Cardiff Oncology (NASDAQ:CRDF) interim CEO Mani Mohindru outlined updated clinical results and development plans for the company’s investigational PLK1 inhibitor onvansertib during a webinar focused on first-line RAS-mutated metastatic colorectal cancer (mCRC), a population she described as having seen “limited progress” despite decades of research. Mohindru framed the discussion in the context of National Colorectal Cancer Awareness Month and cited National Cancer Institute estimates that more than 154,000 U.S. patients would be diagnosed with colorectal cancer in 2025, with nearly 53,000 deaths.
Phase II study design and endpoints
Mohindru recapped top-line data from an ongoing, randomized Phase II dose-finding study in first-line KRAS- or NRAS-mutated, unresectable mCRC patients who had not previously received bevacizumab. The trial is designed to enroll 110 patients across three main arms: standard-of-care chemotherapy plus bevacizumab, and onvansertib at 20 mg or 30 mg in combination with standard-of-care regimens (FOLFIRI-bevacizumab or FOLFOX-bevacizumab). Onvansertib is administered on days 1–5 and 15–19 of a 28-day cycle.
Efficacy highlights: response and durability signals
Using intent-to-treat results assessed by blinded independent central review, Mohindru said the standard-of-care arms performed in line with historical expectations, with ORR “around 40, around 43%.” In contrast, she highlighted the onvansertib 30 mg arm combined with FOLFIRI-bevacizumab, which produced an ORR of 72.2% and “deeper” responses than standard of care. The 20 mg arm showed only a modest increase in the number of responses, although Mohindru said depth of response was improved.
On durability, Mohindru reported that median PFS in the FOLFIRI-bevacizumab control group was approximately 11 months, consistent with prior studies. In the onvansertib 20 mg and 30 mg arms combined with FOLFIRI-bevacizumab, median PFS had not been reached at the time of the update. She also reported dose-dependent PFS hazard ratio improvements versus FOLFIRI-bevacizumab alone (0.56 for 20 mg and 0.38 for 30 mg). When compared against combined standard-of-care arms, the 30 mg arm had a PFS hazard ratio of 0.37 and “did reach the statistical significance,” with a p-value less than 0.05, though she emphasized the study was not powered for PFS differences.
Mohindru added that a landmark 6-month PFS rate analysis also favored the 30 mg arm.
Tolerability and dose selection; FOLFOX combination not advanced
Mohindru said a review of tolerability suggested the company did not observe “much additive toxicity on top of the chemo regimens,” characterizing differences as mostly numerical. Based on the “totality of the data,” Cardiff selected 30 mg onvansertib to move forward in combination with FOLFIRI-bevacizumab in a registrational program, with plans to discuss and finalize the approach with the FDA.
She added that the onvansertib-FOLFOX combination “did not demonstrate consistent benefit across the two dose levels,” and the company is not advancing that regimen into Phase III at this time.
Physician perspectives: unmet need, biomarkers, and clinical significance
Guest speakers Dr. Heinz-Josef Lenz (University of Southern California) and Dr. Scott Kopetz (MD Anderson Cancer Center) discussed how first-line treatment decisions in mCRC are shaped by molecular characterization, including KRAS/NRAS, BRAF, MSI-H status, and HER2. Lenz noted MSI-H patients can respond well to immune checkpoint inhibitors, while KRAS-mutant disease has no approved first-line targeted therapy outside of small subsets such as KRAS G12C.
Kopetz emphasized that, even with advances for MSI-H and BRAF-mutant subsets, they comprise a minority, leaving a large unmet need for the broader RAS-mutated population. Both physicians described standard first-line management for RAS-mutated mCRC as chemotherapy backbones (FOLFOX or FOLFIRI) with bevacizumab, with trial participation considered when available.
In discussing what constitutes meaningful benefit, Kopetz said progression-free survival is “what really matters for getting a drug across the finish line” in first-line studies, while acknowledging response rate is useful in signal-seeking Phase II trials. Lenz added that, in colorectal cancer, tumor shrinkage and depth of response can be particularly important because they may enable conversion to resectable disease and potential cure in some cases. During Q&A, Lenz described curative resection as a “soft endpoint” influenced by patient selection, but said conversion of unresectable disease evaluated by a multidisciplinary tumor board is clinically meaningful. He suggested 10%–20% curative resection rates would be “amazing,” while noting liver-limited disease can be more complex and may have higher conversion rates.
Rationale for onvansertib combinations and future directions
Lenz traced his involvement with onvansertib back to early development and said second-line Phase II data previously showed response rates approximately double those expected for FOLFIRI-bevacizumab alone, with a notable signal in patients without prior bevacizumab exposure. Kopetz discussed translational rationale, describing PLK1 as a vulnerability identified through an “unbiased screen” in KRAS contexts and highlighting PLK1’s role in DNA damage repair, which he said supports synergy with topoisomerase I inhibitors such as irinotecan. He also described a second mechanism involving hypoxia signaling, saying onvansertib can reduce HIF-1 levels, potentially complementing bevacizumab’s VEGF inhibition.
Looking ahead, the physicians discussed allele-specific RAS inhibitors as addressing only “little small wedges” of the overall RAS-mutant population. Kopetz estimated RAS mutations collectively represent roughly half of colorectal cancer patients, with the potentially targetable subset by allele-specific inhibitors representing a smaller fraction. Lenz also pointed to antibody-drug conjugates—many of which use topoisomerase inhibitor payloads—as a potential area where combination strategies could be explored in the future.
About Cardiff Oncology (NASDAQ:CRDF)
Cardiff Oncology, Inc is a clinical-stage biopharmaceutical company headquartered in Cambridge, Massachusetts. The company is dedicated to the discovery, development and commercialization of novel small-molecule therapies designed to modulate the tumor microenvironment and enhance antitumor immune responses. By focusing on unique immuno-oncology targets, Cardiff seeks to address resistance pathways that limit the effectiveness of existing cancer treatments.
Cardiff’s pipeline comprises several small-molecule immunomodulators in various stages of preclinical and clinical development.
