Amidst the buzz of AACR and the excitement surrounding their ongoing CRDF-004 trial, Cardiff Oncology might have inadvertently revealed a hidden gem within their data: a potential advantage in treating patients with liver metastases. While the company hasn't explicitly analyzed this aspect yet, hints from both their Phase 1b/2 and the recently-released ONSEMBLE data suggest a compelling narrative that could revolutionize treatment for this notoriously challenging patient subgroup.

Liver metastases in colorectal cancer are a grim reality for many patients. They represent a significant hurdle in treatment, often associated with poor prognosis and limited therapeutic options. The aggressive nature of these metastases, coupled with the liver's complex microenvironment, presents a unique challenge for oncologists.

Cardiff Oncology's onvansertib, a selective Polo-like Kinase 1 (PLK1) inhibitor, has already shown promising results in treating KRAS-mutated metastatic colorectal cancer (mCRC), particularly in bevacizumab-naïve patients. However, lurking beneath the surface of this data is a possible game-changer: onvansertib's potential to effectively target liver metastases, regardless of prior bevacizumab exposure.

Clues from Clinical Trials

Let's delve into the clues. During the Q4 2023 earnings call, Dr. Fairooz Kabbinavar, Cardiff's Chief Medical Officer and a seasoned expert in colorectal cancer, emphasized the lack of clinical features impacting the robust responses observed in bevacizumab-naïve patients in their Phase 1b/2 trial. Specifically, he noted, "We looked at laterality of the tumors, right and left tumors, both responded equally. We looked at patients with liver met, without liver met, they all seem to respond well."

This statement, while seemingly a passing remark, holds immense weight. It suggests that onvansertib's efficacy isn't restricted by the presence of liver metastases in bevacizumab-naïve patients. This observation, if confirmed, could be a significant breakthrough, as current treatment options often struggle to effectively combat these aggressive metastases.

Further intrigue arises from the ONSEMBLE data presented during the same call. Although the trial was primarily designed for second-line mCRC patients, a subset of seven patients were bevacizumab-naïve. Strikingly, the only objective responses observed in this subgroup were in those receiving onvansertib plus standard of care.

While the company hasn't explicitly correlated liver metastasis status with response in the ONSEMBLE trial, it's noteworthy that liver metastases are common in mCRC, and a high percentage of ONSEMBLE patients likely presented with them.

A Potential Breakthrough in Liver Metastasis Treatment

This raises a tantalizing question: could onvansertib be uniquely suited to target liver metastases, even in patients previously exposed to bevacizumab? The absence of objective responses in the bevacizumab-exposed group of the ONSEMBLE trial, combined with the earlier observation from Phase 1b/2, might be pointing towards a distinct advantage for onvansertib in tackling this difficult-to-treat population.

The potential implications are vast. If further analysis confirms onvansertib's efficacy against liver metastases, it could open a new therapeutic avenue for countless patients facing a challenging prognosis. This could not only extend survival but also significantly improve quality of life, offering hope where conventional treatments often fall short.

Dual Mechanism of Action

The scientific rationale behind this hypothesis might lie in onvansertib's dual mechanism of action. Not only does it inhibit PLK1, a key regulator of cell division, but it also disrupts the hypoxia response pathway, interfering with tumor growth and angiogenesis. This two-pronged attack might be particularly effective in the liver, which is known for its hypoxic microenvironment, providing a plausible explanation for the observed responses.

Cash Runway and Future Catalysts

According to the Q1 2024 earnings call, Cardiff Oncology has a cash runway into the third quarter of 2025. The company expects to release initial data from the CRDF-004 trial in the second half of 2024. This data will include the objective response rate for approximately half of the 90 patients expected to be enrolled in the trial. Other potential catalysts include data readouts from investigator-initiated trials in pancreatic cancer and small cell lung cancer.

Number of Activated Clinical Trial Sites

The following chart illustrates the growth in the number of activated clinical trial sites for the CRDF-004 trial.

Conclusion

While further investigation is undoubtedly necessary, the existing data hints at an exciting possibility: Cardiff Oncology might be on the verge of not only developing a new treatment for KRAS-mutated mCRC but also revolutionizing the way we approach liver metastases in these patients. This potential breakthrough, if confirmed, could redefine the treatment landscape for a significant portion of mCRC patients, offering hope for better outcomes and a brighter future.

"Fun Fact: Cardiff Oncology, named after the capital of Wales, chose the name to represent its commitment to "innovative and pioneering science." The company's initial focus was on developing liquid biopsy diagnostics, but they later pivoted to developing novel cancer therapies with the acquisition of onvansertib."