Pal Sheds Light on Frontline Therapeutic Strategies in mRCC

Sumanta Kumar Pal, MD

Sumanta Kumar Pal, MD

An ongoing clinical trial investigating the combination of a very potent VEGF inhibitor with a very potent immunotherapy-based agent may potentially represent a path forward for patients with metastatic renal cell carcinoma (mRCC), following 2 recent FDA approvals in the field, 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.

In an interview withTargeted Oncology, 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.

TARGETED ONCOLOGY:Can you discuss the first-line treatment of kidney cancer?

Pal: We are really seeing some outstanding efficacy with this combination of agents [bevacizumab (Avastin) and atezolizumab in the IMmotion151 trial]—supporting this premise of using a VEGF inhibitor with an immuno-oncology agent. There are evolving data sets that combine VEGF inhibitors and immunotherapy-based agents, and [there are also] some trials that I’m really excited about.

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.

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

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.

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.

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

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 inLancet 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. 

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

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.

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

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.

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.

TARGETED ONCOLOGY:What are some of the biggest remaining challenges in RCC?