HRQOL Analysis From CLEAR Trial Further Support Pembrolizumab/Lenvatinib Combo for Frontline RCC


Across 3 health-related quality of life scales, the combination of pembrolizumab plus lenvatinib had similar or better outcomes than sunitinib for patients with metastatic renal cell carcinoma receiving treatment in the frontline.

The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for the frontline treatment of metastatic renal cell carcinoma (RCC) led to similar health-related quality of life (HRQOL) outcomes and disease-related symptom scores versus sunitinib (Sutent) for patients treated in the phase 3 CLEAR trial (NCT02811861), according to a presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting.1

Conversely, the combination of lenvatinib and everolimus (Afinitor), another regimen examined in a separate experimental arm of the trial, led to similar or worse HRQOL outcomes versus sunitinib in the trial population.

“The efficacy, safety, and health-related quality of life results from the CLEAR trial support lenvatinib plus pembrolizumab as first-line therapy for patients with advanced RCC,” Robert J. Motzer, MD, PhD, head of the Kidney Cancer Section for the Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology, said during a presentation of the data.

Based on efficacy results from the trial reported earlier this year,2 the FDA accepted and granted priority review to applications seeking approval of the combination as therapy for the indicated patient population. Data showed that lenvatinib plus pembrolizumab led to a 61% reduction in the risk of disease progression or death versus sunitinib. While the median overall survival (OS) was not yet reached in either arm, the hazard ratio indicated a statistically significant benefit with the combination versus standard therapy (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

HRQOL impact for the 3 arms of the trial were performed using 3 scales: the Functional Assessment of Cancer Therapy Kidney Symptom Index–Disease-Related Symptoms (FKSI-DRS), which measures symptoms specific to kidney cancer and for which a higher score equates to better QOL; the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer-Core 30 (EORTC QLQ-C30), which is comprised of 9 multiple item scales and 6 single-item scales to assess function and symptoms in which a higher score indicates poorer QOL; and the European Quality of Life 5-Dimension 3-Level System (EQ-5D-3L) that has 2 scales including a visual analog scale (VAS) and a descriptive system of 5 items.

Longitudinal change from baseline was assessed using a mixed-model analysis and the time to deterioration was assessed using a stratified log-rank test and a Cox model directed at 2 end points. Time to first deterioration was defined as the number of weeks between randomization and the first deterioration event, with time until definitive deterioration defined as the number of weeks between randomization and the earliest deterioration event. There were no adjustments for multiple testing or estimate, with all P values and confidence intervals being nominal and descriptive.

In the comparison of lenvatinib/everolimus with sunitinib, least square mean differences indicated similar to worse HRQOL with the experimental regimen across the different assessment scales. There was a statistically significant difference in the EORTC QLQ-C30 global health scale (GHS)/QOL assessment favoring sunitinib (HR, –2.81; 95% CI, –5.08 to –0.54; P <.05). EORTC QLQ-C30 symptoms scales favoring sunitinib included pain (HR, 2.80; 95% CI, 0.11-5.49; P <.05), appetite loss (HR, 4.23; 95% CI, 1.34-7.13; P <.05), and diarrhea (HR, 5.26; 95% CI, 2.61-7.91; P <.05).

“For diarrhea, the least mean difference score was greater than 5, which may be considered clinically significant,” said Motzer.

Looking at pembrolizumab/lenvatinib versus sunitinib, least square mean differences indicated similar to better HRQOL with the experimental regimen across the different EORTC QLQ-C30 functional and symptom scales. Physical functioning (HR, 3.01; 95% CI, 0.48-5.54; P <.05), fatigue (HR, –2.80; 95% CI, –5.52 to –0.08; P <.05), dyspnea (HR, –2.79; 95% CI, –5.33 to ­–0.25; P <.05), and constipation (HR, –2.19; 95% CI, –4.19 to –0.18; P <.05) all favored the combination.

Time to first deterioration by EORTC QLQ-C30 also favored the immune checkpoint inhibitor/tyrosine kinase inhibitor combination over sunitinib for physical functioning, with a median duration of 15.29 weeks versus 12.71 weeks, respectively (HR, 0.81; 95% CI, 0.68-0.98; P = .03). Similarly, the median duration to onset was 39.29 weeks versus 21.14 weeks, respectively, for dyspnea (HR, 0.79; 95% CI, 0.64-0.97; P = .02) and was 18.29 weeks versus 9.14 weeks for appetite loss (HR, 0.82; 95% CI, 0.68-0.98; P = .03). By EQ-5D-3L, the EQ-VAS similarly favored pembrolizumab plus lenvatinib, at 9.43 weeks versus 9.14 weeks (HR, 0.83; 95% CI, 0.70-0.99; P = .04).

Across all 3 scales, time to definitive deterioration—defined as the number of weeks between randomization and the earliest deterioration event with no subsequent recovery above the deterioration threshold or no subsequent HRQOL assessment data—was significantly improved with the combination of pembrolizumab and lenvatinib versus sunitinib.

By the FKSI-DRS total score, the median time to definitive deterioration was 134.14 weeks with pembrolizumab/lenvatinib versus 117.43 weeks with sunitinib (HR, 0.70; 95% CI, 0.53-0.92; P <.01). Corresponding medians for EORTC QLQ-C30 GHS/QOL (114.29 vs 75.14 weeks; HR, 0.60; 95% CI, 0.47-0.77; P <.0001), EORTC QLQ-C30 Physical Functioning (134.14 vs 78.14 weeks; HR, 0.52; 95% CI, 0.41-0.67; P <.0001), and EQ-5D-3L VAS (124.86 vs 74.86 weeks; HR, 0.67; 95% CI, 0.53-0.85; P <.01) all showed statistically significant benefits to time to definitive deterioration with combination therapy.

“The results suggest that patients who receive lenvatinib and pembrolizumab had longer maintenance of quality of life and symptom control than those in the sunitinib group,” Motzer said. “Other factors that could potentially influence outcome and the time to definitive deterioration analysis include dose modification of lenvatinib for toxicity and then recovery of score based on better tolerability with the lower dose.”

He noted that longer time on treatment through progression-free survival gain or treatment beyond progression led to patients having more assessments and more time to recover. Further analyses will be examined in future research.

“It is notable that almost all comparisons of time to definitive deterioration favor lenvatinib and pembrolizumab over sunitinib,” Motzer concluded.


1. Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2021;39(suppl 15):4502. doi: 10.1200/JCO.2021.39.15_suppl.4502

2. 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(suppl 6):269. doi: 10.1200/JCO.2021.39.6_suppl.269

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