Updated Findings Support Pembrolizumab/Lenvatinib as a Standout Option for Frontline RCC Treatment

Robert J. Motzer, MD

The treatment landscape of renal cell carcinoma (RCC) in the frontline setting has undergone a significant shift with the introduction of tyrosine kinase inhibitor (TKI) and immunotherapy (IO) combinations, thus moving away from the standard single-agent TKIs. A new combination is on track to join these regimens—the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima), based on findings from the 3-arm phase 3 CLEAR trial (NCT02811861).¹

In the study, the regimen led to a significant improvement over sunitinib (Sutent) in both progression-free survival (PFS) (HR, 0.39; 95% CI, 0.32-0.49; P < .001) and overall survival (OS) (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

“I think that it's really a standout for use in first-line therapy and certainly…should be a choice for first-line therapy for RCC,” investigator Robert J. Motzer, MD, told Targeted Oncology^TM.

The FDA has already granted the combination a priority review for the treatment of patients with advanced RCC.²

Updated findings from the study continue to support the use of this regimen. In findings presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, the quality of life (QOL) was maintained over time and symptoms were controlled compared with sunitinib.³

In an interview, Motzer, the 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, explained how further results of the CLEAR trial, including health-related QOL data, suggest the benefit of pembrolizumab and lenvatinib in patients with advanced RCC.

Targeted OncologyTM: What was the rationale for this analysis of the CLEAR trial?

Motzer: So the CLEAR study was a 3-arm trial that compared pembrolizumab plus lenvatinib versus lenvatinib plus everolimus, and both of those arms to sunitinib in patients with clear cell RCC as a first-line therapy. The results showed that both of the lenvatinib-containing arms met their primary end point showing improvement in PFS compared to sunitinib.

But only the lenvatinib plus pembrolizumab [arm] showed an increase in OS. The results for the lenvatinib and everolimus [arm] compared to the sunitinib arm were similar. And the efficacy was really quite striking in this trial, particularly for the lenvatinib plus pembrolizumab arm with a very high response rate over 70%, 16% complete response rate, and median PFS of almost 24 months. The results of that trial were really quite clear with regard to efficacy.

The safety profile was pretty much anticipated for both arms compared to sunitinib and so the results presented this year at ASCO are theresults of the patient-reported QOL study or health-related QOL studies.

What would you say is your expectation for where pembrolizumab/lenvatinib will fit into the RCC treatment landscape and how it will affect subsequent treatment use?

Well, I think that we've been successful in the last few years in terms of developing better regimens in first-line therapy for RCC, largely based on the newer TKIs—axitinib, lenvatinib, cabozantinib—and the use of immunotherapy, both immunotherapy combinations with ipilimumab/nivolumab, or more recently with the TKI-IO combinations and the results have been very striking. So that they've come about in a very short time. Clearly, all these options are better than single-agent TKI. But we're sorting out whether there's a role for one versus the other, or which particular regimen might be best and particularly useful for a community oncologist to administer.

So, I think that lenvatinib/pembrolizumab, we studied that at our center in a large single-arm trial of over 140 patients. I had personal experience with that regimen in many. And 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.

Would you say that there's any subgroups that may benefit a little bit more or less from this regimen?

Well, I think with the lenvatinib/pembrolizumab regimen, one of the best features is it seems to be effective right across the board.

You know, it's very effective in patients regardless of risk group—both the favorable-risk patients did very well with it as well as the intermediate- and the poor-risk patients. It did very well in the patients who had sarcomatoid elements. And so, I think it's a very reliable regimen. There weren't really subgroups that we identified in which I wouldn't see this regimen as being applicable. It's effective right across the board.

What would you say were some of the key takeaways, specifically from the health-related QOL analysis?

Well, when we looked at it, there were 2 main types of analysis. One analysis we looked at was longitudinal changes from the baseline, to patients on study using a mixed model analysis. And the other, we looked at time to deterioration as well as time until definitive deterioration, which gives you a little bit more of a sense over time. And what we found in the analysis is that the QOL studies suggested that they were either similar or better with some scales with lenvatinib plus pembrolizumab compared to sunitinib, and in point of fact, the time until definitive deterioration was the kind of the standout in favor of lenvatinib and pembrolizumab. That and that the hallmark of that analysis is that it looks at QOL by the scales over time.

And so patients who continue on trial, even treated beyond progression or on PFs for a long time, they seem to, over time, have a better QOL. And so I think that was a standout. 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 [Afinitor] for the most part, the scores were the same or worse more severe than sunitinib with lenvatinib plus and everolimus so that appeared to have somewhat lower scores with regard to QOLassessments than sunitinib. And I think that that also makes sense. It's comprised of 2 targeted therapies, there's a fair amount of toxicity that has been associated with that regimen. The results were quite fitting with what we've seen with regard to efficacy and safety for both of those regiments.

What would you say is the take home message from this work?

Well, I think the standout from the trial was the efficacy gain for lenvatinib plus pembrolizumab. I think that results of that were extremely impressive. And I think that's a good choice for first-line treatment for RCC.

The toxicity, which is another metric that we look at, was certainly manageable with lenvatinib plus pembrolizumab. My own experience over time is that the toxicities are quite manageable with dose reduction, as needed, and that patients are able to stay on treatment for long periods of time, and I have patients who are treated on this program for years. And so, those are 2 metrics that are assessed by treating physicians, but the QOL assessments are the perception of a patient. So the health-related QOL assessments are filled out by the patient. They're how they perceive their tolerability to the regimen and how they feel about being on the regimen. And so, I think that they're an extraordinarily important metric that really needs to be considered seriously when interpreting results of trials and choosing a regimen: how does the patient feel about it. And so I was really quite impressed and felt in a very positive respect, that this combination had either similar or better scores than what we've seen with sunitinib, which has been our standard of care for more than a decade.

_References:

_{1. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289-1300. doi:10.1056/NEJMoa2035716}

_{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 and Eisai, Inc. May 6, 2021. Accessed June 30, 2021. https://bwnews.pr/3b9CzzA}

_{3. 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}