Long-Term OS Data Confirm Pembrolizumab/Lenvatinib as a Primary Frontline Option in Advanced RCC

Thomas Hutson, DO, PharmD

The sustained overall survival (OS) benefit observed with the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) in the phase 3 CLEAR study (NCT02811861) solidifies the doublet’s use as a preferred option for the frontline treatment of patients with advanced renal cell carcinoma (RCC), according to Thomas Hutson, DO, PharmD.

Investigators presented a final OS analysis of CLEAR at the 2023 ASCO Annual Meeting, which showed that at a median follow-up of 4 years, patients given pembrolizumab plus lenvatinib (n = 355) experienced a median OS of 53.7 months (95% CI, 48.7–not evaluable [NE]) vs 54.3 months (95% CI, 40.9-NE) for those treated with sunitinib (Sutent) alone (n = 357; HR, 0.79; 0.63-0.99; nominal P = .0424). After adjustment for subsequent anticancer medications, the median OS was not reached (95% CI, 40.9-NE) vs 32.0 months (95% CI, 18.7-NE) in the combination and sunitinib arms, respectively (adjusted HR, 0.55; 95% CI, 0.44-0.69). No new safety signals for the doublet were identified in this analysis, and toxicity was manageable with dose modification.¹

Previously reported data from CLEAR showed that pembrolizumab plus lenvatinib produced superior progression-free survival (PFS), OS, and confirmed objective response rate (ORR) vs sunitinib. These findings supported the FDA approval of pembrolizumab plus lenvatinib for the frontline treatment of adult patients with advanced RCC in August 2021.²

“With final additional follow-up, the OS [benefit] was maintained with robustness, as well as other efficacy end points such as ORR and PFS,” said Hutson, the director of the Urologic Oncology Program, co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center, and a professor of medicine at Texas A&M College of Medicine, Texas Oncology, in Dallas, Texas. “There were no new safety signals, so clinicians should feel comfortable using this regimen as a primary treatment strategy for their patients with advanced RCC.”

In an interview with OncLive®, Hutson expanded on previously reported findings from the CLEAR study, detailed the updated efficacy and safety data from the final OS analysis, and emphasized how these results support the use of this regimen as a mainstay treatment option in the frontline setting for patients with advanced RCC.

OncLive: Could you provide some background on the CLEAR study in advanced RCC, including any key findings that were previously reported?

Hutson: The presentation at the 2023 ASCO Annual Meeting was the final prespecified OS analysis from the CLEAR study, which was an international, randomized trial comparing pembrolizumab/lenvatinib [or] lenvatinib/everolimus [Afinitor] vs sunitinib as initial therapy in patients with [advanced] RCC.

It had previously been reported [that pembrolizumab/lenvatinib] showed a statistically significant and clinically meaningful benefit in PFS—the primary end point—as well as secondary efficacy end points of OS and ORR. This was published in the New England Journal of Medicine [in April 2021], and this resulted in regulatory approval [for lenvatinib and pembrolizumab in August 2021] and rapid uptake in the treatment algorithm as a primary therapy for patients with advanced RCC throughout the world.

What updated efficacy findings were recorded with additional follow-up?

The current presentation was a prespecified final OS analysis occurring after 23 months of additional follow-up, so we were able to address things such as duration of benefit. The OS Kaplan-Meier curves [were] maintained with a hazard ratio of 0.79 for the intent-to-treat patient population of lenvatinib/pembrolizumab vs sunitinib.

The secondary efficacy end points were also robust and maintained, including a [median] PFS of [23.9] months and an ORR of 71.3% for patients in the lenvatinib/pembrolizumab arm [vs a median PFS of 9.2 months and an ORR of 36.7%] for the sunitinib arm.

Could you expand on the safety profile for lenvatinib and pembrolizumab according to data from the CLEAR study and what was observed with longer-term follow-up?

We're pleased to report that there were no additional adverse effects [AEs] with long-term follow-up. The safety profile for lenvatinib and pembrolizumab has previously been reported and includes various [toxicities] that are similar to what we would expect to see given the class of agents we're using. We see traditional VEGF-targeted therapy–related AEs such as hypertension, fatigue, and diarrhea. We also see some immuno-oncology–related toxicities. The [toxicity profile of the combination] is a merger of both.

The strategy [to control AEs when] administering both agents, which is built into the regimen, is the ability to intervene with dose interruption and dose reduction. That allows clinicians to utilize this [combination] readily in the community setting and to provide optimal dosing for patients.

What are some of the next steps for this regimen in advanced RCC?

The lenvatinib/pembrolizumab story is now near completion with maintained benefit. We clearly want to follow patients and the data longer as best we can to try to gain any additional insights into the durability of response.

The field of frontline therapy for advanced RCC is crowded. We have an embarrassment of riches, with several potential therapy options for patients. The lenvatinib/pembrolizumab data confirm that [the combination] is one of the main therapies to choose [from in this space], so the future looks bright for this regimen.

[Going forward], we are looking for other signals in kidney cancer. We want to take the high complete response rates that we see with lenvatinib/pembrolizumab and make that available for more patients. Ultimately, we want to make RCC a chronic illness for most patients but have the ability to cure some patients.

Disclosures: Dr Hutson reported having served as a consultant or in an advisory role for Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, Novartis, and Pfizer; he received institutional research grant/funding from Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; he has served on a speakers’ bureau for Astellas Pharma, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; and he received honoraria from Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, Novartis, and Pfizer.

References

1. Motzer RJ, Porta C, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(suppl 16):4502. doi:10.1200/JCO.2023.41.16_suppl.4502
2. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. News Release. FDA. August 11, 2021. Accessed July 5, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma