A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793)

Abstract

Microsatellite instability-high (MSI-H) is a biomarker for response to immune checkpoint inhibitors (ICIs). Approximately one-third of endometrial cancers (ECs) exhibit an MSI-H phenotype.1Hause R.J. Pritchard C.C. Shendure J. Salipante S.J. Classification and characterization of microsatellite instability across 18 cancer types.Nat Med. 2016; 22: 1342-1350Crossref PubMed Scopus (406) Google Scholar However, these neoplasms originate from different pathways including germinal mutations in mismatch repair (MMR) genes (Lynch syndrome), somatic MMR mutations (Lynch-like), or homozygous methylation of the MLH1 promoter (sporadic).2Pakish J.B. Zhang Q. Chen Z. et al.Immune microenvironment in microsatellite-instable endometrial cancers: hereditary or sporadic origin matters.Clin Cancer Res. 2017; 23: 4473-4481Crossref PubMed Scopus (55) Google Scholar Whether mechanisms underlying MSI alter responses to ICIs is unclear, and resistance to ICIs remains incompletely understood. NCT02899793 was a single-arm, open-label phase II study evaluating pembrolizumab in patients with recurrent deficient MMR (dMMR) and/or MSI-H EC identified by conventional immunohistochemistry (IHC) or polymerase chain reaction, then analyzed by whole exome sequencing (WES) for tumor mutational burden (TMB) and genetic signatures,3Zhao S. Bellone S. Lopez S. et al.Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.Proc Natl Acad Sci U S A. 2016; 113: 12238-12243Crossref PubMed Scopus (116) Google Scholar as well as FoundationOne® (Foundation Medicine, Cambridge, MA) (see protocol in the Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.04.013). Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months. Primary endpoints were objective response rate (ORR) per RECIST v1.1 and toxicity. Secondary endpoints included progression-free (PFS) and overall survival (OS). Tumor was stained for infiltration by CD3-, CD68-, and CD20-positive cells (none = 0 to marked = 3) and combined positive score (CPS) [(programmed death-ligand 1-positive cells)/(total viable tumor cells) × 100]. From September 2016 to March 2020, 25 patients were accrued. One patient was excluded due to MSI-low status upon confirmatory analyses triggered by WES/FoundationOne® analyses. All patients had received ≥1 prior chemotherapy, with a median of 1 (range: 1-5) prior lines. A total of 6 (25%) patients harbored Lynch-like tumors whereas 18 (75%) had sporadic EC. Nineteen patients demonstrated MLH1 promoter methylation and six patients demonstrated somatic loss of MMR proteins by IHC; one participant exhibited both. There were no germline Lynch patients. TMB was higher in Lynch-like (median 2939, interquartile range: 867-5108) versus sporadic tumors (median 604, interquartile range: 411-798) (P = 0.0076). Median follow-up was 25.8 months with an ORR of 58% (95% confidence interval, 36.6% to 77.9%). ORR was 100% in Lynch-like but only 44% in sporadic patients (P = 0.024). The 3-year PFS/OS proportions were 100% versus 30% (P = 0.017) and 100% versus 43% (P = 0.043), respectively. Grade 3/4 treatment-related adverse events (6.8%) occurred in 12 patients. Primary resistance was noted in four patients (16.6%), including a mixed response in which all measurable lesions except one lung nodule decreased. Following resection, this patient continued pembrolizumab off-protocol and is presently progression-free at 41 months from study discontinuation. Seven cases of secondary resistance occurred, including one case of progression limited to a single abdominal lesion. Following resection, the patient continued pembrolizumab off-protocol and remains without disease at 42 months. Lynch-like MSI-H ECs demonstrated significantly higher average infiltration of CD68+ macrophages in tumor/stroma (2.8 versus 2.1, P = 0.022). No significant differences were noted in CD3+ T cells or CD20+ B cells. A total of 17 (70.8%) MSI-H patients had a CPS ≥1% (range: 0-60), 5/6 (83.3%) of Lynch-like, and 12/18 (66.7%) of the methylated patients (Fisher's exact P = 0.63). This study demonstrates the prognostic significance of Lynch-like versus sporadic MSI-H EC on ORR, PFS, and OS when treated with pembrolizumab. Oligo-progression (i.e. progression of a single metastatic lesion) in MSI-H patients appeared salvageable by surgical resection and/or local treatment and continuation of pembrolizumab off-study. Clinical studies evaluating separate subtypes of MSI-H EC treated with ICIs are warranted. We would like to thank Merck USA for its industry support.