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

Overview

Lorigerlimab (MGD019; also reported as AEX-1344) is an investigational, tetravalent bispecific antibody that targets PD‑1 and CTLA‑4 using MacroGenics’ DART platform. It has entered human trials, including a completed first‑in‑human phase 1 study in advanced solid tumors and ongoing phase 2 studies in metastatic castration‑resistant prostate cancer (mCRPC) and gynecologic cancers. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Bispecific IgG4 DART molecule binding PD‑1 and CTLA‑4 (tetravalent: bivalent for each target). Engineered to provide PD‑1–anchored, preferential enhancement of CTLA‑4 blockade on dual‑expressing tumor‑infiltrating lymphocytes, while maintaining strong PD‑1 blockade. In vitro and non‑human primate data show combinatorial pathway inhibition and pharmacodynamic markers consistent with PD‑1 and CTLA‑4 blockade (e.g., increased Ki67+CD8 and ICOS+CD4 T cells). (pubmed.ncbi.nlm.nih.gov)

Efficacy

Phase 1 (MGD019‑01; NCT03761017) dose‑expansion in mCRPC: - Among 35 response‑evaluable patients with measurable disease, objective response rate (ORR) was 25.7% (all partial responses; 9/35). Median duration of response was 16.1 weeks (range 6–25+). PSA responses: PSA50 in 28.6% (12/42) and PSA90 in 21.4% (9/42). Patients were heavily pretreated; most had visceral and/or bone metastases. Data cutoff: September 10, 2022; presented February 2023. (ascopubs.org)

Additional early clinical activity across multiple tumor types was described in the first‑in‑human publication, which reported acceptable safety and preliminary responses in cancers typically less responsive to checkpoint blockade; details were from the dose‑escalation phase and were not tumor‑specific efficacy cohorts. (pubmed.ncbi.nlm.nih.gov)

Ongoing randomized phase 2 (LORIKEET): - Lorigerlimab + docetaxel vs docetaxel alone in second‑line, chemotherapy‑naïve mCRPC; primary endpoint: rPFS. Approximately 150 patients randomized 2:1; study fully enrolled in late 2024 with a clinical update anticipated in the second half of 2025. (No efficacy readout available yet.) (ascopubs.org)

Safety

Phase 1 (all‑comers at 6 mg/kg Q3W; n=127): - Treatment‑related adverse events (TRAEs): 85.8%; grade ≥3 TRAEs: 32.3%; immune‑related AEs: 7.9%; discontinuations due to AEs: 22.8%; no treatment‑related deaths reported. Common TRAEs (≥15%): fatigue, pruritus, hypothyroidism, pyrexia. (ascopubs.org)

The first‑in‑human publication concluded that safety was acceptable with pharmacodynamic evidence of dual checkpoint blockade. (pubmed.ncbi.nlm.nih.gov)

Development status and ongoing trials

• Phase 1 (NCT03761017) first‑in‑human study completed (primary completion August 29, 2024; study completion January 27, 2025). (ichgcp.net)
• Phase 2 LORIKEET (mCRPC; randomized lorigerlimab + docetaxel vs docetaxel) ongoing; fully enrolled, update expected H2 2025. (ascopubs.org)
• Phase 2 LINNET (monotherapy in platinum‑resistant ovarian cancer and clear‑cell gynecologic cancers) initiated; first patient dosed May 2025. (ir.macrogenics.com)

Further reading

• Development and preliminary clinical activity of PD‑1‑guided CTLA‑4–blocking bispecific DART molecule (peer‑reviewed). (pubmed.ncbi.nlm.nih.gov)
• ASCO 2023 GU abstract: Phase 1 mCRPC expansion cohort efficacy and safety. (ascopubs.org)
• JCO 2024 Trial‑in‑Progress abstract: LORIKEET phase 2 design. (ascopubs.org)
• ClinicalTrials.gov record (via registry mirror) for NCT03761017 with study dates and status. (ichgcp.net)
• Company updates on enrollment and new studies (use for status context only). (ir.macrogenics.com)

Notes: As of October 7, 2025, randomized efficacy results have not been publicly reported for lorigerlimab. The most granular response data in humans are from the phase 1 mCRPC expansion cohort summarized above. (ascopubs.org)

Last updated: Oct 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.