A CLEAR Upfront Winner in Advanced RCC?

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Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) improved survival outcomes and response rates as a first-line treatment for advanced renal cell carcinoma (RCC), the randomized phase III CLEAR study showed.

For the primary endpoint, median progression-free survival (PFS) reached a whopping 23.9 months with the anti-PD-1 immunotherapy plus VEGFR tyrosine kinase inhibitor (TKI) combination, as compared with 9.2 months with sunitinib (Sutent), the prior standard in advanced RCC (HR 0.39, 95% CI 0.32-0.49, P<0.001), reported Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City.

Pembrolizumab-lenvatinib also boosted overall survival (OS), with a median not reached in either arm (HR 0.66, 95% CI 0.49-0.88, P=0.005), according to findings presented at the virtual Genitourinary Cancers Symposium and published in the New England Journal of Medicine (NEJM).

Overall response rate (ORR) doubled with the immunotherapy-TKI combination (71% vs 36.1% with sunitinib), and complete responses (CRs) quadrupled (16.1% vs 4.2%).

The PFS improvement of 14.7 months with pembrolizumab-lenvatinib is the largest versus sunitinib in a first-line RCC trial, and the benefit was consistent across International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups:

  • Favorable: HR 0.41 (95% CI 0.28-0.62)
  • Intermediate: HR 0.39 (95% CI 0.29-0.52)
  • Poor: HR 0.28 (95% CI 0.13-0.60)

CLEAR marks the third first-line RCC trial demonstrating a significant PFS and OS improvement with combination immunotherapy-TKI over sunitinib — following KEYNOTE-426 with pembrolizumab plus axitinib (Inlyta), and CheckMate 9ER of nivolumab (Opdivo) plus cabozantinib (Cabometyx), with combinations now FDA approved as first-line options.

Motzer said these three combinations will all be used based on physicians’ experience with their patients and the safety profiles of each.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive,” he said. “It would be an excellent choice for patients.”

A third arm of the CLEAR trial showed a median PFS of 14.7 months with lenvatinib plus everolimus (Afinitor), which was superior to sunitinib (HR 0.65, 95% CI 0.53-0.80, P<0.001). ORR with lenvatinib-everolimus was 53.5%, including CRs in 9.8%.

But no OS improvement was seen with lenvatinib-everolimus (HR 1.15, 95% CI 0.88-1.50, P=0.30), and the relevancy of this combination is unclear in the context of more active and survival prolonging immunotherapy-TKI options, as well as the dual immunotherapy combination of nivolumab plus ipilimumab (Yervoy), which demonstrated improved OS in intermediate- and poor-risk patients versus sunitinib.

In an accompanying NEJM editorial, Alain Ravaud, MD, PhD, of University Hospital Center Bordeaux in France, pointed out that nivolumab-ipilimumab did not show a significant PFS benefit over sunitinib in CheckMate 214.

“Therefore, rapid progression of the disease, especially in symptomatic patients and in patients who have involvement of an unfavorable metastatic site (e.g., liver or large mediastinal lymph nodes) requiring a rapid response to treatment, favors combining two modes of action,” he wrote.

“Nevertheless,” Ravaud said, “only the combination of nivolumab plus ipilimumab resulted in a median overall survival of 48 months in the population with IMDC-defined intermediate or poor risk and in a plateau in the survival curve after prolonged follow-up (>48 months). Follow-up of patients treated with an anti-PD-1 drug and a VEGFR tyrosine kinase inhibitor is currently too short to support similar conclusions.”

CLEAR randomized 1,069 previously untreated advanced RCC patients to one of three study arms:

  • Pembrolizumab (200 mg IV every 3 weeks) plus lenvatinib (20 mg oral/once daily)
  • Lenvatinib (18 mg once daily) plus everolimus (5 mg oral/once daily)
  • Sunitinib (50 mg oral/once daily; 4 weeks on and 2 weeks off)

The study’s primary endpoint was PFS. Patients had a median age of 61-64, about three-fourths were men, and a majority were treated in Western Europe or North America. IMDC breakdown was 27% for favorable-risk, 64% for intermediate-risk, and 9% for poor-risk. About a third of patients had PD-L1 positive disease (≥1%), which is not particularly predictive of response in RCC.

Median durations of response were highest with pembrolizumab-lenvatinib (25.8 months), followed by lenvatinib plus everolimus (16.6 months) and sunitinib (14.6 months).

Grade ≥3 adverse events (AEs) occurred in 82.4% of patients on pembrolizumab-lenvatinib, 83.1% of those on lenvatinib-everolimus, and 71.8% of patients assigned sunitinib. The most common grade ≥3 AEs with pembrolizumab-lenvatinib included hypertension (27.6%), diarrhea (9.7%), weight decrease (8.0%), and proteinuria (7.7%).

AEs led to treatment discontinuation in 37.2% of patients in the pembrolizumab-lenvatinib arm (28.7% pembrolizumab, 25.6% lenvatinib, 13.4% both), in 27% of those on lenvatinib-everolimus (22.0% lenvatinib, 24.8% everolimus, 18.9% both), and in 14.4% of sunitinib. Dose modifications and interruptions were common in all three arms.

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    Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.

Disclosures

The study was funded by Eisai and Merck Sharp & Dohme (MSD).

Motzer disclosed relevant relationships with AstraZeneca, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, Pfizer, and institutional relationships with Bristol Myers Squibb (BMS), Eisai, Exelixis, Genentech/Roche, Merck, Novartis, and Pfizer. Co-authors disclosed multiple relevant relationships with industry.

Ravaud disclosed relevant relationships with Pfizer, Merck GA, BMS, AstraZeneca, Ipsen, Novartis, and MSD.

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