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.
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.
OncLive: Can you discuss the importance of the findings of KEYNOTE-045?
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.
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.
How do these results compare with other checkpoint inhibitors, specifically atezolizumab, which did not meet its OS endpoint in the IMvigor 211 study?
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.