Tukysa (tucatinib) / Pfizer - LARVOL DELTA

HERTHENA-Breast01: A phase Ib/II, multicenter, open-label, dose-finding study to evaluate the safety and antitumor activity of patritumab deruxtecan (HER3-DXd) in HER2+ advanced breast cancer (BC) (ESMO Asia 2025) - P1/2 | "Background: Although HER2-targeted antibody-drug conjugates (ADCs) have improved outcomes in HER2+ advanced BC, safe and effective later-line therapies are needed for patients who have progressed on trastuzumab deruxtecan (T-DXd)...Pts in Arms 2 and 3 receive the same regimen as Arm 1, with either pertuzumab 840 mg IV followed by 420 mg IV Q3W (Arm 2) or tucatinib 300 mg orally BID (Arm 3)...Secondary endpoints are pharmacokinetics of HER3-DXd ADC, total HER3-DXd antidrug antibody and free DXd payload. Enrollment began in early 2025."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

Structure-guided screening identifies Tucatinib as dual inhibitor for MCT1/2. (PubMed, EMBO Rep) - "We show that Tucatinib potently inhibits the proliferation and migration of cervical tumor cells in vitro and tumor growth in a mouse xenograft model, while exhibiting excellent biological safety. These findings offer molecular insights into the structural and functional mechanism of MCT2 and identify Tucatinib as novel dual inhibitor of both transporters."

Journal • Cervical Cancer • Oncology • Solid Tumor • BSG

MODULE 4: Selection and Sequencing of Therapy for Relapsed/Refractory HER2-Positive mBC in the Absence of CNS Involvement (SABCS 2025) - "Sponsored by AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Clinical, biological and practical factors influencing the selection and sequencing of therapy for patients with R/R HER2-positive mBC in the absence of CNS metastases Outcomes documented among patients with previously treated HER2-positive mBC without CNS involvement in pivotal clinical research studies of T-DXd and tucatinib-based combinations Long-term findings with and optimal integration of other evidence-based treatment options, such as neratinib/capecitabine, margetuximab/chemotherapy and T-DM1, into the care of patients with progressive HER2-positive mBC Other promising agents and strategies under investigation for advanced HER2-positive breast cancer Frequency of HER2 mutations in patients with mBC; published findings with neratinib-based therapy for this population"

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

Pre-ispy trial: a phase i/ib oncology platform program (pre-i-spy-p1) nct05868226 (SABCS 2025) - P1 | "The current arms under study are PRE1 ALX-148/T-DXd; PRE2 tucatinib/zanidatamab; and PRE3 vidutolimod/cemiplimab. Conclusion The PRE-ISPY phase I/Ib trial has been successfully implemented nationally as part of the Consortium of I-SPY trials. Once safety is established, promising regimens can be rapidly transitioned to I-SPY2.2, K-SPY or other phase II/III trials."

P1 data • Breast Cancer

Clinicomics for predicting HER2 expression in metastatic colorectal cancer: a multicenter machine learning analysis on real-world data. (PubMed, Oncology) - "Hb 100 ng/mL, height >160 cm, and the presence of lymph node metastases were associated with HER2 expression and positivity. HER2 testing should be considered mandatory when all these factors are present. The mechanisms linking these four factors to HER2 expression require further investigation."

Journal • Real-world evidence • Colorectal Cancer • Oncology • Solid Tumor • CEACAM5 • HER-2

Enhancing responses to trastuzumab deruxtecan using tucatinib in HER2-negative breast cancer (SABCS 2025) - "The combination of T-DXd and tucatinib represents a novel treatment strategy that may expand the patient population that responds to T-DXd, particularly those with HER2-0 BC who tend to have highly variable responses to T-DXd at baseline. Given the increased side effect burden associated with tucatinib when used in combination with HER2-targeted ADCs, further studies evaluating tucatinib pulsing strategies are warranted and ongoing. This approach could optimize treatment efficacy while minimizing toxicity, improving outcomes for BC patients, particularly those with HER2-0 disease."

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

Unexpected B-hCG elevation in metastatic inflammatory breast cancer: A diagnostic dilemma (SABCS 2025) - "She progressed through several lines of therapy, including docetaxel, trastuzumab, and pertuzumab, dose dense doxorubicin and cyclophosphamide, and fam-trastuzumab deruxtecan. She is currently on therapy with tucatinib, capecitabine, and trastuzumab... In summary, this case highlights an instance of moderately elevated B-hCG in a patient with metastatic inflammatory breast cancer, which has not been well described in the literature to our knowledge. We sought to describe this case to alert providers to the possibility of false pregnancy tests in patients with breast cancer with no other known gynecological cancer. As with this patient, next steps include measurement of estradiol and FSH to confirm a post-menopausal state."

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

Efficacy of second- or third-line Tucatinib, Trastuzumab, and Capecitabine (TTC) following trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer: A multicenter French cohort study. (SABCS 2025) - "Prior (neo)adjuvant chemotherapy and anti-HER2 therapy were administered to 55.3% of patients, while 88.3% had received pertuzumab as treatment for metastatic disease. In this multicenter French cohort, TTC showed clinically meaningful activity as a second- or third-line therapy in HER2-positive MBC patients previously treated with T-DXd, especially among long-responders (PFS>18 months) to T-DXd. Final updated results will be presented at the meeting."

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

MODULE 2: Previously Untreated HER2-Positive Metastatic Breast Cancer (mBC) (SABCS 2025) - "Sponsored by AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Historical outcomes with standard HER2-targeted therapies for newly diagnosed HER2-positive mBC; rationale for the evaluation of effective later-line HER2-targeted treatments in the front-line setting Early data with T-DXd in combination with pertuzumab as up-front therapy for HER2-positive mBC in the Phase Ib/II DESTINY-Breast07 study Published efficacy and safety findings from the Phase III DESTINY-Breast09 trial documenting the benefit of T-DXd in combination with pertuzumab versus taxane/trastuzumab/pertuzumab as first-line therapy for HER2-positive mBC Emerging positive findings from the Phase III HER2CLIMB-05 study assessing tucatinib versus placebo, both in combination with standard first-line maintenance therapy, after chemotherapy-based induction for HER2-positive mBC"

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

Etic-lm : a multicenter, single-arm, phase 2 study evaluating the efficacy of oral tucatinib, oral capecitabine, and intrathecal trastuzumab in patients with her2-positive metastatic breast cancer with leptomeningeal metastases, a ucbg study (SABCS 2025) - P2 | "Median overall survival (OS) historically ranges from 4 to 6 months, with poorer outcomes observed in type 1 LM (characterized by the presence of tumor cells in the cerebrospinal fluid (CSF)), and longer OS reported with newer therapies such as trastuzumab deruxtecan (T-DXd), brain-penetrant HER2 tyrosine kinase inhibitors, or intrathecal (IT) trastuzumab. As of June 2025, 11 patients have been enrolled. Recruitment is ongoing (NCT05800275)."

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

Real-world treatment patterns and outcomes in patients with HER2+ metastatic breast cancer after treatment with trastuzumab deruxtecan (T-DXd) in the US (SABCS 2025) - "The most common regimens received as the index LOT were trastuzumab + tucatinib + chemotherapy (TTC; 34.2%), other anti-HER2 (18.9%), trastuzumab + chemotherapy (12.7%), other (12.7%), margetuximab + chemotherapy (8.8%), trastuzumab emtansine (T-DM1; 6.6%), and anti-HER2 TKI + chemotherapy (6.1%). Treatment sequencing data suggest that TTC and other anti-HER2 therapies are being used in the post-T-DXd rw setting, though potential differences by line exist. This study demonstrates an ongoing and substantial unmet need for more effective treatments among patients with HER2+ mBC previously treated with T-DXd, as shown by the short rwPFS/OS and short times on subsequent treatments following T-DXd."

Clinical • HEOR • Metastases • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Real-world time to next treatment in HER2+ breast cancer patients with brain metastases: trastuzumab deruxtecan vs tucatinib based therapy as second-line treatment (SABCS 2025) - "Current guidelines recommend trastuzumab deruxtecan (T-DXd) as the preferred second-line therapy for HER2+ mBC overall, while the combination of tucatinib, trastuzumab, and capecitabine (TTC) remains an important option for pts with active or progressing BrM disease due to its proven intracranial activity...Descriptive statistics were used to summarize demographic and clinical characteristics by treatment group, including age at index date, race, ethnicity, health insurance, BMI, ECOG performance status, estrogen receptor status, first-line metastatic regimen (grouped as ado-trastuzumab emtansine, trastuzumab (H) +pertuzumab (P) + taxane, endocrine therapy +/- HP, or other regimens), and presence of liver, bone, or lung metastases... In this real-world analysis of pts with prior HER2+ therapy and documented BrM, second-line treatment with T-DXd was associated with significantly longer TTNT compared to TTC among pts with BrM. These findings may help inform treatment..."

Clinical • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Us real-world clinical outcomes of tucatinib, trastuzumab, and capecitabine following trastuzumab deruxtecan for the treatment of her2+ metastatic breast cancer (SABCS 2025) - "Patients with HER2+ MBC benefit from TTC immediately after treatment with T-DXd, demonstrating its clinically meaningful activity in a contemporaneous post-T-DXd setting. These results reinforce the effectiveness of tucatinib, with longer TTNT and OS than in previous real-world studies, in a population more applicable to current clinical practice."

Clinical • Clinical data • Metastases • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2

Mechanisms of resistance to anti-HER2 therapies in brain metastatic derivatives of inflammatory HER2-positive breast cancer models (SABCS 2025) - "The HER2-selective tyrosine kinase inhibitor (TKI) tucatinib (Tuca) and the pan-HER TKI neratinib (Nrb), mostly used in the late line setting, are effective, including in treating brain metastases...Drug efficacy studies involved methylene blue-based cell growth and IC50 assays, and included the Akt inhibitor (i), capivasertib (Capi, 1uM), T-DXd (5ug/mL), and the EGFR-specific TKI gefitinib (Gef, 1uM) or monoclonal antibody cetuximab (Cetux, 10ug/mL)... Our findings suggest the role of high EGFR and PIK3CA mutations in resistance to Tuca, which warrants additional preclinical and clinical investigation. This underscores the importance of understanding if PIK3CA mutations are associated with reduced Tuca sensitivity and the testing of new mutant specific PIK3CAi or other PI3K/Akt pathway inhibitors. Our brain tropic TucaR cell and mouse models will be useful to understanding resistance in the brain metastatic setting, and future work will test the most promising..."

Metastases • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

Herthena-breast01: a phase 1b/2, multicenter, open-label, dose-finding study to evaluate the safety and antitumor activity of patritumab deruxtecan (HER3-DXd) in HER2+ unresectable locally advanced or metastatic breast cancer (SABCS 2025) - P1/2 | "Background: Although HER2-targeted antibody-drug conjugates (ADCs) have improved outcomes in HER2+ advanced or metastatic breast cancer, safe and effective later-line therapies are needed for patients who have progressed on trastuzumab deruxtecan (T-DXd)...Participants in Arms 2 and 3 will receive the same regimen as Arm 1, with either pertuzumab 840 mg IV followed by 420 mg IV Q3W (Arm 2) or tucatinib 300 mg orally BID (Arm 3)...AEs are graded per National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Enrollment began in early 2025."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

First Preclinical Evaluation of Inavolisib-Based Combinatorial Strategies in PIK3CA-Mutant Breast Cancer Brain Metastasis Models (SABCS 2025) - "For TNBC models, combinations included PD-1 antibody and albumin-bound paclitaxel. For HER2-positive models, Inavolisib was combined with Trastuzumab + Pertuzumab, T-DXd (Trastuzumab deruxtecan), or Tucatinib...This study provides the first preclinical evidence of Inavolisib-based combination strategies in PIK3CA-mutant breast cancer brain metastases, using both novel intracranial animal models and PDX systems. Our results suggest that: Inavolisib combined with PD-1 antibody is a promising regimen for TNBC with brain metastases; Inavolisib + T-DXd or Trastuzumab + Pertuzumab shows potent activity in HER2-positive BCBM. These findings highlight the potential of PI3K-targeted combinatorial strategies for overcoming the BBB challenge in breast cancer brain metastases and provide a strong rationale for clinical translation."

IO biomarker • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PIK3CA

Outcome of patritumab deruxtecan (HER3-DXd) in patients with HER2-positive metastatic breast cancer and CNS involvement previously treated with T-DXd: A subanalysis of TUXEDO-3 (SABCS 2025) - P2 | "The number of previous treatment lines for advanced disease in the HER2-positive mBC population was 4.0 (range: 2.0-7.0); all patients had received prior T-DXd, three (30.0%) had additional T-DM1, and six (60%) tucatinib as well. In this post hoc analysis of the prospective TUXEDO-3 trial, HER3-DXd showed promising PFS and OS in patients with HER2-positive mBC and active BMs or LMD, previously treated with T-DXd. Despite the small sample size, these findings suggest a potential strategy for sequential ADC treatment in a patient population with no established standard of care. With a median PFS exceeding 6 months, further investigation of HER3-DXd in patients progressing on T-DXd is warranted."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

TrasTUCAN: Efficacy and Safety of the Combination of Trastuzumab Plus TUCAtinib Plus viNorelbine in Patients With HER2-positive Non-resectable Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=13 | Terminated | Sponsor: Spanish Breast Cancer Research Group | Trial completion date: Aug 2026 ➔ May 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2026 ➔ May 2025; The study was closed early due to safety concerns and an unfavorable benefit-risk balance. Unexpected high neutropenia rates required a costly sub-study, which was not feasible, forcing the sponsor to terminate the trial prematurely.

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

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

Caprine herpes virus-1 reduces cell viability and enhances chemosensitivity in breast cancer cells. (PubMed, Front Oncol) - "Additionally, CpHV-1 was tested in combination with Abemaciclib, Tucatinib, and Inavolisib, and synergism was evaluated using Chou-Talalay analysis. These findings highlight CpHV-1 as a promising oncolytic agent capable of targeting multiple breast cancer subtypes. Its ability to significantly reduce viability, impair long-term proliferation, and induce apoptosis, together with its synergistic activity when combined with FDA-approved targeted therapies and its limited toxicity in normal cells, supports further investigation of CpHV-1 for breast cancer treatment."

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

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

TUKYSA Added to First-Line Maintenance Therapy Extends Median Progression-Free Survival by Over 8 Months in Patients with HER2+ Metastatic Breast Cancer (Pfizer Press Release) - "The primary endpoint analysis showed a 35.9% reduction in the risk of disease progression or death among patients treated with TUKYSA, trastuzumab, and pertuzumab compared to those treated with placebo, trastuzumab, and pertuzumab, as assessed by the investigator (hazard ratio [HR] of 0.641, 95% confidence interval (CI): 0.514-0.799; 2-sided p<0.0001). These findings were published today in the Journal of Clinical Oncology, shared in an oral presentation at the 48th San Antonio Breast Cancer Symposium (SABCS)...In HER2CLIMB-05, the median progression-free survival (PFS) was 24.9 months (95% CI: 21.3-not reached) in the TUKYSA arm and 16.3 months (95% CI:12.6-18.7) in the placebo arm, representing an extension in median PFS of 8.6 months....The results from HER2CLIMB-05 will be discussed with regulatory authorities."

P3 data • HER2 Positive Breast Cancer

Resistance to tucatinib associated with hyperactive EGFR could be overcome by co-targeting HER2 and EGFR in HER2-positive breast cancer models (SABCS 2025) - "NSG mice bearing GFP/Luc-tagged TucaR xenografts grown with estrogen supplementation were randomized to vehicle, Tuca (100mg/kg, once daily gavage, 7 days/week), or EGFR-specific inhibitors: 1) the TKI gefitinib (Gef 100 mg/kg, once daily gavage, 5 days/week) or 2) the monoclonal antibody cetuximab (Cetux, 30mg/kg, IP twice a week)), either alone or in combination, and monitored for primary tumor growth (caliper measurement) and spontaneous metastasis (by bioluminescence). Our novel findings have crucial therapeutic implications and suggest that HER2+ primary and metastatic tumors with high EGFR (~30% of HER2+ MBC) may not benefit from Tuca or EGFR inhibitors alone and need dual/pan-HER inhibitor therapy, a strategy that we intend to translate via a prospective trial. Our data also suggest the need for imaging-based endpoints in order to capture the minimal/microscopic residual disease that may otherwise be missed through routine tumor measurements, as well as the..."

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

Harnessing Machine Learning for the Virtual Screening of Natural Compounds as Both EGFR and HER2 Inhibitors in Colorectal Cancer: A Novel Therapeutic Approach. (PubMed, ACS Omega) - "Among these, LTS0131923 demonstrated the highest binding affinity against HER2 (PDB ID: 7MN5), with a binding energy of -11.2 kcal/mol and an inhibition constant of 0.00626 μM, outperforming Tucatinib, a standard CRC treatment. This study reveals the potential of ML-driven approaches to accelerate the discovery of dual-target inhibitors for CRC therapy and highlights Ceratonia siliqua L. as a promising source of bioactive compounds for cancer treatment."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Sarcoma • Solid Tumor • EGFR • KRAS

TRACE: Tucatinib in Patients With Locally Advanced or Metastatic HER2-positive Breast Cancer Who Received at Least Two Prior Anti-HER2 Treatment Regimens. (clinicaltrials.gov) - P=N/A | N=49 | Completed | Sponsor: iOMEDICO AG | Recruiting ➔ Completed | N=300 ➔ 49 | Trial completion date: May 2027 ➔ Jun 2025 | Trial primary completion date: May 2027 ➔ Jun 2025

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