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Among patients with advanced renal-cell carcinoma, overall survival and progression-free survival were longer among patients who received pembrolizumab and axitinib than among those who received sunitinib, and more patients in the pembrolizumab–axitinib group than in the sunitinib group had a response.

Among 886 patients with advanced renal-cell cancer, median progression-free survival was 13.8 months among those assigned to avelumab plus axitinib and 7.2 months among those assigned to sunitinib. Toxic effects of grade 3 or higher were similar in the two groups.

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. 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. 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. 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. Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial ( n  = 886; NCT02684006 ), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC. Biomarker analysis of the phase 3 JAVELIN Renal 101 trial uncovers molecular determinants of therapy-specific outcomes, which may inform personalized treatment strategies for patients with advanced renal cell carcinoma.

Introduction Avelumab + axitinib was approved in Japan in December 2019 for the treatment of curatively unresectable or metastatic renal cell carcinoma (RCC) based on results from the JAVELIN Renal 101 trial. Materials and Methods To evaluate the safety and effectiveness of avelumab + axitinib in older patients in general clinical practice in Japan, an ad hoc analysis of data from post‐marketing surveillance (PMS) by age group was conducted. Results The analysis population included 328 patients who had received ≥1 dose of avelumab and were enrolled between December 2019 and May 2021. In total, 100 patients (30.5%) were aged ≤64 years, 130 (39.6%) were aged 65–74 years, and 98 (29.9%) were aged ≥75 years. Within these age groups, adverse drug reactions (ADRs) of safety specifications of any grade occurred in 46 (46.0%), 71 (54.6%), and 56 (57.1%), and of grade ≥3 in 13 (13.0%), 23 (17.7%), and 20 (20.4%), respectively. The most common ADRs of safety specifications across all age groups were thyroid dysfunction, infusion reactions, and hepatic function disorders. Median overall survival (OS) was not reached in any age group; 12‐month OS rates in patients aged ≤64, 65–74, or ≥75 years were 83.8%, 86.2%, and 80.0%, and objective response rates were 31.0%, 43.8%, and 30.6%, respectively. Discussion Analyses of PMS data show the safety and effectiveness of avelumab + axitinib across all age groups of patients with RCC in general clinical practice in Japan. The favorable benefit–risk profile was generally consistent with that observed in previous clinical trials. We report analyses from post‐marketing surveillance of avelumab + axitinib treatment in patients with advanced renal cell carcinoma in Japan in age subgroups: ≤64 years (n = 100), 65–74 years (n = 130), and ≥75 years (n = 98). Overall, safety and effectiveness were similar across age subgroups, suggesting that age alone is not a relevant consideration for avelumab + axitinib treatment. The favorable benefit–risk profile was generally consistent with that observed in previous clinical studies, further supporting the use of avelumab + axitinib treatment in this disease setting.

In renal cell carcinoma (RCC) patients with inferior vena cava (IVC) tumor thrombus, neoadjuvant therapy could alleviate the burden of tumor thrombus, enhance the safety and feasibility of surgical resection, and improve patient prognosis. The combination of tislelizumab and axitinib has demonstrated efficacy in the treatment of advanced RCC. Our study aimed to evaluate the efficacy and safety in the neoadjuvant therapy setting of tislelizumab and axitinib in RCC patients with IVC tumor thrombus. In this retrospective study, seven patients of nonmetastatic RCC with IVC tumor thrombus who received 3 cycles of neoadjuvant therapy with tislelizumab plus axitinib at the First Affiliated Hospital of Xiamen University from May 2020 to December 2023 were included. The main outcomes included objective response rate (ORR), reduction of tumor thrombus size and level, surgical outcomes, and adverse events (AEs). The median age was 66 (range, 50–72) years, and five (71.4%) patients were male. Five (71.4%) patients were diagnosed with clear cell carcinoma, and two (28.6%) patients were papillary type I carcinoma. Four (57.1%) patients had level II tumor thrombus and three (42.9%) patients had level III. The ORR of patients was 57.1%. The mean decrease in thrombus diameter and length was 5.8 (1.8–17.2) mm and 18.5 (4.4–41.5) mm, respectively. All patients showed a decrease in IVC tumor thrombus. The mean time from the end of neoadjuvant therapy to radical nephrectomy and thrombectomy was 31.7(range, 22–45) days. No intraoperative complications or postoperative Clavien-Dindo grade>3 complications occurred. The most common AEs were all grade 1–2, and only one patient had grade 4 hepatic impairment. No AEs delayed the surgery schedule. This study of RCC patients receiving neoadjuvant combination with tislelizumab and axitinib effectively reduced primary tumor and IVC tumor thrombus with the absence of serious AEs, demonstrating a promising neoadjuvant therapy.

Background The optimal first-line therapy for metastatic renal cell carcinoma (mRCC) remains uncertain, despite recent advancements in immune-based combinations. This retrospective study compares the effectiveness of pembrolizumab plus axitinib (PA) and nivolumab plus cabozantinib (NC) as first-line treatments for mRCC in a real-world setting. Methods Patient data were collected from 55 centers across 16 countries, encompassing individuals diagnosed with mRCC receiving first-line treatment with PA or NC between January 2016 and October 2023. Clinical and tumor features and treatment responses were recorded. The primary endpoints were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to second progression. Statistical analyses included Kaplan–Meier survival estimates, Cox proportional hazard models, and chi-square tests. Results A total of 760 patients with a median age of 64 years (range, 29–88) were included. Of them, 607 received PA, and only 153 NC. In the overall study population, ORR was 59% for and 49% for PA. Median OS was 55.7 months and not reached (NR) for PA and NC, respectively ( P  = .51), while median PFS was longer with NC (27.6 months) than for PA (16.2 months, P  = .003). Subgroup analysis suggested a PFS benefits for NC in male, younger patients, intermediate risk group, clear cell histology, and lung involvement, as well as ORR favored NC in good risk patients. Multivariate analysis identified first-line therapy as a significant factor associated with PFS. Conclusions In this certainly biased retrospective comparison, NC demonstrated superior ORR and longer PFS compared to PA in mRCC. These findings underscore the importance of considering individual patient characteristics and risk profiles when selecting first-line therapy for mRCC.

VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma. This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0–1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2–10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual. Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1–19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6–79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1–90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths. Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials. Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.