Phase 1/2a Trial of Rigosertib/Nivolumab Combo for KRAS-Positive NSCLC Shows Early Anticancer Activity


Patients with KRAS-positive NSCLC being treated with rigosertib plus nivolumab demonstrated early efficacy of the combination in a phase 1/2a trial.

Potential antitumor activity has been detected in patients with advanced or metastatic KRAS-positive non–small cell lung cancer (NSCLC) who are being treated in a phase 1/2a trial (NCT04263090) of oral rigosertib plus nivolumab (Opdivo), according to a press release from Onconova Therapeutics, Inc.1

In the trial’s dose-escalation phase, the maximum tolerated dose of rigosertib and nivolumab was not reached across all 3 cohorts of treated patients. All those enrolled to the trial had previously failed multiple lines of therapy and all patients had failed on combination therapy including checkpoint inhibitors.

“The preliminary results from this 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, M.D., chief medical officer of Onconova, said in a press release.

This phase 1/2a trial was initiated to evaluate the combination of rigosertib and nivolumab for patients with KRAS-positive metastatic adenocarcinoma of the lungs who have progressed on standard of care with anti–PD-1 monotherapy or anti–PD-1 plus chemotherapy.

This study enrollment goal is 30 participants, with a dose-escalation portion for phase 1 and a dose-expansion portion for phase 2. Patients receive rigosertib twice daily on days 1 through 21 and nivolumab intravenously on days 1 and 15 of each 28-day cycle.

Primary end points are safety assessments and overall response rate (ORR). Secondary end points are progression-free survival (PFS) and overall survival (OS).

Patients continue to be recruited to the dose-expansion portion of the trial and a protocol amendment is being considered to increase the highest possible dose of rigosertib. This study is still ongoing with an estimated completion date of January 2022.

“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. This 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 recently published in Molecular Cancer, and strongly supports the continued clinical development of rigosertib-checkpoint inhibitor combination therapy,” Gelder continued.

A preclinical trial (NCT01205815) was done that looked at the effect of rigosertib on immune checkpoint inhibition in melanoma cells and support the therapeutic use of rigosertib and immune checkpoint blockade for patients who do not respond to ICB alone.2 


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. June 28, 2021. Accessed July 6, 2021.

2. 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. Published 2021 Jun 6. doi:10.1186/s12943-021-01366-y

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