Rigosertib/Nivolumab Combo Shows Early Potential in KRAS-Mutated NSCLC

The novel combination comprised of rigosertib and nivolumab showed preliminary evidence of potential anticancer activity in patients with advanced metastatic KRAS-mutated non–small cell lung cancer.

The novel combination comprised of rigosertib and nivolumab (Opdivo) showed preliminary evidence of potential anticancer activity in patients with advanced metastatic KRAS-mutated non–small cell lung cancer (NSCLC), according to an update from an ongoing phase 1/2a trial (NCT04263090).1

The maximum-tolerated dose (MTD) for the doublet has not yet been reached in the 3 cohorts that are being assessed in the dose-escalation phase of the trial. Notably, participants enrolled to the trial have previously received multiple lines of therapy and have progressed on various combinations of immune checkpoint inhibitors.

Investigators continue to enroll patients to the expansion phase of the trial, to examine the highest dose of oral rigosertib defined in the current protocol. Based on positive preliminary data, a protocol amendment is being prepared that will permit the assessment of increased rigosertib doses in combination with the full dose of nivolumab, as recommended in the product label.

“The preliminary results from the phase 1/2a trial are very encouraging and demonstrate the potential of rigosertib to address a critical unmet medical need by overcoming checkpoint inhibitor resistance in KRAS-mutated lung adenocarcinoma,” Mark S. Gelder, MD, chief medical officer of Onconova, stated in a press release. “The observation of preliminary evidence of efficacy in combination with acceptable safety of the doublet in this extremely challenging patient population provides a promising signal.”

The open-label phase 1/2a study enrolled patients aged 18 years or older who had a histologically or cytologically confirmed diagnosis of stage IV metastatic lung adenocarcinoma and progressed on or were intolerant of standard-of-care frontline treatment with PD-1 monotherapy or in combination with platinum-doublet chemotherapy.2

Patients also needed to have measurable disease per RECIST v1.1 criteria and investigator assessment, a life expectancy of at least 3 months, an ECOG performance status of 0 to 2, and acceptable organ function. They could not be receiving any other investigational drugs or have tumors that harbored an EGFR sensitizing mutation or ALK translocation. Patients also could not have untreated central nervous system metastases or carcinomatosis meningitis.

The trial is comprised of 2 phases: the dose-escalation phase 1 portion and the dose-expansion phase 2a portion. Study participants are given oral rigosertib twice daily on days 1 through 21 and intravenous nivolumab at a fixed dose of 240 mg on days 1 and 15 of 28-day treatment cycles. Rigosertib is currently under examination at the following 3 dose levels: 280 mg twice daily, 560 mg in the morning and 280 mg in the evening, and 560 mg twice daily.

The primary end points of the trial are to establish the MTD, and the overall response rate achieved with the regimen. Key secondary end points include progression-free survival and overall survival.

Previously, rigosertib was examined as a single agent and in combination with immune checkpoint blockade in immunocompetent mouse models with BRAF wild-type and BRAF-mutated melanoma.3

Results showed that rigosertib was well tolerated when given at a dose of 300 mg/kg in mice. The agent resulted in approximately 50% inhibition of tumor growth as a single agent and approximately 70% when given in combination with a PD-1 agent and a CTLA-4 agent.

Tumor growth inhibition induced by rigosertib was found to be dependent on CD40 upregulation in melanoma cells followed by immunogenic cell death; this led to enriched dendritic cells and activated T cells in the tumor microenvironment. Moreover, tumor suppression initiated by the drug was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells.

Moreover, treatment with dabrafenib (Tafinlar) and trametinib (Mekinist) or with rigosertib increased the number of CD40+ SOX10+ melanoma cells in the tumors of patients with melanoma, as well as in patient-derived xenografts. A high expression level of CD40 was found to correlate with beneficial T-cell responses and improved survival in a TCGA dataset of patients with melanoma.

“The phase 1 study supports the preclinical observation in melanoma of the up-regulation of crucial cell surface molecules by rigosertib which may synergize with immune checkpoint blockade, as was recently published in Molecular Cancer, and strongly supports the continued clinical development of rigosertib/checkpoint inhibitor combination therapy,” Gelder added.

Preliminary data with the combination will be shared at the 3rd Annual RAS Targeted Drug Development Summit that is being held in September 2021. As the data mature, they will be presented at a future medical meeting.

“We are very pleased both with the safety and preliminary efficacy signal we have seen from the KRAS-mutated NSCLC trial to date, considering the multiple lines of therapy many of these patients have previously failed, including checkpoint inhibitors in various combinations,” Steven M. Fruchtman, MD, president, and chief executive officer of Onconova, added in the release. “We are supportive of the plan to expand dose-escalation of rigosertib to determine the optimal recommended phase 2 dose of the combination; and are eagerly anticipating results of important correlative science that is part of the trial.”


  1. Onconova Therapeutics provides an update on the phase 1/2a trial of rigosertib-nivolumab combination in KRAS+ non-small cell lung cancer. News release. Onconova Therapeutics, Inc. June 28, 2021. Accessed July 6, 2021. https://bit.ly/2SSjJav
  2. Rigosertib plus nivolumab for KRAS+ NSCLC patients who progressed on first-line treatment. ClinicalTrials.gov. Updated July 1, 2021. Accessed July 6, 2021. https://clinicaltrials.gov/ct2/show/NCT04263090
  3. Yan C, Saleh N, Yang J, et al. Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade. Mol Cancer. 2021;20(1):85. doi:10.1186/s12943-021-01366-y