Prof. Yohann Loriot (Université Paris-Saclay, France) discussed novel treatment options beyond immunotherapy1. He urged that a better understanding of the tumor biology is necessary to identify new targets, and will facilitate precision medicine.
Approaches derived from fundamental tumor biology have demonstrated clinical efficacy, including fibroblast growth factor receptor (FGFR) inhibitors and antibody-drug conjugates. In muscle-invasive bladder cancer (MIBC), somatic genetic alterations are potentially targetable, including mutations in FGFR3, HHRm, HER2, components of angiogenesis, and the epigenome.
FGFR3-mutation is associated with luminal-papillary urothelial carcinoma; 70% of this pathology harbors somatic activating mutations, 20% exhibits gene rearrangement, and 10% overexpresses FGFR3. Specific FGFR inhibitors tested in urothelial cancer include BGJ398, rogaratinib, and erdafitinib. In the BLC2001 phase-2 trial, 99 heavily pre-treated FGFR3-mutant patients with complex comorbidities received erdafitinib. Despite being an extremely poor prognosis group, 3% achieved a complete response and 37% a partial response. The confirmed response rate was even better in the patients who had previously failed immunotherapy: 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.
The THOR study is a phase-3 study currently enrolling patients with metastatic urothelial carcinoma, identifying those who have previously been treated with immunotherapy. Those who have been treated with immunotherapy are then randomized to erdafitinib versus chemotherapy, and those without prior immunotherapy are randomized to erdafitinib versus pembrolizumab.
Antibody-drug conjugates showing promise include enfortumab vedotin in nectin 4-expressing urothelial carcinoma. In the EV-101 phase-1 dose-escalation/expansion trial, 112 patients treated with single-agent enfortumab vedotin showed an objective response rate of 43%, with a median overall survival of 12.3 months. The EV-301 phase 3 trial randomized patients that have previously received prior platinum and immunotherapy to either enfortumab vedotin or to taxane, vinflunine, or paclitaxel with a primary outcome of overall survival. This trial has completed enrollment and is awaiting data maturity. The combination of enfortumab vedotin plus pembrolizumab has shown activity in patients regardless of PD-L1 expression, and the EV-302 study will further evaluate this combination. In addition, sacituzumab govitecan has been investigated in the phase-2 TROPHY-U-01 study with metastatic urothelial carcinoma; 74% of patients had target lesion reduction.
Inhibiting vascular endothelial growth factor (VEGF) has also been explored. Anti-VEGF agent bevacizumab did not improve overall survival in combination with chemotherapy in initial studies, but a VEGF receptor-2 inhibitor, ramucirumab, might show clinical benefit when combined with docetaxel, as tested in the RANGE study. Namely, the median progression-free survival (the primary endpoint) was significantly prolonged in patients treated with ramucirumab plus docetaxel versus placebo plus docetaxel (4.1 vs 2.8 months; HR 0.757; 95% CI 0.607-0.943).
In conclusion, FGFR inhibitors and antibody-drug conjugates remain the most promising avenues beyond immunotherapy, but there are some alternative options that require more data. Prof. Loriot suggested that hot topics are how to (i) combine these agents with immunotherapy, (ii) investigate early stage of the disease (i.e. neoadjuvant and adjuvant setting), (iii) investigate in patients with non-muscle invasive bladder cancer, and (iv) the better understanding of the mechanisms in primary and acquired resistance.
1. Loriot Y, et al. Novel Urothelial Cancer Treatment Beyond PD-1/PD-L1 Inhibition. EAU20 Virtual Congress, 17-26 July 2020, State-of-the-art-lecture.