Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy.

The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group. INTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. FUNDING: Merck Sharp & Dohme.

Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma.

Treatment options for relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) are limited, and prognosis is generally poor (overall response rate [ORR] 0% to 25%; 2-year overall survival 15%). PMBCL frequently involves PD-1 ligand overexpression, potentially making PMBCL particularly susceptible to PD-1 blockade. We evaluated safety and antitumor activity of pembrolizumab, an anti-PD-1 antibody, in rrPMBCL as part of the KEYNOTE-013 multicohort phase 1b trial. At time of data cutoff, 18 patients (median age 30 years; median 3 prior lines of therapy) had been enrolled and treated, of whom 17 were included in the efficacy analyses. Eleven patients (61%) experienced drug-related adverse events (mostly grade 1-2); none discontinued treatment due to adverse events. ORR was 41% (7/17); 6 additional patients (35%) had stable disease. Of patients evaluable by imaging, 13 out of 16 (81%) had decreases in target lesions. With a median follow-up of 11.3 months, median duration of response was not reached. Two patients reached the maximum 2-year treatment duration and remain in remission. Median overall survival was not reached for treated patients overall; all responders were still alive at data cutoff. These results in heavily pretreated rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01953692.

Terrestrial dissolved organic matter inputs accompanied by dissolved oxygen depletion and declining pH exacerbate CO2 emissions from a major Chinese reservoir.

Terrestrial inputs and subsequent degradation of dissolved organic matter (DOM) in lake ecosystems can result in rapid depletion of dissolved oxygen (DO). Inputs of terrestrial DOM including organic acids can also lead to decreases in pH. However, to date, few studies have investigated the linkages between terrestrial DOM inputs, DO and pH levels in the water column, and carbon dioxide (CO2) emissions from lake ecosystems. Based on monthly field sampling campaigns across 100 sites in Lake Qiandao, a major man-made drinking water reservoir in China, from May 2020 to April 2021, we estimated an annual CO2 efflux (FCO2) of 37.2 ± 29.0 gC m-2 yr-1, corresponding to 0.02 ± 0.02 TgC yr-1 from this lake. FCO2 increased significantly with decreasing DO, chlorophyll-a (Chl-a) and δ2H-H2O, while FCO2 increased with increasing specific UV absorbance (SUVA254) and a terrestrial humic-like component (C2). We found that DO concentration and pH declined with increasing terrestrial DOM inputs, i.e. increased SUVA254 and terrestrial humic-like C2 levels. Vertical profile sampling revealed that the partial pressure of CO2 (pCO2) increased with increasing terrestrial DOM fluorescence (FDOM), while DO, pH, and δ13C-CO2 declined with increasing terrestrial FDOM. These results highlight the importance of terrestrial DOM inputs in altering physico-chemical environments and fueling CO2 emissions from this lake and potentially other aquatic ecosystems.

Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study.

The phase 1b multicohort KEYNOTE-013 study assessed the safety and antitumor activity of pembrolizumab given at 10 mg/kg/day every 2 weeks for up to 2 years in hematologic malignancies, including myelodysplastic syndromes (MDS) refractory to a hypomethylating agent (HMA). Primary outcomes were safety and objective response rate per International Working Group 2006 criteria. By June 26, 2020, 28 patients were enrolled; median duration of follow-up was 5.6 months (range, 1-78), and 25 patients (89%) had died. Treatment-related adverse events occurred in 10 patients (36%), including 2 (7%) treatment-related discontinuations. No patient achieved complete or partial response. Five patients (19%) had bone marrow complete response, 12 (44%) stable disease, 10 (37%) progressive disease, 6 (22%) cytogenetic response, and 5 (19%) hematologic improvement. Median overall survival (OS) was 6.0 months (95% CI, 4-12); the overall 2-year OS rate was 17%. Pembrolizumab had manageable safety and clinical activity in patients with HMA-refractory MDS.This trial was registered at www.clinicaltrials.gov as #NCT01953692.

Predicting Drug-Drug Interactions Based on Integrated Similarity and Semi-Supervised Learning.

A drug-drug interaction (DDI) is defined as an association between two drugs where the pharmacological effects of a drug are influenced by another drug. Positive DDIs can usually improve the therapeutic effects of patients, but negative DDIs cause the major cause of adverse drug reactions and even result in the drug withdrawal from the market and the patient death. Therefore, identifying DDIs has become a key component of the drug development and disease treatment. In this study, we propose a novel method to predict DDIs based on the integrated similarity and semi-supervised learning (DDI-IS-SL). DDI-IS-SL integrates the drug chemical, biological and phenotype data to calculate the feature similarity of drugs with the cosine similarity method. The Gaussian Interaction Profile kernel similarity of drugs is also calculated based on known DDIs. A semi-supervised learning method (the Regularized Least Squares classifier) is used to calculate the interaction possibility scores of drug-drug pairs. In terms of the 5-fold cross validation, 10-fold cross validation and de novo drug validation, DDI-IS-SL can achieve the better prediction performance than other comparative methods. In addition, the average computation time of DDI-IS-SL is shorter than that of other comparative methods. Finally, case studies further demonstrate the performance of DDI-IS-SL in practical applications.

Controllable growth of ZnO nanorod arrays with different densities and their photoelectric properties.

Since the photoelectric response and charge carriers transport can be influenced greatly by the density and spacing of the ZnO nanorod arrays, controlling of these geometric parameters precisely is highly desirable but rather challenging in practice. Here, we fabricated patterned ZnO nanorod arrays with different densities and spacing distances on silicon (Si) substrate by electron beam lithography (EBL) method combined with the subsequent hydrothermal reaction process. By using the EBL method, patterned ZnO seed layers with different areas and spacing distances were obtained firstly. ZnO nanorod arrays with different densities and various morphologies were obtained by the subsequent hydrothermal growth process. The combination of EBL and hydrothermal growth process was very attractive and could make us control the geometric parameters of ZnO nanorod arrays expediently. Finally, the vertical transport properties of the patterned ZnO nanorod arrays were investigated through the microprobe station equipment, and the I-V measurement results indicated that the back-to-back Schottky contacts with different barrier heights were formed in dark conditions. Under UV light illumination, the patterned ZnO nanorod arrays showed a high UV light sensitivity, and the response ratio was about 104. The controllable fabrication of patterned ZnO nanorod arrays and understanding their photoelectric transport properties were helpful to improve the performance of nanodevices based on them.