Something else happened in this trial that was unexpected; the control arm was much better than expected with more than 10 months median OS, but the difference in OS between the atezolizumab arm and the chemotherapy arm was small. Still, atezolizumab is a very active drug; we know that from IMvigor 210. We have positive signals in all-comers, especially the biomarker-positive patient population.
What are your thoughts on pseudoprogression in bladder cancer?
The topic of pseudoprogression has been known for some time. We have seen it in melanoma, and the pseudoprogression rate is lower in urothelial cancer. We don't see a lot of it in my experience. It is lower than in melanoma, as well as in renal cell cancer.
How are you currently using immunotherapy in bladder cancer?
Currently, I am using checkpoint inhibitors in the second- and third-line settings for patients who have progressed on platinum-based chemotherapy. We have drugs available, and we have EU approval for nivolumab, pembrolizumab, and atezolizumab. This is the spectrum where I use it, but we can use pembrolizumab and atezolizumab in those patients who are not eligible for cisplatin-based chemotherapy. This gives us a much greater spectrum of treatment options for our patients with urothelial cancer, particularly those who are unfit for cisplatin. Some patients with prognostic factors like poor renal function do not benefit from combination chemotherapy, so for these patients we need additional and less toxic treatments. This is where checkpoint inhibitors come in.
What does the future hold for immunotherapy in this disease?
We are looking at a bright future with checkpoint inhibitors in urothelial cancer. There are many ongoing trials, particularly randomized phase III trials in the first-line setting. Some of these trials are comparing standard-of-care cisplatin- or carboplatin-based combination chemotherapy to either the combination of chemotherapy with immunotherapy—pembrolizumab or atezolizumab—and these trials also have a monotherapy arm with a checkpoint inhibitor. The results of those will be very interesting and maybe even practice changing.
There is another trial that is ongoing testing combination immunotherapy durvalumab (Imfinzi) and tremelimumab in the first-line setting. This has finished accrual and we are very eager to see these results. This could be another very interesting option.
Hopefully, in the near future, we will use checkpoint inhibitors in the neoadjuvant or adjuvant settings. There are randomized phase III trials ongoing in the adjuvant setting. Again, these trials may be practice changing.
What is the rationale and hopes for using Bacillus Calmette-Guerin (BCG) with pembrolizumab in the KEYNOTE-054 study?
In the nonmuscle-invasive bladder cancer setting, the poorest population has been treated with BCG for the past 30 years. BCG has shown to improve the recurrence and progression rates, and improved the disease-free survival in those patients. However, it is not an ideal treatment; it has some side effects and some patients can't complete the maintenance part. There are still patients with recurrence and progression, and some patients lose their bladder or die of metastatic disease. This population is a challenge, particularly those patients who progress after BCG. There is a huge unmet with these patients.
We know biomarker PD-L1 testing increases with the use of BCG, as well as with poor-risk patients with nonmuscle-invasive bladder cancer. We also have the understanding that BCG turns “cold” tumors into “hot” tumors, which increases T-cell activity in those tumors. Here, we have the rationale to add checkpoint inhibitors via [KEYNOTE-054]. Pembrolizumab has shown to delay progression and turn [cancerous] bladders into healthy bladders again. This is the rationale, but we will have to see how the results turn out.
De Wit R, Vaughn DJ, Fradet Y, et al. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial. Abstract presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA37.