Expert Shares Upfront Sequencing Strategies in mRCC

Sumanta Kumar Pal, MD

Even with 2 recent FDA approvals in the frontline setting for patients with metastatic renal cell carcinoma (mRCC), an ongoing clinical trial exploring combination therapy with a multikinase inhibitor and an anti—PD-L1 agent could be yet another path forward, according to Sumanta Kumar Pal, MD.

In April 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline therapy for intermediate- and poor-risk patients with RCC, based on phase III data from the CheckMate-214 trial. This decision followed the December 2017 approval of frontline cabozantinib (Cabometyx) in RCC. The approval of the multikinase inhibitor was based on a meaningful improvement in progression-free survival versus sunitinib (Sutent) in the phase II CABOSUN trial.

Now, an open-label, multicenter, phase Ib study (NCT03170960) is looking at the combination of atezolizumab (Tecentriq) with cabozantinib across several tumor types, including in advanced RCC as a frontline treatment. Investigators on the trial, which will have a dose-escalation followed by a dose-expansion stage, will evaluate the safety, efficacy, and pharmacokinetics of the regimen.

OncLive: What did you highlight during your discussion on first-line treatment in kidney cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Pal, a medical oncologist at City of Hope, shed light on the latest frontline therapeutic options for patients with mRCC and other advancements on the horizon.Pal: A lot of discussion hinged on some of the newer data with bevacizumab (Avastin )and atezolizumab in the IMmotion151 trial. We are really seeing some outstanding efficacy with this combination of agents—supporting this premise of using a VEGF inhibitor with an immuno-oncology agent. We discussed the evolving data sets that combine VEGF inhibitors and immunotherapy-based agents, and I also alluded to some of the trials that I’m really excited about.

Can you discuss the frontline approval of nivolumab and ipilimumab? Is this a regimen you’re already using in patients?

For instance, I’m chairing a trial looking at cabozantinib with atezolizumab with Dr Neeraj Agarwal, and that is one that folks should consider enrolling on across a wide spectrum of GU cancers, in fact. I’ve been involved with the development of nivolumab/ipilimumab in RCC from the phase I clinical trial onward. I was on the CheckMate-016 study, which was followed very quickly by the big phase III CheckMate-214. That study showed a very convincing and compelling improvement in overall survival with nivolumab and ipilimumab relative to sunitinib. Those data were very impressive.

We have some data with other VEGF inhibitors combined with immunotherapy. Can you discuss these and what findings they show?

How have you seen the frontline approval of cabozantinib advance the RCC landscape?

What is the design of the atezolizumab plus cabozantinib trial that you are conducting?

It has been somewhat slower to adopt in terms of my clinical practice. I still have a number of frontline clinical trials that are ongoing, one in particular that is looking at cabozantinib with atezolizumab. Frankly, that combination, of a very potent VEGF inhibitor with a very potent immunotherapy-based agent, may potentially be the path forward. There are a number of phase I clinical trials looking at combinations of VEGF inhibitors and immunotherapy-directed therapies. For instance, so far, we saw data for axitinib (Inlyta) and avelumab (Bavencio), and axitinib with pembrolizumab (Keytruda)—both of which were published in Lancet Oncology. We also had data for 2 other evolving combinations; these are cabozantinib with nivolumab, and tivozanib (Fotivda)—a very potent VEGF inhibitor—with nivolumab. Those studies are all probably going to be moving forward in some way, shape, or form. Lenvatinib (Lenvima) with pembrolizumab also seems to be showing promise. All of these are probably going to make a big dent in the way we are treating our patients with RCC. Many folks have had some comfort level of using cabozantinib in the second-line setting; that comfort level is really key. Folks are familiar with toxicity management. There is certainly a role [for cabozantinib] in the frontline setting for intermediate- and poor-risk patients and, frankly speaking, maybe even good-risk patients, depending on their particular phenotype. If patients have bone metastases, for example, that is a setting where we know cabozantinib is very highly active. I certainly encourage consideration of it in that setting.We have actually seen atezolizumab work across a whole spectrum of different cancer types. We have actually seen impressive frontline data for atezolizumab monotherapy in the IMmotion150 trial in advanced RCC. Of course, we have lots of data for atezolizumab in the context of bladder cancer.

What are some of the biggest remaining challenges in RCC?

The trial that Dr Neeraj Agarwal and I are looking at [involves] cabozantinib, a very potent multikinase VEGF inhibitor, alongside atezolizumab in multiple cohorts. We have a cohort of untreated patients with mRCC. We also have multiple cohorts in bladder cancer—for cisplatin- and carboplatin-pretreated patients, for those who are cisplatin ineligible, and a very intriguing cohort of patients who may be eligible for cisplatin and choose not to receive it. In mRCC, one of the biggest questions in the frontline setting is, “What is the role for PD-L1?” I have been asked this question pretty often, and I definitely think there is something to the PD-L1 story. When we look at the CheckMate-214 trial, there is clearly a difference in clinical outcomes for patients who are PD-L1 positive or PD-L1 negative. Whether or not it rises to the level of clinical applicability, I’m not sure. I certainly think that if I had the data at my disposal, it does inform my treatment selection to some extent. More prospective studies of this and some of the genomic classifiers that we have in RCC will certainly have merit.