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Immunotherapy-based combinations including pembrolizumab plus lenvatinib are the standard of care for patients with first-line clear-cell renal cell carcinoma, but these combinations are not well characterised in non-clear-cell renal cell carcinoma. We aimed to assess the activity and safety of pembrolizumab plus lenvatinib as a first-line treatment for patients with advanced non-clear-cell renal cell carcinoma. KEYNOTE-B61 is a single-arm, phase 2 trial being conducted at 48 sites (hospitals and cancer centres) in 14 countries (Australia, Canada, France, Hungary, Ireland, Italy, Poland, South Korea, Russia, Spain, Türkiye, Ukraine, the UK, and the USA). Adult patients (aged ≥18 years) with previously untreated stage IV non-clear-cell renal cell carcinoma and a Karnofsky performance status of 70% or higher were eligible for enrolment. All enrolled patients received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (2 years) plus lenvatinib 20 mg orally once daily or until disease progression, unacceptable toxicity, or withdrawal; lenvatinib could be continued beyond 2 years. The primary endpoint was the proportion of patients with a confirmed objective response as per adjusted Response Evaluation Criteria in Solid Tumours (version 1.1) assessed by independent central review. Activity and safety were analysed in all patients who received at least one dose of study treatment (the as-treated population). This trial is registered with ClinicalTrials.gov (NCT04704219) and is no longer recruiting participants but is ongoing. Between Feb 23, 2021, and Jan 21, 2022, 215 patients were screened; 158 were enrolled and received treatment. Median age at baseline was 60 years (IQR 52–69), 112 (71%) of 158 patients were male, 46 (29%) were female, 128 (81%) were White, 12 (8%) were Asian, three (2%) were Black or African American, and 15 (9%) were missing data on race. As of data cutoff (Nov 7, 2022), median study follow-up was 14·9 months (IQR 11·1–17·4). 78 of 158 patients had a confirmed objective response (49%; 95% CI 41–57), including nine (6%) patients with a confirmed complete response and 69 (44%) with a confirmed partial response. Grade 3–4 treatment-related adverse events occurred in 81 (51%) of 158 patients, the most common of which were hypertension (37 [23%] of 158), proteinuria (seven [4%]), and stomatitis (six [4%]). Serious treatment-related adverse events occurred in 31 (20%) of 158 patients. Eight (5%) patients died due to adverse events, none of which was considered related to the treatment by the investigators (one each of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism). Pembrolizumab plus lenvatinib has durable antitumour activity in patients with previously untreated advanced non-clear-cell renal cell carcinoma, with a safety profile consistent with that of previous studies. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients. Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai.

PD-1 and its ligands are expressed in urothelial cancer, and findings have shown that inhibition of the PD-1 pathway has clinical benefit. We aimed to assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic urothelial cancer. This study was part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket trial. We enrolled patients aged 18 years and older with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic urothelial cancer, including cancers of the renal pelvis, ureter, bladder, or urethra, from eight hospitals in the USA and Israel. Patients were required to have at least 1% PD-L1 expression detected on the tumour cells or in tumour stroma, as determined by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab every 2 weeks until disease progression, unacceptable toxic effects, or the end of the study (ie, 24 months of treatment). Primary endpoints were safety and overall response (defined by Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1), as assessed by a masked, independent central review. Safety was assessed in patients who received one or more doses of pembrolizumab (all-patients-as-treated population); activity was assessed in patients who received pembrolizumab, had measurable disease at baseline, and had one or more post-baseline scans, or discontinued because of progressive disease or treatment-related adverse events (full analysis set). This study is registered with ClinicalTrials.gov, number NCT01848834, and is no longer enrolling patients; follow-up is ongoing. Between May 14, 2013, and Dec 10, 2013, 115 patients were tissue pre-screened as part of a two-part consent process. 61 (53%) patients were PD-L1 positive, of whom 33 were enrolled in this study. All enrolled patients received at least one dose of pembrolizumab and were included in the safety analyses. 27 patients comprised the full analysis set and were deemed assessable for activity. Six patients were not assessable: three discontinued study drug because of a non-treatment-related adverse event before the first post-baseline scan, two withdrew before the first post-baseline scan, and one had no measurable disease at baseline. The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced five serious treatment-related adverse events. After median follow-up of 13 months (range 1–26, IQR 5–23), an overall response was achieved in seven (26% [95% CI 11–46]) of 27 assessable patients, with three (11% [2–29]) complete and four (15% [4–34]) partial responses. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related. Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced urothelial cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population. Merck & Co., Inc.

Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. Eisai and Merck Sharp & Dohme.

The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas. In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788. Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7–40·1). In approach 1, 22 of 50 patients (44% [95% CI 30–59]) had an objective response. In approach 2, 19 of 25 patients (76% [55–91] had an objective response. 23 (46%) of 50 patients had a grade 3–5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents). Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas. Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute.

Hypoxia-inducible factor-2α inhibitor belzutifan is approved for von Hippel-Lindau disease-associated renal cell carcinoma, CNS haemangioblastomas, and pancreatic neuroendocrine tumours, based on previously published initial results from the LITESPARK-004 study. Updated results are presented here after a median follow-up of nearly 50 months. In this single-arm, phase 2 study, participants were enrolled at 11 centres in Denmark, France, the UK, and the USA. Oral belzutifan 120 mg once daily was given to eligible adults aged 18 years or older with a diagnosis of von Hippel-Lindau disease (based on germline VHL alterations), at least one measurable renal cell carcinoma tumour, no tumour larger than 3 cm that necessitated immediate surgery, no metastatic disease, no previous systemic anticancer treatment, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. The primary endpoint was the proportion of participants with an objective response in von Hippel-Lindau disease-associated renal cell carcinoma per Response Evaluation Criteria in Solid Tumours, version 1.1, determined by an independent review committee, and assessed in all participants who received at least one dose of belzutifan. This ongoing study is no longer recruiting and is registered at ClinicalTrials.gov, NCT03401788. Between May 31, 2018, and Mar 29, 2019, 61 participants were enrolled; 36 (59%) were continuing treatment as of April 3, 2023. The median age of all enrolled participants was 41·0 years (IQR 29·0–51·0); 32 (52%) of 61 participants were male and 29 (48%) were female; most were White (n=55; 90%). Median study follow-up was 49·9 months (IQR 48·9–52·2). 41 (67%; 95% CI 54–79) of 61 participants with renal cell carcinoma had an objective response; seven (11%) had a complete response and 34 (56%) a partial response. 13 grade 3 treatment-related adverse events occurred in 11 (18%) participants (anaemia: seven [11%]; fatigue: three [5%]; urinary tract infection: one [2%]; hypoxia: one [2%]; and blister: one [2%]). None of the participants had a grade 4 or 5 treatment-related adverse event. Four (7%) participants had serious treatment-related adverse events (one participant each: anaemia, urinary tract infection, intracranial haemorrhage, and hypoxia). Updated results support the use of belzutifan as systemic treatment for von Hippel-Lindau disease-associated renal cell carcinoma. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA; the Intramural Research Program of the National Institutes of Health, National Cancer Institute Center for Cancer Research; and a grant from the National Cancer Institute.

Results from the phase 3 CLEAR study showed that lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell carcinoma. We aimed to assess the health-related quality-of-life (HRQOL) outcomes from the CLEAR study. This open-label, randomised, phase 3 study was done across 200 hospitals and cancer centres in 20 countries. Patients were required to be 18 years or older, with advanced clear-cell renal cell carcinoma, and a Karnofsky performance status of 70% or higher. Patients who had received previous systemic anticancer therapy for renal cell carcinoma were not eligible. Patients were randomly assigned (1:1:1) to lenvatinib (oral 20 mg per day) plus pembrolizumab (intravenous 200 mg every 21 days), lenvatinib (oral 18 mg per day) plus everolimus (oral 5 mg per day) in 21-day cycles, or sunitinib (oral 50 mg per day, 4 weeks on followed by 2 weeks off). Patients were assigned to treatments with a computer-generated randomisation scheme and were stratified by geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint, previously reported, was progression-free survival, and HRQOL was a secondary endpoint. Most HRQOL analyses were done in patients who underwent randomisation, received at least one dose of study treatment, and had any HRQOL data. Completion and compliance analyses were done in the full analysis set. Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the EQ-5D-3 Level (EQ-5D-3L) preference questionnaire were administered at baseline and on day 1 of each subsequent 21-day cycle. This study is registered with ClinicalTrials.gov, NCT02811861, and is closed to new participants. Between Oct 13, 2016, and July 24, 2019, 355 patients were randomly assigned to the lenvatinib plus pembrolizumab group, 357 to the lenvatinib plus everolimus group, and 357 to the sunitinib group. Median follow-up for HRQOL analyses was 12·9 months (IQR 5·6–22·3). Because of the promising efficacy and safety results of lenvatinib plus pembrolizumab in the first-line setting, we focus the HRQOL results in this report on that combination versus sunitinib. Mean change from baseline in the lenvatinib plus pembrolizumab group compared with the sunitinib group was –1·75 (SE 0·59) versus –2·19 (0·66) for FKSI-DRS, –5·93 (0·86) versus –6·73 (0·94) for EORTC QLQ-C30 global health status/quality of life (GHS/QOL), and –4·96 (0·85) versus –6·64 (0·94) for the EQ-5D visual analogue scale (VAS). Median time to first deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 9·14 weeks (95% CI 6·43–12·14) versus 12·14 weeks (9·14–15·29; HR 1·13 [95% CI 0·94–1·35], log-rank p=0·20) for FKSI-DRS, 12·00 weeks (7·29–15·14) versus 9·14 weeks (6·29–12·14; 0·88 [0·74–1·05], log-rank p=0·17) for EORTC QLQ-C30 GHS/QOL, and 9·43 weeks (6·43–12·29) versus 9·14 weeks (6·29–12·00; 0·83 [0·70–0·99], log-rank p=0·041) for the EQ-5D VAS. Median time to definitive deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 134·14 weeks (95% CI 120·00–not estimable) versus 117·43 weeks (90·14–131·29; HR 0·70 [95% CI 0·53–0·92], log-rank p=0·0081) for FKSI-DRS, 114·29 weeks (102·14–153·29) versus 75·14 weeks (57·29–105·14; 0·60 [0·47–0·77], log-rank p<0·0001) for EORTC QLQ-C30 GHS/QOL, and 124·86 weeks (94·71–134·57) versus 74·86 weeks (54·14–96·00; 0·67 [0·53–0·85], log-rank p=0·0012) for the EQ-5D VAS. No outcomes on any of the instruments significantly favoured sunitinib over lenvatinib plus pembrolizumab. Most HRQOL comparisons of lenvatinib plus everolimus versus sunitinib were similar or favoured sunitinib. These HRQOL results demonstrate that patients given lenvatinib plus pembrolizumab treatment had similar or favourable scores compared with patients given sunitinib, particularly with respect to time to definitive deterioration. These results support the efficacy and safety profile of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma. Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).

Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial. LITESPARK-003 is an open-label, single-arm, phase 2 study at ten hospitals and cancer centres in the USA. In cohort 1, eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received no previous systemic therapy for locally advanced or metastatic renal cell carcinoma. Patients received belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until unacceptable adverse events, disease progression, or patient withdrawal. The primary endpoint was investigator-assessed confirmed objective response according to Response Evaluation Criteria in Solid Tumors version 1.1. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing. Between Sept 27, 2018, and Jan 10, 2023, we screened 138 patients for eligibility, and 50 (36%) were enrolled and assigned to cohort 1. The median age was 64 years (IQR 57–72). 40 (80%) of 50 patients were male and ten (20%) were female. 48 (96%) patients were White, one (2%) patient was Black or African American, and one (2%) was of a race in the other category. As of the data cutoff (May 15, 2023), median follow-up was 24·3 months (IQR 13·9–32·0). 35 (70%, 95% CI 55–82) of 50 patients had a confirmed objective response, including four (8%) who had a complete response and 31 (62%) who had a partial response. The most frequent grade 3–4 treatment-related adverse events were hypertension (six [12%] patients), anaemia (five [10%] patients), and fatigue (four [8%] patients). Seven (14%) of 50 patients had serious treatment-related adverse events. No treatment-related deaths occurred. Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma and further investigation of an HIF-2α inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and the National Cancer Institute.

The first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is approved for patients with advanced renal cell carcinoma previously treated with immune checkpoint and anti-angiogenic therapy based on results of the phase 3 LITESPARK-005 trial. We present patient-reported outcomes (PROs) from LITESPARK-005. LITESPARK-005 was an open-label, multicentre, randomised, active-controlled phase 3 trial conducted at 147 hospitals and cancer centres in six regions. Eligible participants were 18 years or older with advanced clear cell renal cell carcinoma, had a Karnofsky Performance Status score of 70% or higher, had measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, had disease progression on or after treatment with anti-PD-1 or anti-PD-L1 immunotherapy and a VEGF tyrosine kinase inhibitor (in sequence or in combination), and had received no more than three previous systemic lines of therapy. Eligible participants were randomly assigned (1:1) centrally using interactive voice-response and web-response systems to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily. Randomisation was stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and number of previous VEGF-targeted or VEGF receptor-targeted therapies. The dual primary outcomes were progression-free survival and overall survival, results of which have been reported previously. In this study, prespecified secondary patient-reported outcomes (PROs) from LITESPARK-005 were assessed using the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO analysis population included all participants who received at least one dose of study therapy and completed at least one PRO assessment. Least-squares mean change from baseline in PROs at week 17 was assessed using a constrained longitudinal data analysis model. Time to deterioration in physical functioning (prespecified) and role functioning (post hoc), as assessed by the EORTC QLQ-C30, were also evaluated in the PRO analysis population. This trial is ongoing, closed to recruitment, and registered with ClinicalTrials.gov, NCT04195750. Between March 10, 2020, and Jan 19, 2022, 996 participants were screened for eligibility and 746 participants were randomly assigned to belzutifan (n=374) or everolimus (n=372). The PRO full analysis set population included 366 participants in the belzutifan group and 354 in the everolimus group. Median time from randomisation to the database cutoff date (June 13, 2023) was 25·7 months (IQR 21·7–30·4). Completion rates for FKSI-DRS and QLQ-C30 were higher than 94% at baseline and higher than 55% at week 17 in each group. Change from baseline to week 17 in FKSI-DRS score (difference in least-squares mean between groups 1·5 [95% CI 0·7 to 2·2]) and QLQ-C30 global health status–quality of life (QOL) score (6·4 [3·2 to 9·6]) suggested stability with belzutifan versus worsening with everolimus. Change from baseline to week 17 was similar between groups for QLQ-C30 physical functioning (difference in least-squares mean 2·5 [95% CI −0·6 to 5·5]) and QLQ-C30 role functioning (4·2 [0·1 to 8·4]) subscale scores. Time to deterioration was similar between the belzutifan and everolimus groups for EORTC physical functioning (median 19·3 months [95% CI 11·1 to not reached] in the belzutifan group vs 13·8 months [10·6 to not reached] in the everolimus group; hazard ratio 0·93 [95% CI 0·72 to 1·20]) and role functioning (median 12·0 months [9·2 to not reached] vs 10·2 months [4·7 to 14·4]; 0·88 [0·69 to 1·11]). Belzutifan for advanced renal cell carcinoma was associated with improved disease-specific symptoms and QOL compared with everolimus. Taken together with the efficacy and safety data from LITESPARK-005, belzutifan could offer a clinical benefit without compromising the QOL of patients in this setting. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Background In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. Patients and Methods In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. Results No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (–2.5; 95% CI –5.2 to 0.1), EORTC QLQ-C30 physical functioning (–0.87; 95% CI –2.7 to 1.0), and FKSI-DRS (–0.7; 95% CI –1.2 to –0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). Conclusions Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. Trial Registration Clinicaltrials.gov Identifier: NCT03142334 Patient-reported outcomes provide an important measure of health-related quality of life and can complement efficacy and safety results. This article presents analyses of health-related quality of life in patients enrolled in the KEYNOTE-564 trial.

The cause of von Hippel–Lindau disease is excess activity of the HIF-2α pathway. A total of 61 patients with renal cell carcinoma and other proliferative manifestations of the hypoxia-induced signaling pathway received belzutifan, which inhibits the HIF-2α pathway. Nearly half the patients with renal cell carcinoma had a response to treatment, and 98% had disease control.