Updated follow-up from KEYNOTE-057: Phase 2 study of pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG)

Boormans, Joost L.; Wit, Ronald de; Kulkarni, Gauri; Uchio, Edward; Roumiguié, M.; Krieger, Laurence E.; Singer, Eric A.; Bajorin, Dean F.; Kamat, Ashish M.; Grivas, Petros; Seo, Hyung-bum; Nishiyama, Hiroyuki; Konethy, B.; Saretsky, T.; Li, H.; Nam, Kijoeng; Kapadia, Ekta; Balar, Arjun Vasant

doi:10.1016/s2666-1683(20)33372-3

Cited by 3 publications

(3 citation statements)

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“…Overall, the response rate to CPIs in metastatic urothelial cancer is ∼20%, with patients expressing PDL1/PD1 more likely to have a more durable response, a stratified HR 0.68, 95% CI 0.43–1.08 compared to chemotherapy 9,10 . In early-stage BCG unresponsive NMIBC, a similar response was described for patients with CIS, with or without papillary tumors in KEYNOTE057 1,2 and SWOG S1605 11 . These results suggest similar drug activity and provide a rationale for identifying the specific patients who might benefit long-term from CPI.…”

Section: Discussionsupporting

confidence: 57%

“…Yet, at least one-third of NMIBCs treated with BCG will not respond and progress to more advanced stages of bladder cancer. In 2020, following the results of KEYNOTE-057 1,2 , in which 40.6% of patients had a complete response at three months, pembrolizumab monotherapy was approved for use in patients with BCG unresponsive high-risk NMIBC. Unfortunately, response to pembrolizumab is not durable, and overall, 80% of treated patients will have recurred or progressed by 12 months.…”

Section: Introductionmentioning

confidence: 99%

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A Spatial Comparison of Molecular Features Associated with Resistance to Pembrolizumab in BCG Unresponsive Bladder Cancer

Meghani,

Frydenlund,

et al. 2023

Preprint

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BackgroundIntravenous immune checkpoint inhibition achieves a 40% three-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). Yet only half of early responders will continue to be disease free by 12 months, and resistance mechanisms are poorly defined.ObjectiveWe assessed the molecular features associated with response to immunotherapy in BCG unresponsive non-muscle invasive bladder cancers treated with pembrolizumab.Design, Setting, and ParticipantsWe performed digital spatial profiling (DSP) of BCG unresponsive NMIBC tumors before and after IV pembrolizumab therapy.InterventionPembrolizumab was administered intravenously in patients with NMIBC at the time of recurrence after BCG therapy. Biopsies were obtained before starting IV pembrolizumab and three months post-treatment.Outcomes and Statistical AnalysisSpatial gene expression profiling of the tumor niche pre- and post IV pembrolizumab.Results and LimitationsWe evaluated 119 regions of interest (ROIs) from five patients, which included 60 epithelial (PanCK+) and 59 stromal segments (PanCK-). ROIs from responders had distinct expression signatures from non-responders for both the tumor and TME. Responders were more likely to have a dynamic change in expression after pembrolizumab than non-responders. A major limitation of this study was the number of patients evaluated.ConclusionFor the first time, we have identified distinct expression signatures associated with response and resistance to IV pembrolizumab in NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings.Patient SummaryWe identify the molecular features of tumors associated with response to pembrolizumab for patients with BCG unresponsive NMIBCs.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

A Spatial Comparison of Molecular Features Associated with Resistance to Pembrolizumab in BCG Unresponsive Bladder Cancer

Meghani,

Frydenlund,

et al. 2023

Preprint

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“…In high-risk non-muscle invasive bladder cancer (NMIBC), for example, intravesical immunotherapy using a latent form of tuberculosis vaccine [Bacillus Calmette-Guérin (BCG)] induces both BCG-directed and tumor-specific immunity, ultimately decreasing recurrence and progression (2,(6)(7)(8)(9). If BCG is ineffective, a second line option is the Programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab, found to decrease recurrence by 25% at 12 months (10). In the advanced setting, monotherapy with PD1/programmed death ligand 1 inhibitors is both a first-and second-line therapy for patients with metastatic UCa, but only 30% of patients achieve a durable response of more than 12 months, presumably due to innate resistance (11,12).…”

Section: Introductionmentioning

confidence: 99%

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

Piunti

Meghani

et al. 2022

Sci. Adv.

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The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.

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Spatial comparison of molecular features associated with resistance to pembrolizumab in BCG unresponsive bladder cancer

Meghani,

Frydenlund,

et al. 2024

J Immunother Cancer

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Intravenous immune checkpoint inhibition achieves a 40% 3-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ. Yet, only half of the early responders will continue to be disease-free by 12 months, and resistance mechanisms are poorly defined. We performed spatial profiling of BCG-unresponsive tumors from patients responsive or resistant to intravenous pembrolizumab treatment, analyzing samples both before initiating and 3 months post-intravenous pembrolizumab treatment. We analyzed 119 regions of interest, which included 59 pairs of epithelial and adjacent stromal segments across five patients: two responders and three non-responders. We demonstrate that BCG unresponsive tumors with an inflamed PanCK+ tumor area and an infiltrated stromal segment respond better to intravenous pembrolizumab. Furthermore, using segment-specific gene signatures generated from a cohort of BCG unresponsive NMIBC treated with intravesical BCG+pembrolizumab, we find that non-inflamed, immune-cold tumors that do not respond to intravenous pembrolizumab exhibit a favorable outcome to the combined application of BCG and pembrolizumab. For the first time, we have identified molecular features of tumors associated with response and resistance to intravenous pembrolizumab in BCG unresponsive NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. We anticipate that using a transcriptomics signature like the one described here can help identify tumors with a higher possibility of responding to intravenous pembrolizumab.

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Updated follow-up from KEYNOTE-057: Phase 2 study of pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG)

Cited by 3 publications

References 0 publications

A Spatial Comparison of Molecular Features Associated with Resistance to Pembrolizumab in BCG Unresponsive Bladder Cancer

A Spatial Comparison of Molecular Features Associated with Resistance to Pembrolizumab in BCG Unresponsive Bladder Cancer

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

Spatial comparison of molecular features associated with resistance to pembrolizumab in BCG unresponsive bladder cancer

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