Petrylak Discusses Progress With Pembrolizumab in Urothelial Carcinoma

Daniel P. Petrylak, MD

Pembrolizumab (Keytruda) was approved in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The approval was based on the KEYNOTE-045 study, in which the median overall survival was 10.3 months with pembrolizumab versus 7.4 months with chemotherapy (HR, 0.70; P <.001), which consisted of paclitaxel, docetaxel, or vinflunine.

“These patients have prolonged durable responses and that is what is really driving the survival benefit in the situation,” said Daniel P. Petrylak, MD.

OncLive: Can you provide an overview of KEYNOTE-045?

In an interview with OncLive at the 2017 ASCO Annual Meeting, Petrylak, professor of Medicine and Urology, co-director, Signal Transduction Research Program, Yale School of Medicine, discussed the KEYNOTE-045 results and the next steps with pembrolizumab in urothelial carcinoma.Petrylak: KEYNOTE-045 is a randomized trial that compared pembrolizumab to a dealer’s choice chemotherapy in patients with urothelial cancer who had been previously treated with either carboplatin or cisplatin-based chemotherapy regimens. The trial was important since it was the first to demonstrate a survival benefit in favor of checkpoint inhibitor therapy compared to chemotherapy.

How do you anticipate the approval of pembrolizumab in this setting will affect the treatment landscape, given the explosion in immunotherapies?

The chemotherapy arm saw a survival benefit of about 7 months whereas the checkpoint inhibition arm was about 10 months. That is a significant difference and is clinically meaningful when compared to other checkpoint inhibitor regimens. There is a proportion of patients, around 25% who do extremely well. These patients have prolonged durable responses and that is what is really driving the survival benefit in the situation. The trouble is, at this point, we have nothing that differentiates one checkpoint inhibitor from another. We don’t yet know the role of efficacy. There was a phase III trial that was just released in the press with atezolizumab (Tecentriq). We have not seen the full data yet, making it difficult to say what the exact results are, but Genentech announced that they did not meet their primary endpoint. What we need is a careful analysis of that trial before we make any major conclusions. Nonetheless, pembrolizumab has shown a survival benefit in the phase III trial, whereas other checkpoint inhibitors have been approved based on accelerated approval parameters.

Since the side effects and response rates are similar, the only distinguishable feature between these drugs is the schedule. There are some Q2 week, Q3 week, and Q4 week drugs. The real question is how comfortable is the physician or the patient going 4 weeks without being seen. It is important to have a good staff to be sure that the patient is not developing side effects. In my opinion, the Q3 week schedule is the most beneficial, since it’s right in the middle. However, Q2 weeks may also have an advantage, as well.

Any other analyses from KEYNOTE-045 that are going to be done?

Is there anything you would like to share about the quality-of-life findings?

What combinations are being considered right now with pembrolizumab?

We don’t know if anti—PD-1 is better than anti–PD-L1. We don’t have any data to confirm that or know if there is a sequential effect. That is something that needs to be studied in the future.There is a presentation at ASCO about the quality-of-life analyses with KEYNOTE-045 and that’s going to be crucial. It’s obvious that this is going to have a more beneficial side effect profile than chemotherapy. Vinflunine does have severe constipation as well as fatigue as adverse events that go along with it. A question we continue to ask is how these adverse events impact the quality of life, which we will see at this ASCO meeting. In my experience, the patients who are on chemotherapy have different types of side effects, such as fatigue, neutropenia, or neutropenia fevers. The side effects seen with immunotherapy are those with inflammation, diarrhea, skin rash, liver function abnormalities, and thyroid abnormalities. However, these are of an inflammatory nature, making them different than the side effects experienced with chemotherapy. Patients receiving combination immunotherapy tend to experience more long-term side effects, whereas monotherapy seems to be better tolerated. In the future, what we’re going to need is to figure out who is going to benefit from monotherapy and who is going to require more treatment to get them a survival benefit.There are many combinations that are out there right now. We’ve been focusing on a combination of ramucirumab (Cyramza) plus pembrolizumab. We’ve completed a phase I, 3-pronged trial that’s been run at Yale. This is being investigated in lung cancer, gastric cancer, and I am running the bladder cancer portion. We’ve seen some activity. We’re also trying to determine if using antiangiogenesis agents reverses the resistance that is seen with immunotherapy. This trial will be forthcoming.

There are studies that are combining agents such as OX40. Other combinations are currently being studied as well as upfront chemotherapy and immunotherapy. There is a lot being studied right now. The trouble is, do we have enough patients to conduct all of these studies. That is why we have to be very careful about using our science to figure out what is the right combination to go with first and move forward.

Bajorin DF, De Wit R, Vaughn DJ, et al. Planned survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC). J Clin Oncol 35, 2017 (suppl; abstr 4501).