Tukysa (tucatinib) / Pfizer - LARVOL DELTA

HER2 expression and tumor-infiltrating lymphocytes predict response to tucatinib plus trastuzumab in HER2-positive metastatic colorectal cancer (MOUNTAINEER): Exploratory analysis of a multicenter, Phase II trial (AACR 2026) - P2 | "These findings confirm AI-quantified HER2 intensity as a marker of response and suggests the importance of TILs, which may have a role through immunogenic cell death. Stratification by HER2 and TIL may be an approach to consider as this regimen progresses into the first-line setting."

Clinical • Metastases • P2 data • Tumor-infiltrating lymphocyte • Colorectal Cancer • Oncology • Solid Tumor • HER-2

Profiling of reversible and covalent HER2 kinase inhibitors for anti-tumor activity and broader biological effects to evaluate selectivity and functional activity (AACR 2026) - "We evaluated the activity and selectivity of lapatinib, tucatinib, and zongertinib in vitro across a panel of about 300 human tumor cell lines using the OncoPanel® cellular phenotypic platform. To complement these in vitro and in vivo analyses, these HER2 inhibitors were further characterized in the BioMAP® Diversity PLUS® panel of primary human cell systems to assess functional activities across a diverse range of tissue and immune biology contexts. Together, these studies define distinct biological and mechanistic profiles among HER2-targeted TKIs and highlight the evolution of this drug class with increasing selectivity, tolerability, and efficacy."

Breast Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Soluble TNF blockade as a strategy to enhance tyrosine-kinase inhibitor response and control metastatic burden in HER2-positive breast cancer (AACR 2026) - "We have demonstrated that soluble TNF (sTNF) blockade overcomes resistance to trastuzumab-based therapies targeting HER2 by downregulating mucin 4 (MUC4), which shields its epitope on the HER2 molecule. Animals with brain and liver metastases accounted for 50% and 75% respectively, in the vehicle group, and were 90-100% reversed upon treatment with either tucatinib or DN, or the combination.These findings highlight that sTNF blockade can overcome lapatinib resistance and improve tucatinib inhibitory effect on cell proliferation, both in vitro and in vivo. In addition, DN was able to curb brain and liver metastasis and lung metastases in combination with tucatinib, underscoring the potential benefit of its use in combination with TKIs in advanced HER2-positive breast cancer patients."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • MUC4

OB-001 boost the brain penetration of multiple TKIs (AACR 2026) - "OB-001 selectively boosts brain exposure without substantially increasing systemic exposure. These data demonstrate that theoretically a pharmacokinetic window can be achevied with OB-001 whereby enhanced brain metatsases efficacy could be acheived for numerous kinase inhibitors without effecting systemic toxicity. These findings support OB-001 as a first-in-class CNS-targeted efflux modulating adjunct capable of elevating brain drug exposure beyond what is achievable by existing kinase inhibitors alone."

Oncology • Solid Tumor • ABCB1 • ABCG2

JAZMINE: Phase Ib/II Study of Zanidatamab Plus Tucatinib and Chemotherapy in HER2-Positive Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=24 | Not yet recruiting | Sponsor: MedSIR

New P1/2 trial • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Pi3k autoinhibition dictates rras2 dependency across HER2-amplified and PI3K-mutant cancers (AACR 2026) - "RRAS2 knockdown or re-expression of wild-type p110α restored tucatinib sensitivity, confirming that RRAS2 engagement and p110α–p85 regulation form key regulatory nodes.Further, DepMap analyses reveal increased RRAS2 dependency in cells with destabilizing p110α–p85 mutations in the absence of RTK amplification, supporting a model in which RRAS2-driven PI3K signaling requires both relief of autoinhibition and membrane localization.Together, our findings demonstrate that RRAS2 can drive PI3K signaling in contexts previously seen as RAS-independent and where recruitment mechanisms were unclear. Thus, highlighting an additional regulatory node of PI3K activation in HER2-amplified and PI3K-destabilized contexts."

Oncology • ERBB3 • HER-2 • KRAS • PIK3CA • RRAS2

Characterization of HER2-Positive Murine Breast Cancer Models for Investigating HER2-Targeted Therapy and Immunotherapy. (PubMed, Cancers (Basel)) - "Tumors were treated with HER2-targeted therapy (trastuzumab and tucatinib), immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), and anti-HER2 antibody-drug conjugate (ADC) to evaluate treatment efficacy...T-Dxd, but not T-DM1, demonstrated partial treatment response in the EO771-HER2WT model. HER2+ syngeneic tumor models were developed that spontaneously metastasize to the brain and demonstrate variable responses to immunotherapies and ADCs. These models are valuable for advancing molecular imaging modalities for HER2+ brain metastasis, studying blood-brain barrier penetration of HER2-targeted drugs, and exploring the combination of therapies, including immunotherapy."

IO biomarker • Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Molecular Targeting of EGFR, BRAF, and HER2 Signaling in Colorectal Cancer: Contemporary Advances with Panitumumab, Encorafenib, and Tucatinib. (PubMed, J Clin Med) - "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."

Clinical • Journal • Review • Colorectal Cancer • Oncology • Solid Tumor • BRAF • HER-2

Overcoming Trastuzumab-Pertuzumab Resistance and Optimizing Sequential Anti-HER2 Therapy in HER2-Positive Metastatic Breast Cancer. (PubMed, Cancers (Basel)) - "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."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3

Genomic and transcriptomic changes associated with tucatinib exposure in HER2-positive breast cancer brain metastases (AACR 2026) - "Abstract is embargoed at this time."

Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Genomic HER2 amplification predicts for complete clinical response in a phase II study of induction tucatinib and trastuzumab combined with chemotherapy in locally advanced rectal adenocarcinoma (AACR 2026) - "Abstract is embargoed at this time."

Clinical • Metastases • P2 data • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • HER-2

The RAS: PI3Kα breaker BBO-10203 inhibits PI3Kα/AKT activity in HER2+ models through non-canonical RAS signaling blockade (AACR 2026) - P1 | "Treatment with the panRAS inhibitor RMC-6236 showed little effect on pAKT, suggesting that canonical RAS (K-, H- and N-RAS) may not be important players in pAKT signaling. Indeed, BBO-10203 enhanced the anti-tumor activity of HER2-targeted therapies (tucatinib, trastuzumab, or Enhertu) in vivo, leading to tumor regression, even in the trastuzumab-resistant JIMT-1 model. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and is being evaluated in HER2+ breast cancers, both as a monotherapy and in combination with trastuzumab."

Breast Cancer • Esophageal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2 • IR • KRAS • PIK3CA • RRAS2

A phase I/Ib study of IAM1363, a selective and brain penetrant HER2 inhibitor in participants (pts) with advanced cancers harboring HER2 alterations (ESMO 2025) - P1 | "Three of the 4 pts with PRs had received prior T-DXd. The pt with breast cancer had also received prior tucatinib...Most AEs were low grade and manageable in the outpatient setting. Antitumor activity was observed across disease types and HER2 alterations and was evident both systemically and intracranially in heavily pretreated pts."

Clinical • Metastases • P1 data • Breast Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • EGFR

Her2climb-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic breast cancer (SABCS 2025) - P3 | "In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC."

Clinical • Combination therapy • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • HER-2

Tucatinib and trastuzumab for previously treated HER2-mut MBC: Final analysis of a phase II basket study (SGNTUC-019) (ESMO-BC 2025) - P2 | "Tucatinib (TUC) is an oral tyrosine kinase inhibitor that is highly selective for HER2 and approved for previously treated HER2+ MBC with trastuzumab (Tras) and capecitabine...Pts with HR+ disease also received fulvestrant (500 mg IM Q4W starting Cycle (C) 1 Day (D) 1, and on C1D15)... With ∼10 mos of additional follow-up, TUC + Tras has demonstrated clinically meaningful efficacy with durable response to study treatment since the primary analysis and continues to show favorable tolerability in pts with previously treated HER2-mut MBC."

P2 data • Pan tumor • HER2 Positive Breast Cancer • CDK4 • HER-2

Tucatinib-trastuzumab-capecitabine for treatment of leptomeningeal metastasis in women with HER2+ breast cancer: TBCRC049 phase 2 study results. (PubMed, Nat Cancer) - P2 | "These data support systemic therapy as an approach in HER2+ breast cancer LM. ClinicalTrials.gov registration: NCT03501979 ."

Clinical • Journal • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Study of Tucatinib and Doxil in Participants With Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=36 | Recruiting | Sponsor: SCRI Development Innovations, LLC | Trial completion date: Jul 2026 ➔ Nov 2027 | Trial primary completion date: Jul 2026 ➔ Nov 2027

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor

Tucatinib–trastuzumab–capecitabine for treatment of leptomeningeal metastasis in women with HER2+ breast cancer: TBCRC049 phase 2 study results (Nature) - "The trial met its prespecified interim efficacy threshold and exceeded the historical control of 4.4 months. Among 17 enrolled women, all had magnetic resonance imaging-confirmed LM, 15 (88%) were symptomatic and 8 (47%) had abnormal cerebrospinal fluid cytology. For a median follow-up of 18 months (range 9.0–26.7 months), 6 of 17 (41%) remained alive. Tucatinib reached therapeutic levels in the cerebrospinal fluid. The median overall survival was 10 months (95% confidence interval 4.1 months, not reached). The median time to central nervous system progression was 6.9 months (95% confidence interval 2.8, 13.8 months). Of 13 response-evaluable patients, 5 (38%) achieved composite LM objective response. Of 12 evaluable patients, 7 (58%) had improved neurological deficits."

P2 data • HER2 Positive Breast Cancer

PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs in Japan; pembrolizumab for head and neck cancer, tucatinib for breast cancer, and trametinib for ovarian cancer. (PubMed, Int J Clin Oncol) - No abstract available

Japanese regulatory • Journal • Breast Cancer • Head and Neck Cancer • Oncology • Ovarian Cancer • Solid Tumor

SGNTUC 024: Tucatinib Plus Trastuzumab and Oxaliplatin-based Chemotherapy or Pembrolizumab-containing Combinations for HER2+ Gastrointestinal Cancers (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: Seagen, a wholly owned subsidiary of Pfizer | Trial completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gallbladder Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

Clinical Trial of Alpelisb and Tucatinib in Patients With PIK3CA-Mutant HER2+ Metastatic Breast Cancer. (clinicaltrials.gov) - P1/2 | N=40 | Active, not recruiting | Sponsor: Criterium, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Aug 2024 ➔ Mar 2026

Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD4 • EGFR • HER-2 • PIK3CA

Molecular imaging of tucatinib-induced cellular and TME changes in preclinical models of HER2 + breast cancer. (PubMed, Breast Cancer Res Treat) - "Tucatinib significantly decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2 + breast cancer, which can be longitudinally quantified with PET imaging. Our data suggests molecular imaging may improve understanding and prediction of tucatinib response."

Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

HER2CLIMB-05: A Randomized, Double-blind, Phase 3 Study of Tucatinib Versus Placebo Added to Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (MBCC 2026) - No abstract available

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR) (clinicaltrials.gov) - P2 | N=720 | Recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jan 2026 ➔ Dec 2026

Pan tumor • Trial primary completion date • Tumor mutational burden • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BRAF

Dr Lieu on Mapping Third-Line Treatment Strategy in mCRC (OncLive) - "Lieu explained that selecting between these agents is largely informed by the patient’s prior toxicity profile. If a patient has significant bone marrow issues or cytopenias resulting from previous chemotherapy, adding another cytotoxic agent may be inappropriate. Conversely, for patients with cardiovascular concerns such as hypertension, oncologists may steer away from drugs like fruquintinib - which can exacerbate high blood pressure—in favor of an agent with a different adverse effect profile. Ultimately, Lieu concluded that third-line selection is a balance of efficacy and the preservation of quality of life."

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