Immunotherapy Continues to Shape Future Bladder Cancer Paradigm

Maria De Santis, MD

The second-line setting of bladder cancer has historically seen little progress prior to May 2016, the time which atezolizumab (Tecentriq) was approved by the FDA as a treatment for patients with locally advanced or metastatic disease that progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

Now, with 5 checkpoint inhibitors FDA approved that have shown benefit in the second-line setting of this disease, the anti—PD-1 inhibitor pembrolizumab (Keytruda) has impressed researchers and clinicians in the field, as it is the only drug of its class thus far to show an improvement in overall survival (OS).

Mature results of pembrolizumab from the KEYNOTE-045 study were presented at the 2017 ESMO Congress. In the study, pembrolizumab demonstrated an OS benefit compared with chemotherapy in patients with recurrent advanced urothelial carcinoma.

The median OS with pembrolizumab compared with chemotherapy was 10.3 versus 7.4 months (HR, 0.70; P = .0003), and 18-month OS rates were 33.2% (95% CI, 27.5-38.9) compared with 19.7% (95% CI, 14.7-24.8) with pembrolizumab versus chemotherapy, respectively.

OncLive: Can you discuss the importance of the findings of KEYNOTE-045?

In an interview with OncLive during the 2017 EMUC Congress, Maria De Santis, MD, associate clinical professor at the University of Warwick, discussed the findings of KEYNOTE-045 and the future of immunotherapy in the treatment landscape of bladder cancer.De Santis: The importance starts with the history of treatment in the second-line setting for urothelial cancer. For many years, there was quite some uncertainty on how to treat those patients, because we did not have a global standard of care in the second-line setting. In the United States, people used taxanes and, in Europe, there was vinflunine.

With the introduction of the checkpoint inhibitors in urothelial cancer, things changed dramatically. This started with phase I/II trials that showed very interesting and promising early signals with pembrolizumab, atezolizumab, and nivolumab (Opdivo). These trials were positive and they showed good signals; however, there was never any phase III trials. Therefore, KEYNOTE-045 is the first to show positive results in a randomized, controlled trial. That is why KEYNOTE-045 is so important.

How do these results compare with other checkpoint inhibitors, specifically atezolizumab, which did not meet its OS endpoint in the IMvigor 211 study?

KEYNOTE-045 compared pembrolizumab every 3 weeks to investigator choice of chemotherapy. The comparator being chemotherapy goes back to the uncertainty of treating patients with urothelial cancer in the second-line setting. Compared with this variety of chemotherapy, pembrolizumab showed an improvement in survival, most significantly in the intent-to-treat (ITT) population. There was a coprimary endpoint of OS and progression-free survival (PFS). PFS was not positive, but this was not so unexpected because, in the immunotherapy setting, we rarely see the PFS to be positive. However, the OS endpoint was clearly positive, showing a more than 10-month OS compared with the chemotherapy arm that was slightly more than 7 months.The IMvigor 211 study was the other randomized phase III trial in the second-line setting of bladder cancer. The endpoint in this trial was slightly different from KEYNOTE-045, which turned out to be very important. The first endpoint was OS benefit in the biomarker-positive population. Therefore, if this group was not positive for OS, the whole trial would be benefit. However, in the ITT population, it turned out that the trial was statistically positive, yet the numerical gain in OS was small. Still, the trial is a negative trial. The trial design was very similar to the KEYNOTE-045 trial, comparing atezolizumab with investigator’s choice of chemotherapy.

What are your thoughts on pseudoprogression in bladder cancer?

How are you currently using immunotherapy in bladder cancer?

What does the future hold for immunotherapy in this disease?

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.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.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.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.

What is the rationale and hopes for using Bacillus Calmette-Guerin (BCG) with pembrolizumab in the KEYNOTE-054 study?

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.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.