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 |
|---|---|
| Pages (from-to) | 1206-1218 |
| Number of pages | 13 |
| Journal | Cancer |
| Volume | 128 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2022 Mar 15 |
Keywords
- clinical trial results
- endometrial cancer
- gynecologic cancers
- gynecologic oncology
- immunotherapy/checkpoint blockade
- phase 2 clinical trial
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: Cancer, Vol. 128, No. 6, 15.03.2022, p. 1206-1218.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability
AU - Bellone, Stefania
AU - Roque, Dana M.
AU - Siegel, Eric R.
AU - Buza, Natalia
AU - Hui, Pei
AU - Bonazzoli, Elena
AU - Guglielmi, Adele
AU - Zammataro, Luca
AU - Nagarkatti, Nupur
AU - Zaidi, Samir
AU - Lee, Jungsoo
AU - Silasi, Dan Arin
AU - Huang, Gloria S.
AU - Andikyan, Vaagn
AU - Damast, Shari
AU - Clark, Mitchell
AU - Azodi, Masoud
AU - Schwartz, Peter E.
AU - Tymon-Rosario, Joan R.
AU - Harold, Justin A.
AU - Mauricio, Dennis
AU - Zeybek, Burak
AU - Menderes, Gulden
AU - Altwerger, Gary
AU - Ratner, Elena
AU - Alexandrov, Ludmil B.
AU - Iwasaki, Akiko
AU - Kong, Yong
AU - Song, Eric
AU - Dong, Weilai
AU - Elvin, Julia A.
AU - Choi, Jungmin
AU - Santin, Alessandro D.
N1 - Funding Information: This work was supported in part by grants from the National Institutes of Health (U01 CA176067-01), the Tina Brozman Foundation, the Guido Berlucchi Foundation, and Gilead Sciences, Inc (to Alessandro D. Santin). The National Research Foundation of Korea (NRF) founded Jungmin Choi (No. NRF-2019R1A4A1029000). This investigation was also supported by the National Cancer Institute (research grant CA-16359 to Santin) and Stand Up To Cancer (convergence grant 2.0 to Santin). The authors thank Merck-US for its industry support. Dan-Arin Silasi reports consulting fees from Olympus, Intuitive Surgical, and Medtronic and payments or honoraria from Zai Labs. Gloria S. Huang reports grants or contracts from the US Department of Defense Ovarian Cancer Research Program, consulting fees from GlaxoSmithKline and Bristol-Myers Squibb, a patent pending, and stock in Illumina. Julia A. Elvin reports employment by Foundation Medicine and stock or stock options in Hoffman LaRoche. Alessandro D. Santin reports grants or contracts from Immunomedics, Genentech, Puma, Gilead, Synthon, Boehringer-Ingelheim, Tesaro, and Eisai (to his institution) and consulting fees from Merck, Tesaro, and Eisai. The other authors made no disclosures. This was an investigator-initiated pilot study supported in part by Merck (Kenilworth, New Jersey), which supplied pembrolizumab. The company had no influence on the study design, the data derived, or the analyses and interpretations. The trial was approved by the institutional review board at Yale University. All authors had access to the data and participated in the writing, reviewing, and editing of the manuscript. All authors attested that the trial was conducted in accordance with the protocol and amendments with Good Clinical Practice standards in accordance with the Declaration of Helsinki. Patients provided written informed consent. NCT02899793 is an investigator-initiated phase 2 trial evaluating the safety and efficacy of pembrolizumab in patients with recurrent dMMR and/or MSI-H EC identified by conventional immunohistochemistry (IHC) or polymerase chain reaction (PCR) and comprehensively evaluated via WES for TMB and genetic signatures, as described previously.10,11 Key eligibility criteria included histologically documented metastatic/recurrent EC that progressed after standard therapy. All EC subtypes were allowed; sarcomas and mesenchymal tumors were excluded. Patients were required to be 18 years old or older, have measurable disease at the baseline on the basis of the Response Evaluation Criteria in Solid Tumors (version 1.1),12 have an Eastern Cooperative Oncology Group13 performance status of 0 or 1, and demonstrate adequate organ function within 10 days of treatment initiation. Key exclusion criteria included prior anticancer monoclonal antibody therapy ≤4 weeks before treatment initiation; prior chemotherapy, targeted small-molecule therapy, or radiation therapy within 2 weeks of treatment initiation; and prior treatment with an anti–PD-1, anti–PD-L1, or anti–PD-L2 therapy or another ICI (see the full protocol in the supporting appendix). The primary efficacy end point was an objective response (OR) in patients with persistent, recurrent, or metastatic EC harboring an ultramutated or hypermutated (MMR gene–defective) phenotype. OR is defined as the best complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). The primary safety end point was toxicity as assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.0).14 Secondary end points included progression-free survival (PFS; the time from allocation to first disease progression or death resulting from any cause) and overall survival (OS; the time from allocation to death from any cause or loss to follow-up). Efficacy and safety were assessed in all patients who received 1 or more doses. Exploratory objectives included 1) the prospective comparison of WES and IHC/PCR for the identification of MSI-H patients; 2) the correlation of TMB and somatic mutations in MSI-H patients identified by WES with OR, PFS, and OS; and 3) the characterization of immune infiltrates and PD-L1 expression within MSI-H subtypes versus OR, PFS, and OS in pembrolizumab-treated patients. This was an investigator-initiated pilot study supported in part by Merck (Kenilworth, New Jersey), which supplied pembrolizumab. The company had no influence on the study design, the data derived, or the analyses and interpretations. The trial was approved by the institutional review board at Yale University. All authors had access to the data and participated in the writing, reviewing, and editing of the manuscript. All authors attested that the trial was conducted in accordance with the protocol and amendments with Good Clinical Practice standards in accordance with the Declaration of Helsinki. Patients provided written informed consent. This was a single-arm, open-label, phase 2 pilot study using the optimal, flexible 2-stage design of Chen and Ng15 to evaluate the efficacy of the study regimen. The targeted accrual for the first stage was 12 eligible and evaluable patients, but it was allowed to range from 8 to 15. The study would stop early if no ORs occurred among ≤13 first-stage subjects or 1 OR occurred among 14 to 15 such subjects; otherwise, accrual to the second stage would proceed. The cumulative accrual to both stages had a target of 22 with an allowable range of 18 to 25. The treatment regimen was considered successful if 2 or more ORs among 18 subjects or 3 or more ORs among 19 to 25 subjects were observed. The operating characteristics were as follows: with a null-hypothesis response rate of 5%, the study's true α had an average of 9.5% with a 64.9% average probability of early termination; with an alternative-hypothesis response rate of 25%, the study's average power was 90.0% (ie, a 90% average chance of correctly classifying the study regimen as interesting if the true probability of tumor response was 25%). Additional design details are presented in the protocol (see the supporting appendix). The ORR for the entire study was reported with exact binomial 95% CIs and was also compared between MSI-H subgroups with the Fisher exact test. PFS and OS were analyzed with the Kaplan-Meier method and compared between subgroups with log-rank tests. Safety data were summarized with descriptive statistics. The Wilcoxon rank-sum test was used to compare MSI-H subgroups for difference in the mutational burden, whereas the Cochran-Armitage trend test was used to compare them for differences in the average IHC intensity score. Wilcoxon rank-sum tests were also used for patients who achieved an OR to compare MSI-H subgroups for differences in the time to achieve an OR and in the baseline tumor size. All statistical tests used 2-sided significance levels of α =.05. Patients received 200 mg of pembrolizumab as a flat dose intravenously over 30 minutes every 3 weeks for a maximum of 24 months or until disease progression, intolerable toxicity, death, withdrawal of consent, or investigator decision. Safety was assessed throughout the study via history, physical examination, and laboratory assessment before each cycle and for 30 days after discontinuation (90 days for serious adverse events [AEs] and immune-mediated AEs). Immune-mediated AEs were defined as events with potentially drug-related immunologic causes that were consistent with an immune phenomenon, regardless of attribution to treatment or immune relatedness by the investigator. For patients exhibiting prespecified treatment-related toxicities, treatment could be withheld and permanently discontinued if toxicities did not resolve to grade 0 to 1 within 12 weeks of the last pembrolizumab dose. Those with a persistent grade 2 laboratory AE after 12 weeks could continue with sponsor and investigator approval only if the AE was asymptomatic and controlled. Tumor response was assessed with computed tomography or magnetic resonance imaging at 6 weeks, 12 weeks, and every 12 weeks thereafter. If imaging indicated progressive disease (PD), a confirmatory assessment was required ≥4 weeks later. Patients could continue receiving the study treatment during this period. If the repeat scan confirmed progression, the study treatment was discontinued. Tumors were classified as MSI-H/dMMR when expression by IHC of at least 1 MMR protein (MLH1/MSH2/MSH6/PMS2) was absent and/or when an allelic pattern shift involving 2 or more loci among 5 microsatellite markers (BAT25, BAT26, NR21, NR24, and Mono27) was detected by PCR. All tumors were sequenced at the Foundation Medicine central laboratory (Cambridge, Massachusetts) with FoundationOne, a test sequencing the coding region of 324 genes plus introns from 28 genes to a median depth of coverage of >500×,16 and with WES at the West Campus Genomic Facility at Yale University, as previously described by our research group.10,17 Briefly, DNA was isolated from matched normal DNA samples (peripheral blood) and EC samples with RecoverAll Total Nucleic Acid Isolation Kits (Ambion, Austin, Texas) and analyzed according to standardized protocols. Mutational signature analyses were performed as described by Alexandrov et al,18 whereas the neoantigen load (the number of peptides predicted to bind with major histocompatibility complex proteins) was identified on the basis of HLA types derived from sequencing data as previously described by our group.19 The Catalogue of Somatic Mutations in Cancer database was queried for the pathogenicity of mutations.20-22 Four-micrometer sections were cut from formalin-fixed, paraffin-embedded blocks of all 24 evaluable MSI-H patients and stained with the following antibodies according to the manufacturers' instructions: CD3 (clone 2GV6; Ventana), CD68 (clone PG-M1; Dako), CD20 (clone L26, 1:200; Dako), and PD-L1 (clone E1L3N, 1:200; Cell Signaling). The intensity of infiltration for CD3-, CD68-, and CD20-positive cells was scored as none (0), mild (1), moderate (2), or marked (3). Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting membrane staining at any intensity. The Combined Positive Score (CPS) was defined as the number of PD-L1–positive cells (including tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells times 100 for a post hoc analysis. Either a primary or metastatic tumor site could be used. Funding Information: This work was supported in part by grants from the National Institutes of Health (U01 CA176067‐01), the Tina Brozman Foundation, the Guido Berlucchi Foundation, and Gilead Sciences, Inc (to Alessandro D. Santin). The National Research Foundation of Korea (NRF) founded Jungmin Choi (No. NRF‐2019R1A4A1029000). This investigation was also supported by the National Cancer Institute (research grant CA‐16359 to Santin) and Stand Up To Cancer (convergence grant 2.0 to Santin). The authors thank Merck‐US for its industry support. Publisher Copyright: © 2021 American Cancer Society
PY - 2022/3/15
Y1 - 2022/3/15
N2 - 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.
AB - 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.
KW - clinical trial results
KW - endometrial cancer
KW - gynecologic cancers
KW - gynecologic oncology
KW - immunotherapy/checkpoint blockade
KW - phase 2 clinical trial
UR - http://www.scopus.com/inward/record.url?scp=85120636080&partnerID=8YFLogxK
U2 - 10.1002/cncr.34025
DO - 10.1002/cncr.34025
M3 - Article
C2 - 34875107
AN - SCOPUS:85120636080
SN - 0008-543X
VL - 128
SP - 1206
EP - 1218
JO - Cancer
JF - Cancer
IS - 6
ER -