MacroGenics changes its tune on Linnet

MacroGenics has disclosed more bad news for its anti-PD-1 x CTLA-4 project lorigerlimab, ditching development in one of its few remaining hopes, platinum-resistant ovarian cancer. The company snuck the latest setback into its first-quarter results on Tuesday.

The group also disclosed that in clear-cell gynaecologic cancer (CCGC) it’s now taking forward a lower dose than previously tested – apparently a response to previous fears about toxicity. The latest developments come from the uncontrolled phase 2 Linnet trial, which had been testing lorigerlimab in PROC and CCGC, and is now the only ongoing company-sponsored trial of the asset.

The study was put on partial clinical hold in February after three grade 4 events and one death among 41 patients. The dose being tested was 6mg/kg every three weeks, and the adverse events in question were thrombocytopenia, myocarditis, and neutropenia and concurrent septic shock.

The hold was lifted in April after MacroGenics beefed up risk-mitigation measures for potential hematologic and cardiac toxicities.

Ovarian no-go

However, the company now says that in PROC the “predetermined response rate was not achieved”, and it’s abandoning this indication.

Meanwhile, in CCGC MacroGenics plans to test a dose of 3mg/kg every three weeks, “with the goal of improving safety while maintaining clinical benefit”. It plans to enrol an additional 20 patients, with data on these expected in the first half of 2027.

With the 6mg/kg dose, the group reported a 25% ORR among 16 evaluable CCGC patients. MacroGenics added that 47% of patients had adverse events of grade 3 or higher, and two patients discontinued, although there were no treatment-related deaths among this cohort.

But, if the company cannot find a balance between efficacy and safety, lorigerlimab looks destined for the scrapheap. The project has already flunked a prostate cancer trial, Lorikeet.

And MacroGenics, which recently sold off its manufacturing operations and expanded a royalty agreement over its Incyte-partnered PD-1 inhibitor Zynyz, seems more focused on ADCs. These include a next-gen B7-H3 project, vobramitamab tavatecan, and the Adam9-targeting MGC028. 

Initial data on both are due this year, although there are questions about whether vobramitamab tavatecan is differentiated from the company’s first B7-H3 attempt, vobramitamab duocarmazine, which it scrapped last year.