Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis.

Background: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity.
Methods: In this phase 1b study, registered at Clinical.
Trials: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Findings: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients.
Conclusions: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks.
Funding: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).
Competing Interests: Declaration of interests S.N.W. reports grants/contracts to the institution from AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis Oncology, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, Roche/Genentech, and Zentalis; she also reports consulting with AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Verastem, Vincerx, Zentalis, and ZielBio. A.K.S. reports consulting for Kiyatec, Merck & Co., GSK, Valerio Therapeutics (formerly Onxeo), ImmunoGen, Iylon, and AstraZeneca; being a stockholder in BioPath Holdings; and a licensed patent (EGFL6 antibody). A.A.J. received institutional research funding from Bristol Myers Squibb, Iovance, Merck, Pfizer, Imunon, Aravive, MacroGenics, AstraZeneca, Avenge Bio, Greenfire Bio, and Break Through Cancer and consulting fees from Guidepoint, Alkermes, Gerson Lehrman Group, Adicet Bio, Theolytics, Avenge Bio, NuProbe, and Greenfire Bio.
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