ESMO 2019: Multiple-cohort Analysis Investigating FGFR3 Alteration as a Predictor of Non-response to Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer - A Medical Oncologist's Perspective

Barcelona, Spain ( Neoadjuvant platinum-based chemotherapy is the standard of care for muscle-invasive resectable urothelial carcinoma. As many patients are not eligible for chemotherapy or refuse it, the PURE-01 (NCT02736266) study1 examined the efficacy of neoadjuvant pembrolizumab (anti-PD1) immunotherapy on response rates. The authors showed an encouraging 42% pCR after three treatments of pembrolizumab in patients with cT2-T3bN0M0 disease.

In this poster, the authors report the results of molecular analysis in PURE-01 patients to determine whether tumor mutational burden (TMB) and FGFR3 alteration are biomarkers of response to neoadjuvant pembrolizumab. This analysis was accomplished using DNA sequencing to ascertain tumor mutational burden and genomic alteration status of FGFR3, and transcriptomic profiling to look at FGFR3-mediated and immune-associated gene expression profiles.

A total of 17 patients were identified as having an altered FGFR3 gene, though the nature of the DNA alterations was not provided. FGFR3 altered tumors were enriched for clinical T2 tumors (76.5%) and numerically less alterations in DNA damage repair genes as well as RB1. Tumor mutational burden was not different between the FGFR3 altered tumors (mean 13.8 Mut/MB, range 4-45) and FGFR3 intact tumors (mean 12.2, range 0-45). PD-L1 status was also similar between groups.

No association was found between FGFR3 genomic alteration and pathologic response in the PURE-01 cohort (comparing p0-2 versus p-T3/T4 in the table below

ESMO 2019 PURE 01 study baseline molecular alterations

The other major findings from this presentation are that when applying the Immune190 expression signature from immune-cells, complete responders treated with neoadjuvant immunotherapy (top bar graph) were significantly enriched for a higher Immune190 score. This association did not hold true for tumors treated with neoadjuvant chemotherapy (bottom bar graph). This suggests that. 

ESMO 2019 PURE 01 study Graph 1

ESMO 2019 PURE 01 study Graph 1

In summary, although FGFR3 genomic alteration and tumor mutational burden do not appear to be biomarkers for response to neoadjuvant immunotherapy, complete responders tend to have a higher Immune190 transcriptional score, suggesting this could be a potential biomarker for patient selection in future trial efforts.

Presented by: Andrea Necchi, MD, Medical Oncologist at the Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology Congress (#ESMO19), September 27th-October 1st, 2019, Barcelona, Spain