Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEYNOTE-158 study

O’Malley, David M.; Marabelle, Aurélien; Jesus-Acosta, Ana De; Piha‐Paul, Sarina A.; Arkhipov, Alexei; Longo, Federico; Motola-Kuba, Daniel; Rimel, B.J.; Lopez-Martin, J.A.; Hansen, Aaron Richard; Mehnert, Janice M.; Chen, X.; Jin, Fan; Norwood, Kevin; Ott, Patrick A.

doi:10.1093/annonc/mdz250.052

Cited by 24 publications

(24 citation statements)

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“…The safety profile of lenvatinib plus pembrolizumab was generally similar to previously reported profiles of each monotherapy (lenvatinib, 24 mg/d; pembrolizumab, 10 mg/kg every 2 or 3 weeks). 13 , 14 , 16 , 21 , 36 - 38 Although hypothyroidism occurred in a greater proportion of patients in our study than in previous reports of either monotherapy (48% [treatment-related, 43%] v ≤ 37%, respectively), 36 , 37 there was only 1 occurrence of grade 3 hypothyroidism. Overall, the rate of grade 3/4 treatment-related AEs was similar in our study to the interim analysis of lenvatinib plus pembrolizumab in endometrial cancer (67% v 68%, respectively).…”

Section: Discussioncontrasting

confidence: 62%

“…Nearly 84% of patients with recurrent endometrial carcinoma have MSS or microsatellite-indeterminate tumors. 15 Although pembrolizumab is effective for MSI-H disease (objective response, 28/49 [57.1%] patients), 13 , 14 it appears less effective for MSS disease (best response was PR, 2/18 patients). 16 Similarly, in advanced/recurrent previously treated endometrial carcinoma, investigational PD-1 monoclonal antibody dostarlimab (formerly TSR-042) had greater efficacy in patients with MSI-H tumors compared with patients with MSS tumors (ORR, [confirmed and unconfirmed responses] 50.0% and 19.1%, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…In a phase II study of pembrolizumab monotherapy in patients with previously treated advanced MSI-H/dMMR noncolorectal cancer, results from the endometrial cohort (n = 49) demonstrated an objective response rate (ORR) of 57.1% (95% CI, 42.2% to 71.2%), with a median progression-free survival (PFS) of 25.7 months (95% CI, 4.9 months to not reached). 13 , 14 However, MSI-H endometrial cancers comprise only 16% of recurrent disease cases. 15 In a phase Ib study of pembrolizumab for advanced programmed death ligand-1 (PD-L1)–positive endometrial cancer (in patients whose disease progressed after standard therapy or for whom standard therapy was not appropriate), 18 of 19 patients with evaluable tumor samples had microsatellite-stable (MSS) cancer.…”

Section: Introductionmentioning

confidence: 99%

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Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer

Makker

Taylor

Aghajanian

et al. 2020

JCO

407

317

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PURPOSE Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. METHODS Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. RESULTS At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)–high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. CONCLUSION Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer

Makker

Taylor

Aghajanian

et al. 2020

JCO

407

317

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“…This may potentially be explained by better prognosis for patients with MSI-H who would be underrepresented in this study, which focuses on patients with advanced/incurable disease. The KEYNOTE-158 study previously demonstrated the clinical benefit of pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer, providing further evidence to support MSI-H as a predictive biomarker for response to anti-PD-1 therapy [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Association of PD-L1 Expression with Prognosis Among Patients with Ten Uncommon Advanced Cancers

et al. 2020

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Aim: Programmed death ligand 1 (PD-L1) expression and high levels of microsatellite instability (MSI-H) may predict response to checkpoint inhibitors, but their prevalence and prognostic value are unknown in many cancers. Methods: We retrospectively evaluated PD-L1 combined positive score (CPS) and MSI-H and their association with clinical outcomes among patients with ten advanced uncommon cancers. Results: 398 of 426 patients (93%) had a valid PD-L1 result; most (242; 61%) had CPS ≥1. Prevalence of MSI-H tumors was 8/360. Median overall survival was shorter among patients with PD-L1 CPS ≥1 tumors after first-line treatment (23.0 vs 39.7 months, p = 0.014). Conclusion: PD-L1 was commonly expressed in solid tumors, and CPS ≥1 was associated with shorter overall survival. Prevalence of MSI-H was low.

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“…In 2017, pembrolizumab, a mono-clonal antibody targeting programmed death receptor-1 (PD-1), was approved for microsatellite instability-high (MSI-H)/mismatch-repair-deficient (dMMR) solid tumors that have progressed after prior therapy and have no satisfactory alternative treatment options. A phase II study of pembrolizumab monotherapy in patients with MSI-H/dMMR endometrial cancer (n = 49) demonstrated an objective response rate (ORR) of 57.1% (95% CI, 42.2-71.2%), with a median progression-free survival (PFS) of 25.7 months (95% CI, 4.9 months to not reached) (13,14). Tislelizumab, another anti PD-1 antibody, has been approved by NMPA for the treatment of recurrent and refractory classical Hodgkin lymphoma, as well as previously treated locally advanced or metastatic urothelial carcinoma with PD-L1 high expression.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Double Germline Mutations in BRCA1 and MSH2 in a Patient With Mixed Serous-Endometrioid Endometrial Carcinoma

Zheng

Yuan

et al. 2020

Front. Med.

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Mixed serous-endometrioid endometrial carcinoma is a type of endometrial cancer with relatively low incidence. The genetic factors contributing to the tumorigenesis of mixed carcinoma remains to be explored. Here, we report the first identification of two germline mutations in BRCA1 and MSH2 in a woman with mixed serous papillary adenocarcinoma and endometrioid carcinoma. Immunohistochemistry analysis showed loss of MSH2 and MSH6 protein expression in the endometrioid component. The patient showed partial response to tislelizumab treatment following progression on chemotherapy. Two germline mutations in BRCA1 and MSH2 may collectively promote the tumorigenesis of uterine endometrium with two distinct histological components.

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Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEYNOTE-158 study

Cited by 24 publications

References 0 publications

Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer

Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer

Association of PD-L1 Expression with Prognosis Among Patients with Ten Uncommon Advanced Cancers

Case Report: Double Germline Mutations in BRCA1 and MSH2 in a Patient With Mixed Serous-Endometrioid Endometrial Carcinoma

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