the pleura and bone. These results also suggest that rigosertib may augment the response to checkpoint inhibitors, which is consistent with observations from preclinical studies, with potential applicability to indications such as NSCLC, melanoma, and others,” said Steven M. Fruchtman, MD, president, and chief executive officer of Onconova Therapeutic, in the press release.1


Onconova Therapeutics announces encouraging clinical data supporting the anti-cancer activity of rigosertib-nivolumab combination in advanced KRAS+ non-small cell lung cancer. News release. Onconova Therapeutics. September 22, 2021. Accessed September 22, 2021.