CFI-400945 + durvalumab

Based on the search results, I can provide the following information about CFI-400945 + durvalumab: CFI-400945 + durvalumab is a combination therapy being investigated primarily for triple negative breast cancer (TNBC). This combination pairs CFI-400945, a first-in-class oral inhibitor of Polo-like Kinase 4 (PLK4), with durvalumab, a PD-L1 checkpoint inhibitor immunotherapy. ## Drug Information CFI-400945 works by blocking PLK4, a protein involved in centriole duplication and mitotic progression that is overexpressed in various solid tumors. Laboratory studies show that CFI-400945 may slow cancer cell growth or cause cancer cells to die[1][5]. Durvalumab is an immunotherapy that blocks the PD-1/PD-L1 interaction, allowing the immune system to detect cancer and reactivate the immune response[1]. The combination is being studied based on preclinical evidence suggesting that the induction of aneuploidy caused by CFI-400945 could create an immunogenic stimulus, potentially enhancing the effects of immune checkpoint blockade[5]. In animal models, the combination showed increased antitumor activity compared to either agent alone[5]. ## Clinical Development The Canadian Cancer Trials Group (CCTG) is conducting a multi-center, single-arm, open-label phase 2 trial (NCT04176848) to assess the efficacy of this combination in patients with treatment-resistant TNBC[2][4]. The primary endpoint is objective response rate, with secondary endpoints including disease control rate, immune-related response rate, safety and tolerability, and correlative studies including cfDNA analyses[4]. Initially, participating centers included the Princess Margaret Cancer Centre, the Ottawa Hospital Research Institute, and Kingston Health Sciences Centre[4]. ## Safety Profile As individual agents, both drugs have established safety profiles. CFI-400945 has been studied in more than 60 patients and appears to be well tolerated with few side effects at the recommended phase 2 dose of 64 mg[1][3]. The most common high-grade treatment-related adverse event with CFI-400945 was neutropenia (19%) at doses ≥64 mg[3]. Durvalumab has been studied in more than 6000 people and has a well-established safety profile, making it a suitable combination partner for CFI-400945 as overlapping toxicities are not expected[1][5]. ## Rationale for Combination The combination is particularly interesting for TNBC because: 1. Immunotherapy in combination with chemotherapy has shown promise in TNBC, but non-chemotherapy combinations that avoid chemotherapy toxicities are of particular interest[4]. 2. Preclinical studies showed that the combination of CFI-400945 and PD-1 blockade resulted in increased antitumor activity compared to either agent alone in transplantable murine cancer models[5]. 3. Unexpected responses to immune checkpoint blockade were observed in patients who had experienced prior tumor shrinkage with CFI-400945, suggesting potential synergy between these mechanisms[5]. This combination represents a novel approach to treating TNBC by combining targeted therapy with immunotherapy, potentially offering a new option for patients with limited treatment alternatives.