Nerlynx (neratinib)

P1, N=33, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jan 2027 | Recruiting --> Suspended

P2, N=140, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

P1, N=93, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2025 --> Oct 2028 | Trial primary completion date: Oct 2025 --> Oct 2028

P2, N=35, Not yet recruiting, Xijing Hospital

Of translational impact, we observed that neratinib, in conjunction with the use of rosuvastatin (a standard lipid-lowering drug), produced superior antiatherosclerotic effects compared with statin monotherapy. Olink proteomics study pinpointed that combination treatment alleviated inflammation-related cytokines/chemokines in the serum from Ldlr-/- mice. Taken together, these findings support the concept that neratinib could be tested as a repurposed drug for vascular inflammation and atherosclerosis, thereby streamlining efforts to translate preclinical discoveries to clinical testing in humans.

High-risk clinical features significantly influenced neratinib prescribing. Residual disease did not appear to impact prescribing decisions. These findings suggest biologic risk criteria may serve as practical guidelines for adjuvant neratinib use.

More detailed analyses of the most potent mutations, S303F, E452K, and L798R, showed that they are activating, can co-operate with other ERBB receptors and are sensitive to clinically available second-generation pan-ERBB inhibitors neratinib, afatinib, and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer model in vitro and in vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associated ERBB4 mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driver ERBB4 mutations both in the treatment-naïve setting, and upon development of resistance to targeted agents.

P1/2, N=14, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2025 --> Oct 2026

Combination therapy with neratinib and palbociclib demonstrated a favorable safety profile and clinical benefit rate in patients with HER-driven alterations. Pharmacokinetic analysis revealed a CYP3A4-mediated drug-drug interaction, leading to reduced clearance and increased plasma exposure of both agents, underscoring the importance of considering metabolic interactions in future clinical development.

Single-agent neratinib has limited activity in ERBB2-mutated lung cancers. Combinations with temsirolimus or trastuzumab did not markedly improve overall outcomes, producing durable responses in a limited subset of patients.

Lapatinib and neratinib are tyrosine kinase inhibitors (TKIs) approved for treating HER2-positive metastatic breast cancer, but their clinical use is limited by hepatotoxicity. This underscores the importance of targeting senescent cells or SASP factors to reduce liver toxicity and improve treatment outcomes, making the identification of effective senotherapeutics a vital research focus. There hasn't been any literature report demonstrating the effect of TKI-induced liver cell secretome on macrophage polarization.

P=N/A, N=80, Not yet recruiting, West China Hospital of Sichuan University; West China Hospital of Sichuan University