Standard of Care Continues to Shift in RCC

Toni K. Choueiri, MD

The standard of care for patients with renal cell carcinoma (RCC) continues to change as novel therapies and combinations rapidly get approved, says Toni K. Choueiri, MD.

For example, the December 2017 FDA approval of cabozantinib (Cabometyx) was based off of practice-changing data from the phase II CABOSUN trial, in which the multikinase inhibitor reduced the risk of progression or death by 52% compared with sunitinib (Sutent). Additionally, the median progression-free survival was 8.6 months with cabozantinib versus 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74; P = .0008).

After 30.8 months of follow-up, the median overall survival (OS) was 26.6 months (95% CI, 14.6-not evaluable) in the cabozantinib arm versus 21.2 months (95% CI, 16.3-27.4) in the sunitinib arm, representing a nonstatistically significant 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21; P = .29).¹

Immunotherapy combinations are also starting to push the field forward, explains Choueiri. In the CheckMate-214 study, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 37% versus sunitinib in intermediate- and poor-risk RCC (HR, 0.63; P <.0001).² The FDA approved this regimen for frontline treatment of this patient population in April 2018.

OncLive: Please provide an overview of the topics highlighted at the meeting and how they speak to the evolution of genitourinary cancer treatment.

In an interview during the 2018 OncLive^® State of the Science Summit^™ on Genitourinary Cancers, Choueiri, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, discussed the recent advancements considered at the event, of which he was the chair, and shared his insight on the future treatment landscape of patients with kidney cancer.Choueiri: To start, there was a talk about robotic surgery in kidney and bladder cancer. It is very interesting how surgery has evolved from open, to laparoscopic, and now to robotic surgery.

Dr Lauren C. Harshman discussed the evolving role of adjuvant therapy in high-risk patients with RCC in the era of tyrosine kinase inhibitors (TKIs). There are still some ongoing trials that will read out in the next couple of years. She also spoke about integrating high-risk RCC treatments, both in the adjuvant as well as the neoadjuvant settings, followed by adjuvant therapy.

Dr Bradley A. McGregor tackled targeted therapy for patients with advanced RCC, and most recently combinations of immunotherapy. Immunotherapies are being looked at in combination with other immunotherapy regimens, such as nivolumab and ipilimumab, or, with VEGF inhibitors. There is a lot to come in that advanced setting because many of the phase III trials against sunitinib have either finished accrual or are ongoing. The field may change again.

Can you speak to the success of the CABOSUN trial?

We had Dr Guru P. Sonpavde talk about integrating novel immunotherapy with chemotherapy in advanced bladder cancer in the early-stage setting. Finally, Dr Xiao X. Wei discussed systemic therapy management with the focus on PD-1/PD-L1 inhibitors and the management of adverse events (AEs). Immunotherapy is a specific class of agents with a specific management for AEs.We are beyond single-agent VEGF receptors and TKIs. We still use other single agents, such as nivolumab or cabozantinib. In the frontline setting against sunitinib, cabozantinib showed superior response rates and an improved PFS.

What does the future look like? Will it include combinations of immunotherapies and targeted therapies?

This randomized phase II trial was essentially for patients in the poor- and intermediate-risk subgroups. Cabozantinib was approved in December 2017 in the frontline setting.Almost all of the large phase III trials are comparing combinations, such as immunotherapy plus VEGF inhibition, plus another immunotherapy regimen, or plus sunitinib. However, these studies are not head to head, so hopefully we will eventually have a head-to-head study. It is extremely important to compare combinations with the new standard of care. The combinations, especially with the high response rates that we are seeing, are going to be a significant part of the standard of care. However, the combination of nivolumab and ipilimumab has a higher response rate than sunitinib.

Can you discuss any new biomarker development?

Also, with earlier studies, we are seeing TKIs such as axitinib (Inlyta) and lenvatinib (Lenvima). Additionally, the combination of pembrolizumab (Keytruda) and [axitinib] was very well tolerated, resulting in response rates between 50% to 70% and higher. There are also studies with 2 antibodies, the PD-L1 inhibitor atezolizumab (Tecentriq) and bevacizumab (Avastin), which were presented at the 2018 Genitourinary Cancers Symposium. The PD-L1—positive population demonstrated a higher response rate with the combination when compared with sunitinib. However, it is still too early to determine the OS benefit.We are still trying to come up with a biomarker for single-agent PD-1/PD-L1 inhibitors as well as VEGF TKIs. It is not easy, as we do not have anything to guide our clinical decision in practice. PD-L1 via immunohistochemistry was prognostic for nivolumab but when it was combined with ipilimumab in the CheckMate-214 study, it responded differently when looking at PD-L1 status. There was a much higher benefit for patients who were PD-L1 positive. This biomarker could tell us something. It has been integrated in most phase III trials but is still not ready for prime time.

References

1. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.
2. Escudier B, Tannir NM, McDermott DF, et al. CheckMate214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advanced 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. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369.