Onvansertib Plus Standard-of Care-Chemotherapy Meet Primary End Point of ORR in Metastatic Colorectal Cancer

The use of onvansertib in combination with standard-of-care chemotherapy had an increase in the objective response rate and progression-free survival during the phase 1b/2 trial for metastatic colorectal cancer.

Onvansertib (Trovagene) in combination with the standard-of-care (SOC) leucovorin, fluorouracil, and irinotecan (FOLFIRI) or bevacizumab (Avastin) demonstrated an improved objective response rate (ORR) and progression-free survival (PFS) in the second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC), according to results from a phase 1b/2 trial (NCT03829410).

Findings from the trial indicated that the recommended phase 2 (RP2D) dose of onvansertib (15 mg/m2) yielded a partial response (PR) rate of 42% (n = 8) of patients, and 37% (n = 7) achieved a confirmed PR. Among patients who were evaluable for response across all dose levels, including 12 mg/m2, 15 mg/m2, and 18 mg/m2, 38% (n = 12) achieved an initial PR, and 31% (n = 10) had a confirmed PR. The median PFS had not been reached for patients receiving the RP2D, and was 9.4 months (95% CI, 7.8–not reached) among all patients who were evaluable for response (n = 32).

"Our phase 1b/2 trial continues to generate data suggesting that the addition of onvansertib to SOC results in an objective response rate and median [PFS] survival that substantially exceed those previously achieved with SOC alone," Katherine L. Ruffner, MD, chief medical officer of Cardiff Oncology, said in the press release.

The multi-center single-arm study evaluated the safety and efficacy of the regimen, which was administered in 14-day courses during each 28-day cycle.

In phase 1b of the trial, treatment began on an escalating dose of oral onvansertib at a dose of 12 mg/m2 orally on day 1 through 5 every 14 days over 2 treatment courses. Additionally, FOLFIRI was administered at a dose of 180 mg/m2 irinotecan, 400 g/m2 leucovorin, 400 mg/m2 bolus 5-flourouracil (5-FU), and 2400 mg/m2 with continuous intravenous infusion of 5-FU plus 5 mg/kg of bevacizumab.

In phase 2, patients received the RP2D of onvansertib orally on day 1 through 5 every 14 days over 2 treatment courses. Patients also received the same FOLFIRI backbone as phase 1. Additionally, some patients experienced treatment modifications or delays due to unresolved toxicity from the previous cycle.

In the phase 1 portion of the study, the primary end points were to determine the maximum tolerated dose and the number of participants who had adverse effects, as well as ORR in the second phase. The secondary end points in phase 2 were determining the number of patients with complete responses, and those with a PR.

To be enrolled in this study, patients must have histologically confirmed and unresectable CRC with a KRAS mutation in exon 2, 3, or 4 in the primary tumor or metastases. Additionally, an ECOG status of 0 or 1 was required. Patients must also be intolerant to fluoropyrimidine and oxaliplatin with or without bevacizumab.

At data cutoff across all patients, 10% (n = 49) reported treatment-emergent adverse effects of grade 3 or 4, although most were considered to be manageable and reversible with care.

"Radiographic responses have been observed across multiple KRAS mutation variants, which speaks to a key advantage of onvansertib over competing agents targeting individual mutations. These impressive results, which have remained consistent across both academic and community trial sites, highlight the potential for onvansertib to address the unmet need for new second-line therapeutic options to treat patients with KRAS-mutated mCRC. I look forward to the trial's continued advancement and future data readouts,” Ruffner concluded.


Cardiff Oncology announces new data from phase 1b/2 trial in KRAS-mutated metastatic colorectal cancer showing robust pbjective response rate and progression free survival. News release. Cardiff Oncology. September 8, 2021. Accessed September 9, 2021. https://bit.ly/3l7UxqD