Choueiri Reflects on Recent RCC Advances

Toni K. Choueiri, MD

The 2018 ASCO Annual Meeting included a number of clinical highlights in renal cell carcinoma (RCC), according to Toni K. Choueiri, MD. On the heels of multiple FDA approvals throughout the latter half of 2017 and the beginning of 2018, the field continues to rapidly shift.

“RCC today, as well as for the past few years—and certainly for the next 2 to 5 years—is going to be one of the most dynamic fields in solid tumor oncology,” said Choueiri. “I am very glad, blessed, and humbled to be in this field.”

The CARMENA trial (NCT00930033) in patients with synchronous metastatic RCC demonstrated the noninferiority of sunitinib (Sutent) to cytoreductive nephrectomy plus sunitinib, the current standard of care. Phase III findings showed a median overall survival (OS) of 18.4 months for sunitinib compared with 13.9 months for the standard arm (HR, 0.89; 95% CI, 0.71-1.10).

Additionally, sunitinib showed a similar median OS in patients with intermediate (23.4 vs 19.0 months; HR, 0.92; 95% CI, 0.68-1.24) and poor prognosis (13.3 vs 10.2 months; HR, 0.85; 95% CI, 0.62-1.17). Choueiri noted that questions remain, but these results will be referenced and studied for years to come.

Additional studies in RCC are ongoing and of interest. For example, the randomized, double-blind, placebo-controlled, phase II CANTATA study is evaluating CB-839, an oral glutaminase inhibitor, with cabozantinib (Cabometyx) versus cabozantinib with placebo in patients with metastatic RCC (NCT03428217). Cabozantinib was approved by the FDA in December 2017 for previously untreated patients with advanced RCC.

Studies with pembrolizumab (Keytruda), atezolizumab (Tecentriq) plus bevacizumab (Avastin), and sorafenib (Nexavar), are also shaking up the landscape, Choueiri noted.

With all of these advances—and more on the way—optimal sequencing remains a challenge. However, Choueiri said that there may be a future where multiple sequences are plausible.

OncLive: Can you reflect on the CARMENA trial that was presented at the 2018 ASCO Annual Meeting?

In an interview with OncLive, Choueiri, director of the Kidney Cancer Center at Dana-Farber Cancer Institute, recapped some of the most significant data presented thus far in 2018 for the treatment of patients with RCC.Choueiri: It was a big conference for kidney cancer; we had a presentation that made it to the plenary session, [which was] CARMENA. This study asked the question of VEGF-targeted therapy in the modern setting, namely sunitinib, and whether taking the kidney out in metastatic RCC by cytoreductive nephrectomy makes sense. What was presented in the past in the cytokine era, as well as the many retrospective studies, was that cytoreductive nephrectomy helps.

Here in the CARMENA study, there was no difference in OS in the sunitinib monotherapy patients versus those who had sunitinib and then underwent a cytoreductive nephrectomy. This is likely paradigm shifting. Overall, many other clinical endpoints were looked at, such as progression-free survival (PFS), which did not show a difference. The paper was published at the same time as the article in the New England Journal of Medicine.

What other oral presentations took place at this year’s meeting?

We will still look at CARMENA in great detail for the months and years to come. Again, patients with poor-risk RCC should not even be considered. The question is, “Should we consider cytoreductive nephrectomy at baseline or later on in patients with a large primary tumor with great performance status and very limited disease burden outside the kidney?” That is an open question and an important study. One was a study of pembrolizumab (Keytruda), another was a study of the combination of atezolizumab and bevacizumab, and then there was a study of sorafenib. They all happen to be in untreated advanced clear cell RCC.

Pembrolizumab was tested and showed a response rate of 38% in this untreated population. There were usual single-agent immune-related adverse events. In PD-L1—positive patients, the response rate was 50%, which begs the question, “Can this agent be used alone or should we use it in combination?” We do not have a lot of data in this context with single-agent PD-1/PD-L1 inhibitors. We do have data with pembrolizumab and atezolizumab and very little data with nivolumab (Opdivo). The story is evolving, and pembrolizumab is being tested in first-line therapy with axitinib (Inlyta) in combination as well as in the adjuvant setting.

The second presentation again looked at patients with untreated metastatic clear cell RCC with a combination of the PD-L1 inhibitor atezolizumab and bevacizumab versus sunitinib. This was presented at the 2018 Genitourinary Cancer Symposium by Robert J. Motzer, MD, of Memorial Sloan Kettering, but Bernard Escudier, MD, from Institut Gustave Roussy, presented the quality-of-life data at the 2018 ASCO Annual Meeting. Most patients did better with the combination at the price of a little increase in treatment-related death. Though, the treatment of the control arm of sunitinib was the conventional 50 mg at 4 weeks on/2 weeks off, rather than sunitinib 2 weeks on/1 week off, which is used more in emerging data and is better tolerated. This is no surprise.

Can you give an overview of the CANTATA trial?

Reflecting on the exciting research presented this year, what does this mean for the future of RCC?

The third is a very small randomized study using sorafenib in a specific population that we don't usually focus on, the M1 and early-disease patient population. In this study from Italy, patients with resected RCC would normally be followed with serial imaging. These patients were randomized, after being judged by scans to be M1 and early disease, to observation versus sorafenib. Unsurprisingly, it ended up showing that the recurrence-free survival is not different between both arms. Usually, we would extrapolate from the adjuvant setting. Here, we have 4 studies with only 1 being positive, so it isn't surprising that this sorafenib study—called the RESORT study—was negative.A trial in progress that was presented, CANTATA, is a randomized trial of patients in the second-line or later-line setting to cabozantinib plus CB-839, which is an important emerging target in RCC and other tumors. Combining CB-839 with a standard drug like cabozantinib makes sense. This ongoing randomized phase II trial is international, with a primary endpoint of PFS. It is an important study to follow.Hopefully, there will be focus on biomarkers, so that we know who to select for which treatment. We currently do not have something that we use routinely in clinical practice, but we do have large studies that collect tissue and blood for us to ask those questions. In terms of how the field will go, if you look at the phase III studies that are either being reported, have finished accrual, are accruing, or in the making—many of them involve combinations. Most of them are against sunitinib, which is becoming an older standard by the day.

We started with nivolumab plus ipilimumab (Yervoy), then atezolizumab/bevacizumab, and now there are other [emerging combinations]. Any of these studies may change the standard of care and put combinations as the way to go in the frontline setting, at least for the majority of patients. The other thing is that we are learning more and more that clinical stratification is very important.

We should not forget novel targets, especially trials following PD-1 and VEGF or PD-1 and CTLA-4 in the second- or third-line setting. Imagine if you use the 2 or 3 most active drugs first; what is left for second- and third-line agents? There are some concepts that are emerging, such as what us being tested in the CANTATA trial.

Do you believe that this plethora of new information has complicated the sequencing of therapy more, or has it provided clarity?

We have 4 phase III trials that are well powered with checkpoint blockade. If we look at the melanoma setting, trials with CTLA-4 inhibitors and PD-1 inhibitors have been positive. The next setting is in patients with high-risk T3, T4, M1, and early disease who receive a checkpoint blocker for a set period of time. Those studies are accruing and, if they are positive, they are going to change the paradigm. How will that influence metastatic disease? It is an evolving story. I do not think we have an optimal sequence, especially that we are dealing mostly now with VEGF TKIs, targeted therapies, and PD-1/PD-L1 inhibitors. We may end up with multiple plausible sequences, and the choice will be based on the comfort of the physician, toxicities, financial toxicities, or on certain pathways.

In collaboration with multiple investigators, we have created a trial that starts patients on standard nivolumab plus ipilimumab. It is a response- and outcome-based intervention. The second drug is cabozantinib, and if you don't have a complete response or a progression, you go on a combination of cabozantinib and nivolumab versus nivolumab alone. We are trying to come up with an ideal sequence, starting with one drug. Luckily, nivolumab plus ipilimumab is a standard in intermediate- and poor-risk patients.

This is not by lack of attempt, but an embarrassment of riches. At the end of the day, this is good for patients. It is left up to us to create an ideal sequence that will work. This is why RCC will be very dynamic and interesting in the next several years.

Méjen A, Escudier B, Thezenas S, et al. CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial. J Clin Oncol. 2018;36(suppl; abstr LBA3).