OVERVIEW

ABBV-303 c-Met TriNKET is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-303 is a c-Met targeted TriNKET natural killer (NK) cell immune engager being investigated in solid tumors as a monotherapy and in combination with an anti-PD-1 inhibitor.

PROPOSED MECHANISM OF ACTION^1,2

ABBV-303  redirects cytotoxic immune cells and triggers their activity against c-Met expressing cells. The three functional arms of ABBV-303  include: c-Met binding scFv, Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and CD8+ T cells, and a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303  enhances traditional immunotherapy by engaging both the adaptive and innate immune systems, directly and indirectly. In vitro experiments demonstrated that ABBV-303  stimulates both NK cells in the innate immune system, and CD8 T cells in the adaptive immune system to target c-Met expressing tumor cells. ABBV-303 is designed to work with a wide range of other I/O drugs, as well as with other traditional treatment approaches in oncology, such as antibody-drug conjugates (ADCs), chemotherapy and radiation.

DEVELOPMENT

ABBV-303* is being investigated in a Phase 1 trial for the treatment of solid tumors.

*Dragonfly Therapeutics TriNKET® technology

CLINICAL TRIALS

View select clinical trials with ABBV-303 now. To view a full list of clinical trials in which ABBV-303 is being investigated, please visit ClinicalTrials.gov.

1. Platform | Dragonfly (dragonflytx.com). Accessed March 2024.
2. Stone J et al. AACR 2024. Abstract ND01.  

OVERVIEW

ABBV-400 is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-400 is an antibody-drug conjugate (ADC) designed to target c-Met that employs a topoisomerase inhibitor. It is being investigated in colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and gastroesophageal adenocarcinoma (GEA), and MET-amplified solid tumors.

PROPOSED MECHANISM OF ACTION

The protein, mesenchymal-epithelial transition factor (c-Met), which is also known as MET protein, AUTS9, RCCP2, DFNB97, and hepatocyte growth factor receptor (HGFR), is essential for the survival and function of normal cells.¹

In numerous cancers, the MET gene, which encodes the protein c-Met, is either amplified or mutated to constantly activate its downstream signaling pathways to sustain rapid proliferation and survival of cancer cells. In NSCLC, both c-Met and HGF are over-expressed relative to the adjacent normal lung tissues.¹

c-Met antibody drug conjugates are designed to bind to c-Met receptors, which are internalized; cytotoxins attached to the antibody via linkers are then released into the cytosol where they seek to damage cells.

ABBV-400 uses c-Met to deliver a topoisomerase inhibitor to overexpressing cells, which inhibits DNA replication; this helps stop cell proliferation and induce cytotoxicity.

DEVELOPMENT

ABBV-400 is being investigated to treat CRC, NSCLC, GEA and MET-amplified tumors.

CLINICAL TRIALS

View select clinical trials with ABBV-400 now. To view a full list of clinical trials in which ABBV-400 is being investigated, please visit ClinicalTrials.gov.

1. Park KC, Richardson DR. The c-MET oncoprotein: function, mechanisms of degradation and its targeting by novel anti-cancer agents. Biochim Biophys Acta Gen Subjs. 2020;1864(10):129650

OVERVIEW

ABBV-514 is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-514 is an anti-chemokine C-C motif receptor 8 (CCR8) antibody that is being investigated for the treatment of relapsed non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) both as a single agent and in combination with a PD-1 inhibitor.

PROPOSED MECHANISM OF ACTION

CCR8 is a chemokine receptor that has been previously associated with chemotaxis and cell/cell interactions in the context of T-helper type 2 cell responses and T-cell trafficking to the skin^1-2. Within tumors, regulatory T-cells (Tregs) are a key immunosuppressive cell population known to prevent antitumor immune responses; high intratumoral Treg levels have been associated with negative outcomes in several cancers.^3-5 CCR8 is overexpressed in Tregs found in the tumor microenvironment(TME) and is upregulated in tumor tissues, including HNSCC, NSCLC, and colorectal cancer (CRC).^6-8 CCR8 is highly expressed in tumor-infiltrating Tregs and correlates with poor prognosis in both NSCLC and CRC patients.⁷

DEVELOPMENT

ABBV-514 is being investigated in a Phase 1 trial for the treatment of relapsed NSCLC and HNSCC.

CLINICAL TRIALS

View select clinical trials with ABBV-514 now. To view a full list of clinical trials in which ABBV-514 is being investigated, please visit ClinicalTrials.gov.

References

1. Chensue SW, Lukacs NW, Yang TY, et al. Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J Exp Med. 2001;193:573-584.
2. Schaerli P, Ebert L, Willimann K, et al. A skin-selective homing mechanism for human immune surveillance T cells. J Exp Med. 2004;199:1265-1275.
3. Shang B, Liu Y, Jiang SJ, et al. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.
4. Fridman WH, Zitvogel L, Sautes-Fridman C, et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717-34.
5. Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20(11):662-80.
6. Meng L, et al. CCR4, CCR8, and P2RY14 as prognostic factors in head and neck squamous cell carcinoma are involved in the remodeling of the tumor microenvironment. Front Oncol. 2021;11:618187.
7. De Simone M, et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating t regulatory cells. Immunity. 2016;45:1135-1147.
8. Plitas G, Konopacki C, Wu K, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;45(5):1122-34.

OVERVIEW

ABBV-706  is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-706 is a SEZ6-targeted antibody-drug conjugate (ADC) being investigated in advanced solid tumors.

PROPOSED MECHANISM OF ACTION

Seizure-related homolog 6 (SEZ6) is a transmembrane protein found on the cell surface of select neuronal lineage cells.^1,2

SEZ6 is selectively expressed on neuroendocrine tumors, including small-cell lung cancer (SCLC), central nervous system (CNS) tumors, and high-grade neuroendocrine carcinomas (NECs), with minimal normal cell expression.³ SEZ6 was chosen as a target for the development of novel ADCs carrying payloads designed to kill neuroendocrine tumor cells.⁴ ABBV-706 targets tumor cells expressing SEZ6, is rapidly internalized, and delivers a tumor-cell killing topoisomerase 1 inhibitor (Top1i) payload.⁵

DEVELOPMENT

ABBV-706 is being investigated in a Phase 1 trial for the treatment of advanced solid tumors, including small cell lung cancer (SCLC), central nervous system (CNS) tumors, and neuroendocrine carcinomas (NEC). 

CLINICAL TRIALS

View select clinical trials with ABBV-706 now. To view a full list of clinical trials in which ABBV-706 is being investigated, please visit ClinicalTrials.gov.

1. Shimizu-Nishikawa K, et al. Cloning and characterization of seizure-related gene, SEZ-6. Biochem Biophys Res Commun. 1995;216(1):382-9.
2. Gunnersen JM, et al. Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons. Neuron. 2007;56(4):621-39.
3. Kudoh S, et al. Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells. Histochem Cell Biol. 2020;153(6):443-456.
4. Wiedemeyer WR et al. ABBV-011, A Novel, Calicheamicin-Based Antibody–Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors. Mol Cancer Ther. 2022;21:986-98.
5. Faivre E et al, AACR annual meeting 2024 AACR abstract #3148

OVERVIEW

ABBV[CC1] -CLS-484 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-CLS-484 is a PTPN2/N1 small molecule inhibitor (SMI).

PROPOSED MECHANISM OF ACTION^1-11

ABBV-CLS-484 is a small molecule that binds to ubiquitously expressed protein tyrosine phosphatase non-receptor type 2 (PTPN2) and type 1 (PTPN1).  Importantly, PTPN2/N1 inhibition drives both tumor cell dependent and immune cell dependent anticancer mechanisms of action. PTPN2/N1 inhibition in tumor cells promotes IFN signaling through the JAK/STAT pathway resulting in growth delay, increased tumor antigen presentation, and elevated proinflammatory chemokine release. Additionally, PTPN2/N1 inhibition promotes the activation and proinflammatory antitumorigenic function of multiple immune cell subsets. In T cells, PTPN2/N1 act as negative regulators of T-cell receptor (TCR) and cytokine signaling; inhibition of these enzymes augments T cell activation, metabolism, proliferation, and immune effector functions including tumoricidal action. Furthermore, pharmacologic PTPN2/N1 inhibition reduces T-cell exhaustion

DEVELOPMENT

ABBV-CLS-484 is being investigated in a Phase 1 study as a monotherapy and in combination with a PD-1 inhibitor for the treatment of patients with metastatic or locally advanced solid tumor cancer.

ABBV-CLS-484 is being co-developed by Calico and Abbvie. Calico is responsible for advancing into Phase 2a with AbbVie’s support. AbbVie has the option to manage late-stage development and commercial activities.

CLINICAL TRIALS

View select clinical trials with ABBV-CLS-484 now. To view a full list of clinical trials in which ABBV-CLS-484 is being investigated, please visit ClinicalTrials.gov.

1. Simoncic PD, et al. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr Biol. 2002;12(6):446-53.
2. Myers MP, et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem. 2001;276(51):47771-4.
3. Wiede F, et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011;121:4758-4774.
4. Heinonen KM, et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood. 2004;103(9):3457-3464.  
5. Manguso RT, et al. In vivo CRISPR screening identifies PTPN2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.
6. Baumgartner CK, et al. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature. 2023;622(7984):850-862.
   
7. Penafuerte C, et al. Downregulation of PTP1B and TC-PTP phosphatases potentiate dendritic cell-based immunotherapy through IL-12/IFNγ signaling. Oncoimmunology. 2017;6(6):e1321185.
8. Hering L et al. Protein tyrosine phosphatase non-receptor type 2 function in dendritic cells is crucial to maintain tissue tolerance. Front Immunol. 2020;11:1856.
9. Flosbach M, et al. PTPN2 deficiency enhances programmed T cell expansion and survival capacity of activated T cells.  Cell Rep. 2020;32:107957.
   
10. Wiede F, et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 2020;39:e103637.  
11. Wiede, F. et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell anti-tumor immunity. Cancer Discov. 2022;12, 752–773.

OVERVIEW

ABBV-CLS-579 is an unapproved investigational drug under clinical development.  Safety and efficacy have not been established.

ABBV-CLS-579 is a PTPN2/N1 small molecule inhibitor (SMI).

PROPOSED MECHANISM OF ACTION^1-11

ABBV-CLS-579 is a small molecule that binds to ubiquitously expressed protein tyrosine phosphatase non-receptor type 2 (PTPN2) and type 1 (PTPN1).  Importantly, PTPN2/N1 inhibition drives both tumor cell dependent and immune cell dependent anticancer mechanisms of action. PTPN2/N1 inhibition in tumor cells promotes IFN signaling through the JAK/STAT pathway resulting in growth delay, increased tumor antigen presentation, and elevated proinflammatory chemokine release. Additionally, PTPN2/N1 inhibition promotes the activation and proinflammatory antitumorigenic function of multiple immune cell subsets. In T cells, PTPN2/N1 act as negative regulators of T-cell receptor (TCR) and cytokine signaling; inhibition of these enzymes augments T cell activation, metabolism, proliferation, and immune effector functions including tumoricidal action. Furthermore, pharmacologic PTPN2/N1 inhibition reduces T-cell exhaustion.

DEVELOPMENT

ABBV-CLS-579 is being investigated in a Phase 1 study as a monotherapy and in combination with a PD-1 inhibitor for the treatment of patients with metastatic or locally advanced solid tumor cancer.

ABBV-CLS-579 is being co-developed by Calico and Abbvie. Calico is responsible for advancing into Phase 2a with AbbVie’s support. AbbVie has the option to manage late-stage development and commercial activities.

CLINICAL TRIALS

View select clinical trials with ABBV-CLS-579 now. To view a full list of clinical trials in which ABBV-CLS-579 is being investigated, please visit ClinicalTrials.gov.

1. Simoncic PD, et al. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr Biol. 2002;12(6):446-53.
2. Myers MP, et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem. 2001;276(51):47771-4.
3. Wiede F, et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011;121:4758-4774.
4. Heinonen KM, et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood. 2004;103(9):3457-3464.  
5. Manguso RT, et al. In vivo CRISPR screening identifies PTPN2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.
6. Baumgartner CK, et al. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature. 2023;622(7984):850-862.
   
7. Penafuerte C, et al. Downregulation of PTP1B and TC-PTP phosphatases potentiate dendritic cell-based immunotherapy through IL-12/IFNγ signaling. Oncoimmunology. 2017;6(6):e1321185.
8. Hering L et al. Protein tyrosine phosphatase non-receptor type 2 function in dendritic cells is crucial to maintain tissue tolerance. Front Immunol. 2020;11:1856.
9. Flosbach M, et al. PTPN2 deficiency enhances programmed T cell expansion and survival capacity of activated T cells.  Cell Rep. 2020;32:107957.
   
10. Wiede F, et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 2020;39:e103637.  
11. Wiede, F. et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell anti-tumor immunity. Cancer Discov. 2022;12, 752–773.

OVERVIEW

IMGN-151 is an investigational drug under clinical development. Safety and efficacy have not been established.

IMGN-151 is a folate receptor alpha (FRa)-targeting antibody-drug conjugate in development for the treatment of ovarian and endometrial cancer. IMGN-151 is a biparatopic anti-FRα antibody comprised of IMGN853 arm and a scFv-arm targeting an independent epitope of FRα. It contains DM21-L-G, a novel maytansine-derived payload/linker.

PROPOSED MECHANISM OF ACTION^1,2

FRα is a member of a family of cell-surface glycoproteins that facilitate the transport and accumulation of folate, through endocytosis, into cells. FRa is overexpressed in multiple epithelial cancers including ovarian and endometrial and has limited expression on normal tissues making it a useful therapeutic target.¹

IMGN-151 is a next-generation anti-FRa ADC designed for enhanced payload delivery, cell killing, and bystander activity IMGN-151, comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to a highly potent maytansinoid derivative DM21 via a cleavable peptide linker. ²

DEVELOPMENT

IMGN-151: DM21 Biparatropic FRα Antibody-Drug Conjugate is being investigated in a Phase 1 trial for the treatment of ovarian and endometrial cancer.

*ImmunoGen is now part of AbbVie.

CLINICAL TRIALS

View select clinical trials with IMGN-151: DM21 Biparatropic FRα Antibody-Drug Conjugate now. To view a full list of clinical trials in which IMGN-151: DM21 Biparatropic FRα Antibody-Drug Conjugate is being investigated, please visit ClinicalTrials.gov.

1. Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: Implications in targeted therapy. Adv Drug Deliv Rev. 2004;56:1067-1084.
2. Ab O, et al. IMGN151 – A next generation folate receptor alpha targeting antibody drug conjugate active against tumors with low, medium and high receptor expression. Poster 2890. AACR 2020.

OVERVIEW

Livmoniplimab is an investigational drug under clinical development. Safety and efficacy have not been established.

Livmoniplimab (ABBV-151) is a potential first-in-class humanized monoclonal antibody that is designed to bind to the GARP - TGF-β1 complex and is being investigated for the treatment of solid tumors, including non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC).

PROPOSED MECHANISM OF ACTION

Livmoniplimab binds the GARP - TGF-β1 complex on the surface of regulatory T-cells ( T_regs.) Upon binding to the GARP - TGF-β1 complex, livmoniplimab inhibits the release of active TGF-β1. The inhibition of TGF-β1 signaling may enhance the responsiveness to anti-PD1 therapy by helping restore effector CD8+ T-cell activation, expansion, and infiltration within tumors.^1,2,3

^{_{Adapted from Metelli A, et al. 2018.  http://creativecommons.org/licenses/by/4.0/ for CC BY 4.0}}

DEVELOPMENT

Livmoniplimab is being investigated in a Phase 1 study for the treatment of patients with advanced solid tumors and in Phase 2/3 studies for the treatment of patients with NSCLC and HCC.

Livmoniplimab and budigalimab (PD-1 inhibitor) are in clinical development to evaluate the inhibition of signaling pathways known to drive tumor growth and progression.

Livmoniplimab was developed in partnership with Argenx.

CLINICAL TRIALS

View select clinical trials with ABBV-151 now. To view a full list of clinical trials in which ABBV-151 is being investigated, please visit ClinicalTrials.gov.

1. Metelli A, et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. J Hematol Oncol. 2018; 11:24.
2. Metelli A, et al . Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res 2016; 76:7106–7117.
3. Cuende J, et al. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med. 2015;7(284):284ra56.

OVERVIEW

Mirvetuximab soravtansine-gynx (MIRV, IMGN-853) is an approved drug being investigated for additional uses. Safety and efficacy have not been established for these additional uses.

Mirvetuximab soravtansine-gynx (MIRV, IMGN-853) is an antibody-drug conjugate (ADC) designed to target folate receptor alpha (FRᾳ)

PROPOSED MECHANISM OF ACTION^6,7

FRα is overexpressed in ovarian cancer and has minimal expression on normal tissues. MIRV is an ADC comprised of a humanized anti-FRa monoclonal antibody (M9346A) linked to a cytotoxic effector molecule, the maytansinoid DM4.^1,2 MIRV binds with high affinity and specificity to FRa, which upon antigen binding, promotes ADC internalization and intracellular release of DM4.³ Through its ability to inhibit tubulin polymerization and disrupt microtubule assembly, DM4 serves as a potent antimitotic agent to induce cell cycle arrest and apoptosis.⁴ Preclinically, MIRV has exhibited antitumor activity against FRa-expressing tumors, including models of ovarian cancer and NSCLC.⁵

DEVELOPMENT

Mirvetuximab soravtansine is being investigated in platinum-sensitive ovarian cancer as a single agent and in combination with carboplatin and bevacizumab.

ImmunoGen is now part of AbbVie.

MIRVETUXIMAB SORAVTANSINE INDICATION AND SAFETY INFORMATION⁸

Indication:

Ibrutinib is a kinase inhibitor indicated for the treatment of:

• Mirvetuximab soravtansine is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test.

Boxed Warning OCULAR TOXICITY:

• Mirvetuximab soravtansine can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis.
• Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of mirvetuximab soravtansine, every other cycle for the first 8 cycles, and as clinically indicated.
• Administer prophylactic artificial tears and ophthalmic topical steroids.
• Withhold mirvetuximab soravtansine for ocular toxicities until improvement and resume at the same or reduced dose.
• Discontinue mirvetuximab soravtansine for Grade 4 ocular toxicities.

Warning and Precautions

• Ocular disorders: Mirvetuximab soravtansine can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.
  Ocular adverse reactions occurred in 59% of patients with ovarian cancer treated with mirvetuximab soravtansine. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions, including blurred vision, keratopathy (corneal disorders), dry eye, cataract, photophobia, and eye pain; two patients (0.3%) experienced Grade 4 events (keratopathy and cataract). The most common (≥5%) ocular adverse reactions were blurred vision (48%), keratopathy (36%), dry eye (27%), cataract (16%), photophobia (14%), and eye pain (10%).
  The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution; 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up). Ocular adverse reactions led to permanent discontinuation of mirvetuximab soravtansine in 1% of patients.
  Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with mirvetuximab soravtansine are recommended. Advise patients to avoid use of contact lenses during treatment with mirvetuximab soravtansine unless directed by a healthcare provider.
  Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.
  Monitor for ocular toxicity and withhold, reduce, or permanently discontinue mirvetuximab soravtansine based on severity and persistence of ocular adverse reactions.
• Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with mirvetuximab soravtansine.
  Pneumonitis occurred in 10% of patients treated with mirvetuximab soravtansine, including 1% with Grade 3 events and 1 patient (0.1%) with a Grade 4 event. One patient (0.1%) died due to respiratory failure in the setting of pneumonitis and lung metastases. One patient (0.1%) died due to respiratory failure of unknown etiology. Pneumonitis led to permanent discontinuation of mirvetuximab soravtansine in 3% of patients.
  Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold mirvetuximab soravtansine for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue mirvetuximab soravtansine in all patients with Grade 3 or 4 pneumonitis. Patients who are asymptomatic may continue dosing of mirvetuximab soravtansine with close monitoring.
• Peripheral neuropathy: Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with mirvetuximab soravtansine across clinical trials; 3% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (1%), peripheral motor neuropathy (0.9%), polyneuropathy (0.3%), and peripheral sensorimotor neuropathy (0.1%). Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia.  For patients experiencing new or worsening PN, withhold dosage, dose reduce, or permanently discontinue mirvetuximab soravtansine based on the severity of PN.
• Embryo-fetal toxicity: Based on its mechanism of action, mirvetuximab soravtansine can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells.
  Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with mirvetuximab soravtansine and for 7 months after the last dose.

Adverse Reactions

• The most common (≥20 %) adverse reactions, including lab abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils.

Drug Interactions

• DM4 is a CYP3A4 substrate. Closely monitor patients for adverse reactions with mirvetuximab soravtansine when used concomitantly with strong CYP3A4 inhibitors.

Specific Populations

• Lactation: Advise women not to breastfeed during treatment with mirvetuximab soravtansine and for 1 month after the last dose.
• Hepatic Impairment: Avoid use of mirvetuximab soravtansine in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).

Review full US prescribing information for additional information at https://www.rxabbvie.com/

CLINICAL TRIALS

View select clinical trials with mirvetuximab soravtansine now. To view a full list of clinical trials in which mirvetuximab soravtansine is being investigated, please visit ClinicalTrials.gov.

1. Lutz RJ. Targeting the folate receptor for the treatment of ovarian cancer. Transl Cancer Res. 2015;4:118-126.
2. Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Br J Clin Pharmacol. 2013;76:248-262.
3. Erickson HK, Widdison WC, Mayo MF, et al. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody maytansinoid conjugates. Bioconjug Chem. 2010;21:84-92.
4. Hong EE, Erickson H, Lutz RJ, et al. Design of coltuximab ravtansine, a CD19-targeting antibody-drug conjugate (ADC) for the treatment of B-Cell malignancies: structure-activity relationships and preclinical evaluation. Mol Pharm. 2015;12:1703-1716.
5. Ab O, et al. IMGN853, a folate receptor-alpha (FRalpha)-targeting antibody-drug conjugate, exhibits potent targeted antitumor activity against FRalpha-expressing tumors. Mol Cancer Ther. 2015;14:1605-1613.
6. Moore KN, et al. Phase 1 Dose Escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor alpha targeting antibody drug conjugate, in patients with solid tumors. Cancer. 2017;123(16):3080-3087.
7. Moore KN, et al. Mirvetuximab soravtansine in FRα-positive, platinum-resistant ovarian cancer. N Engl J Med. 2023;389:2162-2174.
8. Elahere. US Prescribing Information. March 2024.

OVERVIEW

Telisotuzumab vedotin (Teliso-V; ABBV-399) is an investigational drug under clinical development. Safety and efficacy have not been established.

Telisotuzumab vedotin (Teliso-V; ABBV-399) is an MMAE antibody-drug conjugate (ADC) designed to target c-Met composed of the ABT-700 (c-Met-targeting) antibody conjugated to the cytotoxic microtubule inhibitor monomethylauristatin E (MMAE) via a cleavable valine-citrulline (vc) linker.

PROPOSED MECHANISM OF ACTION

The c-Met receptor tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF) encoded by the MET protooncogene. MET is aberrantly activated in cancers contributing to tumor progression, angiogenesis, invasiveness, metastasis, and resistance and is overexpressed in non-small cell lung cancer (NSCLC; 40%) and several other solid tumor types.¹ Overexpression of c-Met protein has been reported in Teliso-V NSCLC studies at rates of 25-39% across nonsquamous (NSQ) and squamous (SQ) histologies,^3,4 with some other studies reporting ranges of 15-70%.⁵

c-Met inhibitors require MET amplification and/or MET activation for activity; however, as demonstrated in preclinical models, Teliso-V, an ADC designed to target c-Met, uses c-Met to deliver a cytotoxin to c-Met-protein-expressing tumor cells, which enables cell killing regardless of reliance on MET signaling.¹ Although, MET amplification can be a therapeutically actionable target, it generally occurs in 1% to 5% of de novo cancers, whereas c-Met protein overexpression is more common and occurrs in up to 50% of many advanced solid tumors.²

The use of an ADC that is designed to target c-Met–positive cells represents a therapeutic strategy with which to induce tumor cell killing independently of MET signaling pathway inhibition because it involves the delivery of the potent cytotoxin MMAE directly to c-Met–positive cells.²

Although a c-Met–targeting ADC may present the risk of on-target toxicity based on c-Met protein normal tissue  expression, preclinical and early phase results have demonstrated a strong correlation between Teliso-V anti-tumor activity and c-Met protein expression levels because c-Met protein expression is significantly higher in many cancers compared with normal tissue.¹

DEVELOPMENT

Teliso-V is in Phase 3 development in patients with previously treated c-Met-positive (by protein overexpression detected by immunohistochemistry) non-small cell lung cancer (NSCLC).

CLINICAL TRIALS

View select clinical trials with Teliso-V now. To view a full list of clinical trials in which Teliso-V is being investigated, please visit ClinicalTrials.gov.

1. Wang J, Anderson MG, Oleksijew A, et al. ABBV-399, a c-Met antibody-drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res. 2017 23(4):992-1000.
2. Strickler JH, et al. First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors. J Clin Oncol. 2018;36(33):3298-3306.
3. Motwani M, Panchabhai S, Bar J, et al. Prevalence of c-Met overexpression (c-Met+) and impact of prior lines of treatment on c-Met protein expression in NSCLC.  Psoter presented at : World Conference on Lung Cancer (WCLC); 2021.
4. Ansell PJ, Baijal S, Liede A, et al. Prevalence and characterization of c-MET–overexpressing non-small cell lung cancer (NSCLC) across clinical trial samples and real-world patient cohorts from the City of Hope National Medical Center. Poster presented at: Cancer Research UK (CRUK) - Lung Cancer Conference. Manchester, UK; 2022.
5. Liang H, Wang M. MET oncogene in non-small cell lung cancer: Mechanism of MET dysregulation and agents targeting the HGF/c-Met axis. Onco Targets Ther 2020; 13: 2491-2510.

OVERVIEW

TTX-030 is an investigational drug under clinical development. Safety and efficacy have not been established.

TTX-030 is an anti-CD39 monoclonal antibody that is being investigated in solid tumors.

PROPOSED MECHANISM OF ACTION^1,2

In solid tumors, ATP is abundantly released in the extracellular space, leading to an accumulation of eATP levels far in excess of those found in healthy tissues. Extracellular ATP acts as a proinflammatory stimulus by agonizing P2 purinergic receptors in immune cells.

Tumors are proficient at scavenging eATP and converting it to immunosuppressive adenosine by means of two ectonucleotidases, CD39 and CD73. CD39 hydrolyzes eATP, converting it to adenosine monophosphate (AMP); AMP can in turn be converted to adenosine by CD73.  Adenosine acts on P1 receptors found ubiquitously on immune cells, causing immunosuppression; therefore has anti-inflammatory effects.

TTX-030 inhibits CD39 enzymatic activity, thus preventing hydrolysis of proinflammatory ATP to immunosupressive adenosine and resulting in a preservation of immune cell function and tumor clearance.

DEVELOPMENT

TTX-030 is being investigated as a monotherapy and in combination with a PD1 inhibitor or chemotherapy in patients with solid tumors.

*TTX-030 developed by Trishula Therapeutics through Phase 1b and AbbVie has option to lead global development

CLINICAL TRIALS

View select clinical trials with TTX-030 now. To view a full list of clinical trials in which TTX-030 is being investigated, please visit ClinicalTrials.gov.

1. Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di Virgilio F. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One 2008;3:e2599.
2. Takenaka MC, Robson S, Quintana FJ. Regulation of the T cell response by CD39. Trends Immunol 2016;37:427-39.

OVERVIEW

ABBV-303 c-Met TriNKET is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-303 c-Met TriNKET is a c-Met targeted TriNKET natural killer (NK) cell immune engager being investigated in solid tumors as a monotherapy and in combination with an anti-PD-1 inhibitor.

PROPOSED MECHANISM OF ACTION^1,2

ABBV-303 c-Met TriNKET redirects cytotoxic immune cells and triggers their activity against c-Met expressing cells. The three functional arms of ABBV-303 c-Met TriNKET include: c-Met binding scFv, Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and CD8+ T cells, and a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303 c-Met TriNKET enhances traditional immunotherapy by engaging both the adaptive and innate immune systems, directly and indirectly. In vitro experiments demonstrated that ABBV-303 c-Met TriNKET stimulates both NK cells in the innate immune system, and CD8 T cells in the adaptive immune system to target c-Met expressing tumor cells. ABBV-303 c-Met TriNKET is designed to work with a wide range of other I/O drugs, as well as with other traditional treatment approaches in oncology, such as antibody-drug conjugates (ADCs), chemotherapy and radiation.

DEVELOPMENT

ABBV-303* is being investigated in a Phase 1 trial for the treatment of solid tumors.

*Dragonfly Therapeutics TriNKET® technology

CLINICAL TRIALS

View select clinical trials with ABBV-303 now. To view a full list of clinical trials in which ABBV-303 is being investigated, please visit ClinicalTrials.gov.

1. Platform | Dragonfly (dragonflytx.com). Accessed March 2024.
2. Stone J et al. AACR 2024. Abstract ND01.