Novel Combinations Advance Through RCC Pipeline

Peter Van Veldhuizen, MD

Combination immunotherapy approaches have emerged as a key strategy in the frontline paradigm for renal cell carcinoma (RCC). Not only have these combinations improved overall responses, but they have subtly “redefined frontline alternatives,” said Peter J. Van Veldhuizen, MD, a hematologist/oncologist at Sarah Cannon Research Institute.

For example, the results of the phase III CheckMate-214 trial examined the frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with sunitinib (Sutent) and showed a 37% reduction in the risk of death in intermediate- and poor-risk patients (HR, 0.63; P <.0001).¹ In April 2018, the FDA approved the combination for this patient population.

The landscape could add another immunotherapy-based regimen, following the positive results of the phase III IMmotion151 trial. In this study, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) reduced disease progression or death by 26% for patients with previously untreated PD-L1—positive metastatic RCC. Median PFS was 11.2 months with the combination versus 7.7 months with single-agent sunitinib (HR, 0.74; 95% CI, 0.57-0.96; P = .0217).²

Beyond immunotherapy, the FDA approved cabozantinib (Cabometyx) in December 2017 for previously untreated patients with advanced RCC, based on a meaningful improvement in progression-free survival versus sunitinib (Sutent) in the phase II CABOSUN trial.

OncLive: What are the most recent advances in the treatment of patients with kidney cancer?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on A Summer of Progress: Updates from ASCO 2018, Peter J. Van Veldhuizen, hematologist/oncologist, Sarah Cannon Research Institute, discussed available and emerging therapies for patients with kidney cancer.Van Veldhuizen: We looked at some key trials like the CABOSUN trial, which looked at first-line cabozantinib versus sunitinib for intermediate- and high-risk patients. CheckMate-214 compared frontline nivolumab and ipilimumab with sunitinib. Both of those trials showed improved survival in the study arm compared with sunitinib. These trials have somewhat redefined frontline alternatives.

We also reviewed some of the newer combinations, such as atezolizumab and bevacizumab, which showed encouraging results. That combination is another potential frontline treatment, though it is not yet FDA approved.

What factors do you consider in deciding between the available frontline treatments?

In addition, we discussed the CARMENA trial, which looked at debulking nephrectomy in the metastatic setting in patients who received sunitinib alone versus debulking nephrectomy followed by sunitinib. [Debulking nephrectomy followed by sunitinib] did not show a survival advantage with sunitinib alone. There is still some question about the benefit [of nephrectomy] for selected patients.The combination of nivolumab and ipilimumab is exciting because it resulted in some complete responses. The tolerability may be in question for certain patients. Performance status, age, and PD-1 status also play a role in whether or not you select that regimen.

What was the background of the IMmotion151 trial with atezolizumab and bevacizumab?

An exploratory analysis suggests that patients with PD-1 positivity in the intermediate- and high-risk disease categories are the ones who are the most likely to benefit [from immunotherapy]. Attaining PD-L1 status may help sort out whether you choose that regimen versus a tyrosine kinase inhibitor like cabozantinib or pazopanib (Votrient) in good-risk patients.The combination is based on bevacizumab’s potential synergy with immunotherapy. It may help enhance the immune response. Even though those drugs are administered intravenously, they are generally well tolerated. There is good rationale for the combination.

Is there any rationale to combine PD-1/PD-L1 with chemotherapy, which has been evaluated in other solid tumors?

Please expand on the CARMENA findings.

We're seeing more of these potential combinations that can improve outcomes. It is hard to know where it will fit in the scheme of things. If it does get FDA approved, perhaps it may be an alternative to the nivolumab/ipilimumab combination, in which the toxicity may be higher. This will be an immunotherapeutic first-line combination that may have some better tolerability.There are really no active chemotherapeutic drugs in RCC. The combinations [lie] with the targeted agents. In the older studies with immunotherapy and pazopanib (Votrient), there were some concerns about liver toxicity. That combination hasn't really moved forward. Other targeted therapy combinations have unclear potential. As we get more data, axitinib (Inlyta) and a PD-1 inhibitor may be another potential combination.I hope it doesn't shift [the standard] too far away from debulking nephrectomy because there is still a clear benefit in select patients with a large primary lesion, small-volume systemic disease, and better performance status.

What ongoing trials are you looking forward to seeing the results of?

[The trial] helps [show that] those patients who have more extensive metastatic disease or a smaller primary [lesion] are less likely to benefit. [Smart patient] selection is first and foremost. There's a question of how it will be integrated with immunotherapy as well.There's a first-line trial with cabozantinib plus ipilimumab and nivolumab versus sunitinib. There is another first-line trial that’s looking at lenvatinib (Lenvima) and pembrolizumab (Keytruda) versus lenvatinib and everolimus (Afinitor) versus sunitinib. There is a study concept that will hopefully will move forward, which is looking at neoadjuvant ipilimumab and nivolumab and reassessing the role of debulking nephrectomies in that setting.

References

1. 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.
2. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36 (suppl 6S; abstr 578).