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%) pembrolizumab-axitinib 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 aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred. CONCLUSIONS: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment. PATIENT SUMMARY: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

• MeSH
• Alanine Transaminase therapeutic use   MeSH
• Axitinib therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   pathology   MeSH
• Sunitinib adverse effects   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Data in patients with malignant melanoma, who have been previously treated with pembrolizumab as adjuvant therapy, show a reduction in pembrolizumab efficacy upon rechallenge. We examined this scenario in patients with non-metastatic renal cell carcinoma (RCC) eligible for adjuvant pembrolizumab after nephrectomy. We hypothesized that a proportion of such patients will either require re-treatment with pembrolizumab upon metastatic progression prior to cancer-specific mortality (CSM) or die from other cause mortality (OCM). MATERIALS AND METHODS: We identified within the SEER database 10,635 patients, between 2004 and 2017, with a diagnosis of non-metastatic intermediate-high and high risk RCC, who had undergone nephrectomy and fulfilled criteria for enrollment in KEYNOTE-564. Kaplan-Meier analyses addressed overall survival (OS), CSM and OCM. RESULTS: 9,825 (92.4%) of the 10,635 patients had intermediate-high risk RCC and 9,456 (88.9%) underwent radical nephrectomy. Additionally, 760 (7.1%) harbored sarcomatoid features. In Kaplan-Meier analyses, median OS was 9.8 (9.1-11.4) years. At 10-years of follow-up, CSM rate was 36% and OCM rate was 22%. CONCLUSIONS: Based on CSM, our observations indicate that by 10-years of follow-up 36% of patients treated with adjuvant pembrolizumab will require a rechallenge, in a setting where a checkpoint inhibitor may have reduced efficacy. Moreover, at 10-years of follow-up, 22% of patients with RCC, previously treated with adjuvant pembrolizumab, will die of other causes. These percentages should be strongly considered prior to routine use of adjuvant pembrolizumab, especially given an OS benefit has not been proven.

• MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• Carcinoma, Renal Cell * drug therapy   mortality   surgery   MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   mortality   surgery   MeSH
• Nephrectomy MeSH
• SEER Program MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Betacoronavirus MeSH
• COVID-19 MeSH
• Disease Outbreaks MeSH
• Contact Tracing MeSH

• Conspectus
• Veřejné zdraví a hygiena
• NML Fields
• veřejné zdravotnictví
• infekční lékařství
• NML Publication type
• publikace WHO

BACKGROUND: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. METHODS: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. FINDINGS: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. INTERPRETATION: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

• MeSH
• Axitinib administration & dosage   adverse effects   MeSH
• Time Factors MeSH
• Progression-Free Survival MeSH
• Antibodies, Monoclonal, Humanized administration & dosage   adverse effects   MeSH
• Protein Kinase Inhibitors administration & dosage   adverse effects   MeSH
• Carcinoma, Renal Cell drug therapy   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Neoplasms drug therapy   mortality   pathology   MeSH
• Antineoplastic Agents, Immunological administration & dosage   adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   adverse effects   MeSH
• Aged MeSH
• Sunitinib administration & dosage   adverse effects   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

• MeSH
• Information Literacy MeSH
• Information Dissemination MeSH
• Health Communication MeSH
• Publication type
• Collected Work MeSH

• Conspectus
• Výchova a vzdělávání
• NML Fields
• knihovnictví, informační věda a muzeologie

• Keywords
• pembrolizumab, KEYNOTE-001, KEYNOTE-006, KEYNOTE-22, KEYNOTE-10, KEYNOTE-21, MASTERKEY-265,
• MeSH
• Survival Analysis MeSH
• B7-H1 Antigen immunology   MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   adverse effects   therapeutic use   MeSH
• Immunotherapy MeSH
• Clinical Trials as Topic MeSH
• Congresses as Topic MeSH
• Humans MeSH
• Melanoma * drug therapy   MeSH
• Skin Neoplasms drug therapy   MeSH
• Lung Neoplasms drug therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• News MeSH

Brožura a sbírka abstraktů prací přednesených na kongresu, který se zaměřil na klinickou onkologii. Určeno odborné veřejnosti.

• MeSH
• Medical Oncology MeSH
• Neoplasms MeSH
• Publication type
• Abstracts MeSH
• Congress MeSH
• Collected Work MeSH
• News MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• onkologie
• NML Publication type
• brožury

• MeSH
• Medical Informatics MeSH
• Telemedicine MeSH
• Publication type
• Abstracts MeSH
• Congress MeSH
• Collected Work MeSH

• Conspectus
• Lékařské vědy. Lékařství
• NML Fields
• lékařská informatika

• MeSH
• Biomedical Research MeSH
• Biometry methods   MeSH
• Biostatistics methods   MeSH
• Clinical Medicine MeSH
• International Cooperation MeSH
• Statistics as Topic MeSH
• Publication type
• Abstracts MeSH
• Congress MeSH
• Collected Work MeSH

• Conspectus
• Lékařské vědy. Lékařství
• NML Fields
• statistika, zdravotnická statistika

• MeSH
• Skin Diseases, Infectious MeSH
• Sexually Transmitted Diseases MeSH
• Publication type
• Abstracts MeSH
• Congress MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• dermatovenerologie
• infekční lékařství