PD-L1 Inhibitor Avelumab May Improve Survival in Metastatic Urothelial Carcinoma

Article

Andrea B. Apolo, MD, explains the challenges that still remain regarding toxicity and future combination therapies with avelumab, and the potential of checkpoint inhibition in urothelial carcinoma going forward.

Andrea B. Apolo, MD

Urothelial carcinoma, the most common subtype of bladder cancer, presents a host of treatment challenges, says Andrea B. Apolo, MD, a medical oncologist at the National Cancer Institute (NCI) and chief of the Bladder Sancer Section of the NCI’s Genitourinary Malignancies Branch.

According to Apolo, chemotherapy-based first-line therapy for metastatic urothelial carcinoma only achieves a median survival of approximately 14.0 to 15.2 months and the 5-year overall survival (OS) rates range from just 13.0% to 15.3%. The prognosis is even worse for patients with visceral metastases who experience lower OS rates compared with those without visceral metastases (6.8% and 20.9%, respectively).

Currently, there are also no standard therapeutic options for patients with metastatic urothelial carcinoma who fail first-line chemotherapy treatment.

Checkpoint inhibition offers a potential solution, says Apolo. Avelumab (MSB0010718C), an anti—PD-L1 agent, was recently investigated in a phase I study involving patients with refractory metastatic urothelial carcinoma. As of the data cutoff, 44 patients were treated with avelumab for a median of 13 weeks (range, 2-28 weeks), according to Apolo, the study’s lead author. Sixteen patients (36.4%) remained on treatment. Responses were observed in 15.9% of patients (n = 7), with 1 complete response and 6 partial responses. An additional 19 patients experienced stable disease. The proportion of patients alive and progression-free at 12 weeks was 47.2%.

OncLive: What were the goals of the trial?

What were the most significant findings from this study?

In an interview with OncLive, Apolo explains the significance of the trial results, challenges that still remain regarding toxicity and future combination therapies with avelumab, and the potential of checkpoint inhibition in urothelial carcinoma going forward.Dr Apolo: This is a phase I study of patients with refractory metastatic urothelial carcinoma receiving avelumab in the second-line setting and beyond. The primary objectives were safety and tolerability, and the secondary objectives were overall response rate and progression-free survival.Our findings were actually very exciting. First off, we determined that it was safe to give avelumab to this heavily pretreated population, and we also found that it demonstrated clinical activity. We actually saw tumor shrinkage by RECIST criteria. We saw 6 patients with partial responses and one patient with a complete response.

Were there any concerning toxicities found with avelumab?

Are there toxicity concerns that will need to be managed if avelumab is used in combination with other therapies?

What are the next steps planned for this research?

Going forward, where do you see the role of anti—PD-L1 agents, such as avelumab, playing in the treatment of bladder cancer?

What are the biggest challenges in treating metastatic urothelial cancer?

One of the things that was really interesting is that we saw responses in patients with visceral metastasis in addition to patients with lymph node metastases. Those with visceral metastasis tend to have a poorer prognosis, so the fact that we saw tumor shrinkage in this patient population was really, really exciting.Avelumab was actually found to be very safe in this patient population. Patients with bladder cancer tend to be very difficult to treat, as they are older and have a lot of comorbidities. Their comorbidities are often heart disease and renal insufficiency, so they are not the ideal candidates for a clinical trial. However, in this trial, the drug proved to be very safe. The primary toxicity was infusion reactions, which were very manageable. Fatigue and nausea were also observed. There was one grade 3 and no grade 4 or 5 adverse events.While we may see a higher efficacy with combinations, we need a better understanding of toxicities that may arrive from combining therapies. This is especially true in patients with bladder cancer who have renal insufficiency. We generally do not see much renal insufficiency with monotherapy. However, when we use combination therapy, renal toxicity has been seen in some trials. Therefore, that is something that we need to keep a lookout for.We are very excited about the clinical efficacy that we saw and we are going to look at biomarkers and expand the study into larger clinical trials. One of the exciting things about checkpoint inhibitors is the potential for combination therapies to enhance the response, so that is one of the things we are looking into. We see potential for combinations with immunotherapies, targeted therapies, and cytotoxic therapies.It is a very exciting time in bladder cancer research because these drugs demonstrate efficacy. These checkpoint inhibitors actually have clinical activity and we are seeing tumor shrinkage. We do not have data yet regarding how it affects OS, but we are seeing durability of response and that is very important. We do not see that with chemotherapy; with that, patients respond but the tumor comes right back. With these anti—PD-L1 drugs, we are seeing durability.This is really a devastating disease. Patients who are diagnosed with metastatic disease experience a median OS of about 14 months. We really do not have anything to offer these patients once they progress on standard chemo-based treatment. Having another option for treating them will change the way we manage patients with metastatic disease. It is very exciting. We have seen efficacy, and I think an approval for a checkpoint inhibitor in bladder cancer is on the horizon.

Apolo AB, Infante JR, Hamid O, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic urothelial carcinoma: a phase Ib trial. Poster: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2630.

Related Videos
Jaime R. Merchán, MD, professor, co-leader, Translational and Clinical Oncology Research Program, director, Phase 1 Clinical Trials Program, Department of Medicine, Division of Medical Oncology, the University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center
Wenxin (Vincent) Xu, MD,
Wenxin (Vincent) Xu, MD
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
Wenxin (Vincent) Xu, MD
A panel of 5 experts on renal cell carcinoma
A panel of 5 experts on renal cell carcinoma
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer