Immunotherapy Combos Emerge as Standard Frontline Treatment in Advanced RCC


David F. McDermott, MD, discusses developments in the frontline setting for the treatment of patients with advanced renal cell carcinoma.

David McDermott, MD

The standard of care for treatment-naïve patients with advanced renal cell carcinoma (RCC) has shifted from a single-agent VEGF TKI to a checkpoint inhibitor plus either a VEGF TKI or a CTLA-4 inhibitor, explained David F. McDermott, MD.

For example, results of the phase III KEYNOTE-426 trial showed that the frontline combination of pembrolizumab (Keytruda) and axitinib (Inlyta) versus sunitinib (Sutent) led to a 47% reduction in the risk of death in patients with advanced RCC (HR, 0.53; 95% CI, 0.38-0.74;&#8239;P&#8239;<.0001).1 In April 2019, the FDA approved this combination regimen as a frontline treatment for patients with advanced RCC, based on the KEYNOTE-426 findings.

Secondly, the pivotal phase III JAVELIN Renal 101 trial, demonstrated that the combination of avelumab (Bavencio) and axitinib was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.2 Based on these data, the FDA approved this combination in this setting in May 2019.

In April 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC, based on results from the phase III CheckMate-214 trial. In longer follow-up of the study, the combination compared with sunitinib showed a median overall survival (OS) of not reached versus 26.6 months, respectively (HR, 0.66; 95% CI, 0.54-0.80; P <.0001).3

“By bringing PD-1/[PD-L1] into the frontline setting, we're seeing major improvements in the outcomes that patients care about, including long-term survival, for the first time in advanced kidney cancer,” said McDermott. “We're seeing deep responses, complete responses, and occasional remissions of disease, showing a true advance in the field.”

In an interview with OncLive, McDermott, a professor of medicine at Harvard Medical School as well as a staff physician and director of Biologic Therapy and Cutaneous Oncology Programs in Hematology/Oncology at Beth Israel Deaconess Medical Center, discussed developments in the frontline setting for the treatment of patients with advanced RCC.

OncLive: How has immunotherapy transformed the RCC paradigm?

McDermott: In 2015, the standard algorithm for most patients with advanced kidney cancer was a VEGF inhibitor for treatment-naïve patients, and then using a PD-1 inhibitor with nivolumab for patients who fail VEGF inhibitor. However, over the last several years, there has been a wave of new data from phase I to now phase III trials. If you combine VEGF inhibitors with PD-1 inhibitors, you can [get better outcomes] than with a VEGF inhibitor alone.

The best example of that is the KEYNOTE-426 trial, which compared pembrolizumab and axitinib with sunitinib; [the combination] showed clear benefits in objective response rate, progression-free survival, and OS. That has become a standard approach. The same could be said for the combination of axitinib and avelumab.

Another positive study was with the PD-L1 inhibitor atezolizumab (Tecentriq) and bevacizumab (Avastin). There are going to be several other trials, probably showing similar [results]. When you combine VEGF inhibitors with PD-1/PD-L1 inhibitors, you can get some improvements in outcome, including survival. That is probably because by bringing PD-1 inhibition up to the frontline setting, it tends to be most active in some of our most aggressive tumors. By giving [PD-1 inhibition] early, you are preventing those patients from dying before they get to second-line therapy.

Another approach that is now more commonly applied in a variety of other tumors is the combination of PD-1 inhibitors and CTLA-4 inhibitors that has been developed in parallel with PD-1 and VEGF inhibitor strategies. PD-1 inhibitors plus CTLA-4 inhibitors led to a very impressive result from the CheckMate-214 trial, which looked at nivolumab and ipilimumab versus sunitinib in patients with untreated metastatic disease. Those patients did much better as it relates to OS, particularly if they had intermediate- and poor-risk disease. The combination also had encouraging quality-of-life outcomes and deep responses.

The reason deep responses are something we focus on in the immuno-oncology world is because patients who have major tumor shrinkage, with 70%, 80%, or 90% of their tumors disappearing and 100% for complete responders, will have remission of their disease. We're starting to see [remissions] with these combinations at around 10% or so in CheckMate-214. That is something to build on for the future.

Where does immunotherapy fall in terms of sequencing?

Both of the PD-1 combination approaches—PD-1 inhibitors plus VEGF inhibitors and PD-1 inhibitors plus CTLA-4 inhibitors&mdash;have replaced the prior first-line therapy of VEGF inhibitor for most patients. For most of us, we're only using a single-agent VEGF TKI for people who cannot, for whatever reason, receive a PD-1 inhibitor. There are some patients who have significant autoimmune disease and they have [autoimmune disease—related] symptoms or they're receiving treatment for their autoimmune disease.

However, besides that subset of patients, we're using [PD-1 inhibitors plus either VEGF inhibitors or CTLA-4 inhibitors] broadly in patients and seeing improved outcomes. In the future, we will have to address what does and does not work after PD-1 inhibition. In the case of PD-1 inhibition plus CTLA-4 inhibition, most of us believe that VEGF inhibition will work as a salvage therapy in that setting. It's less clear what will work [subsequently] when you start with a PD-1 inhibitor/VEGF inhibitor combination. We need to do trials in both settings.

Many tumor types are bringing PD-1 inhibitors into the adjuvant setting. There are a number of interesting trials in [the adjuvant] setting that may lead to the application of immune checkpoint blockade in the adjuvant setting for some patients with kidney cancer.

What is the safety profile of these immunotherapy regimens?

Toxicities are an issue. What we are seeing in kidney cancer is not much different than what we see in other tumor types. In the case of anti—PD-1 plus anti–VEGF, which is fairly unique to kidney cancer, you don't see an amplification of adverse events (AEs), but you do see chronic AEs—particularly with VEGF inhibition, which is given for a long period of time. We're not seeing new things, but we have to manage chronic and sometimes annoying AEs with PD-1 inhibition plus VEGF inhibition that can impact quality of life and lead to treatment discontinuation.

With the anti—PD-1 plus anti–CTLA-4 combination, we think CTLA-4 adds some benefit, particularly as it relates to durable response; however, it certainly also adds toxicity to the PD-1 inhibitor. In melanoma, unlike kidney cancer, the dose of the PD-1 inhibitor is lower than the dose of the CTLA-4 inhibitor. We have inverted that in our patients with kidney cancer and have significantly reduced toxicity without reducing efficacy. In CheckMate-214, the incidence of grade 3/4 toxicity and the incidence of discontinuation are less by giving more of the PD-1 inhibitor and less of the CTLA-4 inhibitor.

What are other immunotherapy strategies in the pipeline?

There are several interesting agents in clinical trials. Some of the ones that are furthest along involve novel cytokines. NKTR-214, which is a modified version of interleukin-2, is in randomized studies in kidney cancer. The most interesting drug for patients with kidney cancer, in my somewhat biased opinion, is a HIF-2α inhibitor that is now potentially entering a phase III trial in 2020. That's an interesting agent based on its mechanism of action. It targets the HIF-2 transcription factor and produces responses in patients with failed prior therapy. Transcription factors are not easy to drug and the fact that this was a druggable transcription factor was an impressive feat of medicinal chemistry.

Additionally, proving that targeting this transcription factor could improve outcomes was encouraging and, while the response rate in these initial trials are not that high, the toxicity profile is encouraging. Data suggest we might be able to combine this agent with other agents. There are trials trying to do that as well, including immunotherapy agents.

What are some unmet needs in this patient population?

We still have to learn about how to manage toxicities and figure out which [patients should receive which immunotherapy combination]. There are going to be a lot of debates about that in the future. We don't have head-to-head data and we need them. For most practitioners, by bringing PD-1 inhibitors into your practice for untreated patients with kidney cancer, you're delivering significant improvements and outcomes for most of those patients.

Additionally, adjuvant trials are ongoing. If practitioners have patients they might consider for those trials, they should look to see where [the trials] are open and send patients to those centers. We saw in melanoma that adjuvant immune checkpoint blockade makes a difference in relapse-free survival. That may also be the case in kidney cancer. Those trials are worth consideration for patients and practitioners.


  1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.
  2. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med.&#8239;2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.
  3. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20(10):1370-1385. doi: 10.1016/S1470-2045(19)30413-9.
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