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Prognostic Significance of Lynch-like versus Sporadic MSI-H Endometrial Cancer Treated With Pembrolizumab

The results of a phase II study in patients with recurrent mismatch repair deficient and/or microsatellite instability-high endometrial cancer
20 Jul 2021
Cancer Immunology and Immunotherapy;  Gynaecologic malignancies;  Personalised medicine

In a single-arm, open-label phase II study, the investigators led by Prof. Alessandro Santin of the Smilow Comprehensive Cancer Center, Yale University School of Medicine in New Haven, US evaluated pembrolizumab in patients with recurrent mismatch repair deficient (dMMR) and/or microsatellite instability-high (MSI-H) endometrial cancer. They wrote in the Annals of Oncology that their findings demonstrate the prognostic significance of Lynch-like versus sporadic MSI-H endometrial cancer on overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Approximately one-third of endometrial cancers exhibit an MSI-H phenotype. However, these tumours originate from different pathways including germline mutations in MMR genes (Lynch syndrome), somatic MMR mutations (Lynch-like), or homozygous methylation of the MLH1 promoter (sporadic).

The study team explained that it is unclear whether mechanisms underlying MSI alter responses to immune checkpoint inhibitors (ICIs). The resistance to ICIs is not completely understood.

In total, 25 patients who received at least 1 prior chemotherapy line were accrued from September 2016 to March 2020 in the study (NCT02899793). They received pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months. Primary endpoints were ORR per RECIST v1.1 and toxicity. Secondary endpoints included PFS and OS.

In total, 6 (25%) patients harboured Lynch-like tumours whereas 18 (75%) had sporadic endometrial cancer. There were no patients with germline Lynch. Tumour mutation burden was higher in Lynch-like versus sporadic tumours (p = 0.0076).

Upon median follow-up of 25.8 months, the ORR was 58% (95% confidence interval 36.6-77.9). The ORR was 100% in Lynch-like, but only 44% in sporadic tumours (p = 0.024). The 3-year PFS rate was 100% versus 30% (p = 0.017) and OS 100% versus 43% (p = 0.043).

Grade 3/4 treatment-related adverse events (6.8%) occurred in 12 patients.

Primary resistance was found 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 progression-free at 41 months from study discontinuation.

Secondary resistance occurred in 7 cases, including 1 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 endometrial cancer demonstrated significantly higher average infiltration of CD68+ macrophages in tumour/stroma (p = 0.022). No significant differences were noted in CD3+ T cells or CD20+ B cells. In total, 17 (70.8%) MSI-H patients had a combined positive score ≥1%, 5 of 6 (83.3%) of Lynch-like, and 12 of 18 (66.7%) of the methylated patients (Fisher's exact p = 0.63).

The authors wrote that their study demonstrates the prognostic significance of Lynch-like versus sporadic MSI-H endometrial cancer. Clinical studies evaluating separate subtypes of MSI-H endometrial cancer treated with ICIs are warranted.

The study was supported by Merck USA, and in part by grants from the US National Institutes of Health (NIH), the Tina Brozman Foundation, the Guido Berlucchi Foundation, and Gilead Sciences Inc, the National Cancer Institute and Stand-Up-To-Cancer convergence grant.

Reference

Bellone S, Roque DM, Siegel ER, et al. 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). Annals of Oncology 2021;32(8):1045-1046. DOI: https://doi.org/10.1016/j.annonc.2021.04.01

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