Nerlynx (neratinib) / Boryung Group, Puma, Specialised Therap, Knight Therap, Pierre Fabre, Fosun Pharma, Convalife, BIXINK Therapeutics, Er-Kim Pharma - LARVOL DELTA

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

Real-world use of neratinib in her2-positive early breast cancer in korea: updated follow-up from a multicenter observational study (SABCS 2025) - "Post-neoadjuvant HER2-targeted therapies included: trastuzumab emtansine in 20 patients (41.7%), trastuzumab plus pertuzumab in 16 (33.3%), trastuzumab alone in 11 (22.9%), and trastuzumab deruxtecan in 1 patient (2.1%). In this real-world Korean cohort, neratinib was commonly used after pertuzumab or T-DM1. Treatment was feasible and generally well tolerated with appropriate supportive care. No recurrence was observed during early follow-up."

Clinical • Observational data • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive 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

MODULE 1: Considerations in the Care of Patients with Localized HER2-Positive Breast Cancer (SABCS 2025) - "Sponsored by AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Key clinical factors affecting the selection of neoadjuvant and adjuvant systemic therapy for patients with HER2-positive localized breast cancer; effect of various therapeutic approaches on outcomes Recently presented findings from the Phase III DESTINY-Breast11 study evaluating trastuzumab deruxtecan (T-DXd) as a component of neoadjuvant therapy for patients with high-risk HER2-positive localized breast cancer Emerging data from the Phase III DESTINY-Breast05 study of T-DXd versus trastuzumab emtansine (T-DM1) for patients with high-risk HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy; implications for clinical practice Long-term data from the Phase III ExteNET trial of neratinib as extended adjuvant treatment for patients with HER2-positive localized breast cancer Optimal integration of postadjuvant neratinib into routine practice;..."

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

Safety and Dose Finding Study of Neratinib in Children and Young Adults With Cancer That Has Returned or Not Responded to Treatment (clinicaltrials.gov) - P1/2 | N=14 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2025 ➔ Oct 2026 | Trial primary completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Brain Cancer • CNS Lymphoma • CNS Tumor • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • Solid Tumor

Microbiota disruption with oral antibiotics has a detrimental effect on HER2+ breast cancer therapy efficacy (SABCS 2025) - "We utilized orthotopic HER2⁺ breast cancer mouse models, administered an oral broad-spectrum antibiotic cocktail (ABX) to deplete the microbiota, and employed HER2-targeted antibody (anti-HER2/neu) and small molecule (neratinib) therapies, along with high-throughput spectral flow cytometry, to assess treatment efficacy and the immune mechanisms of response...Overall, our results demonstrate that antibiotic-induced disruption of the gut microbiota impairs HER2⁺ breast cancer therapy and the immune response associated with treatment efficacy, both systemically and locally within the tumor bed. These findings underscore innate immune pathways and microbiota-based strategies as potential therapeutic targets to mitigate the detrimental effects of antibiotics in HER2+ BC patients."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CD4 • CD8 • HER-2

EmpowHER-208: A phase 2 neoadjuvant study of zanidatamab in combination with chemotherapy in patients with stage II-III HER2-positive early breast cancer (SABCS 2025) - "One standard-of-care (SOC) neoadjuvant regimen for patients with stage II-III HER2+ early breast cancer is docetaxel (T) and carboplatin (C) + dual HER2-directed therapy (trastuzumab [H] and pertuzumab [P]; collectively TCHP), with single-agent taxane (docetaxel or paclitaxel [T]) + HP regimens becoming increasingly common...Patients who do not achieve pCR will receive fourteen 3-week cycles of SOC ado-trastuzumab emtansine (T-DM1). Adjuvant endocrine therapy, extended neratinib, radiotherapy, or additional chemotherapy (ZT arm only) may be administered based on investigator preference and institutional SOC. The primary endpoint is pCR rate by blinded local assessment. Key secondary endpoints include pathologic response by residual cancer burden score at time of surgery, breast-conserving surgery rate, safety and tolerability, event-free survival, and overall survival."

Clinical • Combination therapy • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2

A real-world prospective observational multi-national study in adult patients with breast cancer treated with extended adjuvant neratinib: interim results from the NERLYFE study (SABCS 2025) - "Overall, 56%, 28% and 11% of patients received adjuvant/post-neoadjuvant trastuzumab monotherapy, trastuzumab-emtansine (T-DM1), and trastuzumab/pertuzumab, respectively, with 5% of patients receiving other anti-HER2 therapy. The overall safety profile of neratinib was consistent with the EU SmPC. These real-world findings support the benefit of anti-diarrhoeal prophylaxis and the use of neratinib in HR+/HER2+ early breast cancer patients in the current treatment landscape."

Clinical • Observational data • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Ner-tree study interim analysis of safety and patient-reported outcomes in patients with human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (eBC) treated with neratinib in China (SABCS 2025) - P | "Dose escalation and drug prophylaxis combined strategy was the most effective approach in reducing the incidence of Grade 3 diarrhea associated with neratinib. Patient-reported outcomes showed an initial deterioration until Day 30 during neratinib treatment initiation, possibly related to the occurrence of treatment-emergent adverse events, followed by a functional/QoL recovery afterward."

Clinical • Patient reported outcomes • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Randomized phase II trial evaluating three anti-diarrheal prophylaxis strategies in patients (pts) with HER2+/HR+ early breast cancer (EBC) treated with extended adjuvant neratinib (dianer geicam/2018-06) (SABCS 2025) - "Prior pertuzumab and T-DM1 were received by76.3% and 43.5% of pts, respectively. Although none of the 3 strategies for reducing the impact of NER-associated diarrheaassessed in DIANER reduced early treatment discontinuation due to diarrhea to ≤5%, the incidence ofearly NER discontinuation observed in the study suggests that NER dose escalation is the best strategy formanaging diarrhea and other AEs."

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

Pan RTK negative regulator LRIG1 as a therapeutic target for endocrine resistance in estrogen receptor-positive breast cancer (SABCS 2025) - "Treatment with RTK inhibitors (Neratinib for HER2 and FIIN3 for FGFR) significantly restored LRIG1 expression in resistant cells... LRIG1 represents a clinically actionable biomarker and potential therapeutic target in endocrine-resistant ER+ breast cancer. The inverse relationship between LRIG1 expression and RTK pathway activation, coupled with the restoration of LRIG1 by RTK inhibitors, suggests a therapeutically exploitable bidirectional relationship. Exogenous LRIG1 supplementation effectively suppresses proliferation in endocrine-resistant models, supporting its development as a first-in-class pan-RTK therapeutic adjuvant."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EGFR • ER • FGFR2 • HER-2 • LRIG1

Proteomic subtyping of stage II/III TNBC from the I-SPY2 TRIAL reveals a druggable steroid hormone receptor signature (SRS) that is associated with poor outcome and enriched in non-pCR patients' residual disease (SABCS 2025) - "HER2/EGFR co-activated TNBC has been previously shown to have elevated levels of ER and were shown to be highly responsive to the EGFR-HER2 TKI inhibitor neratinib2... Proteomic data from I-SPY 2 showed that patients with SRS+ TNBC have a worse prognosis than SRS- TNBC. Surgical samples from non-pCR pts are enriched with SRS+ cancers. Proteomic analysis of SRS+ tumors obtained at pre-treatment baseline or in the residual disease surgical tumor samples from non-pCR SRS+ pts revealed activation of EGFR, HER2 and AKT-mTOR signaling networks."

Clinical • IO biomarker • Residual disease • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Triple Negative Breast Cancer • AR • EGFR • ER • HER-2

Neratinib for NF2-related schwannomatosis with progressive tumors: interim analysis from the INTUITT-NF2 platform-basket trial (SNO 2025) - "CONCLUSIONS : Neratinib treatment showed modest efficacy in treatment of tumors associated with NF2-SWN. Based on this interim analysis, the team will explore whether an additional 20 participants will be enrolled in the two most promising tumor baskets."

Pan tumor • Brain Cancer • Ependymoma • Meningioma • Oncology • Solid Tumor • EGFR

A Sterically Open Ruthenium-Based Photocage Activated by Red and Far-Red Light for a Wide Range of Drugs. (PubMed, J Am Chem Soc) - "A total of ten active pharmaceutical ingredients (L) have been successfully conjugated to this photocage, including well-known agents such as Albendazole, Gemcitabine, Bosutinib, Neratinib, and Ponatinib. Several of the obtained PACT prodrugs exhibited micro- to nanomolar EC50 values upon red light activation, with photoindexes as high as 7.5. [7]Cl2 showed a photoindex of 6.2 upon far-red light activation (730 nm), which is unprecedented for a ruthenium-based PACT, while the ruthenium cage itself showed very low toxicity in both the dark and light irradiation."

Journal • Oncology

Pharmacogenomic Drug-Target Network Analysis Reveals Similarity Profiles Among FDA-Approved Cancer Drugs. (PubMed, Pharmaceutics) - "Well-established drug pairs, such as cytarabine-gemcitabine or afatinib-neratinib, exhibited high B-index and structural similarity values, validating the methodology. Additionally, the B-index provides an alternative to conventional chemical similarity metrics, which can facilitate the identification of new therapeutic relationships and inform new drug applications and repositioning. These findings pave the way for the proposal of novel oncology drug targets."

Biomarker • FDA event • Journal • Oncology

MODULE 5: Tolerability Considerations with HER2-Targeted Therapies (SABCS 2025) - "Sponsored by AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Spectrum, incidence and severity of common and unique adverse events with different HER2-targeted therapies employed in the management of HER2-positive breast cancer Recommended algorithms for monitoring for, mitigating and managing potentially serious toxicities documented with T-DXd, such as interstitial lung disease and left ventricular dysfunction Appropriate monitoring of complete blood counts and other laboratory values during therapy with T-DXd Recommended algorithms for mitigating and managing cytopenias, gastrointestinal (GI) side effects and other complications associated with T-DXd Frequency, severity, prevention and optimal management of neratinib-associated GI toxicities Initial dosing of neratinib and rationale for a dose-escalation strategy with this agent"

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Solid Tumor

Neratinib for NF2-related schwannomatosis with progressive tumors: interim analysis from the INTUITT-NF2 platform-basket trial (WFNOS 2025) - "CONCLUSIONS : Neratinib treatment showed modest efficacy in treatment of tumors associated with NF2-SWN. Based on this interim analysis, the team will explore whether an additional 20 participants will be enrolled in the two most promising tumor baskets."

Pan tumor • Brain Cancer • CNS Tumor • Ependymoma • Meningioma • Solid Tumor • EGFR

Phase I trial of neratinib plus palbociclib in advanced cancers with HER family alterations. (PubMed, ESMO Open) - "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."

Journal • P1 data • Breast Cancer • Febrile Neutropenia • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • CYP3A4 • HER-2

Efficacy of Neratinib-Based Therapy in ERBB2-Mutant Lung Adenocarcinomas: Findings From 2 International Phase 2 Studies. (PubMed, Clin Lung Cancer) - P2 | "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."

Journal • P2 data • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

Product revenue, net consists entirely of sales revenue from NERLYNX, Puma’s first commercial product (Businesswire) - "Product revenue, net in the third quarter of 2025 was $51.9 million, compared to $56.1 million in the third quarter of 2024. Product revenue, net in the first nine months of 2025 was $144.2 million, compared to $140.8 million in the first nine months of 2024."

Sales • HER2 Positive Breast Cancer

Neratinib for NF2-related schwannomatosis with progressive tumors: interim analysis from the INTUITT-NF2 platform-basket trial (WFNOS 2025) - "Neratinib treatment showed modest efficacy in treatment of tumors associated with NF2-SWN. Based on this interim analysis, the team will explore whether an additional 20 participants will be enrolled in the two most promising tumor baskets."

Pan tumor • Brain Cancer • Ependymoma • Meningioma • Oncology • Solid Tumor • EGFR

"Extended adjuvant neratinib in HER2+/HR+ early breast cancer in clinical routine – final results from the multi-national, prospective, observational study ELEANOR" (DGHO 2025) - P | "Of 298 pts enrolled from July 2020 to May 2023 at 66 sites, 285 qualified for the main analysis set (MAS; see table for baseline characteristics), 287 for the safety set (SAF), 279 for the compliance set (CS), and 82 for the patient-reported outcome set (PROS).Baseline characteristicsMAS, N=285Age (at inclusion) in years, median (IQR)52 (44-60)ECOG status (at inclusion), n(%) 0 1 2 Missing210 (73.7)57 (20.0)5 (1.8)13 (4.6)Menopausal status (at primary diagnosis), n (%) pre peri post131 (46.0)18 (6.3)136 (47.7)AJCC stage (clinical, at primary diagnosis), n (%)Tis/N0/M0 I II III Missing2 (0.7)113 (39.6)130 (45.6)31 (10.9)9 (3.2)Prior adjuvant/post-neoadjuvant anti-HER2 treatment, n (%) Trastuzumab Trastuzumab + Pertuzumab T-DM1 Other§ Missing111 (38.9)93 (32.6)67 (23.5)13 (4.6)1 (0.4)§Any other [combination] of trastuzumab, pertuzumab, and T-DM1, including switches of agentsMedian observation time was 29.1 months (IQR 20.5-38.3; MAS) and median duration of..."

Clinical • Observational data • Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

HER2+ early breast cancer - standards and new data (DGHO 2025) - "Based on the APT trial results, primary surgery can also be performed for tumors < 2 cm and cN0, followed by adjuvant therapy with 12x paclitaxel and 1 year of trastuzumab (T). If the tumor is larger than 2 cm or lymph node involvement is detected, polychemotherapy is advisable, and in cases of nodal involvement, pertuzumab (P) needs to be added to T. At the ESMO Breast Cancer Congress 2025, the final analysis of the adjuvant APHINITY trial demonstrated a survival benefit for one year of adjuvant therapy with T+P vs. T alone in N+ and HR+ disease.The neoadjuvant approach is standard for most patients...In case of non-pCR, 14x adjuvant T-DM1 is recommended...In case of HR+ HER2- high-risk disease, neratinib can be prescribed for 1 year after the year of T-based therapy, analogous to the EXTENET trial...Data from two studies on T-DXd are also expected: DB-11 on neoadjuvant use and DB-05 on post-neoadjuvant therapy. All new data published up to and including ESMO 2025..."

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

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity. (PubMed, J Vis Exp) - "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."

Journal • Breast Cancer • Fibrosis • HER2 Breast Cancer • HER2 Positive Breast Cancer • Immunology • Metabolic Disorders • Oncology • Solid Tumor • HER-2

Lower Incidence of Pancreatic Cancer in Patients on HER2-Targeted Therapy: Potential Implications in Pancreatic Cancer Prevention (ACG 2025) - "Cohort 1 comprised patients who received HER2-targeted agents (trastuzumab, pertuzumab, margetuximab, neratinib, lapatinib, tucatinib, trastuzumab deruxtecan); Cohort 2 included patients with a cancer diagnosis but no exposure to HER2-targeted agents. After matching, 54,338 patients were included in each cohort. The incidence of PC was lower in the HER2-targeted group compared to the control group (276 vs. 329)."

Clinical • Addiction (Opioid and Alcohol) • Bladder Cancer • Diabetes • Gastric Cancer • Genetic Disorders • Hepatology • HER2 Positive Breast Cancer • Metabolic Disorders • Nicotine Addiction • Non Small Cell Lung Cancer • Obesity • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatitis • Solid Tumor