Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Patient-Reported Outcomes in KEYNOTE-564: Adjuvant Pembrolizumab Versus Placebo for Renal Cell Carcinoma.

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.

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Oral HIF-2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study.

OBJECTIVE: To report the efficacy of oral HIF-2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in LITESPARK-004. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with ≥1 von Hippel-Lindau disease-associated measurable renal cell carcinoma tumor not requiring immediate surgical intervention were eligible. METHODS AND INTERVENTION: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included optical coherence tomography and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had ≥1 evaluable active retinal hemangioblastoma in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence intervals, 79.4-100.0). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants had additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured ≥500 µm in greatest linear dimension at baseline and were further analyzed. All 10 hemangioblastomas had a mean area reduction of ≥15% by month 12 and ≥30% by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for >2 years while on treatment.

Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai.

Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study.

BACKGROUND: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up. METHODS: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861. FINDINGS: Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93]). INTERPRETATION: Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma. FUNDING: Eisai and Merck Sharp & Dohme.

Efficacy and safety of lenvatinib plus pembrolizumab vs sunitinib in the East Asian subset of patients with advanced renal cell carcinoma from the CLEAR trial.

In the CLEAR trial, lenvatinib plus pembrolizumab met study endpoints of superiority vs sunitinib in the first-line treatment of patients with advanced renal cell carcinoma. We report the efficacy and safety results of the East Asian subset (ie, patients in Japan and the Republic of Korea) from the CLEAR trial. Of 1069 patients randomly assigned to receive either lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib, 213 (20.0%) were from East Asia. Baseline characteristics of patients in the East Asian subset were generally comparable with those of the global trial population. In the East Asian subset, progression-free survival was considerably longer with lenvatinib plus pembrolizumab vs sunitinib (median 22.1 vs 11.1 months; HR 0.38; 95% CI: 0.23-0.62). The HR for overall survival comparing lenvatinib plus pembrolizumab vs sunitinib was 0.71; 95% CI: 0.30-1.71. The objective response rate was higher with lenvatinib plus pembrolizumab vs sunitinib (65.3% vs 49.2%; odds ratio 2.14; 95% CI: 1.07-4.28). Dose reductions due to treatment-emergent adverse events (TEAEs) commonly associated with tyrosine kinase inhibitors occurred more frequently than in the global population. Hand-foot syndrome was the most frequent any-grade TEAE with lenvatinib plus pembrolizumab (66.7%) and sunitinib (57.8%), a higher incidence compared to the global population (28.7% and 37.4%, respectively). The most common grade 3 to 5 TEAEs were hypertension with lenvatinib plus pembrolizumab (20%) and decreased platelet count with sunitinib (21.9%). Efficacy and safety for patients in the East Asian subset were generally similar to those of the global population, except as noted.

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab.

BACKGROUND: Lenvatinib plus pembrolizumab showed significantly improved progression-free and overall survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma in the CLEAR study (NCT02811861). Here, we used CLEAR data to characterize common adverse reactions (ARs; adverse-event preferred terms grouped in accordance with regulatory authority review) associated with lenvatinib plus pembrolizumab and review management strategies for select ARs. MATERIALS AND METHODS: Safety data from the 352 patients who received lenvatinib plus pembrolizumab in the CLEAR study were analyzed. Key ARs were chosen based on frequency of occurrence (≥30%). Time to first onset and management strategies for key ARs were detailed. RESULTS: The most frequent ARs were fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), and hypertension (56.3%); grade ≥3 severity ARs that occurred in ≥5% of patients were hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), weight decreased (8.0%), and proteinuria (7.7%). Median times to first onset of all key ARs were within approximately 5 months (approximately 20 weeks) of starting treatment. Strategies for effectively managing ARs included baseline monitoring, drug-dose modifications, and/or concomitant medications. CONCLUSION: The safety profile of lenvatinib plus pembrolizumab was consistent with the known profile of each monotherapy; ARs were considered manageable with strategies including monitoring, dose modifications, and supportive medications. Proactive and prompt identification and management of ARs are important for patient safety and to support continued treatment. CLINICALTRIALS.GOV ID: NCT02811861.

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma.

Combination treatment with immunotherapy agents and/or vascular endothelial growth factor tyrosine kinase inhibitors are a standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Novel therapeutic combinations that include the hypoxia-inducible factor 2α inhibitor belzutifan and the cytotoxic T-lymphocyte-associated protein 4 inhibitor quavonlimab are being investigated for their potential to further improve patient outcomes. This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab as first-line treatment for advanced ccRCC. Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. METHODS: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. RESULTS: 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 and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group. CONCLUSIONS: 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. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

BACKGROUND: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. METHODS: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. RESULTS: The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). CONCLUSIONS: Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).

Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Merck & Co., Inc.

First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study.

BACKGROUND: More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin-based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer. METHODS: In this multicentre, single-arm, phase 2 study (KEYNOTE-052), cisplatin-ineligible patients with advanced urothelial cancer who had not been previously treated with systemic chemotherapy were recruited from 91 academic medical centres in 20 countries. Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response (the proportion of patients who achieved complete or partial response) in all patients and by PD-L1 expression status according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by independent central review. PD-L1 expression was assessed in tumour and inflammatory cells from tumour biopsies provided at study entry. Activity and safety were analysed in all patients who received at least one dose of pembrolizumab (all-patients-treated population). This study is registered with ClinicalTrials.gov, number NCT02335424, and follow-up is ongoing. FINDINGS: Between Feb 24, 2015, and Aug 8, 2016, 374 patients were enrolled and 370 patients received at least one dose of pembrolizumab. 89 (24%, 95% CI 20-29) of 370 patients had a centrally assessed objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89 responses were ongoing. Median follow-up was 5 months (IQR 3·0-8·6). A PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab; 42 (38%, 95% CI 29-48) of 110 patients with a combined positive score of 10% or more had a centrally assessed objective response. The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis). INTERPRETATION: First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424). FUNDING: Merck & Co.

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer.

BACKGROUND: Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS: A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m(2) loading, 250 mg/m(2) maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS: Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV(max)) for those treated initially with everolimus was -24% (2% to -54%), and with cetuximab was -5% (-23 to 36%). The K(trans) measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS: Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population.

Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.

BACKGROUND: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented. METHODS: LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety. RESULTS: Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred. CONCLUSION: After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety. CLINICALTRIALS: gov. NCT02974738.