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First-Line Combination Treatments Improve Outcomes vs Sunitinib in Advanced Renal Cell Carcinoma


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Two recently reported phase III trials have shown the benefits of combination therapy vs sunitinib in the first-line treatment in advanced renal cell carcinoma. As reported in The New England Journal of Medicine by Brian I. Rini, MD, of Cleveland Clinic Taussig Cancer Institute, and colleagues, the first interim analysis of the KEYNOTE-426 trial showed significant benefits in overall and progression-free survival with the combination of pembrolizumab plus axitinib vs sunitinib in the first-line treatment of advanced renal cell carcinoma.1

As also reported in The New England Journal of Medicine by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center (MSK), and colleagues, the first interim analysis of the JAVELIN Renal 101 trial showed that the combination of first-line avelumab plus axitinib significantly prolonged progression-free survival vs sunitinib in advanced renal cell carcinoma both among programmed cell death ligand 1 (PD-L1)-positive patients and all patients.2

KEYNOTE-426: First-Line Pembrolizumab/Axitinib vs Sunitinib

Study Details: In the open-label trial, 861 patients with previously untreated advanced clear cell renal cell carcinoma from 124 sites in 16 countries were randomly assigned between October 2016 and January 2018 to receive pembrolizumab at 200 mg once every 3 weeks plus axitinib at 5 mg twice daily (n = 432) or sunitinib at 50 mg once daily for the first 4 weeks of 6-week cycles (n = 429).1 Randomization was stratified according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group and geographic region. The co-primary endpoints were overall and progression-free survival in the intention-to-treat population.


Among patients with previously untreated advanced renal cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib.
— Brian I. Rini, MD, and colleagues

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Overall and Progression-Free Survival: On first interim analysis, after a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab/axitinib group vs 78.3% in the sunitinib group (hazard ratio [HR] = 0.53, P < .0001). The median progression-free survival was 15.1 months vs 11.1 months (HR = 0.69, P < .001). A benefit of pembrolizumab/axitinib in both overall and progression-free survival was observed across all subgroups examined, including all IMDC risk groups and PD-L1 expression subgroups (combined positive score of ≥ 1 or < 1 using the PD-L1 IHC 22C3 pharmDx assay). Hazard ratios for progression-free and overall survival were 0.87 (95% confidence interval [CI] = 0.62–1.23) and 0.59 (95% CI = 0.34–1.03) among 325 patients with a PD-L1 combined positive score < 1 and 0.62 (95% CI = 0.47–0.80) and 0.54 (95% CI = 0.35–0.84) among 497 with a PD-L1 combined positive score ≥ 1. The objective response rate was 59.3% vs 35.7% (P < .001).

In the pembrolizumab/axitinib group, 50.0% of patients who discontinued study therapy received subsequent anticancer therapy, most commonly vascular endothelial growth factor (VEGF) or VEGF receptor inhibitors (44.3%). In the sunitinib group, 60.7% of patients who discontinued study therapy received subsequent anticancer therapy, most commonly a programmed cell death protein 1 (PD-1) or PD-L1 inhibitor (37.6%).

Robert J. Motzer, MD

Robert J. Motzer, MD

Adverse Events: Grade ≥ 3 adverse events were observed in 75.8% of the pembrolizumab/axitinib group vs 70.6% of the sunitinib group. Adverse events of grade ≥ 3 that occurred in at least 10% of patients were hypertension and increased alanine aminotransferase in the pembrolizumab/axitinib group and hypertension in the sunitinib group. Adverse events of interest (possible immune-mediated cause and infusion reactions) occurred in 51.3% vs 36.2%, including grade ≥ 3 events in 11% vs 2%. Adverse events led to discontinuation of either drug in 30.5% and both drugs in 10.7% of patients in the combination group and in 13.9% of patients in the sunitinib group.

Death due to treatment-related adverse events occurred in four patients in the combination group (0.9%; due to myasthenia gravis, myocarditis, necrotizing fasciitis, and pneumonitis) and in seven patients in the sunitinib group (1.6%; due to acute myocardial infarction, cardiac arrest, fulminant hepatitis, gastrointestinal hemorrhage, intracranial hemorrhage, malignant neoplasm progression, and pneumonia).

The investigators concluded: “Among patients with previously untreated advanced renal cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib.”

JAVELIN Renal 101: First-Line Avelumab/Axitinib vs Sunitinib

Study Details: In the open-label trial, 886 patients with advanced clear cell renal cell carcinoma from 144 sites in 21 countries were randomly assigned between March 2016 and December 2017 to receive avelumab at 10 mg/kg every 2 weeks plus axitinib at 5 mg twice daily (n = 442) or sunitinib at 50 mg once daily for the first 4 weeks in 6-week cycles.2 Randomization was stratified by Eastern Cooperative Oncology Group performance status (0 vs 1) and geographic region. The two primary endpoints were progression-free survival on independent central review and overall survival among patients with PD-L1–positive tumors, defined as expression on ≥ 1% of tumor immune cells usng the Ventana PD-L1 (SP263) assay. Progression-free survival in the entire population was a key secondary endpoint. Efficacy analyses were performed in intention-to-treat populations.

Progression-Free and Overall Survival: At first interim analysis, with a median follow-up of 9.9 months for progression-free survival in the avelumab/axitinib group and 8.4 months in the sunitinib groups, the median progression-free survival among the 560 patients with PD-L1–positive tumors was 13.8 months in the avelumab/axitinib group vs 7.2 months in the sunitinib group (HR = 0.61, P < .001). With a median follow-up for overall survival of 11.6 months and 10.7 months, death from any cause had occurred in 37 patients (13.7%) in the avelumab/axitinib group and in 44 patients (15.2%) in the sunitinib group (HR = 0.82, P = .38).

Combination Therapies in Kidney Cancer

  • In KEYNOTE-426, pembrolizumab plus axitinib significantly improved overall and progression-free survival vs sunitinib in patients with advanced renal cell carcinoma.
  • In the JAVELIN Renal 101 trial, avelumab plus axitinib significantly improved progression-free survival vs sunitinib in patients with advanced renal cell carcinoma.

The median progression-free survival in the entire study population was 13.8 months vs 8.4 months (HR = 0.69, P < .001). Subgroup analysis showed a progression-free survival benefit with avelumab/axitinib in all subgroups examined, including according to PD-L1 status and MSK and IMDC risk groups. Death from any cause occurred in 63 patients (14.3%) vs 75 patients (16.9%; HR = 0.78, P = .14.). Objective response was observed in 55.2% vs 25.5% of patients with PD-L1–positive tumors and in 51.4% vs 25.7% among all patients.

Subsequent anticancer therapies were used by 20.8% of the combination group and 39.2% of the sunitinib group, with the most frequently used in the combination group being cabozantinib (9.5%) and the most frequently used in the sunitinib group being nivolumab (24.1%, with anti–PD-1 or anti–PD-L1 agents accounting for 66.7% of subsequent treatments).

Adverse Events: Adverse events of grade ≥ 3 occurred in 71.2% of the avelumab/axitinib group vs 71.5% of the sunitinib group, with the most common in the avelumab/axitinib group being hypertension (25.6% vs 17.1% in sunitinib group) and diarrhea (6.7% vs 2.7%). Potential immune-related adverse events occurred in 38.2% of the avelumab/axitinib group, with 9.0% being of grade ≥ 3.

Adverse events led to discontinuation of both avelumab and axitinib in 7.6% of patients and to discontinuation of sunitinib in 13.4%. Treatment-related death occurred in 3 patients in the avelumab/axitinib group (0.7%; due to sudden death, myocarditis, and necrotizing pancreatitis) and in 1 patient in the sunitinib group (0.2%; due to intestinal perforation).

The investigators concluded: “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.” 

DISCLOSURE: The KEYNOTE-426 trial was funded by Merck Sharp & Dohme. The JAVELIN Renal 101 trial was funded by Pfizer and Merck. Dr. Rini has received honoraria from Bristol-Myers Squibb; is a consultant/advisor with Novartis, Pfizer, Merck, and Roche/Genentech; has received institutional research funding from Pfizer, Roche/Genentech, Bristol-Myers Squibb, and Merck; and has received travel/accommodations/expenses from Pfizer. Dr. Motzer is a consultant/advisor with Pfizer, Novartis, Eisai, Exelixis, Merck, and Roche/Genentech; has received institutional research funding from Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, and Eisai; and has received travel/accommodations/expenses from Bristol-Myers Squibb.

REFERENCES

1. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.

2. Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103-1115, 2019.


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