ESMO 2019: FGFR3 Alteration as a Predictor of Non-Response to Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer

Barcelona, Spain (UroToday.com) In the PURE-01 study, neoadjuvant pembrolizumab resulted in a 42% pT0 rate and 54% pathological downstaging rate in patients with muscle-invasive bladder cancer.1 Looking in more detail, pT0 patients had features suggesting pre-existing immunity or higher tumor mutational burden may promote response. At the ESMO 2019 annual congress, Dr. Necchi and colleagues reported results of their investigation into potential mechanisms for resistance to pembrolizumab, including FGFR3 genomic alterations.

Patients enrolled in the PURE-01, which is still recruiting patients in its amended design, had predominant urothelial carcinoma histology and stage cT ≤ 4N0 muscle-invasive bladder cancer. Biomarker analyses in the expanded cohort of 112 patients included PD-L1 combined positive score and comprehensive genomic profiling (FoundationCDx assay). In addition, TCGA muscle-invasive bladder cancer (n = 405) and a prospective commercial cohort of 415 muscle-invasive bladder cancer patients from the clinical use of the Decipher Bladder TURB test from the GRID registry were analyzed. Furthermore, a single-sample genomic classifier was trained to identify FGFR3-active tumors (FGFR3+).

In the PURE-01 cohort, despite a linear association of tumor mutational burden with ypT0 in multivariable models, there was no association between FGFR3 genomic alterations and pathological response nor with PD-L1 expression. FGFR3 genomic alterations were found in 17.6% ypT0 vs 20.7% in ypT3-4 disease (corrected p = 0.82). Applying the genomic classifier to the TCGA muscle-invasive bladder cancer cohort, the authors found 45% of FGFR3+ cases had FGFR3 mutations vs 9% for the rest of the cohort. Applying the genomic classifier to the prospective commercial cohort, they found that the FGFR3+ patients showed significantly lower PD-L1 (-0.03 vs. 0.109, p < 0.001) and PD-L2 (0.184 vs. 0.389, p < 0.001), but consistent PD-1 (0.175 vs. 0.163, p = 0.48) gene expression. Finally, FGFR3+ patients had lower immune and stromal infiltration as measured by the immune190 (0.227 vs. 0.348, p < 0.001) and Estimate (100.14 vs. 1099.2, p < 0.001) gene expression signatures.

 Dr Necchi concluded with several take home messages:
  • There was no statistical association between FGFR3 activity and FGFR3 genomic alteration
  • FGFR3 genomic alterations did no correlate with pathologic response to pembrolizumab
  • However, FGFR3-active tumors tended to have lower immune activity, suggesting that FGFR3 activity may provide a potential tool for further discriminating the mechanisms underlying response and resistance to neoadjuvant pembrolizumab
  • Consistent with this observation, the investigators found the immune signature (immune190 score) allowed discrimination of activity to neoadjuvant pembrolizumab to neoadjuvant chemotherapy

Clinical trial identification : NCT02736266 (PURE01) NCT02609269 (GRID Registry).

Presented by: Andrea Necchi, MD, Department of Medical Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy

Co-Authors: A. Necchi 1, R. Madison 2, J. Chung 2, D. Raggi 1, A. Briganti 3, F. Montorsi 3, J. Boormans 4, Y. Liu 5, J. De Jong 6, J. Chung 2, P. Black 7, J. Ross 2, S. Ali 2, E. Davicioni 5, E. Gibb 5 

1. Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, IT

2. Foundation Medicine, Cambridge, US

3. IRCCS Ospedale San Raffaele, Milan, IT

4. Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, NL

5. Decipher Biosciences, Vancouver, CA

6. Erasmus MC Cancer Institute, Rotterdam, NL

7. Vancouver Prostate Centre, Vancouver, CA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain 

Reference: 

  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 Oct 20 [Epub ahead of print].

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    ESMO 2019: Invited Discussant: (904PD, 905PD, 906PD) NABUCCO (mUC), FGFR3 Alteration as a Predictor of Non-Response to Neoadjuvant Pembrolizumab (mUC), and Adjuvant Sunitinib in Patients with High-Risk (RCC)
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