A Phase 2 Multicohort Study to Evaluate Lorigerlimab in Participants With Advanced Solid Tumors

Overview

Lorigerlimab (MGD019; AEX-1344) is an investigational, bispecific checkpoint inhibitor engineered on MacroGenics’ DART platform to simultaneously target PD‑1 and CTLA‑4. Early clinical data suggest antitumor activity with a manageable safety profile, and multiple phase 2 studies are ongoing. (ncbi.nlm.nih.gov, ascopubs.org, macrogenics.com)

Mechanism of action

• Bispecific, tetravalent IgG4 Fc‑bearing DART molecule that binds PD‑1 and CTLA‑4. It is designed to deliver full PD‑1 blockade broadly while preferentially enhancing CTLA‑4 blockade on dual PD‑1/CTLA‑4–expressing tumor‑infiltrating lymphocytes, potentially concentrating activity in the tumor microenvironment and limiting off‑tumor CTLA‑4 effects. (ncbi.nlm.nih.gov)
• Preclinical and first‑in‑human dose‑escalation data show pharmacodynamic evidence of dual checkpoint blockade (increases in Ki67+ CD8 T cells and ICOS+ CD4 T cells), with the IgG4 backbone minimizing Fc‑mediated effector functions. (ncbi.nlm.nih.gov)

Clinical development

• Phase 1 first‑in‑human study in advanced solid tumors (NCT03761017) completed dose escalation and proceeded to expansion cohorts. (ncbi.nlm.nih.gov, ascopubs.org)
• LORIKEET: randomized phase 2 trial in metastatic castration‑resistant prostate cancer (mCRPC) testing lorigerlimab + docetaxel vs docetaxel alone; fully enrolled in late 2024 with a clinical update planned in H2 2025 (NCT05848011). (ir.macrogenics.com)
• LINNET: phase 2 monotherapy study in platinum‑resistant ovarian cancer and clear cell gynecologic cancers has initiated, with ORR as the primary endpoint. (ir.macrogenics.com)
• A separate phase 1/1b study is evaluating lorigerlimab combined with the B7‑H3 ADC vobramitamab duocarmazine in advanced solid tumors (NCT05293496). (clinicaltrials.ucsf.edu)

Efficacy

mCRPC (phase 1 expansion; ASCO‑GU 2023 poster/abstract): - Among 35 RECIST‑evaluable patients, objective response rate (ORR) was 25.7% (9 confirmed partial responses); median duration of response 16.1 weeks (range 6–25+). PSA50 and PSA90 response rates were 28.6% (12/42) and 21.4% (9/42), respectively. (ascopubs.org)

Broader phase 1 experience: - The dose‑escalation publication reported acceptable safety, pharmacodynamic evidence of dual blockade, and objective responses across multiple tumor types that are often insensitive to checkpoint inhibition (details by tumor type not fully enumerated in the paper). (ncbi.nlm.nih.gov)

Note: No randomized efficacy readout has been reported as of September 2, 2025; LORIKEET results are pending. (ir.macrogenics.com)

Safety

• In the phase 1 expansion (n=127 treated at 6 mg/kg Q3W), treatment‑related adverse events (TRAEs) occurred in 85.8–86.6% of patients; grade ≥3 TRAEs in 32.3–34.6%; immune‑related AEs in 7.9%; discontinuations due to AEs in ~23–24%; no treatment‑related deaths were reported. Common TRAEs (≥15%) included fatigue, rash, pruritus, hypothyroidism, and pyrexia. (ascopubs.org)

Other names/identifiers

• Synonyms: MGD019, AEX‑1344; bispecific PD‑1×CTLA‑4 DART antibody. (ckb.jax.org, go.drugbank.com)

Further reading

• Development and preliminary clinical activity of PD‑1‑guided CTLA‑4‑blocking bispecific DART (Cell Reports Medicine, 2020). (ncbi.nlm.nih.gov)
• ASCO‑GU 2023 abstract: phase 1 mCRPC expansion results (J Clin Oncol 41:6_suppl, 2023; Abstract 155). (ascopubs.org)
• MacroGenics pipeline page for lorigerlimab (program overview and trials). (macrogenics.com)
• Company updates on LORIKEET and LINNET phase 2 studies (2025). (ir.macrogenics.com)
• Ongoing combination study with vobramitamab duocarmazine (NCT05293496). (clinicaltrials.ucsf.edu)

Links above point to meeting abstracts, peer‑reviewed publications, and sponsor disclosures for additional details.

Last updated: Sep 2025

Inclusion Criteria:

* Histologically confirmed high-grade serous epithelial ovarian cancer, including primary peritoneal, or fallopian tube cancer, resistant to platinum based chemotherapy. OR

* Histologically confirmed clear cell ovarian (including primary peritoneal and fallopian tube), endometrial, vaginal, vulval, or cervical cancer.

* Persistent or recurrent disease with documented disease progression.

* Participants with PROC must have received at least 1 but not more than 3 prior lines of therapy for PROC.

* Participants with CCGC must have received at least 1 prior line of therapy for CCGC.

* Participants with a known breast cancer (BRCA) mutation (germline or somatic) must have received a a Poly ADP-ribose polymerase (PARP) inhibitor, if locally approved and available, and experienced disease progression or intolerance on the PARP inhibitor.

* Participants must have at least one lesion that meets the definition of measurable disease by RECIST v1.1.

* Participants must have an available archival or formalin-fixed paraffin-embedded tumor tissue, or be willing to undergo a biopsy procedure to obtain a fresh tumor sample.

* Participants have acceptable physical condition and laboratory values.

* Participants of childbearing potential must agree to use highly effective methods of birth control.

* Participants must not be pregnant, planning to be pregnant, or breastfeeding.

Exclusion Criteria:

* Any underlying medical or psychiatric condition impairing participant's ability to receive, tolerate, or comply with the planned treatment or study procedures.

* Primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first-line platinum- containing chemotherapy.

* Prior treatment with a checkpoint inhibitor (e.g., anti-PD-1/PD-L1, anti-PD-L2, anti-CTLA-4).

* Active brain metastases or leptomeningeal metastases.

* Prior stem cell, tissue, or solid organ transplant.

* Another hematologic or solid tumor ≥ stage 1 malignancy that completed surgery, last dose of radiotherapy, or last dose of systemic anti-cancer therapy ≤ 3 years from first dose of study treatment. Participants with another tumor that has a negligible risk for metastasis or death such as, adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast are eligible.