Limited treatment options in advanced urothelial cancer

Lack of efficacy of cabazitaxel in urothelial cancer

In 2017, a phase II multicenter randomized open-label study comparing cabazitaxel (a taxane with activity in docetaxel-refractory cancers) with vinflunine did not proceed to phase III since the futility analysis showed significantly better efficacy of vinflunine. In 70 patients with one prior platinum-based chemotherapy treatment for locally advanced or metastatic transitional cell carcinoma of the urothelium (TCCU), the partial response (PD) was achieved in 13 % with cabazitaxel compared to 30 % with vinflunine and progression-free survival (PFS) was 1,9 months for cabazitaxel vs. 2,9 months for vinflunine (p = 0,039).

Thus, cabazitaxel had minimal activity in TCCU, not confirming the findings observed with this drug in prostate cancer. Vinflunine is still the only chemotherapy treatment approved by EMA beyond first and second lines of TCUU treatment.

Restricting use of anti-PD-1 drugs for urothelial cancer

In June 2018, EMA announced restricting of pembrolizumab and atezolizumab first-line treatment in advanced TCCU based on early data review that demonstrated reduced survival in patients with low concentrations of PD-L1 using these check-point inhibitors. These results suggest that both drugs might be less effective than chemotherapy in this setting. As EMA recommended: »Health-care providers are advised to use atezolizumab as monotherapy in adult patients with advanced urothelial carcinoma whose tumours have PD-L1 expression of 5 % or higher, and pembrolizumab as monotherapy for patients whose tumours express PD-L1 with a combined positive score of 10 or higher. Patients who have already had chemotherapy or who have had any other cancer, can continue with treatment as before.«

Conclusion

This finding is unexpected because until now PD-L1 expression has not correlated with treatment response to anti-PD-L1 drugs. Nevertheless, limiting use of these drugs to patients who are likely to benefit, makes sense. There is still need for an optimal biomarker to predict response to both checkpoint inhibitors and chemotherapy and to determine the best sequence of therapies. We are still waiting with anticipation to see if combination of immunotherapy with chemotherapy will improve patient outcomes.

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Sources:
1. Bellmunt J, Kerst JM, Vázquez F et al. A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN). Ann Oncol 2017 Jul 1; 28 (7): 1517−1522, doi: 10.1093/annonc/mdx186. 
2. Gourd E. EMA restricts use of anti-PD-1 drugs for bladder cancer. Lancet Oncol 2018 Jul; 19 (7): e341, doi: 10.1016/S1470-2045(18)30433-9.