Expert Highlights Changes in the Treatment Landscape of RCC

Toni K. Choueiri, MD

Toni K. Choueiri, MD

Patients with renal cell carcinoma (RCC) have seen a change in standard of care as novel therapies and combinations are quickly approved, says Toni K. Choueiri, MD.

In December 2017, the FDA approved cabozantinib (Cabometyx) based on practice-changing data from the phase II CABOSUN trial. The multikinase inhibitor reduced risk of progression or death by 52% compared with sunitinib (Sutent) while 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).

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

The field is also pushing toward immunotherapy combinations, Choueiri adds. Combination nivolumab (Opdivo) plus ipilimumab (Yervoy) reduced risk of death by 37% compared with sunitinib in patients with intermediate- and poor-risk RCC (HR, 0.63;P<.0001), according to results from the CheckMate-214 trial.²In April 2018, this regimen was approved by the FDA for frontline treatment of this patient population.

In an interview during theTargeted Oncology, Choueiri, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, discussed the recent advancements in RCC. He also shared his insight on the future outlook of this treatment landscape.

TARGETED ONCOLOGY: Can you speak to the success of the CABOSUN trial?

Choueiri: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.

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.

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

Choueiri: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.

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.

TARGETED ONCOLOGY: Can you discuss any new biomarker development?

Choueiri: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.