Updated Results of CheckMate 025 Confirm Benefits of Nivolumab Over Everolimus in RCC

In the CheckMate 025 trial, nivolumab (Opdivo) remained superior to everolimus (Afinitor) in terms of efficacy and safety in patients with advanced renal cell carcinoma (aRCC) at a >5-year minimum follow-up and had continued responses in 28% of patients, according to a presentation at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium.¹

“Nivolumab continues to show significant overall survival [OS] benefit, higher objective response rate [ORR], and improved progression-free survival [PFS] over everolimus with long-term follow-up,” Robert J. Motzer, MD, said during his presentation of the updated, final analysis. “A lower proportion of nivolumab-treated patients experienced treatment-related adverse events [TRAEs], and no new safety signals were observed with the long follow-up. Nivolumab was associated with rapid and sustained improvement in quality of life.”

Of the 821 patients evaluated in CheckMate 025 (NCT01668784), those randomized to nivolumab (n = 410) demonstrated a better OS benefit over those randomized to everolimus (n = 411) at long-term follow-up (median 72 months follow-up), with a median OS of 25.8 versus 19.7, respectively (HR, 0.73; 95% CI, 0.62-0.85;P<.0001). The OS rate at 60 months was 26% with nivolumab and 18% with everolimus.

PFS also favored nivolumab; the median PFS per investigator was 4.2 months for patients receiving nivolumab and 4.5 months for those receiving everolimus (HR, 0.84; 95% CI, 0.72-0.99;P=.03). The rate of patients with PFS at 60 months was 5% and 1% for nivolumab and everolimus, respectively.

The ORR was 23% with nivolumab, 1% of which were complete responses and 22% were partial responses; everolimus had a 4% ORR with 0.5% complete responses and 4% with partial responses (odds ratio, 6.86; 95% CI, 4.01-11.74,P<.0001). Stable disease was observed in 34% of the patients in the nivolumab abd 35% of patients had progressive disease. In the everolimus arm, 55% of patients has stable disease and 26% had progressive disease. Patients&rsquo; median duration of response was longer for nivolumab as well (18.2 vs 14.0 months). Investigators of the study observed ongoing response in 28% of patients on nivolumab and 18% on everolimus.

There were no new safety signals or deaths due to treatment in either arm at the time of follow-up. Patients on everolimus experienced more grade 3/4 TRAEs than those on nivolumab, at 37% versus 21%, respectively. The most common TRAE was fatigue, at 35% for any grade and 3% for grade 3/4 in both arms.

At the &ge;64 months follow-up, 276 patients (67%) on nivolumab went on to subsequent systemic anticancer therapy, 35% receiving everolimus and 33% receiving axitinib (Inlyta). Similarly, 296 patients (72%) on everolimus got subsequent therapy, 41% receiving axitinib and 26% receiving nivolumab.

Randomized 1:1, patients in the CheckMate 025 trial received either 3 mg/kg of nivolumab intravenously every 2 weeks or 10 mg of daily everolimus orally until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. The primary end point was OS and secondary end points included PFS, ORR, and safety. In August of 2015, a month after the minimum follow-up date, the protocol of the trial was amended to allow crossover from everolimus to nivolumab.

For patients who crossed over to nivolumab, there was a median OS of 65.9 months, median PFS of 7.4 months, and ORR of 8% by investigator assessment. The median duration of response was 8.8 months for these patients.

Patients in the trial had to have aRCC; &le;3 prior lines of treatment; 1 to 2 antiangiogenic therapies; progression &le;6 months before enrolling in the study; a Karnofsky performance status of &ge;70; and no central nervous metastases, prior mTOR inhibitor therapy, or condition requiring glucocorticoids.

There was a minimum of 14 months follow-up for the primary analysis. The median OS at that point was 25.0 months with nivolumab and 19.6 with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93;P=.002); median PFS was 4.6 months and 4.4 months for nivolumab and everolimus, respectively (HR, 0.88; 95% CI, 0.57-0.93;P=.11). The investigator-assessed ORR was 25% in the nivolumab arm and 5% in the everolimus arm (odds ratio, 5.98; 95% CI, 3.68-9.72,P<.001).²

Of the baseline characteristics from the primary analysis, the ones highlighted Motzer&rsquo;s presentation were the Memorial Sloan Kettering Cancer Center risk groups and previous antiangiogenic regimens for treatment of aRCC. The risk groups for nivolumab had 35% of patients with favorable risk, 49% with intermediate-risk, and 16% with poor risk; everolimus had 36% of patients with favorable risk, 49% with intermediate-risk, and 15 with poor risk. In both groups, 72% had 1 previous antiangiogenic regimen and 28% had 2.

References

1. Motzer RJ, Tykodi SS, Escudier B, et al. Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with >5 years of follow-up in patients with advanced renal cell carcinoma (aRCC).J Clin Oncol. 2020;38(suppl 6):617. doi: 10.1200/JCO.2020.38.6_suppl.617.
2. Motzer RJ, Escudier B, McDermott DF, et al; the CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015;373(19):1803