Interview: Pembrolizumab Plus Lenvatinib as a Treatment for Renal Cell Carcinoma

Renal cell carcinoma (RCC) is typically treated with single-agent tyrosine kinase inhibitors (TKIs). Now, this may be changing as research demonstrates the potential of the combination of TKIs and immunotherapy. The Phase 3 CLEAR trial focused on pembrolizumab (Keytruda) plus lenvatinib (Lenvima), showing a significant improvement in comparison to sunitinib alone. Targeted Oncology interviewed Robert J. Motzer, MD, focusing on the results of this trial and what it means for RCC treatment.

Pembrolizumab Plus Lenvatinib

This drug combination demonstrated promising results in the Phase 3 CLEAR trial. When compared to sunitinib, it led to significant improvement in both progression-free survival (PFS) and overall survival (OS).

  • PFS: HR, 0.39; 95% CI, 0.32-0.49; < .001
  • OS: HR, 0.66; 95% CI, 0.49-0.88; = .005

In addition to these findings, updated data was presented at the 2021 ASCO Annual Meeting. It showed that pembrolizumab plus lenvatinib controlled symptoms and maintained quality of life (QOL) over time in comparison to sunitinib.

Findings like these have led the FDA to grant this combination priority review for advanced RCC.

Interview with Robert J. Motzer, MD

Robert J. Motzer, MD, is head of the Kidney Cancer Section, Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center. He spoke about the CLEAR trial and this drug combination’s potential as a treatment for advanced RCC.

The CLEAR Trial

Interviewers asked Motzer about the rationale behind the latest analysis of data from the CLEAR trial, to which he gave an overall explanation of the study. He explained that it contained three arms, one of which compared pembrolizumab and lenvatinib to lenvatinib plus everolimus, while the other two compared each combination to sunitinib. All were assessed as a first-line therapy in patients with clear cell renal cell carcinoma.

Both arms containing combinations met their primary endpoints, as they demonstrated improvements in PFS over sunitinib. However, only one arm – lenvatinib plus pembrolizumab – showed improvements in OS. Additionally, this combination showed a high response rate of over 70%, a median PFS of nearly 24 months, and a complete response rate (CRR) of 16%.

As there were no new safety data, researchers chose to present quality of life data based on health-related QOL studies and the patient-reported QOL study.

RCC Treatment Landscape

The interview then moved to this new drug combination’s place in the RCC treatment landscape. Motzer spoke of the recent advancements that have happened recently, such as new TKIs, immunotherapies, or combinations of the two. While these developments are very positive, medical professionals are still figuring out each therapy’s specific role and the ideal treatment regimen.

Moving specifically to pembrolizumab plus lenvatinib, he spoke of his own personal experience studying a portion of the trial. From his time with the drug combination, he stated,

“…it really appeared to be an excellent regimen with regard to efficacy and manageable safety. And so I think what I was most impressed with in the phase 3 trial was the magnitude of efficacy that we saw with this trial, and with manageable toxicity.”

Motzer was asked about any specific subgroups that may benefit more than others from this therapy next. In his opinion, it’s applicable across subgroups; they could all benefit from this combination.

Looking Forward

Motzer labeled some of the key takeaways towards the end of the interview. Based on the various analyses of the Phase 3 CLEAR trial data, one takeaway was the improvements in QOL over time when patients remained in their treatment regimen. He also pointed out that there were no surprises when it came to safety or efficacy, which is very positive.

In the end, the key takeaway is the impressive results from the trial, as they indicate this combination as a “good choice for first-line treatment for RCC.” The toxicity was manageable, and there were improvements in QOL, all of which point to pembrolizumab plus lenvatinib as a viable treatment option for advanced RCC.

About RCC

RCC is a form of kidney cancer that typically begins with a single tumor in one kidney but easily spreads to the lungs and throughout the body. Symptoms often do not appear until this spread has occurred, which can impact diagnosis and intervention. They include abdominal pain, fatigue, high blood pressure, bloody or discolored urine, weight loss, fever, enlarged testicles, varicose testis vein, and vision abnormalities.

While medical professionals are unsure as to what exactly causes RCC, they do know that there are a number of risk factors. These include smoking and a history of kidney problems. Research has also linked mutations in the TFE 3, PRC, and VHL genes to this cancer. Treatment consists of removing the kidney, bladder, and any necessary surrounding tissue. Other treatment options include:

  • Proleukin
  • Chemotherapy
  • Sorafenib
  • Hormone treatments
  • Afinitor
  • Ablation

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