FDA Lifts Clinical Hold on Lorigerlimab Trial in Ovarian Cancer

The FDA has removed the partial clinical hold on the phase 2 LINNET trial (NCT06730347), clearing the path for renewed enrollment of patients with platinum-resistant ovarian cancer or clear cell gynecologic cancer in the study of lorigerlimab, an investigational bispecific dual-affinity re-targeting (DART) molecule that simultaneously inhibits PD-1 and CTLA-4.¹ 

The hold was lifted following a comprehensive safety data review and implementation of a revised study protocol with additional risk-mitigation measures.

MacroGenics, the sponsor, had placed the partial clinical hold in February 2026 after investigators observed serious adverse events in newly enrolled participants, including 2 cases of grade 4 neutropenia and 1 case of grade 4 myocarditis. A fourth newly enrolled patient experienced concurrent grade 4 neutropenia and septic shock, which resulted in a grade 5 fatal outcome. Patients already receiving lorigerlimab at the time of the hold were permitted to continue treatment; only new enrollment was suspended.

The revised protocol introduces enhanced monitoring and risk-mitigation strategies specifically targeting hematologic and cardiac toxicities. The safety profile observed in newly enrolled patients, particularly the clustering of grade 4 hematologic events and immune-mediated cardiac toxicity, is consistent with the known class effect of combined PD-1/CTLA-4 blockade, though the severity and clustering in newly enrolled patients prompted the agency's initial action.

MacroGenics' president and chief executive officer Eric Risser credited productive dialogue with reviewers in the FDA's Office of Oncologic Diseases and indicated that enrollment will resume, with a mid-2026 clinical update planned from the ongoing LINNET study.¹

LINNET Trial Design and Eligibility

The LINNET study is an open-label, multicenter phase 2 trial evaluating lorigerlimab monotherapy administered intravenously once every 21 days across 2 cohorts. The primary end point is objective response rate; secondary end points include duration of response, progression-free survival, and overall survival.^2,3 To date, 41 participants have been dosed across the 2 cohorts.

For the PROC cohort, patients must have received between 1 and 3 prior lines of systemic therapy and demonstrated platinum-resistant disease. For the CCGC cohort, at least 1 prior line of therapy for advanced or recurrent disease is required. All participants must have measurable disease per RECIST v1.1 criteria. Patients with prior immune checkpoint inhibitor (ICI) exposure are generally excluded from the PROC cohort, though prior ICI use is permitted for select cases of clear cell endometrial or cervical cancer in the CCGC cohort.³

Tumor assessments are performed approximately every 9 weeks during the first year and every 12 weeks thereafter. A safety follow-up is required within 30 days of treatment discontinuation, and patients who stop treatment for reasons other than disease progression continue CA-125 and radiographic assessments every 12 weeks.³

The reinitiation of the LINNET study reopens a referral pathway for eligible patients. The concurrent PD-1/CTLA-4 targeting mechanism of lorigerlimab distinguishes it from approved single-checkpoint inhibitors and may offer incremental benefit in immunologically active tumor types, though efficacy data from the current cohorts remain forthcoming. The mid-2026 data update will be critical in assessing whether the ORR signal justifies the toxicity profile observed during the hold period.

Clinicians should note that the safety events prompting the clinical hold—particularly immune-mediated cardiotoxicity and severe neutropenia—warrant close hematologic and cardiac monitoring in patients enrolled or considered for enrollment. The revised protocol's risk-mitigation framework has not yet been publicly detailed, and community practices that enroll patients in LINNET should confirm updated monitoring requirements with the study sponsor and site principal investigator.

REFERENCES

1. FDA removes partial clinical hold on MacroGenics' LINNET study. News release. MacroGenics, Inc. April 8, 2026. Accessed April 10, 2026. https://tinyurl.com/2rnndbfp

2. MacroGenics announces pausing of enrollment of new study participants in LINNET trial. News release. MacroGenics Inc. February 24, 2026. Accessed April 10, 2026. https://tinyurl.com/2uak5zt6

3. A study of lorigerlimab in participants with advanced solid tumors (LINNET). ClinicalTrials.gov. NCT06730347. Updated March 5, 2026. Accessed April 10, 2026. https://tinyurl.com/38ckwxz9