Lenvatinib/Pembrolizumab’s Favorable HRQoL Leads to “Standout” Option for Frontline RCC

Robert J. Motzer, MD

The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) is not only efficacious but has also proven to improve health-related quality of life (HRQoL) vs sunitinib (Sutent) in the first line treatment of patients with advanced renal cell carcinoma (RCC), according to Robert J. Motzer, MD, who added that the regimen represents a “standout” option for this setting.

Results from the phase 3 CLEAR trial (NCT02811861) presented during the 2021 ASCO Annual Meeting showed that the median progression-free survival (PFS) with lenvatinib/pembrolizumab was 23.9 months (95% CI, 20.8-27.7) vs 14.7 months (95% CI, 11.1-16.7) with lenvatinib and everolimus (Afinitor) and 9.2 months (95% CI, 6.0-11.0) with sunitinib.¹ The stratified hazard ratio with lenvatinib/pembrolizumab vs sunitinib was 0.66 (95% CI, 0.49-0.88; P <.001).

Lenvatinib plus pembrolizumab was also found to showcase similar or improved HRQoL and disease-related symptom scores compared with sunitinib, and lenvatinib plus everolimus was found to have similar or worse HRQoL and symptom scores vs those observed with sunitinib.

“The quality-of-life assessments are the perception of a patient. The HRQoL assessments are filled out by the patient on how they perceive their tolerability to the regimen, and how they feel about being on the regimen,” Motzer said. “They are an extraordinarily important metric that needs to be considered seriously when interpreting results of trials, and choosing a regimen.”

Earlier data from the trial supported the submission of a biologics license application for pembrolizumab and a supplemental new drug application for lenvatinib for the frontline treatment of patients with advanced RCC. In May 2021, the FDA granted priority review to the applications in May 2021.²

In an interview with OncLive^®, Motzer, medical oncologist, Kidney Cancer Section head in the Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, discussed the efficacy and HRQoL benefits of lenvatinib/pembrolizumab in patients with advanced RCC, and projected where the regimen might fit into the treatment paradigm.

OncLive^®: Could you speak to the rationale of conducting the HRQoL analysis of the CLEAR trial?

Motzer: CLEAR was a 3-arm trial that compared pembrolizumab plus lenvatinib with everolimus plus lenvatinib, and [then compared] both of those arms with sunitinib in patients with clear cell RCC as a first-line therapy.

Results showed that both lenvatinib-containing arms met their primary end point, showing improvement in progression-free survival [PFS] compared with sunitinib. [However,] only the lenvatinib/pembrolizumab [arm] showed an increase in overall survival [OS]; the results for lenvatinib plus everolimus compared with sunitinib were similar.

The efficacy observed in this trial was quite striking—particularly for the lenvatinib plus pembrolizumab arm, with a very high response rate of over 70%, a 16% complete response rate, and a median PFS of approximately 24 months. The safety profile was as anticipated for both arms compared with sunitinib. The results presented during the 2021 ASCO Annual Meeting [focused on] HRQoL [outcomes].

What is your expectation for where the combination of pembrolizumab plus lenvatinib will fit into the RCC treatment landscape? How will this regimen impact subsequent treatment use?

We have been successful in the past few years, in terms of developing better regimens [for the] first-line treatment [of patients with] RCC. [This success is] largely based on the [emergence of] newer TKIs, [such as] axitinib [Inlyta], lenvatinib, cabozantinib [Cabometyx], and the use of immunotherapy. [This includes] both immunotherapy combinations, such as ipilimumab [Yervoy] and nivolumab [Opdivo], and more recently, TKI/immunotherapy combinations. Results [with these combinations] have been very striking. [These regimens] have come about in a very short time, but clearly, all these options are better than a single-agent TKI.

However, we are still sorting out whether there is a role for one vs the other, or which regimen might be best or particularly useful for a community oncologist to administer. We studied lenvatinib plus pembrolizumab at our center in a large, single-arm trial of over 140 patients and I had personal experience with that regimen. It really appeared to be an excellent regimen in terms of efficacy and manageable safety.

What I was most impressed with in the phase 3 trial is the magnitude of efficacy that we saw, coupled with manageable toxicity. It is a standout [option] for use in first-line therapy, and certainly, along with the others, it should be a choice [in this setting].

Do any subgroups appear to derive more benefit with this treatment regimen than others?

With the lenvatinib/pembrolizumab regimen, one of its best features are that it seems to be effective across the board. [We see efficacy] in patients, regardless of risk group. The favorable-risk patients did very well with [this approach], as well as the intermediate- and the poor-risk patients. Those who had sarcomatoid elements also did very well [with the doublet]. It is a very reliable regimen, [for which we know that] we are going to see a positive effect.

What were the key findings from the HRQoL analysis of the trial?

We performed several analyses. In a mixed-model analysis, we looked at longitudinal changes from baseline to [time] on study. In the other [analysis], we looked at time to deterioration, which was one end point [of the trial], as well as time until definitive deterioration, which served as another end point. [Results from the] QoL studies suggested that [these end points] were either similar or better with some scales with [regard to] lenvatinib plus pembrolizumab compared with sunitinib.

The time until definitive deterioration was the standout [finding because it was] in favor of lenvatinib plus pembrolizumab. The hallmark of that analysis is that it looks at QoL, by these scales, over time. As such, patients who continue on the trial, even those who were treated beyond progression or those with a [long] PFS, appear to, over time, have a better QoL.

In general, I would say that the scores were the same, or better, with lenvatinib plus pembrolizumab. On the other side of the coin, when we looked at lenvatinib plus everolimus, for the most part, the scores were either the same or worse [than what we saw with sunitinib]. This makes sense because the combination is comprised of 2 targeted therapies, and there is a fair amount of toxicity that has been associated with it. The results were quite fitting with what we have seen in terms of efficacy and safety for both of these regimens [in the past].

What is the take-home message from this research?

The standout from the overall trial was the efficacy gain [observed with] lenvatinib plus pembrolizumab. Those results were extremely impressive, and [demonstrate that this regimen] is a good choice for the first-line treatment [of patients with] RCC. The toxicity was certainly manageable with lenvatinib plus pembrolizumab. In my own experience, is that over time, the toxicities are quite manageable with dose reduction, as needed. Patients can stay on treatment for long periods of time. I have patients who were treated on this program for years. Those metrics are assessed by clinicians and research staff.

[However, we always need to ask ourselves,] how does the patient feel about [the regimen]? I was quite impressed that this [efficacious] combination had either similar or better scores than what we have seen with sunitinib, which has been our standard of care for more than a decade.

References

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. Merck and Eisai receive priority review from FDA for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) applications for advanced renal cell carcinoma and for advanced endometrial carcinoma. News release. Merck. May 6, 2021. Accessed July 9, 2021. https://bit.ly/2PYnqtM