Onvansertib With FOLFIR/Bevacizumab Induces Responses With Manageable Safety in KRAS-Mutant mCRC

Heinz-Josef Lenz, MD

Onvansertib, an oral, highly selective PLK1 inhibitor, administered with irinotecan, fluorouracil (5-FU), and folinic acid (leucovorin; FOLFIRI) and bevacizumab (Avastin) was well-tolerated in patients with KRAS-mutated metastatic colorectal cancer (mCRC), while demonstrating encouraging efficacy, according to phase 1b/2 data presented in a poster at the 2022 Gastrointestinal Cancers Symposium.¹

“The addition of the PLK1 inhibitor onvansertib to FOLFIRI/bevacizumab shows very promising efficacy results with response rates of over 30% and PFS over 9 months in second-line mCRC KRAS-mutant colon cancer. The treatment is well-tolerated,” said Heinz-Josef Lenz, MD, professor of medicine, J. Terrence Lanni Chair in Gastrointestinal Cancer Research, co-director of the USC Center for Molecular Pathway and Drug Discovery, and co-director of the USC Norris Center for Cancer Drug Development at the Keck School of Medicine at USC told Targeted Oncology, in an interview.

Patients with KRAS-mutant mCRC have limited treatment options in the second-line setting. For example, with most chemotherapy and targeted therapy combinations, the prognosis is poor with an overall response rate (ORR) of between 5% and 13%, a median progression-free survival (PFS) of about 5.7 months, and a median overall survival (OS) of roughly 11.5 months, according to earlier studies highlighted on the poster.

Other strategies for targeted KRAS-positive tumors include the use covalent KRAS G12C inhibitors, which have modest activity, and targeting synthetic lethal partners of mutant KRAS. PLK1 inhibition with agents like onvansertib has been identified as being synthetically lethal with mutant KRAS in CRC cells. Moreover, the agent demonstrated potent activity as monotherapy in an HCT-116 KRAS-mutant xenograft model and was synergistic with both irinotecan and 5-FU.

Therefore, investigators aimed to further determine the efficacy and safety of onvansertib in KRAS-mutant mCRC in the phase 1b/2 study. Patients received onvansertib (starting dose, 12 mg/m² orally on days 1 through 5 and days 15 through 19 of each 28-day cycle) in combination with FOLFIRI (irinotecan 180 mg/m², leucovorin 400 mg/m2, and 5-FU 400 mg/m²)plus bevacizumab (5 mg/kg).

In the phase 1b portion of the study, the coprimary end points included characterization of dose-limiting toxicities, adverse events (AEs), and tolerability along with determining the maximum-tolerated dose and recommended phase 2 dose (RP2D). The phase 2 primary end point was ORR by RECIST v1.1., while PFS and reduction in KRAS mutant allelic frequency (MAF) in the ctDNA served as secondary study end points.

Results were from a group of 50 patients who had a median age of 61 years (range, 35-83) and were 56% male. Most of the patients (69%) had an Eastern Cooperative Oncology Group score of 0 while the remaining 31% had a score of 1. Primary tumor sites among the study cohort were the colon (55%), rectum (35%), and other areas (10%).

Most patients (59%) had metastasis of the liver and other organs, 18% had only liver metastasis, and 22% had no liver metastasis. Notably, 65% of patients had 2 or more metastatic sites, and 35% had 1.

Sixty-seven percent of patients in the study had been previously treated with bevacizumab.

In the overall study population who were treated with either the initial dose of onvansertib with FOLFIR and bevacizumab or those escalated to 15 mg/m2 or 18 mg/m2, 33% experienced either a partial response (PR) or complete response (CR) to therapy. In addition, 58% of patients had stable disease (SD) and only 8% had progressive disease (PD).^1,2

At the RP2D of onvansertib 15 mg/m2, 31% of patients achieved a PR or CR, 63% had SD, and only 6% had PD. The study investigators noted that 3 PRs were not confirmed due to discontinuation to pursue curative therapy, an unrelated AE, or the patients regressed to SD.¹

Nineteen PFS events occurred during the study in the 48 evaluable patients. The median PFS was 9.37 months. Further, there were changes from baseline in tumor mutational burden based on the level of response that patients experienced. Among those who achieved a CR or PR, there was a mean change from baseline in KRAS MAF of 96% (P < .05). In those with SD, the mean change was 74% (P < .01), while those with PD experienced a mean change of 63%, however, this was not statistically significant.

Onvansertib with FOLFIRI and bevacizumab appeared to be a tolerable second-line therapy for the KRAS-mutant mCRC population. The majority of the AEs were low grade and only 11% of patients experienced grade 3 or 4 AEs. The most common grade 1 AEs were nausea (n = 24), fatigue (n = 15), diarrhea (n = 15), and abdominal pain (n = 13). The grade 4 AEs included neutropenia (n = 7), decreased white blood cell count (n = 2), neutropenic fever (n = 1), and hyperphosphatemia (n = 1).

These study findings suggest the decline in plasma mutant KRAS that was demonstrated after the first cycle of treatment is correlated with radiographic disease response and may be a viable biomarker for exploration in the future, according to Lenz et al.

The study continues to enroll patients with KRAS-mutant mCRC who had failure or intolerance to first-line treatment with fluoropyrimidine and oxaliplatin with or without bevacizumab. Currently, 16 patients are receiving the onvansertib combination, and of those, 15 are being treated with the RP2D of onvansertib.

_References:

_{1. Lenz H, Kasi A, Mendelsohn L, et al. A phase 1b/2 trial of the PLK1 inhibitor onvansertib in combination with FOLFIRI-bev in 2L treatment of KRAS-mutated (mKRAS) metastatic colorectal carcinoma (mCRC). Presented at: 2022 ASCO Gastrointestinal Cancers Symposium; January 20-22, 2022; Virtual. Abstract #100.}

_{2. Onvansertib in combination with FOLFIRI and bevacizumab for second line treatment of metastatic colorectal cancer patients with a KRAS mutation. Clinicaltrials.gov. Accessed January 22, 2022. https://bit.ly/342iz1n}