AUA 2020: Association of Pathologic Response to Neoadjuvant Pembrolizumab with Tumor Subtype from the PURE-01 Study

(UroToday.com) In the initial publication of the PURE-01 study, Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma (PURE-01), neoadjuvant immunotherapy with three cycles of pembrolizumab was associated with a complete response (pT0N0) of 42% and a partial (pT1N0 or less) of 54%.1 While biomarkers associated with pathologic response included higher tumor mutational burden and alterations in DNA damage response, the role of tumor subtyping in this disease space has not been investigated. To investigate tumor subtyping, Dr. Meeks and colleagues performed whole transcriptome RNA-Seq on transurethral resection specimens of 88 patients prior to receiving three cycles of pembrolizumab. For patients with residual cancer, subtyping was performed on 33 tumors after pembrolizumab (at radical cystectomy). At the American Urologic Association (AUA) 2020 virtual meeting, the results of this study were presented.



Formalin and embedded in paraffin (FFPE) from transurethral resected tumors from 88 patients with histologically muscle-invasive bladder cancer were evaluated by transcriptome profiling. Post-pembrolizumab tumors from radical cystectomy were available for 35 patients. Genomes were aligned with STAR to GRCh38, FPKM values were calculated with Cufflinks, and subtypes were identified with Consensus muscle-invasive bladder cancer (MIBC) and BLCAsubtyping. 

From the 88 patients, 34 had a complete response (39%), 20 a partial response (pT1N0 or less, 23% totaling 61% with complete response) and 39% had no response (pT2N0 or greater). Basal tumors had the greatest response to pembrolizumab with 60% complete response, 13% partial response, and 27% no response, followed by luminal infiltrated tumors 36% complete response, 32% partial response, and 32% no response.  Luminal papillary tumors had the least response with 34% complete response and 17% partial response with 48% no response. The more recent ConsensusMIBC subtyping method produced similar results with basal/squamous tumors showing the greatest response to pembrolizumab with 48% complete response, 29% partial response, and 24% no response, followed by stroma-rich tumors 47% complete response, 20% partial response, and 33% no response. Luminal non-specified tumors had the least response 22% complete response and 22% partial response with 56% no response.

Basal/squamous tumors had the greatest CPS score (mean of 53%) compared to luminal tumors (12.6%). The authors also compared pre- to post-treatment subtypes of 35 tumors with residual cancer after pembrolizumab. Conversion to luminal infiltrated subtype occurred in 80% of luminal papillary tumors, 83% of luminal, 100% of neuronal, and 33% of basal tumors, while 67% of basal tumors remained basal. Luminal papillary tumors were significantly enriched for alterations in FGFR3 (10/15, 67%, p=0.044) compared to other subtypes. 

Dr. Meeks concluded his presentation noting that basal subtype tumors had a greater pathologic response to pembrolizumab compared to other subtypes, while residual luminal tumors were often classified as luminal infiltrated. If validated, basal subtypes may be preferentially treated with neoadjuvant immunotherapy to achieve a pathologic response. 

 

Presented by: Joshua J Meeks, MD, Ph.D., Assistant Professor of Urology and Biochemistry and Molecular Genetics Northwestern University, Chicago, Illinois

Co-Authors: Leigh Ann Fall, Arighno Das, Kimberly McLaughlin, Daniele Raggi, Alberto Briganti, Elena Farè, Patrizia Giannatempo, Laura Marandino, Andrea Gallina, Maurizio Colecchia, Roberta Luciano, Francesco Montorsi, Andrea Necchi

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020

References:
1.  Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018 Dec 1;36(34):3353-3360.

Related Content: AUA 2020: Planned Secondary Analysis of PURE-01: Role of FDG-PET/CT in Evaluating Lymph Node Involvement of Patients with Muscle-Invasive Bladder Cancer Receiving Neoadjuvant Pembrolizumab and Radical Cystectomy

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