A series of abstracts and data presentations on new clinical trials in metastatic colorectal cancer (mCRC) generated expert interest and discussion at the American Society of Clinical Oncology (ASCO) 2026 meeting, held May 29–June 2, 2026.
Two of these reports concerned the randomized phase II CRDF-004 trial of onvansertib, conducted by Cardiff Oncology, and the randomized, open-label phase III trial of Kolupin, sponsored by Shanghai Kechow Pharma. Analysts at GlobalData Healthcare took a closer look at how these treatments might impact patient populations.
Cardiff Oncology's drug onvansertib has been added to the list of drugs used at Cardiff Cancer Centre.
The randomised phase II study CRDF-004 (NCT06106308) at Cardiff Cancer Centre enrolled patients with unresectable metastatic colorectal cancer with a RAS gene mutation (rat sarcoma) who received standard first-line chemotherapy FOLFIRI (leucovorin + fluorouracil + irinotecan) or FOLFOX (leucovorin + fluorouracil + oxaliplatin) plus bevacizumab.
Cardiff Oncology's onvansertib, an oral small-molecule polo-like kinase 1 (PLK1) inhibitor, was added to this baseline in two doses, 20 mg and 30 mg, and compared with standard therapy. The primary endpoint was objective response rate (ORR), and key secondary endpoints were progression-free survival (PFS), duration of response (DOR), and safety.
While the data are still being processed, the presented results indicate that the study is on track to achieve its primary objectives, as onvansertib in combination with FOLFIRI and bevacizumab demonstrated promising antitumor activity and acceptable safety. In contrast, the combination of onvansertib with FOLFOX showed no benefit in this context.
A total of 110 patients were included in the study and randomized to six groups: bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX, each with or without onvansertib 20 mg or 30 mg. Baseline characteristics were generally balanced between groups. The onvansertib 30 mg plus FOLFIRI plus bevacizumab group achieved the highest confirmed objective response rate (ORR) of 72.21 TP3T, compared with 42.11 TP3T in the control FOLFIRI plus bevacizumab group and 44.41 TP3T in the FOLFOX plus bevacizumab group.
Furthermore, when onvansertib (20 mg and 30 mg) in combination with FOLFIRI-bevacizumab was compared with standard therapy, the median progression-free survival (PFS) was not reached in the experimental groups, while the median PFS for FOLFIRI plus bevacizumab was 10.97 months as assessed by the investigator, yielding a PFS hazard ratio (HR) of 0.53.
The safety profile is reported to be manageable, with neutropenia being the most common adverse event of grade 3 or higher. While the results are encouraging, the sample sizes in each arm remain small, and confirmatory data are needed. The company has already announced the initiation of a Phase III clinical trial of onvansertib 30 mg in combination with FOLFIRI and bevacizumab.
Treatment of RAS-mutated metastatic colorectal cancer represents one of the most significant unmet needs in this indication. According to GlobalData's report, "Colorectal Cancer: Drug Market Forecast by Eight Markets and Market Analysis 2021-2032," KRAS and NRAS mutations occur in approximately 45% patients with metastatic colorectal cancer and are associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy. The KRAS G12C mutation, for which targeted agents have become available in later stages, is relatively rare, occurring in 3-4% cases of metastatic colorectal cancer. As a result, bevacizumab in combination with chemotherapy remains the standard of first- and second-line treatment, a paradigm that has remained unchanged for two decades, yet progression-free survival with this regimen remains low, ranging from nine to eleven months, highlighting the urgent need for more effective therapeutic strategies.
Against this backdrop, onvansertib has become a unique drug in development. It is currently the only drug in late-stage development offering a mutation-agnostic approach, making it potentially applicable to the full spectrum of RAS-mutated diseases, regardless of the specific mutation subtype. In addition to colorectal cancer, onvansertib is also undergoing clinical trials in a wide range of malignancies, including pancreatic cancer, chronic myelomonocytic leukemia, breast cancer, small cell lung cancer, and skin cancer. Commercial expectations reflect this breadth of opportunity. According to the consensus forecast from analysts at GlobalData, onvansertib sales are expected to reach $1 billion by 2032.
Shanghai Kechow Pharma's combination drug Kolupin has achieved the primary objective of the study.
Results from a Shanghai Kechow Pharma-sponsored randomized, open-label phase III clinical trial (NCT06008119) in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) who had previously received at least one course of systemic therapy were also presented.
Patients in the experimental arm received Colupin (tunlametinib), a novel oral mitogen-activated extracellular signaling kinase (MEK1/2) inhibitor from Shanghai Kechow Pharma, in combination with Zelboraf (vemurafenib) from Roche, a BRAF inhibitor, versus the investigator's choice of therapy. The primary endpoint was progression-free survival (PFS), and key secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.
The combination of tunametinib and vemurafenib demonstrated a statistically significant improvement in progression-free survival compared with the control group. The median progression-free survival was 4.2 months in the experimental group versus 1.5 months in the control group, with a hazard ratio of 0.342.
The confirmed objective response rate was 26.7% versus 3.7%, and the disease control rate was 85.7% versus 40.4%, respectively. Overall survival data are still incomplete. However, baseline characteristics were not completely balanced between groups: ≥3 metastatic lesions were present in 61.9% of patients in the experimental group versus 46.2% in the control group, which may have biased the results.
Notably, the study of tunlametinib in combination with vemurafenib was initiated before the results of the BREAKWATER trial (NCT04607421) were available. At study entry, patients were not receiving BRAF inhibitors, and doublet or triplet chemotherapy was used as first-line therapy. An important question, therefore, is how these results fit into the changing treatment landscape, given that the BREAKWATER trial has since set a new standard of care for first-line treatment: Pfizer's Braftovi (encorafenib), in combination with cetuximab and chemotherapy, has received FDA approval, demonstrating a doubling of overall survival in BRAF V600E-mutated metastatic colorectal cancer, with a median progression-free survival of 12.8 months and a median overall survival of 30.3 months, representing one of the most significant advances in colorectal cancer treatment in recent years.
The BEACON CRC trial, conducted in previously treated patients, established a benchmark: the combination of Braftovi and cetuximab achieved a median progression-free survival (PFS) of 4.2 months and a median overall survival (OS) of 8.4 months. This further raises the question of whether replacing vemurafenib with encorafenib in this combination could lead to a significant improvement in outcomes. The VIC regimen (vemurafenib, irinotecan, and cetuximab/panitumab) was the first BRAF V600E mutation-targeted combination to receive a National Comprehensive Cancer Network (NCCN) recommendation for colorectal cancer, but it was subsequently delisted in favor of newer BRAF-targeted regimens that offer more comprehensive efficacy data and an improved tolerability profile. The BREAKWATER trial reduced the number of patients who had not previously received BRAF inhibitors in later stages of treatment, and this population was studied in this study. The field of retreatment after encorafenib, although an active area of research, appears to be shifting toward strategies for rechallenging with encorafenib in combination with cetuximab rather than alternative BRAF inhibitor combinations, further limiting the potential niche for the combination of tunlametinib and vemurafenib.
The applicability of these results to a global context remains uncertain. Notably, more than 50% patients included in the study had tumors on the left side, despite the fact that colorectal cancer with the BRAF V600E mutation is known to predominantly affect the right side. The presenter attributed this to geographic differences in the Chinese population. Because the study was conducted exclusively in China, differences in tumor biology may limit the applicability of the results to patients in Western countries, and regulatory authorities such as the FDA and the European Medicines Agency (EMA) may require additional comparative studies before granting approval.
The article "ASCO 2026: Interim data released for upcoming BRAF- and RAS-targeted therapies in metastatic colorectal cancer" was originally created and published by Clinical Trials Arena, a brand owned by GlobalData.
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