Tukysa (tucatinib) / Pfizer - LARVOL DELTA

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, trastuzumab, and capecitabine with stereotactic radiosurgery in patients with brain metastases from HER-2 positive breast cancer (TUTOR): Study protocol for a multicenter phase 1 clinical trial. (PubMed, BMC Cancer) - P1 | "This trial has been approved by the Institutional Review Board (IRB) and began patient enrollment in January 2024. The trial will provide insights into the safety and effectiveness of a novel combinatorial therapy for BCBM."

Journal • P1 data • Brain Cancer • Breast Cancer • Febrile Neutropenia • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Neutropenia • Solid Tumor • Thrombocytopenia • HER-2

Gene Expression Profiling to Unveil Novel Biomarkers for Early Diagnosis and Therapies for Breast Cancer. (PubMed, Curr Top Med Chem) - "The stability of the top three receptor-ligand complexes was validated through molecular dynamics simulations. Therefore, our findings could be a valuable resource for researchers and medical professionals, aiding in BC diagnosis and treatment."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • BRCA1 • CAV1 • CD31 • CD34 • CD36 • CXCL10 • CXCL12 • EGFR • MIR155 • MIR16 • MIR23b • PACERR • PECAM1 • PTGS2 • SCARB1 • STAT3 • TP53

Additional analyses of MOUNTAINEER: A phase II study of tucatinib and trastuzumab for HER2-positive mCRC (ESMO 2022) - P2 | "Editorial acknowledgement Under guidance of the authors, assistance in medical writing was provided by Irene Park, PhD, of Seagen Inc. Disease stabilization was observed in most pts on TUC monotherapy; radiographic responses increased slightly after Tras addition. Monotherapy, crossover, and response data from the primary analysis show that concurrent initiation of dual HER2 blockade with TUC + Tras achieves optimal clinical benefit."

Late-breaking abstract • P2 data • Colorectal Cancer • Oncology • HER-2

Zanidatamab (Zani) + chemotherapy (Chemo) for patients (Pts) with HER2-expressing metastatic breast cancer (mBC): Final results of a phase I trial (ESMO-BC 2025) - P1 | "We report the final analysis of a phase I trial of zani + chemo in pts with HER2-expressing mBC. Part 3 of the phase I trial (NCT02892123) evaluated zani + chemo (paclitaxel [pac], capecitabine [cap] or vinorelbine [vin]) or zani + cap + tucatinib (tuc) in pts with HER2-expressing mBC...Prior (>5% of pts) anti-HER2 therapies included trastuzumab (93%), T-DM1 (91%), pertuzumab (80%), lapatinib (24%), T-DXd (9%), tuc (9%), and neratinib (7%)... Zani + chemo had a manageable safety profile and good tolerability with promising antitumour activity and durable responses in heavily pretreated pts with HER2-expressing mBC. Among pts with HER2+ mBC with prior HER2-targeted regimens, adding zani to chemo showed encouraging PFS."

Clinical • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

HER2CLIMB-05: A Phase 3 Study of Tucatinib Versus Placebo in Combination with Trastuzumab and Pertuzumab as First-line Maintenance Therapy for HER2+ Metastatic Breast Cancer. (PubMed, J Clin Oncol) - P3 | "Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC."

Journal • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Case Report: Pathological complete response yet early brain relapse in HER2-positive breast cancer: a case-based review. (PubMed, Front Immunol) - "We report a 60-year-old woman with HER2-positive, hormone receptor-negative breast cancer who achieved pCR after neoadjuvant docetaxel combined with trastuzumab and pertuzumab, followed by 12 months of maintenance trastuzumab and pertuzumab. Emerging CNS-active therapies, including small-molecule tyrosine kinase inhibitors (TKIs) such as tucatinib and next-generation antibody-drug conjugates (ADCs) like trastuzumab deruxtecan, have shown promising intracranial activity. In addition, advanced strategies such as intensified MRI surveillance, radiomics, liquid biopsy, focused ultrasound-mediated BBB disruption, nanoparticle delivery systems, and radionuclide therapy offer potential avenues for early identification and prevention of cerebral metastases."

Journal • Review • Brain Cancer • Breast Cancer • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • HER-2

Indirect comparisons of tucatinib in combination with trastuzumab for patients with previously treated HER2-positive metastatic colorectal cancer. (PubMed, J Comp Eff Res) - P2, P3 | "Materials & An unanchored, matching-adjusted indirect comparison was conducted following a systematic literature review that identified the CORRECT trial (NCT01103323), which investigated regorafenib, and the RECOURSE trial (NCT01607957), which investigated trifluridine-tipiracil, as comparators for tucatinib in combination with trastuzumab. ORR also favored tucatinib in combination with trastuzumab across analyses. These data support that tucatinib in combination with trastuzumab is an effective therapy option in patients with previously treated mCRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • HER-2

ERASE-CRC: Exploiting Circulating Tumour DNA to Intensify the Postoperative Treatment Resected Colon Cancer Patients (clinicaltrials.gov) - P2 | N=477 | Suspended | Sponsor: Gruppo Oncologico del Nord-Ovest | Trial completion date: Dec 2027 ➔ Dec 2029 | Recruiting ➔ Suspended | Trial primary completion date: Oct 2025 ➔ Oct 2027

Circulating tumor DNA • Trial completion date • Trial primary completion date • Trial suspension • Colon Adenocarcinoma • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • HER-2

Screening of anticancer drugs against potential carcinogenic bacterial virulence proteins in colorectal cancer: An in silico approach. (PubMed, J Pharmacol Exp Ther) - "We explored the interaction of clinically used anticancer drugs (bevacizumab, capecitabine, fluorouracil, fruquintinib, leucovorin calcium, regorafenib, and tucatinib) with virulence proteins of oncomicrobes including Helicobacter pylori (cytotoxin-associated gene A), Fusobacterium nucleatum (Fusobacterium adhesion A), Bacteroides fragilis (Bfragilis toxin). Overall, the present study provides computational evidence over anticancer drugs that may interact with bacterial virulence mechanisms implicated in anaerobic bacteria induced CRC, offering novel insights into therapeutic avenues capable of mitigating bacterial contributions in CRC initiation and progression. SIGNIFICANCE STATEMENT: The study focuses evaluating anticancer drugs targeting carcinogenic virulence proteins associated with bacterial biofilm mediated colorectal cancer."

Journal • Colorectal Cancer • Infectious Disease • Oncology • Solid Tumor

Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ breast cancer brain metastases (BCBM) (SABCS 2022) - "We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts)...Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib... Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib- based combinations in pts with HER2+ BCBM."

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

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and modified FOLFOX6 as first line treatment in HER2+ metastatic colorectal cancer. (ASCO 2023) - P2, P3 | "Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab)...Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651."

Clinical • Metastases • P3 data • Breast Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRAF • HER-2

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress. (ASCO-GI 2023) - P2, P3 | "Approximately 400 pts will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combo w/ either bevacizumab or cetuximab)...Enrollment is ongoing in the US, w/ global sites planned. Clinical trial information: NCT05253651."

Clinical • Metastases • P3 data • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2

MOUNTAINEER-03 phase III study design: first-line mFOLFOX6 + tucatinib + trastuzumab for HER2+ metastatic colorectal cancer. (PubMed, Future Oncol) - P3 | "The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC...Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests.Clinical trial registration: NCT05253651 (ClinicalTrials.gov)."

Journal • P3 data • Colorectal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS

A Study of Tucatinib and Trastuzumab in People With Rectal Cancer (clinicaltrials.gov) - P2 | N=37 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Oncology • Rectal Adenocarcinoma • Rectal Cancer • Solid Tumor • HER-2 • KRAS

CLIMB-LMD: Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Sunnybrook Health Sciences Centre | Trial primary completion date: Oct 2025 ➔ Dec 2026

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

Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study. (PubMed, J Clin Oncol) - P2 | "Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC."

Journal • Metastases • P2 data • Pan tumor • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • HER-2

Impact of baseline molecular alterations on the efficacy of tucatinib (TUC) plus trastuzumab (Tras) for HER2+, RAS WT metastatic CRC (mCRC) in MOUNTAINEER (ESMO 2023) - P2 | "Conclusions This exploratory analysis of the MOUNTAINEER trial found generally consistent clinical efficacy of TUC + Tras to the primary analysis across subsets of pts w/ HER2+ RAS-WT mCRC and other clinically relevant genomic alterations. Table: 551O cORR DOR n % 95% CI n Months 95% CI Mutations Tissue NGS 45 46.7 31.7 – 62.1 21 15.3 8.9 – 25.5 ERBB2 6 66.7 22.3 – 95.7 - APC 36 44.4 27.9 – 61.9 16 16.6 6.1 – NE TP53 40 45.0 29.3 – 61.5 18 16.6 8.9 – NE ctDNA NGS 66 39.4 27.6 – 52.2 26 12.4 8.3 – 20.5 PIK3CA 7 28.6 3.7 – 71.0 - ERBB2 15 46.7 21.3 – 73.4 7 11.4 6.1 – NE APC 37 45.9 29.5 – 63.1 17 15.3 6.2 – NE Amplifications Tissue NGS 45 46.7 31.7 – 62.1 21 15.3 8.9 – 25.5 ERBB2 44 47.7 32.5 – 63.3 21 15.3 8.9 – 25.5 BRCA2 5 80.0 28.4 – 99.5 - ctDNA NGS 66 39.4 27.6 – 52.2 26 12.4 8.3 – 20.5 BRAF 7 14.3 0.4 – 57.9 - CCND1 7 14.3 0.4 – 57.9 - CDK6 10 30.0 6.7 – 65.2 - EGFR 19 36.8 16.3 – 61.6 7 12.5 4.2 – NE ERBB2 57 40.4 27.6 – 54.2 23 12.4 6.2 – 38.3 PIK3CA 5 40.0..."

Clinical • Metastases • Colorectal Cancer • Oncology • BRAF • BRCA2 • CCND1 • CDK6 • EGFR • HER-2 • PIK3CA • RAS • TP53

HER2CLIMB-05: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer. (ASCO 2023) - P3 | "Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582."

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

Tucatinib and trastuzumab for previously treated HER2−mutated metastatic breast cancer (SGNTUC−019): A phase 2 basket study. (ASCO 2024) - P2 | "Tucatinib (TUC) is a tyrosine kinase inhibitor highly selective for HER2 and is approved for previously treated HER2+ MBC with or without brain metastases in combination with trastuzumab (Tras) and capecitabine...Pts with HR+ disease also received fulvestrant (F; 500 mg IM once every 4 wks starting from cycle 1 day 1, and cycle 1 day 15)... The investigational combination of TUC and Tras, plus F in pts with HR+ disease, was well tolerated and had clinical activity in pts with previously treated HER2-mut MBC. The results support further evaluation of the combination of TUC and Tras as a potential treatment option for this pt population."

Metastases • P2 data • Pan tumor • Breast Cancer • Cardiovascular • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Hypertension • Oncology • Solid Tumor • HER-2

Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. (PubMed, JAMA Oncol) - P2 | "The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs. ClinicalTrials.gov Identifier: NCT02614794."

Clinical • Combination therapy • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Immunology • Oncology • Solid Tumor • HER-2

Anti-HER2-targeted therapies: effects on human in vitro blood-brain barrier models. (PubMed, Front Drug Deliv) - "Established therapies such as trastuzumab, pertuzumab, trastuzumab/pertuzumab, lapatinib and tucatinib are widely used and are selectively toxic to HER2-positive breast cancer cell line. In conclusion, we demonstrate different time- and concentration-dependent effects of anti-HER2-targeted therapies for the treatment of advanced HER2-positive breast cancer on the BBB in vitro. Further experiments are required to assess the clinical relevance of our results."

Journal • Preclinical • Brain Cancer • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • CCL2 • CD34 • CLDN5 • OCLN • SLC2A1

Tucatinib-trastuzumab-capecitabine for treatment of leptomeningeal metastasis in HER2+ breast cancer: TBCRC049 phase 2 study results. (ASCO 2024) - P2 | "This is the first prospective evidence of clinically meaningful benefit including objective responses, symptom improvement, and quality of life, along with extended survival, with a systemic regimen for LM from HER2+ BC. These data support the trend toward using systemic therapy as an initial approach in CNS metastases."

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

Safety and efficacy of tucatinib, letrozole and palbociclib in patients with previously treated HR+/HER2+ breast cancer. (PubMed, Clin Cancer Res) - P1/2 | "TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing."

Journal • Breast Cancer • CNS Disorders • Fatigue • Hematological Disorders • HER2 Breast Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor • CCND1 • HER-2