Expert Discusses Immunotherapy Advancements in a Rapidly Changing GU Field

Ani S. Balmanoukian, MD

Ani S. Balmanoukian, MD

The landscape of genitourinary (GU) malignancies is changing at a rapid pace, with promising immunotherapy advancements in both renal cell carcinoma and urothelial carcinoma.

The phase III randomized CheckMate-214 trial, for example, compared frontline treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) versus sunitinib (Sutent) in patients with metastatic RCC. The combination reduced the risk of death by 32%, and the median overall survival (OS) was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95;P= .0003). Among patients with intermediate- and poor-risk disease the risk reduction was 37%.

In urothelial carcinoma, there are 5 approved checkpoint inhibitors: nivolumab, pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

In an interview withTargeted Oncology, Ani S. Balmanoukian, MD, director of Thoracic Oncology, and associate director of the Phase I Immune-Oncology Program at The Angeles Clinic and Research Institute, discussed immunotherapy developments in GU malignancies.

TARGETED ONCOLOGY:Please give an overview of your lecture on advances with immunotherapy in GU cancers.

Balmanoukian:The field has come a long way since the initial introduction of checkpoint inhibitors a few years ago. There have been significant advancements in checkpoint inhibitors in the last 2 years in both RCC and urothelial carcinoma. At the 3-year mark, we are seeing significant differences and improvements in median OS with nivolumab versus everolimus in RCC.

Beyond that, combinations with immune checkpoint inhibitors seem to be carving out a place in the treatment of various malignancies in GU cancers, including RCC. The CheckMate-214 trial showed promising results in the newly diagnosed setting, with the combination of ipilimumab and nivolumab versus sunitinib. The combination of checkpoint inhibitors showed significant improvements in median OS for patients with RCC with intermediate- and poor-risk disease versus sunitinib.

We are also seeing interesting new combinations with immunotherapy, including IDO inhibitors plus pembrolizumab (Keytruda), and IDO plus other checkpoint inhibitors. These combinations are showing promising activity in both RCC and urothelial carcinoma.

In RCC, there are some interesting results combining VEGF tyrosine kinase inhibitors with immunotherapy. Those are predominantly early-phase trials, but we are seeing some nice responses using those combinations, and more advanced trials are forthcoming. We will see if those combinations pan out as options for patients in the future.

In urothelial carcinoma, we are seeing some new novel immunotherapy combinations that we are hoping will become options for patients in the future.

TARGETED ONCOLOGY:Can you speak to the importance of clinical trials of immunotherapy?

Balmanoukian:One of the most interesting clinical trials—and we were honored to be a part of it—was with atezolizumab. We were a part of the initial phase I trial using atezolizumab in various diseases. It was during that phase I trial that [the investigators] decided to use a checkpoint inhibitor in urothelial cancer, given that urothelial cancers are known to have high mutation burdens. We were one of the first sites to enroll patients with urothelial cancer. Seeing that pan out, seeing results in patients, and then taking that onto a phase II trial was impressive and satisfactory. It gave us a sense that we were doing something for patients while moving the field forward. Prior to this trial, other than local immunotherapy, systemic immunotherapy had not been used in urothelial carcinoma. Just being a part of that was exciting.

TARGETED ONCOLOGY:With all of this success, will chemotherapy and surgery eventually become obsolete?

Balmanoukian:I don't think we are there yet. Chemotherapy is still important, and it still has a role in some patients' treatment regimens. That lends to the fact that we need to select which patients are suited to receive immunotherapy and which patients should still receive chemotherapy or undergo surgery or radiation.

TARGETED ONCOLOGY:Is there a commonality among patients who are responding well to immunotherapy across GU cancers?

Balmanoukian:That is a great question. Thus far, we have not found a specific commonality between patients. PD-L1 expression is used as a marker [for immunotherapy] in lung cancer, but it is not used as a significant marker in GU malignancies. Now, we do see that patients with urothelial carcinoma who have PD-L1—positive tumors do respond better. Also, in CheckMate-214, we saw that PD-L1–expressers responded better to the combination regimen. However, it is not a selective marker for patients to receive immunotherapy. Currently, we don't know a good characteristic to select patients with either RCC or urothelial carcinoma for immunotherapy.

Markers of response are desperately needed. Dr Edwin Posadas of Cedars-Sinai Medical Center asked about sequencing immunotherapy drugs now that more agents are becoming available. Right now, we essentially just give these drugs to everyone. However, better markers are necessary to definitively identify who can benefit from these drugs.

TARGETED ONCOLOGY:What advice can you provide to community oncologists treating patients with GU cancers?

Balmanoukian:The one thing to note for any community oncologist nowadays is that the field is changing at a rapid pace, so it is important to be aware of all of the options available. Also, clinical trials are very important. Anyone treating [patients with] RCC has great tools in their pocket, but they should remember clinical trials are an option as well, as they can offer new agents to patients. The same is true for urothelial carcinoma.

Reference:

Escudier B, Tannir NM, McDermott DF, et al. CheckMate-214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5.