lucitanib (E 3810)

P1/2, N=180, Completed, Sun Yat-sen University Cancer Center; Haihe Biopharma Co.,Ltd.

Current clinical trials, including those evaluating FGFR inhibitors like erdafitinib, lucitanib, and dovitinib, have demonstrated mixed outcomes, underscoring the complexity of FGFR signaling in breast cancer. In conclusion, targeting FGFR signaling in ER+ breast cancer presents both challenges and opportunities. A deeper understanding of the molecular mechanisms and resistance pathways is crucial for the successful integration of FGFR inhibitors into clinical practice, aiming to improve outcomes for patients with endocrine-resistant breast cancer.

P1/2, N=25, Terminated, pharmaand GmbH | Phase classification: P1b/2 --> P1/2

Using available genetic atlas data, potential drug candidates for treatment of PDAC were identified based on differentially expressed genes, protein interaction analysis and connectivity mapping. These results may help focus efforts on identifying targeted agents with potential therapeutic efficacy for evaluation in prospective clinical trials of patients with PDAC.

These data indicate that lucitanib can modulate vascular and immune components of the tumor microenvironment and cooperate with immunotherapy to enhance antitumor efficacy. They support the clinical development of lucitanib combined with immune pathway modulators to treat cancer.

P1b/2, N=25, Terminated, Clovis Oncology, Inc. | N=329 --> 25 | Trial completion date: Mar 2024 --> Apr 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Mar 2022; Due to a change in development priorities, no further clinical development of the lucitanib plus rucaparib or lucitanib plus sacituzumab govitecan combinations is planned at this time.

Lucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. Lucitanib is now being evaluated in phase II/III studies.

P1b/2, N=329, Active, not recruiting, Clovis Oncology, Inc. | Recruiting --> Active, not recruiting

We newly proposed a pentapeptide mn with superb αvβ3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.

Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ inhibitors...Ponatinib binds to FGFR4 in a DFG-D conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, fisogatinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures...The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms.

Funding: Clovis Oncology, Inc. Clinical trial identification: NCT04042116.

Funding: Clovis Oncology, Inc. Clinical trial identification: NCT04042116.

ALKS 4230, an engineered cytokine designed for selective binding to the intermediate affinity interleukin-2 receptor (IL-2R), is being evaluated as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. The combination led to a significant (p<0.05) increase in intratumoral CD8+ T cells and dendritic cells (CD11c+F4/80-), together with a reduction in tumor-associated macrophages (CD11b+F4/80+). The combination treatment elicited a distinct gene expression profile in tumors by RNA-Seq, merging the immunostimulatory effects of RDB 1462 with the anti-angiogenic effects of lucitanib.The combination of an intermediate affinity IL-2R-selective cytokine and an angiogenesis inhibitor resulted in durable dose-dependent antitumor efficacy in the MC38 mouse tumor model.

The genetic algorithm provided similar results to the more computationally demanding method of grid searching. Compared with a fixed-dose regimen, body weight-based regimens showed a small reduction in PK variability for lucitanib in the overall population, suggesting that there is limited benefit with body weight-based dosing. Dose optimization will be further evaluated with a growing understanding of the target therapeutic range and exposure-response relationships.

Although CON exhibited higher incidence, drug-related TEAEs at both groups were expected and manageable. Lucitanib exhibited better efficacy profile when administrated 10mg QD continuously. Further safety and efficacy of lucitanib is being evaluated in phase II/III studies.

In this exploratory study, total FGFR1-4 mRNAh is a predictive biomarker for FGFRinh (e.g. rogaratinib) but not for MTKI such as lucitanib in BC PDXs. MTKI efficacy does not rely on mRNAh levels of its targets in BC.