CDK4/6 inhibitor dalpiciclib combined with mFOLFOX6 in pretreated metastatic colorectal cancer: Results from a Simon two-stage phase II study

Background: Treatment options for pretreated metastatic colorectal cancer (mCRC) remain limited, underscoring the need for rational combination strategies. Dysregulated cell-cycle control is a hallmark of colorectal cancer and may contribute to treatment failure. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S transition and represent a therapeutic target. Preclinical studies have demonstrated that CDK4/6 inhibition can enhance the antitumor activity of cytotoxic chemotherapy in colorectal cancer models. We conducted a phase II study to evaluate dalpiciclib, an oral CDK4/6 inhibitor, combined with mFOLFOX6 in pretreated mCRC. Methods: This was an open-label, single-arm, Simon two-stage phase II study in patients with mCRC who had progressed after standard therapies, including prior oxaliplatin-based therapy. Dalpiciclib was administered at 125 mg orally once daily (21 days on/7 days off) with mFOLFOX6 every 2 weeks at standard doses. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), safety (CTCAE v5.0), progression-free survival (PFS), and overall survival (OS). The prespecified stage 1 criterion to proceed to stage 2 was ≥3 partial responses among the first 18 patients. Results: At the data cutoff of December 10, 2025, 17 patients were enrolled (median age, 57.9 years; 52.9% female). All had multi-organ metastases and prior anti-EGFR and/or anti-VEGF therapy; all tumors were pMMR, and 10 (58.8%) harbored KRAS mutations. Among evaluable patients (n=15; ≥1 post-baseline assessment), 3 achieved PR and 4 achieved SD, yielding an ORR of 20.0% and a DCR of 46.7%, meeting the prespecified criterion to proceed to stage 2. Median PFS and OS were 3.7 and 10.3 months, respectively; these estimates are preliminary and survival data remain immature. Treatment-related adverse events were manageable and primarily hematologic. Grade 3 neutropenia occurred in 29.4% of patients and grade 3 thrombocytopenia in 17.6%; no grade 4-5 treatment-related adverse events or treatment-related deaths were observed. Conclusions: Dalpiciclib plus mFOLFOX6 showed acceptable tolerability and preliminary antitumor activity in pretreated mCRC, supporting continuation to the second stage. Ongoing enrollment and correlative analyses will further define durability of benefit and identify molecular subgroups most likely to respond. Clinical trial information: NCT05480280