Expert Assesses Rapidly Expanding Therapeutic Options in RCC

Sumanta Kumar Pal, MD

The treatment landscape of renal cell carcinoma (RCC) is changing at a remarkably fast pace, says Sumanta Kumar Pal, MD.

“It’s incredible to see just how quickly the field of immunotherapy is evolving,” he said. “I definitely think there will be a lot of interest over the next couple of years in looking at the outcomes of some of these trials that combine checkpoint inhibitors, or potentially look at pairings of VEGF inhibitors with checkpoint inhibitors.”

Among these many advancements, the field has also seen the FDA approval of the combination of lenvatinib (Lenvima) and everolimus (Afinitor) in May 2016 as a treatment for patients with advanced RCC following prior antiangiogenic therapy.

Cabozantinib (Cabometyx) received its own FDA approval in this setting as well in April 2016, following the results of the phase III METEOR trial, in which the agent demonstrated a 42% reduction in the risk of progression or death compared with everolimus in patients with advanced RCC.

OncLive: What were some of the main highlights from your presentation?

What is the potential impact of a study like this, and what are you thinking in terms of the overall potential impact of atezolizumab if it is approved in this paradigm?

In an interview with OncLive, Pal, medical oncologist, assistant clinical professor, Department of Medical Oncology and Therapeutics Research, co-director, Kidney Cancer Program, City of Hope, delves into the recent progress seen in this rapidly growing field, and sheds light on some of the therapeutic options currently available for patients with RCC.Pal: We had a great opportunity at this year’s meeting to highlight our adjuvant clinical trial of atezolizumab (Tecentriq). The study is going to take patients with high-risk or metastatic RCC who have been fully resected and will randomize them to either atezolizumab for a year, or placebo.There have been multiple efforts to demonstrate the benefit of therapy in the adjuvant setting. We can think of 6 to 7 clinical trials that have been done using so-called VEGF inhibitors. To date, the results that we have, I would say, are actually somewhat disappointing.

Are you thinking that some of these combination strategies looking at immunotherapy with VEGF inhibitors will enhance activity? Is there any synergy there?

What about immunotherapy in the preoperative setting?

We do have the phase III ASSURE trial, which is reported out by the US cooperative groups, and that study yielded a negative result. We also have the phase III S-TRAC clinical trial, which is led by Pfizer, and although that study demonstrated a delay in tumor recurrence, we still don’t really see a signal of overall survival (OS). I actually think that immunotherapy may potentially overcome that hurdle.If we’re just talking about the adjuvant setting in this scenario, I think it might be a little too early to start exploring combinations. Right now, I think that the key in the adjuvant setting is really to demonstrate that there are improved outcomes, but at the expense of very limited toxicity. That’s one of the challenges with both the S-TRAC and ASSURE trials. I think that both of those studies demonstrated a fair amount of toxicity in the adjuvant setting. What we’re hoping to do with single-agent immunotherapy, as opposed to a combination, is really yield some benefit and survival and recurrence rates, but also limit the scope of toxicity that patients are experiencing.There are 2 clinical trials in this space. One is the phase III trial of atezolizumab, which is purely an adjuvant study that I’m involved in the leadership of. There’s also a study through the Eastern Cooperative Oncology Group (ECOG) called the PROSPER trial, which is looking at a short duration of nivolumab (Opdivo) therapy, followed by surgery, followed by extended nivolumab. The comparison there is to observation, not to placebo.

How have you seen this field grow in the past year or so?

As an expert in the field, is it interesting to see this plethora of immunotherapy agents taking over?

I think that both studies certainly have merits. I do think that the ECOG study may have issues in terms of accrual for various reasons. It’s very, very challenging in this day and age to facilitate that neoadjuvant window of therapy. There’s always a theoretical risk of progression, but perhaps the biggest challenge really is accrual. It’s hard to come across these patients.It’s incredible—last year [at this meeting], the debate was so different. We were still talking about the essential second-line debate of VEGF TKI versus mTOR. Now we’re talking about VEGF TKI plus mTOR versus cabozantinib, versus PD-1 inhibition. It’s just a lot more exciting, and I think we saw a lot of that showcased today. So there are really dramatic changes, and the pace of the evolution is just remarkable to me.It’s incredible to see just how quickly the field of immunotherapy is evolving. I definitely think there will be a lot of interest over the next couple of years in looking at the outcomes of some of these trials that combine checkpoint inhibitors, or potentially look at pairings of VEGF inhibitors with checkpoint inhibitors. I think the real challenge for us, as practicing clinicians seeing patients with kidney cancer, is going to be deciphering which is the optimal data set to rely upon. Certainly, dual checkpoint inhibition has its merits, but I firmly believe that there’s going to be a population of patients (and this is borne out already in the literature) that aren’t going to respond to those therapies. So there’s always the possibility that this combination of VEGF inhibition and checkpoint inhibition may be the superior approach.

What are some factors that you take into consideration when choosing from these different second-line therapies?

I’d also like to highlight some of the data that we have coming out now looking at the combination of cabozantinib with nivolumab. This is a study led by Dr Andrea Apolo, and I think that’s a real game-changer, particularly in kidney and bladder cancer, where we know that both of those drugs have activity.I tend to be fairly dogmatic when it comes to second-line therapy. At this point in time, I really feel like my preferred agent of choice would be cabozantinib. And the reason for that is it really has this veritable trifecta in terms of clinical outcomes. It improves progression-free survival, OS, and response rate.

The challenge with nivolumab is that a large majority of patients will not respond to the drug, and we’re not actually delaying cancer growth with that model. Although it may potentially spare some degree of toxicity—and I’m not necessarily sure I actually believe that, as I still think there are some toxicities associated with the drug—there are going to be a lot of patients who don’t yield benefit from the drug.

What do you think we’re going to accomplish going forward in the next 1 to 2 years?

Cabozantinib, on the other hand, has a primary progressive disease rate of only 19%, and with that in mind, the vast majority is going to derive some benefit from the agent.Dr. Bernard Escudier gave a great talk at the meeting that sort of looked ahead at different designs that we could employ in clinical trials going forward. I personally think that 1 of the goals in upcoming years will be to take agents that are in our current arsenal, and I think that this trial of cabozantinib with nivolumab is a great one. It allows us to use agents that we know have a track record in the context of RCC. We’re hopefully going to see those regimens push forward aggressively.