Dysfunctional CD8+ T cells in the tumor microenvironment are associated with response to nivolumab in mismatch repair deficient (dMMR) or hypermutated ovarian (OVCA) or endometrial cancer (EC).
Authors: Friedman Claire Frances , Zhou Qin , Iasonos Alexia , Holland Aliya , Ramirez Lizbeth , Grisham Rachel N. , Guo Robin , Lichtman Stuart M. , Kyi Chrisann , Makker Vicky , Mueller Jennifer Jean , O'Cearbhaill Roisin Eilish , Schram Alison M. , Tew William P. , Konner Jason A. , Troso-Sandoval Tiffany A. , Wibmer Andreas Georg , Aghajanian Carol , Hensley Martee Leigh , Zamarin Dmitriy 
Published: June 2022

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Background: EC and a subset of OVCA are associated with high rates of dMMR and are responsive to PD-1 blockade. It is unknown what additional biomarkers beyond dMMR may enrich for benefit in these patients (pts). Methods: This was an investigator-initiated, single-arm, phase II study. Eligible pts had recurrent EC or OVCA that met one of the following criteria: 1) dMMR, as determined by immunohistochemical loss of expression of 1+ MMR genes; 2) MSI-H, as determined by next generation sequencing (MSK-IMPACT); or 3) hypermutated, defined as 20+ non-synonymous somatic mutations. Pts received nivo 240mg IV every 2 weeks or 480mg IV every 4 weeks until toxicity or progression. The co-primary endpoints were 1) the progression-free survival (PFS) rate at 24 weeks (PFS24) and 2) the objective response rate (ORR) by RECIST v1.1. The study was designed using Simon’s two-stage design, with a sample size of 40 pts based on a promising ORR of 25% with a type I error rate of 0.025 and a type II error rate of 0.05. Overall survival (OS), PFS and duration of response (DOR) were calculated using the method of Kaplan-Meier. Adverse events (AEs) were graded per CTCAE and tabulated. Biomarker analyses on the available archival tissue were performed using multiplex immunofluorescence (mIF) labeling for CD8, PD-1, TOX, PD-1, PD-L1, and FoxP3. Quantification of immune phenotypes and interaction studies between CD8+ T cells and PD-L1+ cells was performed in HALO. Results: Between 9/2017 and 5/2021, 35 pts were enrolled; the study closed early due to slow accrual. The median duration of follow-up was 33.2 months. The median age was 64 years (range 36-87); 82% of pts were white, 54% had high grade EC, and 65% had confirmed MLH1 hypermethylation. The ORR was 57.1% (97.5% CI 39.4-100%) [37% PR, 20% CR]. The PFS24 was 62.9% and median PFS was 26.7 months (95% CI 4.9-NE). Neither median DOR nor OS was reached. OS at 1 year was 76.4% (95% CI 58.2-87.4%). The ORR in patients with MLH1 hypermethylation was 52%; 4 of 5 patients with confirmed germline MMR alterations had a response by RECIST. AEs were consistent with the reported literature. Notable treatment related AEs included Grade 4 myocarditis with associated grade 4 AV block, grade 2 extraocular paresis, grade 3 Type 1 diabetes mellitus, and grade 3 elevations in AST/ALT. On mIF analysis, PD-L1 expression did not distinguish responders from non-responders, though interaction between CD8+ T cells and PD-L1+ cells was associated with CR/PR. Increase in relative fraction of dysfunctional CD8+ T cells (characterized by CD8+TOX+PD-1+ phenotype) was also associated with CR/PR. Conclusions: Nivo is an effective and tolerable treatment option for patients with MMR-D/MSI-H or hypermutated EC or OVCA. Presence of dysfunctional CD8+ T cells in the tumors was associated with response, while expression of PD-L1 was not predictive. Clinical trial information: NCT03241745.