Breadth of RCC Treatment Options Includes Novel Agents and Combo Strategies

Kathryn E. Beckermann, MD, PhD

A slew of monotherapy and combination approvals has reshaped the frontline treatment landscape for patients with metastatic renal cell carcinoma (mRCC), said Kathryn E. Beckermann, MD, PhD.

"We now have a breadth of options for first-line treatment," said Beckermann. "It is wonderful to have patients for whom we are turning their kidney cancer into a chronic disease."

For example, results from the randomized phase II CABOSUN trial demonstrated a 52% reduction in the risk of disease progression or death with cabozantinib (Cabometyx) compared with sunitinib (Sutent) for patients with advanced RCC (HR, 0.48; 95% CI, 0.31-0.74; P = .0008).¹ Additionally, the overall response rate (ORR) was 20% versus 9%, respectively.

In November 2019, results of an updated subgroup analysis of CABOSUN showed superiority for cabozantinib over sunitinib in terms of progression-free survival (PFS) and ORR across patients regardless of age, brain metastases, and tumor burden.²

However, despite these findings, combination treatments are a preferred approach for several patient subgroups, said Beckermann. Over the past 2 years, nivolumab (Opdivo) plus ipilimumab (Yervoy), pembrolizumab (Keytruda) plus axitinib (Inlyta), and avelumab (Bavencio) plus axitinib were FDA approved for first-line treatment of patients with advanced RCC. The nivolumab/ipilimumab approval is specific to intermediate- and poor-risk patients.

Though sequencing the abundance of therapies available remains a challenge in RCC treatment, investigators are encouraged by the influx of options that continue to emerge.

"These improvements in the frontline setting have been exciting," said Beckermann. "Still, we have so many patients who go on to progress. In addition to asking sequencing questions in the second-line setting, we need to look at third- and later-lines of therapy as well."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Beckermann, an instructor of medicine in the Division of Hematology/Oncology in the Department of Medicine at Vanderbilt University Medical Center, discussed the available single-agent and combination options for the treatment of patients with mRCC.

OncLive^®: What factors do you consider when deciding whether to use TKIs or immunotherapy up front?

Beckermann: The data primarily show an increased ORR and OS improvement with single-agent therapy. A VEGF inhibitor alone may be appropriate to use if I am concerned about giving a patient immune-related toxicities. Perhaps that patient already has an active autoimmune disease, or they had a transplant for which I am worried about graft rejection.

What data support TKI monotherapy for mRCC?

We have a long history of using VEGF inhibitors. The CABOSUN trial looked at cabozantinib versus sunitinib in the first-line setting and, of course, we have the nivolumab study [looking at that agent as a PD-1 inhibitor alone]. The trial data we have for the benefit of PD-1 inhibitor therapy is in the second-line setting.

How do you choose among the available TKI/immunotherapy combinations of avelumab/axitinib or pembrolizumab/axitinib, or the immunotherapy combination of nivolumab/ipilimumab?

Patients with favorable-risk disease should be considered for VEGF inhibitor plus checkpoint inhibitor combinations, because their disease biology was based on a VEGF-designed prognostic score. We know that their biology is likely to respond to a VEGF inhibitor, but the immunotherapy may provide a durable response that the patient would not receive with a single-agent VEGF inhibitor.

For poor- and intermediate-risk patients, it is a very patient-derived decision. Again, if the patient has an active autoimmune disease, concerning [effects after] transplant, or perhaps treatment-resistant hypertension, an immunotherapy combination may be more appropriate.

Has any information on sequencing these combinations become available?

No, but I know there are active trials looking to answer this question. The phase III PEDIGREE trial is asking whether can we go from an immunotherapy combination to an immunotherapy/VEGF inhibitor combination. As we learn more about mechanisms of resistance, [we can attempt to answer] what the optimal sequencing should be.

There are additional trials looking at adding CTLA-4 inhibitors for patients who do not respond to PD-1 inhibition alone. That is not a combination, but it would be interesting in terms of sequential development.

Is there any real-world experience of having to sequence these regimens?

There is some anecdotal evidence we see from patients in later-lines of treatment. In that setting, we are trying to give every available option. We have seen some benefit in giving PD-1 inhibitors plus CTLA-4 following single-agent PD-1 inhibitor. Whether or not that combination will be beneficial is to be determined.

What other strategies are in development for the newly diagnosed setting?

That is an interesting question. There are ongoing strategies looking at targeting other areas of the VHL pathway. Also, there are ongoing trials looking at triplet combinations. We want to know if triplets can greater improve ORR and durable disease control with manageable toxicity.

References

1. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017;35(6):591-597. doi: 10.1200/JCO.2016.70.7398.
2. George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for untreated patients with advanced renal cell carcinoma of intermediate or poor risk: Subgroup analysis of the Alliance A031203 CABOSUN trial. The Oncologist. 2019;24(11):1497-1501. doi: 10.1634/theoncologist.2019-0316.