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Clinical Trial
. 2019 Mar 21;380(12):1103-1115.
doi: 10.1056/NEJMoa1816047. Epub 2019 Feb 16.

Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Robert J Motzer  1 , Konstantin Penkov  1 , John Haanen  1 , Brian Rini  1 , Laurence Albiges  1 , Matthew T Campbell  1 , Balaji Venugopal  1 , Christian Kollmannsberger  1 , Sylvie Negrier  1 , Motohide Uemura  1 , Jae L Lee  1 , Aleksandr Vasiliev  1 , Wilson H Miller Jr  1 , Howard Gurney  1 , Manuela Schmidinger  1 , James Larkin  1 , Michael B Atkins  1 , Jens Bedke  1 , Boris Alekseev  1 , Jing Wang  1 , Mariangela Mariani  1 , Paul B Robbins  1 , Aleksander Chudnovsky  1 , Camilla Fowst  1 , Subramanian Hariharan  1 , Bo Huang  1 , Alessandra di Pietro  1 , Toni K Choueiri  1
Affiliations
Clinical Trial

Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Robert J Motzer et al. N Engl J Med. .

Abstract

Background: In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.

Methods: We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.

Results: A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.

Conclusions: Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).

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Figures

Figure 1.
Figure 1.. Progression-free Survival.
Progression-free survival among patients with programmed death ligand 1 (PD-L1)–positive tumors (Panel A) and among patients in the overall population (Panel B) is shown. NE denotes could not be estimated.
Figure 2.
Figure 2.. Subgroup Analyses of Progression-free Survival and Best Percentage Change in Target Lesions among Patients with PD-L1–Positive Tumors.
Panel A shows the results of a subgroup analysis of progression-free survival among the patients with PD-L1–positive tumors. Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5,with higher numbers reflecting greater disability. Patients with favorable risk had a Memorial Sloan Kettering Cancer Center (MSKCC) score of 0, those with intermediate risk had a score of 1 or 2, and those with poor risk had a score of 3 or more. MSKCC risk scores are defined according to the number of the following risk factors present: a Karnofsky performance-status score of less than 80 (on a scale from 0 to 100, with lower scores indicating greater disability; patients with a performancestatus score of <70 were excluded from the trial), less than 1 year from the time of initial diagnosis to the start of therapy, a hemoglobin level below the lower limit of the normal range, a lactate dehydrogenase level more than 1.5 times the upper limit of the normal range, and a corrected serum calcium concentration of more than 10 mg per deciliter (2.5 mmol per liter). Patients with favorable risk had an International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score of 0, those with intermediate risk had a score of 1 or 2, and those with poor risk had a score of 3 to 6. IMDC risk scores are defined according to the number of the following risk factors present: a Karnofsky performance-status score of less than 80, time from initial diagnosis to randomization of less than 1 year, hemoglobin level below the lower limit of the normal range, corrected serum calcium level above the upper limit of the normal range, absolute neutrophil count above the upper limit of the normal range, and platelet count above the upper limit of the normal range. Body-mass index is the weight in kilograms divided by the square of the height in meters. Panel B shows the best percentage change from baseline in the sum of the longest diameters of target lesions in the patients with PD-L1–positive tumors. Dotted lines indicate Response Evaluation Criteria in Solid Tumors (RECIST)–defined progressive disease (≥20% increase in the sum of target-lesion diameters, with baseline as the reference) and partial response (≥30% decrease in the sum of target-lesion diameters, with baseline as the reference).
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