Skip to main content
Premium Trial:

Request an Annual Quote

Cardiff Oncology Eyes Accelerated Approval for Onvansertib in KRAS-Mutant Colorectal Cancer


NEW YORK – Cardiff Oncology executives were optimistic about the market prospects of its PLK1 inhibitor onvansertib on Tuesday after sharing promising Phase II data on the drug's activity as part of a combination regimen in KRAS-mutant metastatic colorectal cancer patients.

The San Diego-based drugmaker is studying onvansertib plus standard-of-care FOLFIRI chemotherapy and bevacizumab (Genentech's Avastin) as a second-line treatment for KRAS-mutated metastatic colorectal cancer patients in a Phase Ib/II trial. As of Jan. 18, there were 35 evaluable patients who had received the recommended Phase II dose of onvansertib, and the response rate was 34 percent.

Nearly all patients, 92 percent, achieved disease control on the onvansertib-containing regimen, which included complete responses, partial responses, and stable disease. There was one complete response, 17 partial responses, and 26 patients with stable disease across 48 patients in all dose cohorts. While this study did not compare onvansertib plus FOLFIRI and bevacizumab against standard-of-care treatment, Cardiff CEO Mark Erlander noted in a webcast presentation to investors on Tuesday that previous studies of standard-of-care therapies in this setting showed response rates between 5 percent and 13 percent.

Responses were seen among patients with seven KRAS mutations, including in the most common in colorectal cancer: KRAS G12D, G12V, and G13D. Erlander said onvansertib's ability to target several KRAS mutations by inhibiting the PLK1 pathway sets it apart from other drugs in this space, including Amgen's KRAS G12C inhibitor sotorasib (Lumakras), approved in the US last year for advanced, previously treated KRAS G12C-mutated non-small cell lung cancer.

"Onvansertib has the potential to benefit all metastatic colorectal cancer patients who harbor a KRAS mutation, not just the small proportion with a G12C mutation," Erlander said. "Because PLK1 is active downstream of the RAS mutations that drive the proliferation of tumor cells, we believe that inhibiting PLK1 can then target any KRAS tumor subtype."

Across all dose levels, the median progression-free survival was 9.4 months. In the recommended Phase II dose cohort, median progression-free survival has not yet been reached. Katherine Ruffner, Cardiff's chief medical officer, noted that the onvansertib combination treatment appears to be effective in getting patients to have durable responses and stable disease. About half of the partial responses reported in the data were detected after week 16 on treatment. Six of the 17 observed responses also occurred at week 24 and week 32 scans, she said.

"Persistent, stable disease on onvansertib does not necessarily mean a partial or complete response cannot be achieved," Ruffner said. "There is a fairly steady decrease in measurable tumor burden over time that continues to depend on treatment."

Further, Ruffner observed that the long duration of stable disease in some patients may still translate into a progression-free survival benefit. "Patients, who remain early in treatment and whose measurable disease continues to decrease, may well achieve a partial or complete response," she added.

Despite seeing some benefit from the onvansertib combination treatment, a small portion of patients on the study — five of 48 evaluable patients across all dose levels — also went off trial to pursue potentially curative metastasis-directed therapy, like surgery or microwave ablation.

In the trial, Cardiff is also testing patients' circulating tumor DNA for KRAS mutational burden using droplet-based digital PCR and trying to predict their response to the onvansertib regimen. They found that most patients who later achieved a partial response confirmed by radiographic scan had a 90 percent or greater decrease in KRAS mutant allele frequency, or MAF, after the first 28-day cycle of treatment. None of the progressive disease patients experienced such a dramatic decrease in KRAS MAF after 28 days, and only 35 percent of stable disease patients did.

Ruffner said this suggests an early and substantial decrease of KRAS mutational burden in ctDNA could be used to determine which patients will benefit from treatment. However, she said this exploratory endpoint requires further study.

"We were looking at these changes in mutant allele frequency at day 28 and the patients don't get scans until four weeks later, so we're looking at this assay as a potential way to give us an indication of whether a patient may eventually obtain a radiographic response," Ruffner explained.

The company is now planning to expand the Phase II portion of this study. Ruffner said they have submitted a protocol amendment with the US Food and Drug Administration asking to enroll another 40 to 50 patients and give them the Phase II onvansertib dose. With these additional patients Cardiff hopes to generate more overall response data, and have a better understanding of the regimen's safety and pharmacokinetics. The researchers will also continue exploring the ctDNA-based KRAS mutational burden biomarker.

Meanwhile, Cardiff is planning a pivotal Phase III study of onvansertib plus standard of care in the colorectal cancer population; however, company executives declined to share details on the call because its design isn't finalized.

"For now, we can say that we will be aggressively pursuing a regulatory path that follows the strength of our data," Ruffner said. "We are currently planning a randomized Phase III trial that will support full approval and may allow the opportunity to pursue accelerated approval from an interim analysis."

If successful, KRAS-mutated colorectal cancer could be the first indication in which onvansertib, Cardiff's only clinical-stage product, achieves market approval. The KRAS-mutated colorectal cancer indication is becoming a particularly competitive setting after Amgen's sotorasib demonstrated limited efficacy in KRAS G12C-mutated advanced colorectal cancer patients. Subsequently, Amgen has decided to study sotorasib in combination with its anti-EGFR monoclonal antibody panitumumab (Vectibix) in a Phase III colorectal cancer trial.

Similarly, Mirati Therapeutics, which at the end of 2021 submitted a new drug application with the FDA for adagrasib in second-line KRAS G12C-mutated advanced NSCLC, is also studying its drug in combination with cetuximab (Eli Lilly's Erbitux) in second- and third-line colorectal cancer.

In addition to colorectal cancer, Cardiff is also studying onvansertib in pancreatic cancer and castration-resistant prostate cancer in Phase II trials, and is exploring the drug's preclinical efficacy in triple-negative breast cancer, small cell lung cancer, chronic myelomonocytic leukemia, medulloblastoma, and ovarian cancer.