PURPOSE Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non–clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC. METHODS Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1. RESULTS Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest). CONCLUSION First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.

Background/Aims: This retrospective analysis compared progression-free survival (PFS) in 111 patients who developed or had preexisting hypertension with those who did not during treatment with second-line sunitinib. Secondary objectives included overall survival (OS) and safety. Methods: Patients with metastatic renal cell carcinoma (mRCC) received sunitinib 50 mg orally once daily in 6-week cycles according to a 4-week on/2-week off treatment schedule. Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. Resting blood pressure (BP) was monitored by clinic and home measurements. Hypertension was defined as systolic BP ≧140 and/or diastolic BP ≧90 mm Hg. Subsequent antihypertensive treatment was empirical, depending on the patient. Results:Fifty-four (48.6%) patients experienced elevated BP related to sunitinib. Of these, 10 had preexisting hypertension. Patients who developed hypertension related to sunitinib treatment experienced significantly longer PFS and OS compared to those who did not (p < 0.00001). Patients who required at least 3 antihypertensive drugs had the longest PFS (p = 0.00002) and OS (p = 0.00001). Conclusions: The development of hypertension during sunitinib treatment was a positive predictive factor associated with a significantly longer PFS and OS in patients with mRCC.

Further evaluation of the effect of these therapies on bone metastases in RCC is warranted.

Background: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed. Objective: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib. Design, setting, and participants: Patients enrolled in KEYNOTE-426 were included in this study. Outcome measurements and statistical analysis: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s). Results and limitations: The HEAS comprised 189/429 (44%) pembrolizumabaxitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/ 425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotrans-* Corresponding author.

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