Combo more than doubled progression-free survival compared to sunitinib monotherapy

Combining lenvatinib and pembrolizumab more than doubled progression-free survival compared to sunitinib monotherapy in patients with advanced renal cell carcinoma. When lenvatinib was combined with everolimus, progression free survival was also significantly longer.

These findings from the Compare the Efficacy and Safety of Lenvatinib in Combination with Everolimus or Pembrolizumab versus Sunitinib Alone in First-Line Treatment of Subjects with Advanced Renal Cell Carcinoma (CLEAR) trial were published online by The New England Journal of Medicine and concurrently reported at the virtual Genitourinary Cancers Symposium (ASCO-GU).

In the phase III trial of more than 1,000 patients “Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 versus 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32-0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 versus 9.2 months; hazard ratio, 0.65; 95% CI, 0.53-0.80; P<0.001),” wrote Robert Motzer, MD, of Memorial Sloane Kettering Cancer Center in New York City, and the CLEAR co-investigators.

Overall survival was also “longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49-0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88-1.50; P= 0.30).”

But the observed benefits came at the cost of greater toxicity as 82.4% of patients in the lenvatinib plus pembrolizumab group and 83.1% of those given lenvatinib plus everolimus reported grade 3 or higher adverse events (AEs) during treatment. Those rates were about 10% higher than adverse event rates seen with sunitinib monotherapy. The most common AEs reported were high blood pressure, diarrhea, and elevated lipase levels.

In an editorial accompanying the study, Alain Ravaud, MD, PhD, of Hospital Saint-André, University Hospital Center Bordeaux, France, wrote that the trial was “a step forward in that it provides data that will assist in determining which combination of anti–PD-1 drug and VEGFR tyrosine kinase inhibitor may be effective as an alternative to nivolumab and ipilimumab for some patients.”

Because the investigators combined an anti-PD-1 drug (pembrolizumab) with a VEGFR tyrosine kinase inhibitor (lenvatinib), they provided evidence that the combination has a “greater chance of achieving control of the disease early on, as measured by progression-free survival, than do combinations of immune-checkpoint inhibitors only,” Ravaud wrote, but he added that what is still needed are biomarker studies that further hone the targeting of therapies.

All of the participants in the CLEAR trial had advanced renal cell carcinoma but no previous systemic therapy. The patients in the lenvatinib/pembrolizumab arm received oral lenvatinib (20 mg daily) plus 200 mg IV pembrolizumab once every three weeks, while those in the lenvatinib/everolimus arm received 18 mg lenvatinib daily plus plus 5 mg everolimus (oral) daily, sunitinib 50 mg orally, alternating four weeks on treatment and two weeks off treatment.

Progression-free survival was the primary endpoint.

The median age of the 355 patients in the lenvatinib plus pembrolizumab group was 64, while patients in the lenvatinib plus everolimus (n=357) and sunitinib group (n=357) were slightly younger —median ages 62 and 61 respectively, but in each treatment group more than half of the participants were younger than 65. Overall, only about a quarter of the participants were women, and more than half were from Western Europe or North America.

Participants were enrolled from Oct. 13, 2016 through July 24, 2019. Data cutoff was Aug. 28, 2020 for progression-free survival, “with a median follow-up for overall survival of 26.6 months.” At that time, 40% of lenvatinib-pembrolizumab patients versus 31.4% of lenvatinib-everolimus patients and 18.8% of sunitinib patients were still receiving assigned treatment. “Among patients who discontinued therapy, 54.9% in the lenvatinib-plus-pembrolizumab group, 68.2% in the lenvatinib-plus-everolimus group, and 71.0% in the sunitinib group received subsequent systemic therapy during follow-up,” they wrote.

On the one hand, although the differences observed in progression free survival were significant, overall survival was not so markedly different and no treatment group reached median overall survival: “79.2% of the patients in the lenvatinib-plus-pembrolizumab-ab group, 66.1% of the patients in the lenvatinib-plus-everolimus group, and 70.4% of the patients in the sunitinib group were alive at 24 months,” the study authors wrote.

On the other hand, confirmed objective response was markedly different: “71.0% with lenvatinib plus pembrolizumab, 53.5% with lenvatinib plus everolimus, and 36.1% with sunitinib (relative risk with lenvatinib plus pembrolizumab versus sunitinib, 1.97 [95% CI, 1.69-2.29]; and with lenvatinib plus everolimus vs. sunitinib,1.48 [95% CI, 1.26-1.74]). The per-percentage of patients with a complete response was 16.1% in the lenvatinib-plus-pembrolizumab group, 9.8% in the lenvatinib-plus-everolimus group, and 4.2% in the sunitinib group,” they wrote.

The investigators noted that an important limitation was the lack of blinding — physicians and patients knew the treatment they were receiving. Moreover, “different percentages of patients with known prognostic risk features, including poor IMDC risk and sarcomatoid histologic features, should be considered in cross-trial comparisons.”

  1. Be aware that the findings from this study suggest that combining an anti-PD-1 drug with a VEGFR tyrosine kinase inhibitor may achieve better progression-free survival than combinations of immune check-point inhibitors.

  2. In the CLEAR trial in patients with metastatic renal cell carcinoma combining lenvatinib with either pembrolizumab or everolimus achieved significant gains in progression-free survival versus sunitinib monotherapy.

Peggy Peck, Editor-in-Chief, BreakingMED™

The CLEAR trial was supported by Eisai and Merck Sharp and Dohme.

Motzer reported grants and personal fees from Eisai, personal fees from Merck, during the conduct of the study; grants and personal fees from Pfizer, grants and personal fees from Novartis, personal fees from Exelixis, grants and personal fees from Genentech, personal fees from Incyte, personal fees from Lilly, grants and personal fees from Roche, grants and non-financial support from Bristol Myers Squibb, personal fees from Astra Zeneca, personal fees from EMD Serome, outside the submitted work.

Ravaud reported grants, personal fees, and non-financial support from Pfizer, grants and non-financial support from Merck GA, personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Ipsen, non-financial support from Novartis, and non-financial support from MSD outside the submitted work.

Cat ID: 451

Topic ID: 78,451,730,451,835,935,127,192,925,450

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