Margenza (margetuximab-cmkb) / MacroGenics, GC Biopharma, ZAI Lab, TerSera Therap - LARVOL DELTA

The impact of ethnicity on benefit from novel drugs approved for breast cancer treatment: a systematic review and meta-analysis of randomized phase 3 trials of the last decade. (SABCS 2024) - "23 phase III RCTs were identified in the aBC setting, with 1547 (11.1%) patients of Asian ethnicity. Experimental drugs tested included CDK4/6i (palbociclib, ribociclib, abemaciclib), SERD (elacestrant), PI3Ki (alpelisib), PARPi (olaparib, talazoparib), broad variety of anti-HER2 drugs (tucatinib, trastuzumab deruxtecan, pertuzumab, T-DM1, neratinib, margetuximab), anti-PD-1 and anti-PD-L1 drugs (pembrolizumab, atezolizumab) and anti-TROP2 drug (sacituzumab govitecan). 16 RCTs provided HR (95%CI) for PFS in the subgroup of Asians and 17 RCTs for Non-Asians."

IO biomarker • P3 data • Retrospective data • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

MAHOGANY: Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer (clinicaltrials.gov) - P2/3 | N=82 | Completed | Sponsor: MacroGenics | Active, not recruiting ➔ Completed

Trial completion • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • PD-L1

Combination Margetuximab and Pembrolizumab for Advanced, Metastatic HER2(+) Gastric or Gastroesophageal Junction Cancer (clinicaltrials.gov) - P1/2 | N=95 | Completed | Sponsor: MacroGenics | Phase classification: P1b/2 ➔ P1/2

Phase classification • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • HER-2

Monoclonal Antibodies in Metastatic Gastro-Esophageal Cancers: An Overview of the Latest Therapeutic Advances. (PubMed, Int J Mol Sci) - "Combination treatments and new molecules have changed the face of the disease, while more therapies are getting approved on a daily basis. This review aims to analyse the major up-to-date clinical trials using mAbs and immunotherapy for the treatment of advanced gastro-esophageal cancers."

Journal • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor

Complete response with Alpelisib and Trastuzumab in a patient with ER/PR-negative, HER2-positive refractory metastatic breast cancer (SABCS 2024) - "Introduction: Metastatic HER2-positive breast cancer is treated with regimens such as taxane with trastuzumab and pertuzumab followed by trastuzumab deruxtecan (T-DXd). The third line options are ado-trastuzumab emtansine (T-DM1), tucatinib with capecitabine, and trastuzumab...Alpelisib is an oral, α-specific PI3K inhibitor that is approved in combination with fulvestrant in hormone receptor positive, HER2-negative, PIK3CA-mutated advanced breast cancer following progression on or after endocrine therapy...Since 2018, right axillary nodal and chest wall metastases progressed on several lines of systemic therapy including lapatinib and capecitabine, trastuzumab and paclitaxel, trastuzumab and vinorelbine, fam-trastuzumab-deruxtecan-nhki (Enhertu), T-DM1, margetuximab with eribulin, and finally trastuzumab with capecitabine... Alpelisib and trastuzumab can be a viable treatment option for patients with HER2-positive and PIK3CA-mutated metastatic breast cancer. Our case..."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR • PIK3CA

Safety and Preliminary Efficacy of Tucatinib and Alpelisib in Patients with HER2-positive PIK3CA-Mutated Metastatic Breast Cancer (SABCS 2024) - P1/2 | "Treatment consists of twice-daily tucatinib and daily alpelisib at prespecified dose level (DL) with concurrent fulvestrant for hormone receptor-positive cases...Prior HER2-targeted therapies included trastuzumab and pertuzumab (8 patients), T-DM1 (5 patients), tucatinib (4 patients), T-DXd (4 patients), and margetuximab (1 patient)... The combination of tucatinib and alpelisib is tolerable at DL1 and shows remarkable antitumor activity with partial responses in 3 out of 5 evaluable patients (60% overall response rate), including responses in patients treated with prior tucatinib and TDXd. Enrollment continues at DL1. Updated safety and efficacy findings will be presented at SABCS 2024 conference."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Bispecific antibodies will be unveiled at the 2024 SABCS to explore new prospects for neoadjuvant treatment of HER2-positive breast cancer [Google translation] (163.com) - P2 | N=174 | MARGOT (NCT04425018) | "Professor Adrienne G. Waks...reported the latest data from the MARGOT/TBCRC052 trial...The MARGOT/TBCRC052 trial included 171 patients with previously untreated stage II-III HER2-positive early breast cancer...The results showed that the pCR rate in the TMP group was 56% (95% CI 47%-65%) and that in the THP group was 46% (95% CI 33%-60%), with a numerical difference of 10% (p=0.25)....Efficacy data in patients grouped by hormonal status constituted secondary endpoints of the study: In HR+ patients (n=111), the pCR rate was 48% (TMP 54% vs THP 35%); in HR- patients (n=59), the pCR rate was 63% (TMP 60% vs THP 71%); In patients with HER2 IHC 3+ (n=130), the pCR rate was 62% (TMP 66% vs THP 55%); in patients with HER2 IHC <3+ (n=40), the pCR rate was 23% (TMP 27% vs THP 10%)....In terms of safety, more than 90% of patients completed all 4 neoadjuvant cycles."

P2 data • HER2 Positive Breast Cancer

MARGOT/TBCRC052: A randomized phase II trial comparing neoadjuvant paclitaxel/margetuximab/pertuzumab (TMP) vs paclitaxel/trastuzumab/pertuzumab (THP) in patients (pts) with stage II-III HER2+ breast cancer. (SABCS 2024) - "There was no statistically significant improvement in pCR rate with neoadjuvant TMP vs THP for pts with HER2+ EBC and CD16A FF/ FV genotype. Safety and tolerability were similar between the two regimens, aside from increased rates of infusion-related reactions and alopecia in the margetuximab arm (scalp-cooling use was not recorded). Given numerical improvement in pCR rate, comparative analysis of immune activation biomarkers between the two tx arms will be performed."

Clinical • Late-breaking abstract • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • FCGR3A • HER-2

PDX models with differential HER2 expression for preclinical HER2-targeted therapy evaluation (SITC 2024) - "All HER2-targeted drugs, including Trastuzumab (Herceptin), Margetuximab, and DS-8201a, inhibited tumor growth in the model with HER2-positive expression. Notably, only DS-8201a continued to significantly inhibit tumor growth in the model with heterogeneous HER2 expression. Conclusions Therefore, Gempharmatech utilized PDX gastric cancer models to present detailed and realistic assessments of drug effects and assist in predicting phase I and II clinical efficacy as well as response rates for new drugs."

Preclinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor

MODULE 1: Optimizing the Care of Patients with HER2-Positive Metastatic Breast Cancer (mBC) (SABCS 2024) - "This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, and Puma Biotechnology Inc. Clinical factors affecting the selection and sequencing of therapy for patients with HER2-positive mBC Published findings from key studies (eg, DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03) establishing the efficacy of trastuzumab deruxtecan (T-DXd) for patients with HER2-positive mBC Key efficacy and safety data from the HER2CLIMB and HER2CLIMB-02 trials evaluating tucatinib combined with trastuzumab/capecitabine and T-DM1, respectively, for HER2-positive mBC Incidence of brain metastases in patients with HER2-positive mBC; published research documenting the CNS activity of T-DXd and tucatinib-based therapy Designs, eligibility criteria and key endpoints of ongoing studies attempting to further define the role of T-DXd and tucatinib in the management of HER2-positive mBC Long-term findings with and optimal integration of..."

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

MacroGenics Enters Into Agreement With TerSera Therapeutics for the Sale of MARGENZA (Businesswire) - "MacroGenics, Inc...and TerSera Therapeutics LLC...nnounced today that they have entered into an agreement in which TerSera will acquire global rights to MARGENZA (margetuximab-cmkb)....Pursuant to the terms of the agreement, TerSera will pay MacroGenics $40 million at closing. MacroGenics may receive additional sales milestone payments of up to an aggregate of $35 million. The transaction is expected to close in the fourth quarter of 2024, subject to customary closing conditions."

Commercial • HER2 Positive Breast Cancer

Expanding treatment options for patients with HER2+ metastatic breast cancer with margetuximab plus chemotherapy: a case report series. (PubMed, Front Oncol) - "Margetuximab plus chemotherapy was used as fourth- or later-line treatment in patients who had received multiple HER2-targeted agents, including trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, tucatinib, and neratinib. Patients responded to margetuximab plus chemotherapy with real-world progression-free survival (PFS) of 3, 4, and 7 months. Clinical outcomes from three heavily pretreated patients with metastatic HER2+/HR+ MBC demonstrated that margetuximab plus chemotherapy resulted in real-world PFS comparable to that reported in the controlled pivotal clinical trial and support use of this targeted therapy option in appropriately identified patients."

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

Patient-derived xenograft (PDX) models with varying levels of HER2 expression are utilized for the preclinical evaluation of HER2-targeted therapies (IDDF 2024) - "Therefore, Gempharmatech utilized PDX gastric cancer models to present detailed and realistic assessments of drug effects and assist in predicting phase I and II clinical efficacy as well as response rates for new drugs."

Preclinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer. (PubMed, World J Gastrointest Oncol) - "The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified...Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role."

Journal • Metastases • Review • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

Interim safety analysis of phase IB trial of HER2 inhibitor tucatinib combined with PI3Kα inhibitor alpelisib in HER2+ PIK3CA-mutated metastatic breast cancer. (ASCO 2024) - P1/2 | "Treatment consists of twice-daily tucatinib and daily alpelisib at prespecified dose level (DL) with concurrent fulvestrant for hormone receptor-positive cases...Previous HER2-targeted therapies included trastuzumab and pertuzumab (6 pts), T-DM1 (5 pts), tucatinib (4 pts), T-DXd (3 pts) and margetuximab (1 pts)... Tucatinib and alpelisib combination is tolerable at DL1 and demonstrates promising antitumor activity, including responses in pts treated with prior tucatinib and T-DXd. Enrollment continues at DL1. Updated safety and efficacy findings will be presented at ASCO 2024 conference."

Clinical • Metastases • P1 data • Breast Cancer • Diabetes • Eosinophilia • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Infectious Disease • Mucositis • Oncology • Solid Tumor • PIK3CA

Treatment outcomes in previously treated patients with advanced/metastatic HER2+ biliary tract cancer: A systematic review (ESMO-GI 2024) - "Nine therapies (pertuzumab + trastuzumab [P+T], pyrotinib, SHR-A1811, TAS0728, T-deruxtecan [T-DXd], tebotelimab + margetuximab, T+FOLFOX [T+F], tucatinib + T and zanidatamab [zani]) were assessed... HER2 targeted therapies demonstrated promising benefit in patients with previously treated advanced/metastatic HER2+ BTC."

Clinical • Metastases • Review • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

MARGetuximab Or Trastuzumab (MARGOT) (clinicaltrials.gov) - P2 | N=174 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting | Trial primary completion date: Jul 2024 ➔ Oct 2024

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

MAHOGANY: Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer (clinicaltrials.gov) - P2/3 | N=82 | Active, not recruiting | Sponsor: MacroGenics | Trial completion date: Mar 2024 ➔ Jun 2025

Combination therapy • Metastases • Trial completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • PD-L1

Patient-derived xenograft (PDX) models with differential HER2 expression for preclinical evaluation of HER2-targeted therapies (AACR 2024) - "These models were subsequently treated with HER2-targeted drugs, including Trastuzumab (Herceptin), Margetuximab, and Enhertu.Our results demonstrated differential drug responses corresponding to the varying HER2 expression levels in the PDX samples. This underscores the significance of selecting the right therapeutic approach based on the HER2 status of individual patient.Our collection of PDX models with differential HER2 expression levels provides a robust platform for preclinical evaluation of HER2-targeted therapies. This approach not only addresses the clinical challenge of HER2 heterogeneity but also facilitates a more personalized and effective treatment strategy for gastric cancer patients."

Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Development and application of the NCG-hIL2 mouse model: A humanized platform for enhanced NK cell evaluation in ADCC efficacy testing (AACR 2024) - "Moreover, we demonstrate its utility in the evaluation of therapeutic antibodies, specifically Trastuzumab and the ADCC-enhanced Margetuximab, in the context of ADCC efficacy testing. By reconstituting human NK cells and leveraging the role of IL2, this model offers an enhanced platform for preclinical evaluation of therapeutic antibodies, ultimately advancing our ability to harness NK cell-mediated antitumor responses. It is poised to contribute significantly to the field of cancer immunotherapy and drug development."

Preclinical • Oncology • IL2

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021). (PubMed, Anticancer Agents Med Chem) - "In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab)..."

FDA event • Journal • Biliary Cancer • Cervical Cancer • Cholangiocarcinoma • CNS Tumor • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Malignancies • Leukemia • Lung Cancer • Lymphoma • Multiple Myeloma • Neuroblastoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Liquid Chromatography Tandem Mass Spectrometric Method for Quantification of Margetuximab in Rat Plasma and Application to a Pharmacokinetic Study. (PubMed, AAPS PharmSciTech) - "Also, the findings of pharmacokinetic parameters such as Cmax, tmax, AUC0-∞, AUC0-t, and half-life results of margetuximab showed that the technique was helpful for accurately measuring drug concentrations in rat plasma. The method that was developed was useful and effective for quantifying margetuximab."

Journal • PK/PD data • Preclinical • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2

MAHOGANY: Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer (clinicaltrials.gov) - P2/3 | N=82 | Active, not recruiting | Sponsor: MacroGenics | Trial completion date: Dec 2023 ➔ Mar 2024 | Trial primary completion date: Dec 2023 ➔ Mar 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • PD-L1

Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST (SABCS 2023) - "This concept was demonstrated in preclinical in vivo models showing increased efficacy of the combination therapy with the murine surrogate of BI-1607 and an anti-HER2, an anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and an anti-CD20 (rituximab) as compared to monotherapy...The choice of trastuzumab as the combination agent in this trial was based on promising preclinical studies, a recognized need for additional options for those patients who fail to respond or stop responding to trastuzumab, and promising results from the newly approved Fc-engineered anti-HER2 mAb margetuximab...Phase 2a will enroll 15 subjects each in two cohorts of HER2+ advanced/metastatic breast cancer or HER2+ gastric/GEJ adenocarcinoma respectively. For information regarding the study, please contact: anna.ropenga@bioinvent.com"

Clinical • Combination therapy • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CTLA4 • HER-2

New developments and standard of care in the management of advanced gastric cancer. (PubMed, Clin Res Hepatol Gastroenterol) - "More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This..."

Journal • Metastases • Review • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18