Immunotherapy Combinations in Renal Cell Carcinoma

Immune checkpoint inhibitors have shown clinical activity in patients with advanced renal cell carcinoma (RCC). The distinct mechanism of action of these therapies represents the potential for combination strategies, suggests Thomas Hutson, DO, PharmD. In early studies assessing the combination of VEGF inhibitors with anti—PD-1 or –PD-L1 antibodies, adverse events (AE) were a challenge, particularly hepatotoxicity, although promising activity was also observed, Hutson notes.

The AE profile with immune checkpoint inhibition is different than experienced with therapies against VEGF and mTOR, Hutson notes. Immune checkpoint inhibition causes the activation of T-cells against normal host cells along with tumor cells. This activation can cause flu-like symptoms, along with damage to the skin, gastrointestinal tract, adrenal glands, and pituitary gland.

As a single-agent, the PD-1 inhibitor nivolumab demonstrated activity in patients with metastatic clear-cell RCC. At a 2.0 mg/kg dose, the treatment showed a progression-free survival of 4 months, an objective response rate of 22%, and a median overall survival (OS) of 25.5 months in patients with previously treated mRCC. Interestingly, since these therapies are immune-based, histology should not significantly impact efficacy, suggesting that there should be activity in both clear cell and non-clear cell histologies, Hutson notes.

Top-line findings from the pivotal phase III CheckMate-025 study revealed that second-line nivolumab improved OS compared with everolimus for patients with metastatic RCC, although full data were not yet released. Results from this study are eagerly anticipated, particularly since profound and prolonged responses have been observed in a subset of patients, Eric Jonasch, MD comments. There are very limited data in untreated patients, which is the setting that is ideal for immunotherapy, notes David F. McDermott, MD.

In untreated patients with RCC, a number of trials are assessing combination strategies. In the phase III CheckMate-214 trial, nivolumab is being explored in combination with the CTLA-4 inhibitor ipilimumab in comparison with sunitinib (NCT02231749). Another phase III study is exploring the anti—PD-L1 therapy atezolizumab (MPDL3280A) combined with bevacizumab (NCT02420821) in comparison with sunitinib (NCT02420821).

As these therapies move into the frontline setting, it is important to understand responses, as patients appear to respond differently to an immune checkpoint inhibitor than has been seen with other therapies, says Hutson. In some situations, the tumor may grow momentarily before shrinkage is observed, in a phenomenon known as pseudoprogression, explains Hutson. While tumors do ultimately regress, it can be challenging for clinicians to distinguish pseudoprogression from true progression, adds David F. McDermott, MD, who emphasizes the importance of maintaining therapy and not discontinuing treatment too soon.