Recap: Implications of TKI Plus Immunotherapy Combinations for RCC


A panel of oncologists reviews a publication by Robert J. Motzer, MD, and colleagues on data from the CLEAR trial examining lenvatinib plus either pembrolizumab or everolimus for advanced renal cell carcinoma.

Newer combination regimens involving immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are unseating older single-agent targeted therapies as the standard of care (SOC) in renal cell carcinoma (RCC). As such, frontline treatment of patients with RCC requires a nimble approach and a close eye on emerging data.

To put the progress made in treating RCC in perspective, Thomas Powles, MD, MBBS, looks no further than another genitourinary malignancy: bladder cancer.

“In bladder cancer, we’re struggling to push median survival from 10 months to 14 months,” said Powles, professor of genitourinary oncology, Solid Tumor Research lead, and director of the Barts Cancer Centre at St Bartholomew’s Hospital in London. “And yet, huge progress has been made in kidney cancer with 2 big groups of drugs: the ICIs and VEGF-targeted therapies.”

Last year, the FDA approved use of the TKI lenvatinib (Lenvima) in combination with the ICI pembrolizumab (Keytruda) as a first-line treatment for adults with advanced RCC.1 The approval was based on data from the phase 3 CLEAR trial (NCT02811861), which showed improvement in the primary end point of progression-free survival (PFS) with the combination vs SOC sunitinib (Sutent).2

Powles joined Rana R. McKay, MD, an associate professor of medicine at the University of California, San Diego, to discuss CLEAR and its implications in a recent Between the Lines series hosted by CancerNetwork®. Additionally, Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology and Section Head of Kidney Cancer for the Genitourinary Oncology Service, and Marie Carlo, MD, a medical oncologist, both from Memorial Sloan Kettering Cancer Center in New York, New York, hosted their own discussion about the field and how it plays into their practice.

Progression-Free Survival Superiority

In the CLEAR trial, 1069 patients were randomized 1:1:1 to receive either daily oral lenvatinib at 20 mg plus 200 mg of intravenous pembrolizumab every 3 weeks (n = 355); or daily lenvatinib at 18 mg along with a 5-mg daily oral dose of everolimus (Afinitor; n = 357); or daily oral sunitinib at 50 mg for 4 weeks on/2 weeks off (n = 357).

Lenvatinib plus pembrolizumab led to a median PFS of 23.9 months vs 9.2 months for sunitinib (HR, 0.39; 95% CI, 0.32, 0.49; P <.0001). Lenvatinib plus everolimus also outperformed sunitinib, with a median PFS of 14.7 months vs 9.2 months (HR, 0.65; 95% CI, 0.53-0.80; P <.001). Benefits of lenvatinib plus pembrolizumab compared with sunitinib also extended to overall survival, with medians that were not reached in either group and rates at 24 months of 79.2% vs 70.4%, respectively (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

Setting New Benchmarks

Motzer said the results were noteworthy, including an objective response rate of 71.0% (95% CI, 66.3%-75.7%) with lenvatinib plus pembrolizumab vs 53.5% (95% CI, 48.3%-58.7%) with lenvatinib/everolimus vs 36.1% (95% CI, 31.2%-41.1%) with sunitinib. “It was the longest median PFS we’ve seen in any of the phase 3 trials for RCC, with an objective response rate that, for the first time crossed, 70%,” he said.

Carlo said there has long been a debate about whether double immunotherapy, such as nivolumab (Opdivo) plus ipilimumab (Yervoy), is preferable to the combination of a PD-1 inhibitor such as pembrolizumab plus a TKI like lenvatinib. She noted that the clinical trial data for nivolumab plus ipilimumab in the setting of intermediate- to poor-risk RCC from the CheckMate 214 trial (NCT022331749) showed a complete response (CR) rate of 9%.3 However, the new data for lenvatinib plus pembrolizumab are even stronger.

“With its 16.1% CR rate, this trial is certainly, numerically, quite impressive and [shows that lenvatinib plus pembrolizumab is] comparable with double immunotherapy. This encourages a lot of people who are still thinking that only double immunotherapy would lead to such high CRs,” she said.

Dosing and Dose Reduction Are Key

Looking at the intended dose, McKay said it was notable that patients in the lenvatinib-plus-pembrolizumab group started on a 20-mg dose of lenvatinib. “The strategy here was to start higher and rapidly dose-reduce if patients ran into toxicity, as opposed to starting with a middle-of-the-road dose and allowing dose escalation,” she said.

In the trial, 68.8% of patients in the ICI/TKI group reduced their lenvatinib dose due to adverse events (AEs) such as diarrhea and hypertension.

Powles said it is critical for providers to prepare their patients for the possibility of dose reduction, making it clear that such changes are normal and far preferable to ignoring the AEs. “What’s important is that we don’t treat through AEs because patients can have a terrible experience and [end up] stopping a drug early [for that reason],” he said.

Assessing Quality of Life

In April 2022, investigators published health-related quality-of-life (QOL) data from the CLEAR study. The data showed that patients in the lenvatinib-plus-pembrolizumab group had a shorter median time to first deterioration compared with those treated with sunitinib, at 9.14 weeks vs 12.14 weeks per Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS; HR, 1.13; 95% CI, 0.94-1.35; log-rank P = .20), 12.00 weeks vs 9.14 weeks by European Organisation for the Research and Treatment of Cancer QOL Questionnaire-Core 30 global health status/QOL (EORTC QLQ-C30 GHS/QOL; HR, 0.88; 0.74-1.05; log-rank P = .17), and 9.43 weeks vs 9.14 weeks by the EQ-5D visual analogue scale (EQ-5D VAS; HR, 0.83; 95% CI, 0.70-0.99; log-rank P = .041).4

However, the results were reversed for median time to definitive deterioration by FKSI-DRS (134.14 vs 117.43 weeks; HR, 0.70; 95% CI, 0.53-0.92; log-rank P = .0081) with pembrolizumab/lenvatinib vs sunitinib, respectively. Similarly, longer median time to definitive deterioration was maintained in the experimental cohort vs sunitinib for EORTC QLQ-C30 GHS/QOL (114.29 vs 75.14 weeks, respectively; HR, 0.60; 95% CI, 0.47-0.77; log-rank P <.0001) and EQ-5D VAS (124.86 vs 74.86 weeks; HR, 0.67; 95% CI, 0.53-0.85; log-rank P = .0012). None of the instruments showed significant QOL differences between the regimens.

Powles said his main takeaway is that lenvatinib plus pembrolizumab does not seem to be detrimental, but he and McKay noted that it is important to have a nuanced interpretation of QOL data, since they are not always straightforward. For instance, McKay said a patient who is asymptomatic at the start of therapy will probably experience a negative impact on their QOL, “because they were feeling OK to begin with.”

Frontline Therapy Options

When choosing frontline therapy, McKay said she likes to think of the choice as one between playing the “long game” or the “short game.” The durability of nivolumab/ipilimumab makes it an attractive “long-game” option.

However, McKay likes lenvatinib and pembrolizumab for certain patients—such as those with locally advanced unresectable disease—who need to play the short game. “The perfect population for this combination [are those in whom] I want to see an immediate short-term response, to get them resected,” she said. “The response rate is so high and the primary [progressive disease] rate is so low.”

Powles said he thinks that smaller health care centers, those treating just a handful of patients per year, might prefer to pick one regimen and stick with it. In such cases, he said it is probably easier to use a combination containing a VEGF TKI plus immunotherapy. But he said that for some patients, a combination such as ipilimumab and nivolumab would work well.

“For example, patients with intermediate-risk disease and perhaps low-volume metastases, in whom I’m not worried about primary progression of disease, would be good candidates for nivolumab/ipilimumab,” he said.

Minding Risk Factors

Carlo said it is important for physicians to pick a regimen that they are comfortable with, taking into account its AE profile and dose-adjustment strategy. She takes an open-minded approach and is quick to consult other specialists when necessary. For instance, she said she has had success treating patients with mild autoimmune diseases with immuno-oncology regimens.

“I do use the help of my colleagues in different [departments, including] dermatologists and gastroenterologists, because the benefit to overall survival is there and I want to make sure I evaluate everything before deciding to give them that [immuno-oncology] option or not,” Carlo said.

Carlo and Motzer both said they would avoid lenvatinib/pembrolizumab in patients with a history of uncontrolled hypertension or a recent cardiac event or stroke. When he does prescribe the regimen, Motzer said, he cautions patients to look for blood pressure changes.

“I always counsel them that [elevated blood pressure] is an AE that could happen early on,” Motzer said. He gives the patient parameters, a blood pressure cuff, and instructions to call if their blood pressure worsens.

In patients with RCC who don’t have significant risk factors, Powles said combination therapy appears to be the best option, given all the data. “You don’t have to treat everyone immediately,” he said, “but for [favorable-risk] patients, when you decide that they need treatment, sunitinib seems a suboptimal option from my perspective.”

Pursuing Better Biomarkers

Despite all the excitement around these combination approaches, choosing the right therapy is not just about deciding if a patient has a favorable- or poor-risk disease profile, the panel said. McKay said that one of the biggest unmet needs in this area is to find a more precise way to predict which patients will succeed on a particular therapy. Although more and more effective treatments are available, finding reliable biomarkers remains a key challenge.

“There’s a lot of excitement in the space,” McKay said. “But I also think we need to learn a lot more to find the right biomarker.”


  1. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 11, 2021. Accessed June 16, 2022.
  2. Motzer R, Alekseev B, Rha S-Y, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
  3. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
  4. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780. doi:10.1016/S1470-2045(22)00212-1
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