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.

Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.

INTRODUCTION: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented. METHODS: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively. RESULTS: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. CONCLUSIONS: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03284424-September 15, 2017.

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study.

PURPOSE: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048.

BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

Real-world outcomes of systemic therapy in locally advanced, recurrent or metastatic cutaneous squamous cell carcinoma.

Aim: Real-world treatment patterns and clinical outcomes in advanced cutaneous squamous cell carcinoma were evaluated. Methods: Adults receiving their first systemic therapy for unresectable, locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma from 4 September 2014 to 30 June 2017, were evaluated. The primary end point was real-world overall response rate per Response Evaluation Criteria in Solid Tumors or physician assessment. Time-to-event outcomes were assessed using the Kaplan-Meier method. Results: Of 51 eligible patients, the median age was 76 years, 80% were male and 65% had an Eastern Cooperative Oncology Group score of 0-1. The most common regimens were cetuximab (51%) and carboplatin + paclitaxel (22%). Median real-world overall response rate ranged from 9.8% per Response Evaluation Criteria in Solid Tumors to 43.1% when supplemented by physician assessment. Median overall survival was 10.7 months, and median time to next treatment was 7.5 months. Conclusion: Survival in advanced cutaneous squamous cell carcinoma was short. Real-world overall response rate was lower with Response Evaluation Criteria in Solid Tumors than physician assessment.

This study looked at chemotherapy treatments and responses in patients receiving treatment for advanced cutaneous squamous cell carcinoma, a type of skin cancer. Patients had advanced and metastatic cancer that could not be cured by radiation or surgery. Most of the patients were white males, and their median age was 76 years. About two-thirds of the patients in the study had their original cancer in the head and neck, and in most patients (approximately 80%), the cancer had spread, mostly to the lungs or lymph nodes. Half of the patients in the study were treated with cetuximab, and about a quarter received platinum chemotherapy or other cetuximab-based treatment. The study examined how response to treatment may be measured in clinical care and clinical trials. Response to treatment and length of survival were short: patients responded to treatment for a median of 9 months and survived for a median of 10.7 months.

Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score.

PURPOSE: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS: Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS: Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION: Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC.

Health-Related Quality of Life of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma Treated with Pembrolizumab in KEYNOTE-629.

INTRODUCTION: Pembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629. METHODS: Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method. RESULTS: Analyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, -1.00 to 10.90) and physical functioning (-3.38 points; 95% confidence interval, -8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%). CONCLUSIONS: In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03284424.

Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancer. cSCC is usually caused by cumulative exposure to sunlight and often occurs in exposed parts of the body such as the head and neck. cSCC is most often seen in older people. If cSCC is detected early, it can be removed by surgery; however, if left untreated, the cancer can spread throughout the body and cause death. The disease itself and its treatment can be painful, cause scarring, or change the patient's physical appearance. Hence, people with cSCC often have poor quality of life. It is therefore important to develop new drugs to help patients with cSCC live longer without worsening their quality of life. The phase 2 KEYNOTE-629 study investigated how well the drug pembrolizumab treated cSCC and whether it was safe. KEYNOTE-629 included patients who were mostly older and had advanced cSCC. The results showed that pembrolizumab was effective and safe. Here, we investigated how pembrolizumab affected the quality of life of these patients. To do this, we asked patients to answer questionnaires on important aspects of their experience, such as their general health status, physical functioning, emotional wellbeing, and symptoms. We found that patients who were treated with pembrolizumab had stable quality of life during treatment. Furthermore, patients whose cancer responded well to pembrolizumab were more likely to have an improved quality of life. These results support the use of pembrolizumab in patients with advanced cSCC.

Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study.

PURPOSE: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. PATIENTS AND METHODS: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. RESULTS: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3-24.2). One DLT of T-VEC-related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0-5.8] and 5.8 months (95% Cl, 2.9-11.4), respectively. CONCLUSIONS: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).

Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629).

PURPOSE: Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort-locally advanced and R/M-phase II KEYNOTE-629 study. PATIENTS AND METHODS: Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety. RESULTS: At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; '+' refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy. CONCLUSION: Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.

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.

Potential role of a new PEGylated recombinant factor VIII for hemophilia A.

Hemophilia A, a deficiency in the activity of coagulation factor (F) VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG) to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half-life will become available in a very short time. With all the promise of these new agents, many questions still remain.

Well-differentiated neuroendocrine tumor of the stomach: A rare case at an uncommon site.

INTRODUCTION: A 13-year-old African-American female presented to her primary care physician's office with fatigue, syncope, and hematemesis. After initial evaluation, the patient was referred to pediatric gastroenterology clinic for further evaluation. MAIN CONCERNS, IMPORTANT FINDINGS: An upper gastrointestinal endoscopy was performed to evaluate the source of her bleeding. Endoscopy revealed a 3-cm mass in the lesser curvature of the stomach, and a biopsy of the mass revealed a concern for carcinoid (neuroendocrine) features. DIAGNOSIS: She underwent an open gastrectomy. Post-surgical pathology reports confirmed a well-differentiated neuroendocrine tumor of the stomach. CONCLUSION: Neuroendocrine tumors of the stomach in children are rare and we presently do not have pediatric-specific diagnostic and treatment guidelines. Although adult-based The North American Neuroendocrine Tumor Society (NANETS) guidelines are helpful, they are clearly not geared toward pediatric patients. To establish pediatric guidelines and to assess effectiveness of treatments, multicenter data collection is essential. In the long run, accumulation of clinically useful treatment information and long-term follow-up guidelines should enable clinicians to improve standard of care given to children with neuroendocrine tumors.

Successful unrelated cord blood transplantation for homozygous α-thalassemia.

A now 10-year-old Laotian female was delivered at 30-week gestation by cesarean section because of severe hydrops. Fetal blood sampling revealed homozygous α-thalassemia. After immediate resuscitation, the infant was supported with frequent red cell transfusions. At 44 months of age, she received a 5 of 6 human leukocyte antigen-matched unrelated cord blood transplantation. She was treated with phlebotomy and chelation therapy with Deferasirox for correction of hemosiderosis and has been transfusion-independent since 41 days after transplant. She is currently 6 years after transplantation with stable, 100% donor engraftment, resolved iron overload, and normal growth and development.

Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retina.

Epidermal growth factor (EGF) is known to promote proliferation of both retinal progenitors and Muller glia in vitro, but several questions remain concerning an in vivo role for this factor. In this study, we investigated whether the EGF receptor (EGFR) is necessary for the maintenance of normal levels of progenitor and Muller glial proliferation in vivo. Here, we show that (1) mice with homozygous deletion of the Egfr gene have reduced proliferation in late stages of retinal histogenesis, (2) EGF is mitogenic for Müller glia in vivo during the first two postnatal weeks in the rodent retina, (3) the effectiveness of EGF as a Müller glial mitogen declines in parallel with the decline in EGFR expression as the retina matures, and (4) following damage to the retina from continuous light exposure, EGFR expression is up-regulated in Müller glia to levels close to those in the neonatal retina, resulting in a renewed mitotic response to EGF. Together with previous results from other studies, these data indicate that the downregulation of a growth factor receptor is one mechanism by which glial cells maintain mitotic quiescence in the mature nervous system.

Notch activity is downregulated just prior to retinal ganglion cell differentiation.

The Notch signaling pathway is important at several stages of retinal development including the differentiation of retinal ganglion cells and Muller glia. The downstream effectors of Notch signaling, Hes1 and Hes5, have been shown to be critical in the retina as well. While Notch activity directly regulates Hes1 and Hes5 elsewhere in the nervous system, it has been unclear whether Hes1 and/or Hes5 are directly regulated by Notch activity in the developing retina. Here, we report that both Hes1 and Hes5 are directly regulated by Notch activity during retinal development. Using fluorescence-based Hes1 and Hes5 reporter constructs, we can monitor Notch activity in progenitor cells in the intact retina, and we find that Notch activity is downregulated just prior to retinal ganglion cell differentiation.

Retinal neurons regulate proliferation of postnatal progenitors and Müller glia in the rat retina via TGF beta signaling.

The number of proliferating cells in the rodent retina declines dramatically after birth. To determine if extrinsic factors in the retinal micro-environment are responsible for this decline in proliferation, we established cultures of retinal progenitors or Muller glia, and added dissociated retinal neurons from older retinas. The older cells inhibited proliferation of progenitor cells and Muller glia. When these experiments were performed in the presence of TGF(beta)RII-Fc fusion protein, an inhibitor of TGF(beta) signaling, proliferation was restored. This suggests a retina-derived TGF(beta) signal is responsible for the developmental decline in retinal proliferation. TGFbeta receptors I and II are expressed in the retina and are located in nestin-positive progenitors early in development and glast-positive Muller glia later in development. RT-PCR and immunofluorescence data show TGF(beta)2 is the most highly expressed TGF(beta)ligand in the postnatal retina, and it is expressed by inner retinal neurons. Addition of either TGF(beta)1 or TGF(beta)2 to postnatal day 4 retinas significantly inhibited progenitor proliferation, while treatment of explanted postnatal day 6 retinas with TGF(beta) signaling inhibitors resulted in increased proliferation. Last, we tested the effects of TGF(beta) in vivo by injections of TGF(beta) signaling inhibitors: when TGF(beta) signaling is inhibited at postnatal day 5.5, proliferation is increased in the central retina; and when co-injected with EGF at postnatal day 10, TGF(beta)inhibitors stimulate Muller glial proliferation. In sum, these results show that retinal neurons produce a cytostatic TGF(beta) signal that maintains mitotic quiescence in the postnatal rat retina.

Clinical implications of concomitant variations of the testicular, suprarenal and renal veins: a case report.

Multiple venous anomalies have been observed during dissection of the posterior abdominal wall in a 65-year-old, white male cadaver. The left testicular and suprarenal veins united inferior to the superior mesenteric artery, coursed anterior to the abdominal aorta and drained into the inferior vena cava (IVC). Further the left renal vein coursed retroaortically and divided into three branches. The superior branch coursed on the vertebral column and drained into the azygos vein while middle and inferior branches drained into the IVC. The right renal vein was double and both drained into the IVC separately. Due to implications for numerous therapeutical and diagnostic procedures in the retroperitoneal region knowledge of these variations could be useful for clinicians in its recognition and protection.