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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.).

Background This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and Methods This was an open-label, two-part, multicenter study involving treatment-naive patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.

Summary 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.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC. A first-in-human trial of hypoxia-inducible factor (HIF)-2α inhibitor belzutifan (MK-6482) has a favorable safety profile and shows promising clinical activity for the treatment of patients with renal cell carcinoma who have been heavily pre-treated.

Background Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46–55 months from study initiation (data cut-off date, 23rd July 2019). Methods Fifty-two treatment-naive patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan–Meier method. Results At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1–44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1–79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4–30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1–34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths. Conclusions In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.

Background Urothelial carcinoma (UC) is the most common subtype of bladder cancer. The randomized phase 3 KEYNOTE-045 trial showed that pembrolizumab, used as second-line therapy significantly prolonged overall survival with fewer treatment-related adverse events than chemotherapy for advanced UC. Pembrolizumab has been approved by the European Medicines Agency for the treatment of locally advanced or metastatic UC in adults who have received platinum-containing chemotherapy. Many European countries use cost-effectiveness analysis to inform reimbursement decisions. Objective To assess the cost-effectiveness of pembrolizumab as second-line therapy for the treatment of advanced UC from a Swedish health care perspective. Design, setting, and participants We developed a partitioned-survival model to assess the costs and effectiveness of pembrolizumab compared with vinflunine (base case), paclitaxel, or docetaxel monotherapy in patients with advanced UC over a 15-yr time horizon. We obtained Kaplan-Meier estimates for survival endpoints, adverse events, and utility data from KEYNOTE-045. Outcome measurements and statistical analysis We performed parametric extrapolations to estimate overall and progression-free survival beyond the clinical trial period. Swedish costs and utility weights were used to estimate total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We performed deterministic and probabilistic sensitivity analyses to assess the robustness of the model results. Results and limitations In the base-case analysis, pembrolizumab resulted in a mean survival gain of 1.66 years (1.38 QALYs) at an incremental cost of €69 852 and an ICER of €50 529/QALY gained versus vinflunine monotherapy. ICERs for other chemotherapies were €81 356/QALY for pembrolizumab versus paclitaxel or docetaxel monotherapy, and €71 924/QALY for pembrolizumab versus paclitaxel, docetaxel, or vinflunine monotherapy. Long-term follow-up from KEYNOTE-045 and real-world data are needed to validate the extrapolations. Conclusions The results indicate that pembrolizumab improves survival, increases QALYs, and is cost-effective as second-line therapy at a willingness-to-pay threshold of €100 000/QALY for the treatment of advanced UC. Patient summary To date, pembrolizumab is the only treatment associated with a significant overall survival benefit compared with chemotherapy in a randomized controlled trial as second-line therapy for advanced urothelial carcinoma. Our trial-based cost-effectiveness analysis suggests that pembrolizumab is a cost-effective option over chemotherapy in patients with advanced urothelial carcinoma after platinum-based therapy in Sweden.

The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible.SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases.Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network's recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98).The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.

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

269 Background: In pts with advanced RCC, second-line treatment with LEN + EVE prolonged progression-free survival (PFS) compared with EVE alone. LEN + PEMBRO, also showed preliminary efficacious evidence in a phase 1/2 RCC study. Here, we describe the investigational study results of first-line LEN + PEMBRO or LEN + EVE versus SUN in pts with advanced RCC. Methods: Pts were randomized (1:1:1) to receive LEN 20 mg orally once daily + PEMBRO 200 mg IV every 3 weeks (wks); or LEN 18 mg + EVE 5 mg orally once daily; or SUN 50 mg orally once daily (4 wks on/2 wks off). Eligible pts had advanced RCC with no prior systemic therapy. Randomization was stratified by geographic region and MSKCC prognostic group. The primary endpoint was PFS by Independent Review Committee per RECIST v1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. A sequential approach was used to test PFS first, then OS and ORR. PFS and OS were compared across arms by a stratified log-rank test; hazard ratios (HRs) were estimated by a stratified Cox regression model. Results: 1069 pts were randomized (Table). After a median follow-up of 27 months (data cutoff August 28, 2020), PFS was significantly improved with LEN + PEMBRO (median 24 months [mos]) vs SUN (median 9 mos; HR 0.39, 95% CI 0.32–0.49) and LEN + EVE (median 15 mos) vs SUN (HR 0.65, 95% CI 0.53–0.80). OS was significantly longer with LEN + PEMBRO vs SUN (HR 0.66, 95% CI 0.49–0.88), whereas OS with LEN + EVE vs SUN was not statistically different (HR 1.15, 95% CI 0.88–1.50). ORR was significantly greater with LEN + PEMBRO (ORR 71%; complete response [CR] 16%) vs SUN (ORR 36%; CR 4%; odds ratio 4.35, 95% CI 3.16–5.97) and LEN + EVE (ORR 54%; CR 10%) vs SUN (odds ratio 2.15, 95% CI 1.57–2.93). Grade ≥3 treatment-related adverse events occurred in 72% of pts in the LEN + PEMBRO arm and 73% of pts in the LEN + EVE arm compared with 59% of pts in the SUN arm. Conclusions: LEN + PEMBRO demonstrated significant improvements in PFS, OS and ORR vs SUN. LEN + EVE demonstrated significant improvements in PFS and ORR vs SUN. Safety was manageable and consistent with the known single-agent profiles. Clinical trial information: NCT02811861 . [Table: see text]

Objective: Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS) and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective. Methods: A partitioned survival model with three states (progression-free, progressed, death) evaluated lifetime costs and quality-adjusted life-years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib, pazopanib, and avelumab/axitinib in the overall population; and sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with intermediate/poor prognostic risk. Costs of treatments, adverse events, and medical resources were estimated. OS, PFS, and treatment duration were extrapolated using parametric models fitted to KEYNOTE-426 data and hazard ratios from network meta-analyses. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EuroQol-5 Dimensions-3 Levels data. Results: In the overall population, pembrolizumab/axitinib was associated with incremental cost-effectiveness ratios (ICERs) of $95,725/QALY versus sunitinib and $128,210/QALY versus pazopanib, and was dominant (lower cost, higher effectiveness) versus avelumab/axitinib, with incremental QALY gains of 2.73, 2.40, and 1.80 versus these therapies, respectively. In the intermediate/poor-risk subgroup, base-case ICERs for pembrolizumab/axitinib were $101,030/QALY versus sunitinib, $6,989/QALY versus cabozantinib, and $130,934/QALY versus nivolumab/ipilimumab, with incremental QALY gains of 2.62, 1.78, and 1.06 versus these therapies. Conclusions: In this economic evaluation, pembrolizumab/axitinib was associated with higher life expectancy and QALYs and, based on typical willingness-to-pay thresholds of $150,000-$180,000/QALY, was found cost-effective versus other first-line treatments for advanced RCC in the US.

Purpose:Molecular profiling of large databases of human tumor gene expression profiles offers novel opportunities for informing decisions in clinical development programs.Experimental Design:Gene expression profile of programmed death ligand 1 (PD-L1) was explored in a dataset of 16,000 samples, including approximately 4,000 metastatic tumors, across >25 tumor types prevalent in the United States, looking for new indications for the programmed death 1 (PD-1) inhibitor pembrolizumab. PD-L1 expression was highly concordant with several genomic signatures indicative of immune-inflamed tumor microenvironment. Prevalence of activated immune-inflamed tumors across all tumor types was explored and used to rank tumor types for potential response to pembrolizumab monotherapy.Results:The analysis yielded 3 tiers of indications in which high levels of PD-L1 and immune-inflamed signatures were found in up to 40% to 60%, 20% to 40%, and 0% to 20% of tumors. Tier 1 contained novel indications known at the time of analysis to be responsive to PD-1 checkpoint blockade in the clinic (such as melanoma and non–small cell lung cancer), as well as indications not studied in the clinic previously, including microsatellite instability–high colorectal, head and neck, bladder, and triple-negative breast cancers. Complementary analysis of an Asian/Pacific cancer dataset (gastric cancer) revealed high prevalence of immune-inflamed tumors in gastric cancer. These data contributed to prioritization of these indications for clinical development of pembrolizumab as monotherapy.Conclusions:Data highlight the value of molecular profiling in identifying populations with high unmet needs with potentially favorable response characteristics and accelerating development of novel therapies for these patients.See related commentary by Mansfield and Jen, p. 1443

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

BackgroundPembrolizumab + vascular endothelial growth factor (VEGF) inhibitor lenvatinib demonstrated antitumor activity as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC) in phase 3 trial KEYNOTE-581/CLEAR (NCT02811861). Hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) showed antitumor activity in ccRCC, and a coformulation of pembrolizumab and CTLA-4 inhibitor quavonlimab (MK-1308A) showed antitumor activity in non–small cell lung cancer. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will be conducted to compare novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) and MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C).MethodsApproximately 1431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and Karnofsky Performance Status Scale score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg oral once daily + pembrolizumab 400 mg IV every 6 weeks), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV every 6 weeks and lenvatinib 20 mg oral once daily), or arm C (pembrolizumab 400 mg IV every 6 weeks + lenvatinib 20 mg oral once daily). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (approximately 2 years). Patients will be stratified by International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of the world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, every 6 weeks through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival. Primary end points will be assessed in arm A compared with arm C and in arm B compared with arm C for patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA,Eisai Inc., Woodcliff Lake, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04736706Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Summary 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.

Background Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. Patients and methods Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. Results A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. Conclusions Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. Trial registration ClinicalTrials.gov: NCT02256436.

Background: PD-1/L1-based combination regimens are the standard of care for first-line treatment of advanced clear cell RCC (ccRCC); however, there is no standard of care in the postimmunooncology/post-VEGF patient population, resulting in a high-unmet need. This umbrella platform study is an open-label, rolling-arm, multicenter phase 1b/2 trial in advanced ccRCC with an adaptive design that will evaluate safety and efficacy of experimental combinations of investigational agents targeting various mechanisms of action such as CTLA-4 (quavonlimab [MK-1308]), HIF-2α (belzutifan [MK-6482]), LAG-3 (MK-4280), ILT4 (MK-4830), PD-1 (pembrolizumab) and VEGF-TKI (lenvatinib). Substudy 03B (NCT04626518) will evaluate patients who progressed on PD-1/L1 inhibitors and VEGF-TKIs. Given the promising results of the phase 1b/2 KEYNOTE-146 study, pembrolizumab (400 mg IV Q6W) in combination with lenvatinib (20 mg orally QD) will be used as the reference arm. Methods: Patients will be aged ≥18 years with histologically confirmed diagnosis of ccRCC and KPS ≥70, and experience progression on or after having received treatment with a PD-1/L1 inhibitor and a VEGF-TKI (in sequence or in combination), as defined by RECIST v1.1). Progression on PD-1/L1 inhibitors is defined as receiving 2 doses of treatment, demonstrating radiographic disease progression per RECIST v1.1, and having documented disease progression within 12 weeks of last dose. The study will comprise a safety lead-in phase for experimental combinations with investigational agents without an established recommended phase 2 dose (RP2D) followed by an efficacy phase. Patients will be randomized 1:1 to an experimental arm (approximately 50 pts per arm) or the reference arm. If more than 1 experimental arm is open for enrollment, the pts in the reference arm can be shared. Experimental arms are pembrolizumab (400 mg Q6W IV) + belzutifan (MK-6482, 120 mg orally QD); lenvatinib (20 mg orally QD) + belzutifan (120 mg orally QD); MK-1308A (coformulation of quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W); MK-4280A (coformulation of MK-4280 800 mg and pembrolizumab 200 mg IV Q3W); and pembrolizumab (200 mg IV Q3W) + MK-4830 (800 mg IV Q3W). Treatments will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors are IMDC risk group (favorable, intermediate, or poor) and use of a CTLA-4 inhibitor (yes vs no). Primary end points for safety lead-in phase (if applicable) are safety and tolerability to establish an RP2D; co-primary end points for efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival, and clinical benefit rate per RECIST v1.1 (BICR), and overall survival. Citation Format: Hans Hammers, Toni Choueiri, Elizabeth Plimack, Brian Rini, Robert Motzer, Lina Yin, Rodolfo Perini, Jaqueline Willemann-Rogerio, Laurence Albiges. A phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced renal cell carcinoma (RCC) who progressed on PD-1/L1 and VEGF inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT243.

TPS4595 Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEYNOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no prior systemic therapy for nccRCC, and KPS score ≥70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219.

TPS372 Background: There is an unmet need for treatment options in the second-line or later setting following anti–PD-1/L1 or VEGF tyrosine kinase inhibitor (TKI) therapy in patients with advanced RCC. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). Promising antitumor activity has been reported for the first-in-class small molecular HIF-2α inhibitor, MK-6482, in heavily pretreated patients with ccRCC and patients with VHL disease–associated RCC. HIF-2α also regulates VEGF gene expression and plays a role in resistance to anti-VEGF therapy. Therefore, combining MK-6842 with a VEGF receptor TKI, such as lenvatinib, is an attractive treatment option in the advanced RCC setting. Methods: This is a randomized, open-label, active-controlled, multicenter phase III trial evaluating the efficacy and safety of MK-6482 + lenvatinib compared with cabozantinib in patients with advanced ccRCC who have progressed on prior anti–PD-1/L1 therapy (NCT04586231). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or metastatic ccRCC; disease progression on or after first- or second-line systemic treatment with an anti–PD-1/L1 therapy (monotherapy or in combination with other agent[s]) for locally advanced or metastatic disease, the immediately preceding line of treatment must be an anti–PD-1/L1 therapy; no more than 2 prior systemic regimens, with only 1 prior anti–PD-1/L1 therapy; measurable disease per RECIST v1.1; and Karnofsky performance status ≥70%. Patients must provide tissue for biomarker analysis. Approximately 708 patients will be randomly assigned in a 1:1 ratio to receive MK-6482 120 mg orally once daily (QD) + lenvatinib 20 mg orally QD or cabozantinib 60 mg orally QD. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are International mRCC Database Consortium prognostic scores (0, 1-2, or 3-6), number of prior lines of therapy (1 or 2), and geographic region (North America, Western Europe, or rest of the world). Imaging will be assessed by CT or MRI every 8 weeks through week 80, then every 12 weeks thereafter. The dual primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Secondary end points are objective response rate and duration of response per RECIST v1.1 as assessed by BICR, and safety. Safety and tolerability will be evaluated using a tiered approach. Clinical trial information: NCT04586231 .

327 Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .

TPS369 Background: Treatment options for RCC in the late-line setting after immunotherapy and vascular endothelial growth factor (VEGF)-targeted therapy are limited. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). The first-in-class small molecular HIF-2α inhibitor, MK-6482, recently showed promising antitumor activity in a cohort of heavily pretreated ccRCC patients (pts) and in pts with von Hippel-Lindau–disease-associated RCC for which the FDA granted Breakthrough Therapy Designation to MK-6482. Methods: This randomized, open-label, multicenter phase II trial will evaluate the efficacy and safety of 2 doses of MK-6482 in pts with advanced RCC who have experienced progression after prior systemic therapy (NCT04489771). Eligible pts are male or female aged ≥18 years with histologically confirmed locally advanced or metastatic ccRCC (measurable disease per RECIST v1.1) who have experienced progression after 1-3 prior systemic therapies comprising an anti-PD-1/L1 agent combined with a VEGF-targeted tyrosine kinase inhibitor (TKI) or an anti-cytotoxic T lymphocyte-associated antigen-4 agent and have undergone no more than 3 prior systemic regimens; and a Karnofsky Performance Scale ≥70. Treatment progression on anti-PD-1/L1 combination therapy was defined as pts who received at least 2 doses of anti-PD-1/L1 therapy and demonstrated radiographic disease progression as assessed by the investigator. Pts who have received prior treatment with MK-6482 or another HIF-2α inhibitor, and those requiring intermittent or chronic supplemental oxygen, or with a baseline hemoglobin less than 10 g/dL, a history of human immunodeficiency virus, hepatitis B or hepatitis C infection, or active central nervous system metastases will be excluded. Approximately 150 pts will be randomly assigned 1:1 to oral MK-6482 120 mg once daily (QD) or 200 mg QD; treatment will continue until progression, unacceptable toxicity, or withdrawal. Pts will be stratified by International Metastatic RCC Database Consortium prognostic scores (0, 1-2, 3-6) and the number of prior TKI-containing therapies (0, 1, or 2-3). Imaging with computed tomography or magnetic resonance imaging will be undertaken on Week 9 from the date of randomization, every 8 weeks through Week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. Safety will be analyzed using a tiered approach. This study is recruiting. Clinical trial information: NCT04489771 .

5080 Background: Axitinib (AXI) plus pembrolizumab (pembro) showed superior overall survival (OS), progression-free survival (PFS) and response rate compared with sunitinib in a randomized Phase 3 trial in advanced renal cell carcinoma (RCC). Here, we report long-term efficacy and safety data of the combination AXI/pembro from the Phase 1 trial, with almost 5 years of follow-up. Methods: 52 treatment-naïve patients with advanced RCC were enrolled between 23 September 2014 and 13 October 2015, and were treated with oral AXI 5 mg twice daily and intravenous pembro 2 mg/kg every 3 weeks. Planned treatment duration was 2 years for pembro and not limited for AXI. Based on International Metastatic Database Consortium (IMDC) criteria, 46.2%, 44.2% and 5.8% of patients were reported as having favourable, intermediate and poor risk. Results: At data cut-off date (July 3, 2019), median OS was not reached; 38 (73.1%) patients were alive. 14 (26.9%) patients had died, none were related to treatment. The probability of being alive was 96.1% (95% CI 85.2–99.0) at 1 year, 88.2% (95% CI 75.7– 94.5) at 2 years, 82.2 % (95% CI 68.5– 90.3) at 3 years, and 66.8 % (95% CI 49.1–79.5) at 4 years. Median PFS was 23.5 (95% CI 15.4–30.4) months. Median duration of response was 22.1 (95% CI 15.1–not evaluable) months. Median time on treatment with the combination AXI/pembro was 14.5 months (n=52), median time on pembro after AXI discontinuation was 9.0 months (n=10), and median time on AXI after pembro discontinuation was 7.5 months (n=11). After stopping study treatment, 22 patients received subsequent systemic therapy, including nivolumab and cabozantinib (n=6 each). Grade 3/4 AEs were reported in 38 (73.1%) patients. 20 (38.5%) patients discontinued either drug due to AEs: 17 (32.7%) patients discontinued AXI, and 13 (25.0%) patients discontinued pembro with 10 (19.2%) discontinuing both drugs. Dose reduction of AXI due to AEs was reported in 16 (30.8%) patients. The most common AEs reported were diarrhea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%), and dysphonia (48.1%). Increased alanine aminotransferase and aspartate aminotransferase occurred in 44.2% and 36.5% of patients, respectively. With this longer follow-up, there were no cumulative AEs or new AEs. OS by IMDC risk group will be presented. Conclusions: In patients with advanced RCC with almost 5 years of follow-up, the combination of AXI/pembro continues to demonstrate clinical benefit with no new safety signals. Clinical trial information: NCT02133742 .

5034 Background: KEYNOTE-427 (NCT02853344), a single-arm, open-label, phase 2 study, showed antitumor activity with first-line pembro monotherapy in nccRCC (cohort B). Studies of RCC and immune-oncology have shown that depth of tumor response may correlate with long-term benefit. We present the association between depth of response and OS plus updated efficacy and safety data in cohort B. Methods: Pts with histologically confirmed nccRCC, who did not receive prior systemic therapy, and who have measurable disease (RECIST v1.1) received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points were ORR (primary), DOR, and PFS (RECIST v1.1); OS; and safety. Association between depth of response, defined as maximum reduction from baseline in sum of target lesions, and OS was evaluated using a Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: Of 165 pts, 72% had papillary histology, 13% had chromophobe histology, and 16% were unclassified. Median time from enrollment to data cutoff was 18.7 mo (range, 9.9-26.0). ORR was 26.1% (95% CI, 19.5-33.5; 10 CRs, 33 PRs). Median (range) DOR was 15.3 mo (2.8-21.0+); 57.3% had DOR ≥12 mo. At 18-mo, PFS rate was 18.9% and OS rate was 67.0%. Most pts (58.8%) had some reduction in target lesions. Pts with a > 30% reduction in target lesions had an increased probability of survival (Table). ORR (95% CI) was similar for papillary (28.0% [20.1-37.0]) and unclassified (30.8% [14.3-51.8]) histology but lower for chromophobe (9.5% [1.2-30.4]). OS rates at 18 mo were 70.8%, 66.7%, and 50.0 in the papillary, chromophobe, and unclassified groups, respectively. Treatment-related AEs (TRAEs) occurred in 67.9% of all pts, primarily pruritus (19%), hypothyroidism (14%), and fatigue (14%). Grade 3-5 TRAEs occurred in 14% of pts; 2 pts died of TRAEs (pneumonia and cardiac arrest). Conclusions: First-line pembro monotherapy continued to show antitumor activity in nccRCC with no new safety concerns. In general, for pts who had greater reductions in target lesions, the trend was toward improved OS; pts with reduction of tumor burden ≥80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344 . [Table: see text]

5024 Background: We assessed the association of baseline RNA-sequencing–based gene expression signatures and DNA alterations with response or resistance to pembrolizumab in patients with advanced renal cell carcinoma in cohorts A (clear cell; n = 110) and B (non-clear cell; n = 165) of the phase 2 KEYNOTE-427 study (NCT02853344). Methods: Using RNA-sequencing, we analyzed the association of gene expression signatures (18-gene T-cell–inflamed gene expression profile [GEP]; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying tumor microenvironment elements (TME) with objective response rate (ORR) and progression-free survival (PFS). Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were analyzed through regression testing of response for association with consensus signatures after adjusting for T-cell–inflamed GEP and International Metastatic RCC Database Consortium scores in the model. P values were adjusted for multiplicity. Using whole exome sequencing, we also summarized the association of renal cell carcinoma driver gene mutations with ORR. Clinical data cutoff: Jan 30, 2019. Results: Patient characteristics for this analysis were comparable to the overall population. In cohort A, T-cell–inflamed GEP (n = 78) was statistically significantly associated with a better ORR ( P = 0.021; AUROC = 0.65) but not PFS ( P = 0.116). No other TME canonical signatures showed a correlation with ORR or PFS. ORR was estimated for mutations (Table). Conclusions: RNA-sequencing–based, T-cell–inflamed GEP was associated with ORR in patients with clear cell renal cell carcinoma receiving first-line pembrolizumab. Precision was limited by sample size for estimating ORR by specific gene mutation status. Evaluation of tissue-based biomarkers in larger studies are planned. Biomarker analyses from patients in cohort B will also be presented. Clinical trial information: NCT02853344 . [Table: see text]

Purpose In the phase III KEYNOTE-045 study ( ClinicalTrials.gov identifier: NCT02256436), pembrolizumab significantly prolonged overall survival compared with investigator’s choice of chemotherapy in patients with previously treated advanced urothelial cancer. Here, we report the results of health-related quality-of-life (HRQoL) analyses from the KEYNOTE-045 trial. Patients and Methods Patients were randomly assigned 1:1 to pembrolizumab 200 mg or investigator’s choice of docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 administered intravenously every 3 weeks. Key prespecified HRQoL analyses were time to deterioration (TTD) and mean change from baseline to week 15 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 global health status/quality-of-life score. Results Of 542 patients who were randomly assigned, 519 were included in HRQoL analyses (pembrolizumab, n = 266; chemotherapy, n = 253). HRQoL compliance was > 95% at baseline and approximately 88% at week 15 for both groups. Pembrolizumab prolonged TTD in global health status/quality-of-life score compared with chemotherapy (median, 3.5 months v 2.3 months; hazard ratio, 0.72; nominal one-sided P = .004). Mean (95% CI) change from baseline to week 15 in global health status/quality-of-life score was 0.69 (−2.40 to 3.77) with pembrolizumab and −8.36 (−11.84 to −4.89) with chemotherapy (mean difference, 9.05 points; 95% CI, 4.61 to 13.50; nominal two-sided P < .001). Conclusion Pembrolizumab prolonged TTD in HRQoL compared with chemotherapy. Patients who were treated with pembrolizumab had stable or improved global health status/quality of life, whereas those who were treated with investigator’s choice of chemotherapy experienced declines in global health status/quality of life. Combined with efficacy and safety outcomes, these data support pembrolizumab as standard of care for patients with platinum-refractory advanced urothelial cancer.

716 Background: Pembrolizumab/axitinib significantly prolonged progression-free survival (PFS) and overall survival (OS) vs. sunitinib in a phase 3 trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib vs. other first-line treatments of advanced RCC from a US payer perspective. Methods: A partitioned survival model with 3 states (progression-free, progressed, death) evaluated costs and quality-adjusted life years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib and pazopanib in the overall population; sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with poor/intermediate IMDC risk. Time on treatment, PFS, and OS were extrapolated using parametric models fitted to KEYNOTE-426 data (24 Aug 2018 cutoff) for pembrolizumab/axitinib and sunitinib, and hazard ratios from network meta-analyses for other comparators. Costs of first-line and subsequent treatment, adverse events, medical resources, and terminal care were estimated based on trial results, drug labels, and published sources. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EQ-5D data. Results: Over a lifetime, the incremental cost-effectiveness ratios (ICERs) for pembrolizumab/axitinib were below willingness-to-pay thresholds of $150,000/QALY or $180,000/QALY (approx. 3 × gross domestic product per capita) vs. all comparators in the overall and intermediate/poor risk populations (table). Results were robust in deterministic and probabilistic sensitivity analyses. Conclusions: Pembrolizumab/axitinib is associated with higher QALYs and considered cost-effective vs. other first-line treatments of advanced RCC in the US.[Table: see text]

729 Background: We evaluated the association (assoc) of baseline RNA-seq–based signatures with response/resistance to pembro from the phase 2 KEYNOTE-427 study (NCT02853344) in pts with advanced clear cell RCC enrolled in cohort A (n = 110). Methods: In pembro-treated pts with RNA-seq and clinical data (N = 78), we analyzed the assoc of signatures (18-gene tumor T-cell–inflamed GEP; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying the TME with clinical outcomes. Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were also analyzed through regression testing of response and the residuals of consensus signatures after adjusting for T-cell–inflamed GEP and IMDC scores in the model. P values were adjusted for multiplicity. Database cutoff date for clinical data: March 12, 2019. Results: Pt characteristics for this analysis were similar to those of the overall cohort A population. T-cell–inflamed GEP was statistically significantly assoc with ORR ( P = 0.021) but not PFS ( P = 0.116). When adjusting for PD-L1 expression (CPS by IHC) and IMDC scores, T-cell–inflamed GEP remained statistically significantly assoc with ORR ( P = 0.059). The angiogenesis signature was not assoc with response. PD-L2 RNA-seq expression was not assoc with response with multiplicity-adjusted P values. Like PD-L1 IHC, PD-L2 RNA-seq expression moderately correlated with T-cell–inflamed GEP and did not show independent predictive value when adjusted for T-cell–inflamed GEP and IMDC scores. Conclusions: RNA-seq–based, T-cell–inflamed GEP was assoc with ORR in pts with clear cell RCC receiving first-line pembro monotherapy; no canonical signatures showed statistical significance. Future directions for these data include whole exome sequencing analysis. Clinical trial information: NCT02853344.

733 Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]

4570 Background: KEYNOTE-427 (NCT02853344) is an open-label, single-arm, phase 2 study to evaluate efficacy and safety of first-line single-agent pembro, a programmed death 1 (PD-1) inhibitor, in patients (pts) with ccRCC (cohort A) and non–clear cell RCC (cohort B). Updated follow up from cohort A are presented. Methods: Pts with histologically confirmed ccRCC, measurable per RECIST v1.1, and no prior systemic therapy were eligible. Pts received pembro 200 mg IV Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point was objective response rate (ORR; per RECIST v1.1 blinded independent central review). Additional end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: 110 pts enrolled; median (range) follow-up was 18.0 (2.5-22.7) mo. Median age (range) was 64 (29-87); 38.2%, 47.3%, and 14.5% had favorable, intermediate, and poor IMDC risk, respectively; 47.3% were PD-L1 positive. Confirmed ORR was 36.4% with 3 (2.7%) CRs and 37 (33.6%) PRs. Median DOR was not reached. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached. Results by IMDC category are outlined in the table. By PD-L1 status, confirmed ORR was 44.2% and 29.3% for positive and negative, respectively. By sarcomatoid differentiation (n=11), confirmed ORR was 63.6%. Treatment-related AEs occurred in 80.9%, with pruritus (28.2%) and fatigue (28.2%) most commonly reported. One pt died of treatment-related pneumonitis. Conclusions: With a median 18-months’ follow up, first-line pembro monotherapy continued to show antitumor activity in pts with ccRCC. Meaningful responses were observed in pts with intermediate/poor IMDC risk, PD-L1 positive and sarcomatoid differentiated tumors. Safety profile was comparable to previously reported. Clinical trial information: NCT02853344. [Table: see text]

4569 Background: Efficacy of PD-1 inhibitors (or any therapy) in NCC-RCC has not been established. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced clear cell RCC (cohort A) and NCC-RCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed NCC-RCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Additional end points: duration of response (DOR), population description by sarcomatoid differentiation, histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26); 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At median follow-up of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CR, 33 [20.0%] PR). Median DOR was not reached. For responding pts, 81.5% had a response ≥6 mo. 12-mo PFS and OS rates were 22.8% and 72.0%, respectively. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified NCC-RCC; for responding pts, 82.1%, 50.0%, and 87.5% had a response ≥6 mo, respectively. Median DOR was not reached in any group. ORR (95% CI) was 44.7% (28.6-61.7) for pts with sarcomatoid differentiation (n = 38). ORR (95% CI) was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS < 1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts. 6 pts died of AEs, 2 of TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in NCC-RCC, especially with papillary or unclassified histology. Safety profile of pembro was as expected. Updated data with additional follow-up will be presented. Clinical trial information: NCT02853344.

4500 Background: In KEYNOTE-426, pembro + axi significantly improved OS (HR 0.53, P < .0001), PFS (HR 0.69, P = .0001), and ORR (59.3% vs 35.7%, P < .0001) vs sunitinib and had manageable toxicity as first-line therapy for mRCC (NCT02853331). The pembro + axi benefit was observed across all IMDC risk groups and regardless of PD-L1 expression. We present data for the combined intermediate/poor risk group and for patients (pts) with sarcomatoid features. Methods: 861 eligible pts with clear-cell mRCC, no prior systemic therapy for mRCC, and KPS ≥70 were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID (N = 432) or sunitinib 50 mg orally QD (4-wk on/2-wk off) (N = 429). Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR (RECIST v1.1 by BICR) was the key secondary endpoint. The intermediate/poor risk group was prespecified; the sarcomatoid group was exploratory. HRs and their 95% CIs were calculated with a Cox proportional hazards model. None of the analyses were multiplicity-controlled. Results: 592 (68.8%) of all randomized pts were of IMDC intermediate/poor risk — 294 in the pembro + axi arm, 298 in the sunitinib arm. Pembro + axi improved OS (HR 0.52, 95% CI 0.37-0.74; 12-mo rate 87.3% vs 71.3%), PFS (HR 0.67, 95% CI 0.53-0.85; median 12.6 vs 8.2 mo), and ORR (55.8% [95% CI 49.9-61.5] vs 29.5% [24.4-35.1]) in pts with intermediate/poor risk; CR rates were 4.8% (95% CI 2.6-7.9) vs 0.7% (0.1-2.4). Of the 578 pts with known status, 105 (18.2%) had sarcomatoid features — 51 in the pembro + axi arm, 54 in the sunitinib arm. Pembro + axi improved OS (HR 0.58, 95% CI 0.21-1.59; 12-mo rate 83.4% vs 79.5%), PFS (HR 0.54, 95% CI 0.29-1.00; median not reached vs 8.4 mo), and ORR (58.8% [95% CI 44.2-72.4] vs 31.5% [19.5-45.6]) in pts with sarcomatoid features; CR rates were 11.8% (95% CI 4.4-23.9) vs 0% (0.0-6.6). Conclusions: Pembro + axi provides benefit in the combined population of pts with IMDC intermediate or poor risk and in pts whose tumors had sarcomatoid features. The observed benefits were consistent with those seen in the total population. Clinical trial information: NCT02853331.

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/m2 loading, 250 mg/m2 maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [18F]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 (SUVmax) for those treated initially with everolimus was −24% (2% to −54%), and with cetuximab was −5% (−23 to 36%). The Ktrans 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. Cancer 2014;120:77–85. © 2013 American Cancer Society.

Contains fulltext : 170338.pdf (Publisher’s version ) (Open Access) 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 IgG4kappa 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 .).

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

Summary 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.

546 Background: PD-1/L1 pathway inhibitors are effective in clear cell (cc)RCC, but efficacy of PD-1 inhibitors (or any therapy) in nccRCC has not been established. KEYNOTE-427 is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced ccRCC (cohort A) and nccRCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed nccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts were followed after PD for overall survival. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Secondary end points included duration of response (DOR) and population description by International Metastatic RCC Database Consortium (IMDC) risk. Exploratory end points: ORR by histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). 68% of patients were at intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At a median follow-up duration of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CRs, 33 [20%] PRs); median DOR was not reached. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified nccRCC. ORR (95% CI) was 28.3% (16.8-42.3) with favorable and 23.2% (15.8-32.1) with intermediate/poor IMDC risk and 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS

543 Background: A phase 1b study of pembro (anti–PD-1) plus axi (VEGFR-TKI) showed promising antitumor activity and manageable safety in patients (pts) with previously untreated mRCC. The global, open-label, phase 3 KEYNOTE-426 study assessed the efficacy and safety of pembro + axi vs sunitinib as first-line therapy for mRCC (NCT02853331). Methods: Eligible pts with clear-cell mRCC, no previous systemic therapy for mRCC, and KPS ≥70% were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID or sunitinib 50 mg orally QD (4-wk on/2-wk off schedule). Treatment was given until PD, intolerable toxicity, or pt/investigator decision. Randomization was stratified by IMDC risk group and geographic region. Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR was the key secondary endpoint. At the protocol-specified first interim analysis, the superiority thresholds were P = 0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR (if OS and PFS were significant). Results: 861 pts were randomized: 432 to pembro + axi, 429 to sunitinib. After a 12.8-mo median follow-up, 59.0% of pts in the pembro + axi arm and 43.1% in the sunitinib arm remained on treatment. Pembro + axi significantly improved OS (HR 0.53 [95% CI 0.38-0.74]; P < 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P < 0.0001). Duration of response was prolonged with pembro + axi (median not reached vs 15.2 mo). The pembro + axi benefit was observed in all subgroups tested, including all IMDC risk and PD-L1 expression subgroups. Treatment-related AEs were grade 3-5 in 62.9% of pts in the pembro + axi arm vs 58.1% in the sunitinib arm and led to regimen discontinuation in 6.3% vs 10.1%. Conclusions: Pembrolizumab + axitinib provided superior OS, PFS, and ORR compared with sunitinib and had manageable safety in pts with previously untreated, advanced or metastatic clear-cell RCC. These data suggest that pembrolizumab + axitinib should be a new standard of care for this population. Clinical trial information: NCT02853331.

4500Background: Programmed death-1 (PD-1) inhibitor–based combination therapy shows clinical benefit in first-line accRCC. However, data are limited on clinical impact of first-line PD-1 inhibitor ...

Portal hypertensive gastropathy (PHG) is often seen in patients with portal hypertension, and can lead to transfusion-dependent anemia as well as acute, life-threatening bleeding episodes. This Review focuses on the mechanisms that underlie the pathogenesis of PHG that provide reasonable grounds for the treatment of this condition, and ultimately enable translation of basic research into clinical practice. Increased portal pressure associated with cirrhosis and liver dysfunction is critical for the development of clinically significant PHG, and leads to impaired gastric mucosal defense mechanisms that render the stomach susceptible to mucosal injury. The use of pharmacological agents such as beta-blockers reduces the frequency of bleeding episodes in PHG. As a last resort, surgical decompression of the portal system, transjugular intrahepatic stent placement and liver transplantation can resolve this condition. Elimination of known risk factors for gastric injury such as alcohol, aspirin and traditional NSAIDs is critical. The role of Helicobacter pylori colonization of the gastric mucosa in PHG is not clear. Careful and critical interpretation of human and experimental data can be helpful to establish a rationale for the medical management of this important condition.

Radioiodinated metaiodobenzylguanidine (MIBG) imaging has been used to evaluate adrenergic nerve activity in different organs. Cardiac and pulmonary MIBG uptake is important in predicting the prognosis of certain cardiopulmonary diseases. It has been reported that cardiac MIBG uptake decreases with age and is significantly lower in the elderly. However, there has been no systemic study on age-related changes in cardiac and pulmonary MIBG uptake in children. This study was undertaken to determine the changes in MIBG uptake in the developing heart and lung in children and adolescents.MIBG scans of 44 children (16 female and 28 male; age range, 2 months to 19 years) without abnormal uptake were selected from a large pool of patients with whole-body MIBG imaging performed for evaluation of neuroblastoma. All of the selected subjects had a normal physiologic distribution of MIBG and no history of heart or lung diseases. The patients were divided into 4 groups by age: group 1, 0 to 24 months; group 2, 25 to 48 months; group 3, 49 to 72 months; and group 4, 73 months or greater. Cardiac and pulmonary MIBG uptake values (expressed as heart-to-mediastinum [H/M] ratio and lung-to-mediastinum [L/M] ratio, respectively) were determined and compared among the 4 groups. H/M and L/M ratios were noted to decrease with age. The mean H/M and L/M ratios were in group 1, 4.13 +/- 0.66 and 1.53 +/- 0.18, respectively; in group 2, 3.46 +/- 0.71 and 1.26 +/- 0.18, respectively; in group 3, 3.19 +/- 0.94 and 1.13 +/- 0.17, respectively; and in group 4, 2.84 +/- 0.48 and 1.14 +/- 0.14, respectively. There was a significant inverse correlation between H/M ratio and age (r = 0.711, P.001) as well as between L/M ratio and age (r = 0.718, P.001).Cardiac and pulmonary MIBG uptake is inversely related to age in children.

Importance Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. Objective Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. Evidence Review On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms “PD0332991,” “palbociclib,” and “CDK4/6 inhibitor” to find all published articles of interest, without limitation as to publication date. Findings Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein–expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy–naive and endocrine therapy–resistant metastatic settings. Conclusions and Relevance Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.

Trace amines, including tyramine, octopamine and synephrine, are closely related to classic biogenic amines. In one study, where these substances were found elevated in plasma of migraineurs, it was hypothesized that trace amine metabolism is deranged in migraine. To confirm these findings, we studied, using a multichannel electrochemical high-performance liquid chromatography system, the concentrations of trace amines in platelets of migraine without aura (MoA) and migraine with aura (MA) patients in headache-free period, compared with controls. Platelet concentrations of trace amines, although elevated in both migraine types, showed a different profile in MoA and MA. Octopamine was significantly higher in MoA sufferers (0.69 ± 0.43 ng/108platelets) compared with both control subjects (0.22 ± 0.16 ng/108platelets) and MA patients (0.39 ± 0.37 ng/108platelets). Synephrine was significantly higher in MA patients (0.72 ± 0.44 ng/108platelets) with respect to both controls (0.33 ± 0.25 ng/108platelets) and MoA sufferers (0.37 ± 0.29 ng/108platelets). These results strengthen the hypothesis that tyrosine metabolism is deranged in migraine and may participate in its pathophysiology.

The pain of cluster headache attacks is severe, excruciating and selectively responsive to subcutaneous sumatriptan. Serious cardiovascular events attributed to sumatriptan are extremely rare and have most often been reported in patients at significant cardiovascular risk, or in overt cardiovascular disease. They also have occurred, however, in patients without evidence of cardiovascular disease. We describe a 42-year-old man with episodic cluster headache without history of coronary artery disease who was admitted to our coronary care unit for acute myocardial infarction after 3 h of subcutaneous injection of sumatriptan. During hospitalisation cluster headache attacks were successfully treated with e.v. indomethacin.

Background.—The vasoactive peptide, calcitonin gene-related peptide (CGRP), is released from primary afferent neurons in the trigemino-vascular circulation during migraine headache. CGRP at physiological concentrations and possibly via stimulation of its selective receptors on T-cells, triggers the secretion of cytokines. Cytokines play an important role in several physiological and pathological settings such as immunology, inflammation, and pain. Objective.—To investigate plasma levels of pro- and anti-inflammatory cytokines in migraineurs and healthy controls. Methods.—We studied 25 migraine patients, during and outside attacks, and 18 healthy control subjects measuring plasma levels of IL-6, IL-10, tumor necrosis factor alpha (TNFα), IL-4, IL-1β, and IL-2 using ELISA. Results.—Circulating levels of IL-10, TNFα, and IL-1β during attacks were significantly higher in comparison to their levels outside attacks (P = .0003, P = .03, and P = .05, respectively). IL-10 and TNF serum levels were higher in patients studied soon after headache onset and lower over time (P = .004 and P = .05). Conclusion.— Our results suggest that TNFα, IL-1β, and IL-10 may be involved in the pathogenesis of migraine attacks. Ke yw ords: migraine, cytokines, inflammation, pain, sensitization