glembatumumab vedotin (CDX-011) / Celldex - LARVOL DELTA

GPNMB immunohistochemistry is a useful ancillary tool for the diagnosis of pulmonary lymphangioleiomyomatosis. (PubMed, Histopathology) - "Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB."

Journal • Melanoma • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • GPNMB

Model-optimized bispecific antibodies improve antibody-drug conjugate localization to tumors (AACR-NCI-EORTC 2025) - "For example, anti-HER2 ADCs have been shown to induce serious cardiac toxicity related to HER2 expression in the heart and glembatumumab vedotin is thought to cause severe rash due to expression of its target, gpNMB, in the skin... Bispecific antibodies with model-optimized affinities for two tumor-associated antigens are predicted to improve the ratio of target-mediated on-tumor to off-tumor ADC engagement compared to single-target ADCs. This concept may be more broadly applicable to antibody-based therapeutics."

Oncology • GPNMB

Single-Cell RNA Sequencing Identifies ALCAM and Gpnmb as Therapeutic Targets for ADC Development in Squamous Cell Carcinoma of the Lung (IASLC-WCLC 2025) - "ALCAM's expression profile suggests susceptibility to maytansinoid-based ADCs such as Praluzatamab Ravtansine, due to its association with endocytosis and absence of efflux resistance signals. GPNMB, while a promising target, is associated with expression of multiple efflux transporters, raising concerns about resistance to ADCs like Glembatumumab Vedotin. These findings support a tailored approach to ADC design based on tumor subtype and resistance landscape."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • ABCB1 • ABCC2 • ABCG2 • ALCAM • CD8 • CLTC • GPNMB

First-in-Human Phase 1/2 Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors. (PubMed, Clin Cancer Res) - P1/2 | "INCAGN01876 was generally well tolerated; fatigue was the most frequent TRAE. INCAGN01876 elicited transient and variable Treg depletion and limited antitumor activity. Future studies will explore combinatorial approaches."

IO biomarker • Journal • P1/2 data • Appendix Cancer • Colorectal Cancer • Dermatology • Fatigue • Melanoma • Mucinous carcinoma • Oncology • Pruritus • Respiratory Diseases • Solid Tumor • TNFA

Systematic review of 2L+ ADC strategies in triple-negative breast cancer (TNBC). (ASCO 2025) - P2 | "ASCENT, EVER-132-001, and NCT05113966 examined 3L+ sacituzumab govitecan (SG); OptiTROP-Breast01 evaluated 3L+ sacituzumab tirumotecan (ST); METRIC examined 2/3L glembatumumab vedotin (GV); EV-202 assessed 2L+ enfortumab vedotin (EV) efficacy and DESTINY-Breast04 evaluated 2L+ trastuzumab deruxtecan (T-DXd)...SG after Trilaciclib (NCT05113966), in contrast to SG monotherapy, exhibited fewer adverse events (AE), especially neutropenia and diarrhea, and slightly higher preliminary mOS... Emerging data from P2/3 trials highlight ADCs potential in the 2/3L setting for TNBC. SG has established its superiority over SoC, receiving FDA approval for TNBC after 2+ prior systemic therapies, ³1 for metastatic stage. Its combination with CDK/6 inhibitors should be further evaluated."

Review • Breast Cancer • Neutropenia • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK6

Triple-negative breast cancer with bone marrow involvement and response after use of antibody-drug conjugate (ADC) (SABCS 2024) - "Case report: R. V. B., female, 60-year-old patient, previously healthy, ECOG 0, was diagnosed in 2018 with luminal breast carcinoma (HER-2 0, negative PDL-1, negative BRCA), and was treated with neoadjuvant AC-T regimen (doxorubicin and cyclophosphamide followed by paclitaxel), with pathological partial response...Therefore, the antibody-drug conjugate (ADC) sacituzumab-govitecan (SG) was prescribed on April 12th, 2024...More than 50 ADCs are being studied, such as SG and glembatumumab-vedotin, which have already been approved for breast cancer...Other similar cases were reported by the literature, with positive responses to the use of SG and disitamab-vedotin (RC48) in patients with advanced breast cancer and bone marrow infiltration, resulting in the increase of hemoglobin levels without need of further blood transfusions. Although the metastatic TNBC has a median overall survival of less than two years, the use of ADCs is a good therapeutic option for patients with..."

Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • HER-2 • PD-L1

Targeting GPNMB in Renal Tumors in Tuberous Sclerosis Complex and Translocation Renal Cell Carcinoma (KCRS 2023) - "GPNMB is a transcriptional target of the MiT/TFE family and a potentially oncogenic cell-surface protein which is highly amenable to therapeutic targeting using fully human and clinically tested anti-GPNMB antibodies such as glembatumumab (CR011)...Innovation: We will be the first to test the hypothesis that GPNMB is an oncogenic driver and biomarker of tumorigenesis in the context of high MiT/TFE activity in tRCC or TSC1/2-deficient renal tumors. Moreover, we will be the first to develop and examine the efficacy of an alpha particle-based radiopharmaceutical therapy (aRPT) for tRCC and tumors with TSC1/2 loss, representing an entirely new and targeted treatment paradigm for these molecular RCC subtypes."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • GPNMB • MITF • PRCC • TFE3 • TFEB • TSC1 • TSC2

High-throughput and targeted drug screens identify pharmacological candidates against MiT-translocation renal cell carcinoma. (PubMed, J Exp Clin Cancer Res) - "The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC."

Journal • Genito-urinary Cancer • Oncology • Ophthalmology • Renal Cell Carcinoma • Solid Tumor • GPNMB • MITF • TFE3 • TFEB

Overall survival (OS) in metastatic uveal melanoma: A summary of recent prospective trials. (ASCO 2022) - "Tebentafusp (tebe), a TCR bispecific (gp100 x CD3), is the first therapy to demonstrate an OS benefit in a mUM randomized trial (IMCgp100-202) against pembrolizumab (pembro), ipilimumab (ipi) or dacarbazine... A literature review of prospective Ph2/3 clinical trials of systemic therapies in mUM published recently (2019-2021) identified 8 trials: in 1L mUM (n = 2) a randomized Ph3 of tebe (N = 252) vs investigator’s choice (IC; N = 126) of pembro, ipi or dacarbazine (IMCgp100-202) and a single arm Ph2 of nivolumab (nivo) + ipi (N = 52; Piulats, 2021) (Table); in 2L+ mUM (n = 1) a single arm Ph2 of tebe (N = 127; IMCgp100-102); and in mixed line mUM (n = 5) a randomized Ph2 of cabozantinib (N = 31) vs chemotherapy (N = 15; Luke, 2019), a single arm Ph2 of nivo + ipi (N = 35; Pelster, 2021), a single arm Ph2 of pembro + entinostat (N = 29; Ny, 2021), a single arm Ph2 of glembatumumab (N = 37; Hasanov, 2020), and a single arm Ph2 of IMC-A12 (IGF-1 receptor inhibitor; N = 18;..."

Clinical • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • IGF1

ImmunoPET Imaging Identifies the Optimal Timepoint for Combination Therapy in Xenograft Models of Triple-Negative Breast Cancer. (PubMed, Cancers (Basel)) - "(4) Dasatinib upregulated gpNMB expression in gpNMB-positive MDA-MB-468 xenografted tumors at 14 days post treatment initiation, which can be quantified by PET imaging with [Zr]Zr-DFO-CR011. Furthermore, combination therapy with dasatinib and CDX-011 appears to be a promising therapeutic strategy for TNBC and warrants further investigation."

Combination therapy • Journal • Preclinical • Breast Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • GPNMB

A phase II study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma. (ASCO 2017) - P2; "Clinical trial information: NCT02302339 GV has promising activity (primary endpoint of ORR was met) with a manageable safety profile in heavily pre-treated melanoma pts. Additional cohorts evaluating GV with either varlilumab, an activating anti-CD27 monoclonal antibody, or PD-1 inhibitors are open to accrual to provide further insights into the synergy of ADC and immunotherapy."

Checkpoint inhibition • Clinical • P2 data • Biosimilar • Gene Therapies • Hormone Receptor Breast Cancer • Melanoma • Pain

From seaside to bedside: Current evidence and future perspectives in the treatment of breast cancer using marine compounds. (PubMed, Front Pharmacol) - "The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents (eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders-trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs)...Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • HER-2

Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinal Investigation to Clinic. (PubMed, Cancers (Basel)) - "Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla, Enhertu, Trodelvy, and Abraxane)...In TNBC these conjugates (Trodelvy, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody-drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work,..."

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

BARONESS CHARLOTTA CASTELLI GLEMBAY - WAS SHE HYPERSEXUAL? (PubMed, Acta Med Hist Adriat) - No abstract available

Journal

HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin. (PubMed, Oncogene) - "Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MITF

AOST1521: Glembatumumab Vedotin in Treating Patients With Recurrent or Refractory Osteosarcoma (clinicaltrials.gov) - P2; N=22; Completed; Sponsor: National Cancer Institute (NCI); Active, not recruiting ➔ Completed

Clinical • Trial completion • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

[89Zr]ZrDFO-CR011 positron emission tomography correlates with response to glycoprotein non-metastatic melanoma B-targeted therapy in triple negative breast cancer. (PubMed, Mol Cancer Ther) - "However, pre-treatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will re-grow over time. Other methods will be needed to predict resistance to treatment."

Journal • Breast Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer

Efficacy and Safety of Glembatumumab Vedotin in Patients With Advanced or Metastatic Squamous Cell Carcinoma of the Lung (PrECOG 0504). (PubMed, JTO Clin Res Rep) - "Modest anticancer activity was observed with a recommendation for a phase 2 dose of 1.9 mg/kg. This portion of the study was not undertaken owing to the company's decision to discontinue drug development."

Clinical • Journal • Fatigue • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Renal Disease • Respiratory Diseases • Solid Tumor • Squamous Cell Carcinoma

[VIRTUAL] Outcome of patients with recurrent/refractory osteosarcoma enrolled in three recent phase II trials: A report from the Children’s Oncology Group. (ASCO 2021) - P2 | " In each of the three phase II trials (unresected group of AOST1321, AOST1322, AOST1521), the drugs tested (denosumab, eribulin and glembatumumab) were concluded to be not effective due to a failure of the patient populations to meet the prespecified active 4-month progression free survival endpoint . The EFS at 4 months in the three new phase II trials is similar to the previous seven phase II single arm trials . The combined analysis of 153 patients from 10 trials tightens the confidence interval, moving the upper 95% CI to 15% . Modification to future study designs could be considered based on this updated analysis ."

Clinical • P2 data • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

[VIRTUAL] Efficacy and Safety of Glembatumumab Vedotin in Patients With Advanced or Metastatic Squamous Cell Carcinoma of the Lung (PrECOG 0504) (IASLC-WCLC 2020) - "The phase 2 portion of the study was not undertaken due to the company’s decision to discontinue further development of this drug. Table: Patient demographics and details"

Clinical • Dermatology • Fatigue • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pruritus • Renal Disease • Respiratory Diseases • Solid Tumor • Squamous Cell Carcinoma

METRIC: A randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC) (SABCS 2018) - "Background: gpNMB is an internalizable transmembrane protein overexpressed in ~40% of TNBC, and associated with a worse prognosis. While anticancer activity was seen with GV, it was comparable to capecitabine with no therapeutic advantage of GV in terms of ORR, PFS, or OS. The safety profile of GV was consistent with prior experience with no new safety signals identified. "

Clinical • P2b data • Breast Cancer • Oncology • Triple Negative Breast Cancer

"Glemba, for me, as my late wife missed enrolling in the study by literally one day. I'm not happy that study failed, obviously, but it did lessen the sting of "what if" a bit." (@Kratisto_Invest)

"Remember Rintega? Remember glembatumumab? Now $CLDX reckons it has a future in autoimmune disease. Via @evaluatevantage https://t.co/of6PbZqjTd $MGTA" (@JacobPlieth)

Immunology

Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer ("METRIC"): a randomized multicenter study. (PubMed, NPJ Breast Cancer) - "The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine."

Clinical • Journal • Breast Cancer • Dermatology • Fatigue • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Solid Tumor • Triple Negative Breast Cancer

Glembatumumab Vedotin in Treating Patients With Recurrent or Refractory Osteosarcoma (clinicaltrials.gov) - P2; N=22; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Completed ➔ Active, not recruiting

Enrollment closed • Oncology • Osteosarcoma • Sarcoma • Solid Tumor