Abstract
Background: Microsatellite instability–high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). Methods: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). Results: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P =.0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P =.024). The 3-year PFS and OS proportions were 100% versus 30% (P =.017) and 100% versus 43% (P =.043), respectively. Conclusions: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.
Original language | English (US) |
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Pages (from-to) | 1206-1218 |
Number of pages | 13 |
Journal | Cancer |
Volume | 128 |
Issue number | 6 |
DOIs | |
State | Published - Mar 15 2022 |
Externally published | Yes |
Keywords
- clinical trial results
- endometrial cancer
- gynecologic cancers
- gynecologic oncology
- immunotherapy/checkpoint blockade
- phase 2 clinical trial
ASJC Scopus subject areas
- Oncology
- Cancer Research