Microsatellite instability (MSI-H) is a biomarker for response to immune-checkpoint inhibitors (ICIs). Approximately one-third of endometrial cancers (EC) exhibit an MSI-H phenotype,1 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).2 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 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,3 as well as FoundationOne® (online Protocol). 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, [PD-L1-positive cells]/[total viable tumor cells]×100).
From September 2016-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 ≥ prior chemotherapy, with a median of 1 (range: 1–5) prior lines. Six (25%) patients harbored Lynch-like tumors while 18 (75%) had sporadic EC. Nineteen patients demonstrated MLH1 promoter methylation, and 6 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, IQR:867–5108) versus sporadic tumors (median 604, IQR:411–798) (P=0.0076).
Median follow-up was 25.8 months with an ORR of 58% (95% CI, 36.6–77.9%). 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 4 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. Seventeen (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.
Supplementary Material
AKCNOWLEDGMENT
We would like to thank Merck-US for its industry support.
FUNDING
This work was supported in part by grants from NIH U01 CA176067-01, the Tina Brozman Foundation, the Guido Berlucchi Foundation and Gilead Sciences Inc., Foster City, CA to Alessandro Santin. This investigation was also supported by NIH Research Grant CA-16359 from NCI and Stand-up-to-cancer (SU2C) convergence grant 2.0 to Alessandro Santin.
Footnotes
DISCLOSURES
The authors declare no conflicts of interest.
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