The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial.
Adult
Aged
Antibodies, Monoclonal, Humanized
/ adverse effects
Ataxia Telangiectasia Mutated Proteins
/ genetics
B7-H1 Antigen
/ antagonists & inhibitors
Female
Forkhead Box Protein L2
/ genetics
Granulosa Cell Tumor
/ drug therapy
Humans
Immune Checkpoint Inhibitors
/ adverse effects
Lymphocytes, Tumor-Infiltrating
/ immunology
Middle Aged
Mutation
Neoplasm Recurrence, Local
/ drug therapy
Neurofibromin 1
/ genetics
Ovarian Neoplasms
/ drug therapy
Treatment Outcome
Tumor Suppressor Protein p53
/ genetics
Young Adult
Case report
Granulosa cell tumor of the ovary
Immunotherapy
Pembrolizumab
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
23
10
2020
accepted:
27
11
2020
pubmed:
9
1
2021
medline:
15
2
2022
entrez:
8
1
2021
Statut:
ppublish
Résumé
Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.
Identifiants
pubmed: 33415580
doi: 10.1007/s10637-020-01043-9
pii: 10.1007/s10637-020-01043-9
pmc: PMC8076052
mid: NIHMS1661877
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
B7-H1 Antigen
0
CD274 protein, human
0
FOXL2 protein, human
0
Forkhead Box Protein L2
0
Immune Checkpoint Inhibitors
0
NF1 protein, human
0
Neurofibromin 1
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
pembrolizumab
DPT0O3T46P
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Banques de données
ClinicalTrials.gov
['NCT02721732']
Types de publication
Case Reports
Clinical Trial, Phase II
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
829-835Subventions
Organisme : NCI NIH HHS
ID : T32 CA101642
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA217685
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA209904
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA109298
Pays : United States
Organisme : National Institutes of Health (US)
ID : P30CA016672
Références
Schumer ST, Cannistra SA (2003) Granulosa cell tumor of the ovary. J Clin Oncol 21(6):1180–1189
doi: 10.1200/JCO.2003.10.019
Malmström H et al (1994) Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol 52(1):50–55
doi: 10.1006/gyno.1994.1010
Levin G et al (2018) Granulosa cell tumor of ovary: A systematic review of recent evidence. Eur J Obstet Gynecol Reprod Biol 225:57–61
doi: 10.1016/j.ejogrb.2018.04.002
Chen VW et al (2003) Pathology and classification of ovarian tumors. Cancer 97(10 Suppl):2631–2642
doi: 10.1002/cncr.11345
Young RH, Dickersin GR, Scully RE (1984) Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases. Am J Surg Pathol 8(8):575–596
doi: 10.1097/00000478-198408000-00002
Mangili G et al (2013) Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary. Br J Cancer 109(1):29–34
doi: 10.1038/bjc.2013.241
Gurumurthy M, Bryant A, Shanbhag S (2014) Effectiveness of different treatment modalities for the management of adult-onset granulosa cell tumours of the ovary (primary and recurrent). Cochrane Database Syst Rev 2014(4):Cd006912
Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454
doi: 10.1056/NEJMoa1200690
Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723
doi: 10.1056/NEJMoa1003466
Le DT et al. (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science (New York, N.Y.) 357(6349):409–413
Naing A et al (2020) Phase 2 study of pembrolizumab in patients with advanced rare cancers. J Immunother Cancer 8(1):e00034
Frumovitz M et al (2020) Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract. Gynecol Oncol 158(3):570–575
doi: 10.1016/j.ygyno.2020.05.682
Fujii T et al (2018) Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience. Invest New Drugs 36(4):638–646
doi: 10.1007/s10637-017-0534-0
Hua C et al (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152(1):45–51
doi: 10.1001/jamadermatol.2015.2707
Hosoya K et al (2020) Association between early immune-related adverse events and clinical outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors. Clin Lung Cancer 21(4):e315–e328
doi: 10.1016/j.cllc.2020.01.003
Taube JM et al (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20(19):5064–5074
doi: 10.1158/1078-0432.CCR-13-3271
Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264
doi: 10.1038/nrc3239
Fujii T et al (2018) Biomarkers of response to immune checkpoint blockade in cancer treatment. Crit Rev Oncol Hematol 130:108–120
doi: 10.1016/j.critrevonc.2018.07.010
Mills AM et al (2019) Emerging biomarkers in ovarian granulosa cell tumors. Int J Gynecol Cancer 29(3):560–565
doi: 10.1136/ijgc-2018-000065
Zamarin D et al (2020) Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study. J Clin Oncol 38:1814–1823. https://doi.org/10.1200/jco.19.02059
doi: 10.1200/jco.19.02059
pubmed: 32275468
Curran MA et al (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 107(9):4275–4280
doi: 10.1073/pnas.0915174107
Cocquet J et al (2002) Evolution and expression of FOXL2. J Med Genet 39(12):916–921
doi: 10.1136/jmg.39.12.916
Shah SP et al (2009) Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 360(26):2719–2729
doi: 10.1056/NEJMoa0902542
Yanagida S et al (2017) Clinical and genetic analysis of recurrent adult-type granulosa cell tumor of the ovary: Persistent preservation of heterozygous c.402C > G FOXL2 mutation. PLoS One 12(6):e0178989
doi: 10.1371/journal.pone.0178989
Hillman RT et al (2018) KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary. Nat Commun 9(1):2496
doi: 10.1038/s41467-018-04950-x
Paula Da C, A, et al (2020) Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary. Mod Pathol 33:1606–1617
doi: 10.1038/s41379-020-0514-3
Roze J et al (2020) Whole genome analysis of ovarian granulosa cell tumors reveals tumor heterogeneity and a high-grade TP53-specific subgroup. Cancers (Basel) 12(5):1308
doi: 10.3390/cancers12051308
Goodman AM et al (2017) Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 16(11):2598–2608
doi: 10.1158/1535-7163.MCT-17-0386
Tao X et al (2009) Anti-angiogenesis therapy with bevacizumab for patients with ovarian granulosa cell tumors. Gynecol Oncol 114(3):431–436
doi: 10.1016/j.ygyno.2009.04.021
Färkkilä A et al (2011) Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors. Eur J Endocrinol 164(1):115–122
doi: 10.1530/EJE-10-0849
Brown J et al (2014) Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. Cancer 120(3):344–351
doi: 10.1002/cncr.28421
Ray-Coquard I et al (2020) Effect of weekly paclitaxel with or without bevacizumab on progression-free rate among patients with relapsed ovarian sex cord-stromal tumors: the ALIENOR/ENGOT-ov7 randomized clinical trial. JAMA Oncol:e204574. https://doi.org/10.1001/jamaoncol.2020.4574