Weighing Options for the Frontline Treatment of Metastatic Renal Cell Carcinoma

Sumanta (Monty) K. Pal, MD, evaluated combination regimes, in particular the use of lenvatinib plus pembrolizumab, and what factors are taken into consideration for deciding on treatment.

With various options either approved or in the pipeline for the treatment of metastatic renal cell carcinoma (mRCC), there may be a variety of factors that play a role in determining which option is best for a patient.

Following data from trials like Checkmate 214, to evaluate ipilimumab (Yervoy) and nivolumab (Opdivo); Keynote-426, to evaluate axitinib in combination with pembrolizumab (Keytruda); Checkmate 9ER, to evaluate cabozantinib (Cabometyx) and nivolumab; and the CLEAR study, to evaluate lenvatinib (Lenvima) with pembrolizumab (Keytruda),

In a recent interview, Sumanta (Monty) K. Pal, MD, clinical professor, Department of Medical Oncology & Therapeutics Research, and co-director, Kidney Cancer Program, City of Hope, evaluated these regimes, and what factors are taken into consideration when deciding on treatment.

“It's amazing, the developments that we've made in the frontline setting, really quite incredible,” he explained. “I think that the challenge is that I think that many of us know that ultimately, perhaps after a longer duration of time, but after some duration of time nonetheless, our patients are going to progress on these therapies, and it's just so critical for us to really take into account the availability of second- and third-line strategies and beyond.”

Lenvatinib Plus Pembrolizumab

At the 2021 Genitourinary Cancers Symposium, Robert J. Motzer, MD, presented data on the phase 3 CLEAR trial (NCT02811861), which demonstrated that combining lenvatinib with either pembrolizumab or everolimus (Afinitor) improved progression-free survival (PFS) and objective response rate (ORR) over sunitinib (Sutent) for the treatment of patients with advanced RCC receiving therapy in the frontline setting.

In particular, the median PFS with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; P < .001). The lenvatinib plus everolimus treatment arm achieved a median PFS of 14.7 months (95% CI, 11.1-16.7) compared to the 9.2 months in the sunitinib arm (HR, 0.65; 95% CI, 0.53-0.8; P < .001).

Moreover, a median overall survival was not reached in any of the 3 treatment arms; however, the data indicated the endpoint was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; P = .005). ORR was higher in both the lenvatinib plus pembrolizumab (71%; 95% CI, 66.3-75.7) and lenvatinib plus everolimus (53.5%; 95% CI, 48.3-58.7) treatment arms compared to sunitinib (36.1%; 95% CI, 31.2-41.1).

Lastly, patients in the lenvatinib plus pembrolizumab arm achieved the longest median duration of response at 25.8 months (95% CI, 22.1-27.9), compared to 16.6 months (95% CI, 14.6-20.6) in the lenvatinib plus everolimus arm and 14.6 months (95% CI, 9.4-16.7) in the sunitinib arm.

While there are a variety of combination regimens for the treatment of first-line mRCC, Pal said that toxicity may play a role in choosing which option is best for a patient. He noted that quality of life data exist for other regimens; however, health care providers await such data from the CLEAR trial.

“I think it's a really key question from the standpoint of adding toxicity, adding quality-of-life, and adding cost, frankly, to patients, with the addition of [immunotherapy],” Pal explained. “We have to know whether or not that's justified, so I think that's a real key.”

Selecting Treatment

Pal explained that there can be caveats to determining whether or not a patient is eligible to receive an immunotherapy or tyrosine kinase inhibitor.

“This is a really difficult bar to establish. For instance, what you do for that patient that comes to clinic that has a diagnosis of mild psoriasis, and that individual, who doesn't require corticosteroids or any biologic therapies, I would actually pretty much have a low threshold for administering immunotherapy, so I would feel quite comfortable in that context,” he explained.

“On the other hand, I mean, it's not rare for us to see patients with very severe rheumatoid arthritis, psoriatic arthritis, other conditions that really mandate much more intensive therapy, and there, I'm really shying away from using frontline immunotherapy. So in that context, I've really kind of gone back to my roots, if you will, and I'm using cabozantinib [Cabometyx] as monotherapy.”

As a result, Pal pointed health care providers to reference the International MRCC Database Consortium Criteria.

“We're playing the long game with our patients,” he said. “They're going to be on these therapies for a long time, and I really have some reluctance in giving treatments that may potentially be toxic over the long term. … So I would suggest that when you look at the amalgam of characteristics, and when you look at your own clinical experiences with drugs, use that to weigh in whether or not you would offer those regimens in the frontline setting.”


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(suppl6):269. doi: 10.1200/JCO.2021.39.6_suppl.269.