CLEAR Study Highlights Promise of I/O and TKI Regimens in Advanced RCC

Advanced renal cell carcinoma (RCC) treatment has seen a transformation in how patients respond to therapy, especially now that immune checkpoint inhibitors (ICIs) are increasingly being utilized. The agents add on to the activity that has already been demonstrated with single-agent VEGF inhibitors, without worsening toxicity.

Two combinations of ICIs and VEGF-targeting tyrosine kinase inhibitor (TKIs) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and lenvatinib plus everolimus (Afinitor) were compared with the standard of care anti-VEGF agent sunitinib (Sutent) in the frontline setting in the phase 3 CLEAR trial (NCT02811861). The immuno-oncology (I/O) and TKI combination of lenvatinib/pembrolizumab achieved an objective response rate (ORR) of 71.0% (95% CI, 66.3%-75.7%) and the lenvatinib/everolimus combination led to an ORR of (53.5%; 95% CI, 48.3%-58.7%). Both were compared with sunitinib, which led to an ORR of only 36.1% (95% CI, 31.2%-41.1%), signaling that the addition of an ICI improves outcomes in these patients.1,2

Responses to either I/O and TKI combination also appeared to be more durable compared with sunitinib at 25.8 months (95% CI, 22.1-27.9) for lenvatinib plus pembrolizumab and 16.6 months (95% CI, 14.6-20.6) for lenvatinib plus everolimus versus 14.6 months (95% CI, 9.4-16.7) in the sunitinib arm.

Further, the level of toxicity observed with both combinations was similar and the rates of treatment-related adverse events (AEs) were not significantly higher with the addition of an I/O agent.

In an interview with Targeted Oncology, Thomas Hutson, DO, PharmD, director of the Urologic Oncology Program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center, and professor of medicine at Texas A&M College of Medicine, reviewed findings from the CLEAR study and how these data are set to re-shape the treatment landscape of advanced RCC.

TARGETED ONCOLOGY: Why is the efficacy data from this trial important compared with other treatment options in this space?

Hutson: Kidney cancer continues to go through changes for the better as new therapies become available, but we still don't cure patients. The biggest advance has been the development of checkpoint inhibitors, which have allowed a small group of patients to have what appears to be durable responses, with a percentage of them being complete responses. That's somewhat amazing to sit there and think that in 2021 we're able to have long-term survivors in a cancer that was untreatable just 2 decades earlier.

The checkpoint inhibitors have revolutionized the treatment of advanced cancer for many different tumor types. We have been needing effective therapies for so long, and it's been so amazing for me to have been involved in the early drug development with the original FDA approvals of serotonin syndrome, and to be continuing on in helping to develop some of the newer agents. So, I've been able to witness this advance.

What were the key results of this study?

The CLEAR trial was an international phase 3 study that was 3-armed and powered as such where patients were with clear cell histologies and any risk groups. We enrolled both favorable, intermediate, and poor IMDC [International Metastatic RCC Database Consortium] class risk patients, and they were randomized to receive 1 of 3 therapies. They received either the lenvatinib/pembrolizumab, lenvatinib/everolimus, or sunitinib. Sunitinib was chosen as the gold standard as it has been for over 12 years as the frontline therapy of choice. The sunitinib was administered [at] 15-mg orally for a 4-week on, 2-week off schedule, which was the traditional dosing regimen for that.

The way the study was designed was to look at the lenvatinib and pembrolizumab versus sunitinib, and then also the lenvatinib plus everolimus versus sunitinib.

The greatest efficacy we saw when we looked at this first analysis, which is now after about 27 months follow-up, was that lenvatinib/pembrolizumab had a significant level of efficacy. The primary end point is overall survival [OS] and that has not been reached in either of the combination arms compared with sunitinib, and the hazard ratio is 0.66. The OS landmarks when one compares lenvatinib/pembrolizumab to sunitinib at 12 months is 90% versus 79%. Then at 2 years, it is 79% for lenvatinib/pembrolizumab versus 70% for sunitinib.

If one looks at other efficacy endpoints like progression-free survival [PFS], we see 23.9 months for lenvatinib/pembrolizumab versus 9.2 months for sunitinib. The ORR using RECIST criteria was 71% for the combination versus 36% with sunitinib. Finally, the complete response [CR] rate, which is what we come to expect when one thinks about checkpoint inhibitors, it was 16% for lenvatinib/pembrolizumab versus 4% for sunitinib. So, this trial showed that this I/O and TKI combination had a significant level of activity in the 3 main efficacy end points of OS, PFS, and response rate, including this subset of CRs when compared to the traditional sunitinib.

The other side of the equation is when you have such great efficacy in recognizing that this is not the only I/O and TKI combination that would be potentially on the market to be chosen. One needs to look at other things besides efficacy, such as safety and tolerability. That was evaluated and will continue to be evaluated in this trial. Although the combination of I/O and TKI has more AEs than with a single-agent TKI, the AEs were predictable and manageable, and what one would expect when combining checkpoint inhibitors such as pembrolizumab with a VEGF inhibitor such as lenvatinib. It was nice to see that there was not any worrisome safety signal of the combination. Following up from there is just looking at how people do over the length of their illness. Patients will be assessed not only for their responses and how they performed on initial therapy, but we will also make sure that that patients that do get that combination are faring well, or are better, when they start going on to sequences that all patients ultimately go through.

What is important to note about the safety profile of these combinations? How does safety come into play when you are considering these treatment options for patients?

The safety profile is important because I think one of the things that we need for cancers that are terminal in this stage, is we want to make sure that that the efficacy we're gaining is worth the price that they're going to pay when it comes down to adverse events [AEs] and quality-of-life impact, since most patients are not being cured. We want to make sure that when we make these steps forward in efficacy, that we're not dramatically worsening the QoL or AEs over what had been the standard therapy.

It's important when one starts [a new therapy] to compare across similar agents. For I/O and TKI combinations, we already have a few [options]. We now have cabozantinib [Cabometyx] plus nivolumab [Opdivo], pembrolizumab plus axitinib [Inlyta], and avelumab [Bavencio] plus axitinib. [The CLEAR study regimen] would potentially be the fourth to be approved in the United State, so one would need to be able to compare and contrast efficacy and safety. We hedge a little bit about doing that because we realize that cross-trial comparisons are not statistically valid. But all we have to do as clinicians is to look across the trials to do the best we can and try to find a regimen that we think is going to be the most tolerable.

With all those caveats said, I believe that the AE types listed among the various /O plus TKI combinations are quite similar. There may be some variations and slight differences in the percentages of grade 1, 2, and 3/4 toxicities, but they're all in the same ballpark.

It’s hard to show a winner when it comes to just AEs. So, it is very encouraging to the community oncologists. They can focus then on choosing the agents they want to choose based upon efficacy. When we start looking at just efficacy, we can start seeing that not all of the regimens are made the same.

Can you discuss the dose reduction and treatment discontinuation rates for this trial? What would these rates come into consideration when deciding on the best treatment option for a patient?

Outside of just looking at tables with percentages, which sometimes are difficult to translate into the real-world setting, another way to look at tolerability is looking at the dose reduction rate and the discontinuation rate with an understanding that if you do dose reductions, that's okay as long as you are able to dose reduce the drug and [keep] the patient on the therapy. But, if you find that you're reducing the drug a lot, you’ll have discontinuation. That would indicate maybe there's a toxicity concern.

Looking at lenvatinib and pembrolizumab, we see a discontinuation rate of 9.7% versus 18.5% with sunitinib. Then, as single agents, pembrolizumab or everolimus was 25%. Putting that into context, if one just looks at lenvatinib and everolimus, which is an approved regimen for refractory kidney cancer, there’s a 16.1% discontinuation rate versus 18.5% for lenvatinib plus pembrolizumab. I think that shows that by combining these 2 agents, there may be a little bit more toxicity than what we've seen previously. But that does not result in some excess amount of treatment discontinuation. Then, if we look at just dose reductions, if we go back to that original investigation of everolimus, dose reductions were seen in 67.3%. So, the combination of lenvatinib and pembrolizumab is not causing any more issues with dose reductions as already see with the newer-generation TKI combination, lenvatinib/everolimus.

Compared with sunitinib, which is an older-generation agent, treatment-related AEs leading to dose reductions were [seen in] 49.7%. So, it is 20% less than the newer-generation TKIs, but we have seen that already across the board. When one compares the older-generation TKIs to the newer-generation agents like lenvatinib and cabozantinib, we do see there is an uptick in toxicity with the newer agent. But the majority of patients are still able to stay on therapy at that reduced dose and gain efficacy.

What do the data from the CLEAR trial mean for patients and their treatment options moving forward?

It’s a significant step forward. We know we've made an advance with the newer generation TKIs, like the cabozantinib, lenvatinib, and everolimus regimens. That's been established, and they have become now the go-to therapies in this disease. Also, with the approval of checkpoint inhibitors—and realizing that has a significant role to play in the management of this disease is significant—so naturally, combining the 2 together was the next step.

It seems like combining the 2 together is taking us even further when it comes to what the gold standard would be [for] prolonging life. We are making these incremental advances by prolonging the time to progression, and hopefully that translates into survival of 6 months above what we had before.

What are the key takeaways from this research?

For healthcare providers in general, especially oncologists, the key takeaway is the recognition that kidney cancer treatments continue to evolve and that the new advances that we've made with understanding and harnessing the immune system are translating to continued benefits in kidney cancer. Also, oncologists should understand that the combinations of these new ICIs with our traditional VEGF inhibitors improve outcomes greater than ever before.

Oncologists are facing a whole new set of data to try to digest and understand and to apply to the real world. So, I encourage them to review the data that comes out about these agents [because] not all of them are the same. Although they have very AEs and through management of the AEs properties, we're seeing that same play out when we combine them with checkpoint inhibitors, they're not all the same. There are some [patients] that seem to do better than others. It’s really going to call upon the community oncologist to educate themselves as these newer regimens come out, and make sure that they are selecting the most active agent for their individual patient.

What are the next steps?

The field continues to evolve.Understanding the I/O and TKI combination and how to sequence them is important. We need to know the therapy to use after progression. What does that look like? Is there an optimal sequence if a patient gets exposed to a checkpoint inhibitor in one combination, are they eligible, or will they have benefit from using it in a late-line setting?

We also have some novel agents that are being developed, especially the HIF2-α agents, which by themselves have some degree of activity that may be in excess of the traditional VEFG inhibitor, and seeing what that agent would do in combination. Those trials are ongoing, so I think we'll get answers to some of these.

Finally, we want to get beyond just the individual doctor’s bias on choosing agents. We want to have more science that helps guide the selection of agents. That's going to come down to next-generation sequencing to see if we can find a genetic profile or signature that we can test for easily in the clinic. That would allow predicting of which patients would benefit from what type of therapy approach.I think that's what we want to get to in kidney cancer as well as in other cancers to achieved more individualized patient care.

_References:

_{1. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). J Clin Oncol. 2021; 39(suppl6):269. doi: 10.1200/JCO.2021.39.6_suppl.269.}

_{2. Motzer RJ, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Published online February 13, 2021. N Engl J Med. doi:10.1056/NEJMoa2035716}