Tukysa (tucatinib)

P1/2, N=129, Not yet recruiting, Medica Scientia Innovation Research S.L.

On the basis of 110 ns MD simulations, it was concluded that trilaciclib, tucatinib and olmutinib can be considered candidate inhibitors for HsFN3K inhibition. These drugs are expected to have favourable in-vitro and in-vivo activity inhibiting HsFN3K on the basis of our results. The online version contains supplementary material available at 10.1007/s40203-026-00635-2.

Strikingly, knock-in mice expressing a patient-derived HER2 variant and mice maternally exposed to Tucatinib, a recently approved anti-HER2 drug, both replicated patient phenotypes: retarded growth and diverse craniofacial abnormalities, including ocular dysgenesis, short jaws, and cleft palate. Collectively, our findings define a developmental disorder that we designate GRACE syndrome (Growth Retardation and Craniofacial Malformations Caused by HER2 Deficiency), establish HER2's essential role in human growth and craniofacial morphogenesis, and reveal that HER2-targeted therapies during pregnancy can induce craniofacial defects and lifelong growth impairment in fetuses. 5.

P2/3, N=107, Not yet recruiting, F. Hoffmann-La Roche AG

In the PATINA trial, the addition of palbociclib to trastuzumab, pertuzumab, and endocrine therapy was associated with a clinically meaningful improvement in progression-free survival in hormone receptor-positive, HER2-positive metastatic breast cancer...More recently, HER2-CLIMB-05 demonstrated that the addition of tucatinib to dual HER2 antibody therapy significantly prolonged progression-free survival, supporting a model of sustained, multi-agent HER2 pathway suppression...Collectively, these advances support a translational framework in which antibody therapy serves as a central component of treatment strategies, with targeted partners selected according to tumor biology and prior therapy. This review summarizes the biological basis, clinical evidence, and future perspectives of antibody-driven maintenance in HER2-positive metastatic breast cancer.

The HER2 inhibitors represent different mechanisms of actions, including trastuzumab, pertuzumab, tucatinib, and lapatinib, all of which are clinically approved, as well as PEPDG278D, a recombinant human protein which was previously shown to induce the degradation of HER2 and epidermal growth factor receptor (EGFR). Despite p95HER2 expression and resistance to current HER2 inhibitors, HER2-positive BC cells and tumors are highly vulnerable to PEPDG278D-induced degradation of HER2 and EGFR. By inducing HER2 degradation, PEPDG278D eliminates p95HER2 in HER2-positive BC cells and tumors.

A number of BM treatment-effective drugs have shown BM-preventive effects: In NSCLC, the EGFR-inhibitor osimertinib and ALK inhibitors like alectinib, brigatinib and lorlatinib lower the incidence of BM. In HER2-positive breast cancer, tucatinib and trastuzumab deruxtecan have preventive activity in patients without BM at baseline...Preventing BM requires a personalized, multidisciplinary approach, integrating tumor biology, individual risk assessment, and therapeutic advances. Secondary prevention in patients with BM is as vital as tertiary prevention, warranting prospective validation of preclinical concepts.

P1/2, N=24, Not yet recruiting, MedSIR

Trastuzumab deruxtecan demonstrates substantial antitumor activity through potent cytotoxic effects and a bystander effect, supporting its efficacy in tumors with intratumoral heterogeneity or downstream pathway activation. In contrast, tucatinib-based regimens represent an important option for patients with brain metastases and tumors expressing p95HER2. The ongoing development of novel antibody-drug conjugates and bispecific antibodies is expected to further advance personalized sequential therapy targeting composite resistance mechanisms.

Trastuzumab-based combinations and HER2-selective tyrosine kinase inhibitors such as tucatinib have demonstrated durable responses and favorable safety profiles in heavily pretreated patients. This review summarizes current evidence from pivotal phase II and III clinical trials, translational studies, and real-world data evaluating EGFR-, BRAF-, and HER2-directed therapies in colorectal cancer. Particular emphasis is placed on biomarker-guided patient selection, mechanisms of resistance, and emerging combination strategies that continue to refine precision oncology approaches in mCRC.

P2, N=36, Recruiting, SCRI Development Innovations, LLC | Trial completion date: Jul 2026 --> Nov 2027 | Trial primary completion date: Jul 2026 --> Nov 2027

These data support systemic therapy as an approach in HER2+ breast cancer LM. ClinicalTrials.gov registration: NCT03501979 .