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)

Barcelona, Spain (UroToday.com) Dr. Joaquim Bellmunt provided the invited discussant for: 

Dr. Bellmunt highlighted that NABUCCO was a single-arm phase IB trial testing the feasibility of pre-operative ipilimumab + nivolumab in stage III urothelial carcinoma patients who were either cisplatin ineligible or refused chemotherapy. Feasibility was the primary endpoint, which was met in that 96% of patients had a radical cystectomy within 12 weeks of the first infusion. Safety was a secondary endpoint: 55% of the total population had grade 3-4 treatment related adverse events, which decreased to 42% when excluding clinically insignificant lipase elevations. 30-day mortality was 0% and one patient suffered 90-day mortality from progression of disease. Although a small study, it was quite efficacious given the setting of locoregionally advanced disease and a pCR rate of 46%, as well as a noninvasive disease rate of 58%. A subset of patients showed a pCR in the bladder, with an abundant immune infiltration, accompanied by lymph node micrometastasis (mixed response) – the clinical significance of a mixed response is not yet known. As such, we have good evidence that neoadjuvant/preoperative immunotherapy works for bladder cancer with pCR rates ranging from 29%-46%:
ESMO2019 MIBC

Dr. Bellmunt notes that there are other ongoing nivolumab/ipilimumab neoadjuvant trials ongoing:

  • CA209-9DJ: A pilot study evaluating the safety of neoadjuvant nivolumab alone or in combination with ipilimumab for cisplatin ineligible patients with MIBC

  • CA017-078: Peri-surgical phase III trial of nivolumab +/- BMS-986205 (IDO inhibitor) + chemotherapy in MIBC


Dr. Bellmunt highlighted the following comments for the NABUCCO trial:

  • This is a different population than those in the PURE-01 and ABACUS trials
  • This highlights an unmet clinical need: Surgically incurable/resectable after treatment didn’t have a different outcome than M1, despite surgery (EORTC 30987 [1])
  • Long-term follow-up is needed, specifically regarding the patients with a better response in the primary than in the lymph nodes
  • Other schedules are begin explored in order to minimize toxicity

The subset analysis of the PURE-01 study investigated FGFR3 alteration as a predictor of non-response to neoadjuvant pembrolizumab for patients with muscle-invasive bladder cancer. The PURE-01 protocol was amended to include a more heterogeneous population (n=136) and focused on potential predictive markers. Necchi and colleagues found that FGFR3 alterations are not associated with pathologic response to pembrolizumab: 29.5% of patients harbored ESCAT tier >=1-2 genomic alterations suggesting benefit from approved or investigational targeted therapies. Tier 1B was represented by FGFR3 genomic alteration (n=17, 15.2%). Furthermore, there were no significant differences in the frequency of genomic alterations between the pathologic response categories, including FGFR3 genomic alteration. The Immune190 score is an expression of immune genes inversely correlated with PPAR-gamma expression. The RNA immune signatures are statistically significantly associated to pathological response to neoadjuvant pembrolizumab but not neoadjuvant chemotherapy. Dr. Bellmunt notes that genetic alteration is a vague term and we need to better define SNV or mRNA expression. Additionally, he notes that there is conflicting evidence as to what FGFR alteration tumors response best to: in 22 patients previously treated with immunotherapy, the ORR was 59% for erdafitinib. Further work assessing how best to treat FGFR alteration patients is required.

The phase 3 trial of adjuvant sunitinib for patients with high-risk RCC (S-TRAC) assessed comprehensive tumor genomic and transcriptomic analyses. Overall, there were 171 patients (sunitinib, n = 91; placebo, n = 80) were genotyped and 133 (sunitinib, n = 72; placebo, n = 61) were included in the gene expression signature analyses. Patients in the placebo arm with mutations in WDFY4 or CSPG4 had shorter DFS compared with sunitinib treated patients who had no mutation detected in either gene. Low tumor mutational burden was associated with a longer DFS in patients in the placebo arm (HR 0.289, 95% CI 1.405-5.932), but did not influence DFS in the sunitinib arm. Ultimately, different effects on DFS were observed between treatment groups according to the expression of specific genes. When assessed by various gene expression signatures, low-angiogenesis gene expression signature showed a modest association with shorter DFS vs high- angiogenesis gene expression signature in placebo (HR 1.912; 95% CI 0.829-4.409) but did not differentiate DFS in sunitinib. Patients with low-Minf gene expression signature in sunitinib had longer DFS vs those with high-Minf gene expression signature (HR 0.304; 95% CI 0.132-0.702). Using the new JAVELIN Renal 101 signature, high expression of the signature showed a modest association with prolonged DFS vs low expression in the placebo (HR 0.42; 95% CI 0.18-0.98) and in the sunitinib arm (HR 0.51; 95% CI 0.24-1.08). Dr. Bellmunt concluded that genomic analysis of high-risk RCC can help identify patients who may benefit from adjuvant sunitinib. 

Presented by: Joaquim Bellmunt, MD, Associate Professor of Medicine, Beth Israel, Boston, MA

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. Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012 Apr 1;30(10):1107-1113.



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