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PURPOSE MicroRNAs (miRNAs) have been evaluated as biomarkers in cancers. Therefore, we aimed to identify a prognostic miRNA signature from The Cancer Genome Atlas (TCGA) database and validate it in the Ramathibodi (RA) locally advanced head and neck squamous cell carcinoma (LA-HNSCC) cohort. METHODS The correlation between candidate miRNAs and the survival of patients with LA-HNSCC in TCGA database was analyzed. A prognostic miRNA signature model was generated that classified patients into high-risk and low-risk groups. This candidate miRNA signature was further validated in the independent RA cohort using droplet-digital polymerase chain reaction. RESULTS In TCGA database, we compared the expression of 277 miRNAs between 519 head and neck squamous cell carcinoma tissues and 44 normal tissues. The expression of hsa-miR-10b, hsa-miR-148b, hsa-miR-99a, hsa-miR-127, hsa-miR-370, and hsa-miR-500a was independently associated with overall survival (OS). Thus, we established the miRNA signature risk score from these six miRNAs and categorized patients into low-risk and high-risk groups. The median OS of TCGA patients was significantly shorter in the low-risk group than in the high-risk group ( P < .001). The six-miRNA signature was further validated in the RA cohort (N = 87). The median OS of the low-risk group was significantly shorter compared with the high-risk group ( P = .03). In multivariate analysis, the six-miRNA signature was an independent prognostic factor for OS in the RA cohort (HR, 1.958; 95% CI, 1.006 to 3.812; P = .048). CONCLUSION We identified a prognostic six-miRNA signature for patients with LA-HNSCC from TCGA cohort and validated it in our independent cohort. However, larger studies are warranted to confirm these results.

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Malnutrition and weight loss are commonly observed in patient with esophageal and esophagogastric junction (EGJ) cancers. Chemoradiotherapy (CRT) is a mainstay of treatment for locally advanced esophageal and EGJ cancers. Impact of weight loss on patients with treated with CRT was not well studied.Patients with locally advanced esophageal and EGJ cancer who received CRT were identified in our institutional database and allocated into low (LWL) and high (HWL) weight loss groups. HWL was defined as weight loss5% of baseline during CRT.A total of 167 patients were underwent definitive (n=89) or preoperative (n=78) CRT, respectively. HWL was observed in 46% and 55% of patients treated with definitive and preoperative CRT, respectively. Cisplatin/5FU regimen used during CRT was a significant predictive factor for weight loss in multivariate analysis (OR 2.07, 95% CI 1.09-3.94; p=0.026). In the definitive CRT group, patients in the HWL group experienced significantly worse overall survival than those in the LWL group (1.2 years vs 1.95 years; p=0.003). Multivariate analysis revealed that baseline albumin (3.0 g/dL) was significantly associated with longer OS of definitive CRT patients (HR 2.15, 95% CI 1.1-4.19; p=0.024). Tolerability and toxicities during CRT were not statistically different between groups.Significant weight loss during CRT was frequently observed in patients with locally advanced esophageal and EGJ cancers. Baseline hypoalbuminemia was an independent prognostic factor for OS in patients treated with definitive CRT. Nutritional support before and during treatment should be considered to potentially improve patients' outcomes.br /.

Background: Gastric cancer is one of most common cancers worldwide with a high mortality rate. Lymphedema and chyle leakage are unusual presentations of metastatic gastric carcinoma. We present a rare case of advanced stage gastric carcinoma presenting with lower limb lymphedema, bilateral chylothorax, and chylous ascites caused by metastatic infiltration of the lymphatics. Case presentation: A 62-year-old Thai man with a 2-year history of bilateral lymphedema and an unprovoked left axillary vein thrombosis presented with progressive leg, scrotal, and abdominal swelling, and shortness of breath. He denied any gastrointestinal (GI) symptoms. His lymphedema had initially been diagnosed as chronic filariasis due to positive blood tests for anti-filarial antibodies, however treatment with anti-filarial drugs failed to improve his symptoms. Subsequently, he underwent surgical lymphaticovenular anastomosis with scrotal reduction, which proved to be of limited symptomatic relief. Later investigations revealed bilateral chylothorax and chylous ascites, with the presence of metastatic adenocarcinoma. Histopathological examination of the patient’s skin and scrotum biopsy from his previous surgery revealed invasion of the lymphatics by neoplastic cells with signet ring cell formation. Gastroscopy uncovered a gastric mass, and biopsy confirmed the diagnosis of stage IV gastric adenocarcinoma with signet ring cell. He later received palliative chemotherapy. For the management of chyle leakage, he was prescribed a very low-fat diet and supplemented with parenteral nutrition. Despite treatment, he developed cutaneous metastasis and was transitioned to best supportive care. The patient passed away 14 months after diagnosis. Conclusion: The differential diagnosis of uncertain causes of lymphedema and chyle leakage should include metastatic gastric cancer, regardless of GI symptoms. Early upper GI endoscopy is a crucial diagnostic tool, as imaging alone may be insufficient to detect the primary lesion. Nutritional interventions form an integral component of chyle leakage management as it may help to reduce chyle flow, minimise nutrient loss, and improve patients’ nutritional status, leading to better survival and quality of life.

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.

Quimioteràpia; Carcinoma de cèl·lules escamoses de cap i coll Quimioterapia; Carcinoma de células escamosas de cabeza y cuello Chemotherapy; Head and neck squamous cell carcinoma 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. Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ.

Background Lower prevalence HPV infection has been previously reported in Thai population when compared with Western countries. p16 expression indicates HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but not non-OPSCC. We therefore evaluated the characteristic and association of p16 and HPV in Thai patients with HNSCC. Methods We used immunohistochemistry and qPCR, respectively, to detect p16 and HPV DNA in archrival formalin-fixed paraffin-embedded HNSCC tissues. Patient characteristics and survival were analyzed. Results p16 expression was detected in tumors of 72 of 662 (10.9%) patients with HNSCC and was significantly associated with higher-grade histology, advanced nodal stage, and oropharynx. p16 was expressed in 28 and 6.5% of patients with OPSCC or non-OPSCC, respectively, and HPV DNA was detected in 15.6 and 1% of patients, respectively. Using p16 as a surrogate for HPV status, sensitivities were 80 and 25% in OPSCC and non-OPSCC, respectively. Positive and negative predictive rates of OPSCC were 38 and 95%. Discordance rates between HPV and p16 were 23 and 7% in OPSCC and non-OPSCC, respectively. Overall survival (OS) were significantly longer in both p16-positive OPSCC (p = 0.049), and non-OPSCC (p = 0.003). Conclusions Low prevalence of p16 and HPV associated OPSCC and non-OPSCC were confirmed in Thai patients. High discordance and low positive predictive rates of p16 were observed in HPV-associated OPSCC. p16 was a significant prognostic factor for OS for patients with OPSCC or non-OPSCC. Therefore, HPV testing should be performed to assess the association of HPV with HNSCC regardless of p16 expression.

Immunotherapy; Pembrolizumab; Quality of life Inmunoterapia; Pembrolizumab; Calidad de vida Immunoteràpia; Pembrolizumab; Qualitat de vida Objectives To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). Materials and Methods HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer–specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. Results Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, −3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, −3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95–2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94–2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. Conclusions Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Background Chemoradiotherapy (CRT) with high cumulative doses (CDs) of cisplatin has been considered the standard of care for non-metastatic nasopharyngeal carcinoma (NPC). However, given most patients’ inability to tolerate high CDs due to cisplatin-related toxicities, the optimal CD of cisplatin during CRT remains undetermined. Methods Patients with non-metastatic NPC who received CRT with cisplatin between 2007 and 2017 were identified through the Thai head and neck cancer multicenter database and then categorized according to cisplatin CD (mg/m2) received. All complications and cisplatin-related toxicities during CRT were recorded. Results We identified 779 non-metastatic NPC patients receiving low (≤150; n = 97), intermediate (151–250; n = 411), and high (> 250; n = 271) CDs of cisplatin. Low CD patients had significantly lower mean actual radiation dose (p p = 0.010), while intermediate CD patients had the least hospitalization (p p = 0.001). Acute kidney injury was observed in 7% in all patients, which was highest among low CD patients (15.5%; p = 0.002). Intermediate CD patients had significantly longer median OS than the low and high groups (64 vs. 49.8 vs. 53.2, respectively; p = 0.015). Univariate, but not multivariate, analysis showed that CD of cisplatin was significantly associated with OS. Conclusion CD of cisplatin during CRT was not an independent prognostic factor for OS. An intermediate CD induced minimal toxicity without compromising survival and should be considered the optimal CD. Nonetheless, a randomized phase 3 study evaluating the optimal CD of cisplatin is warranted.

Background/aim Two-thirds of head and neck squamous cell carcinoma (HNSCC) patients present with locally advanced (LA) stages and have a poor survival rate. The aim of this study was to investigate the roles of the long non-coding RNAs MALAT1 on radiation and cisplatin sensitivity of HNSCC cells. Materials and methods Clonogenic, cell viability, and apoptosis assays were performed in cells following MALAT1 knockdown using CRISPR/Cas9 system. Results MALAT1 was overexpressed in HNSCC cell lines as compared to a non-tumorigenic cell line. The number of colonies formed after radiation was significantly reduced in MALAT1 knockdown cells. The IC50 value of cisplatin in MALAT1 knockdown cells was lower than that of the control cells. MALAT1 knockdown resulted in cell cycle arrest at G2/M phase, DNA damage and apoptotic cell death. Conclusion MALAT1 knockdown enhanced the sensitivity of HNSCC cells to radiation and cisplatin partly through the induction of G2/M cell cycle arrest resulting in DNA damage and apoptosis.

Background Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted. Methods A total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1–2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4–5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period. Discussion This trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development. Trial registration This trial was prospectively registered on Thai Clinical Trials Registry (registration number: TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.

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], pINTERPRETATION: 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.

Sarcoma describes a rare and heterogeneous group of diseases. Current treatment options for metastatic sarcoma are quite limited. Conventional treatments with chemotherapy or anti-angiogenic agents result in a non-durable response and a survival rate of approximately 12 to 18 months. In addition, the benefits of such treatments remain limited in some sarcoma subtypes only. Immunotherapy is an emerging treatment for several cancer types with promising outcomes. Studies at the cellular level have shown a relatively high immunogenicity in some subtypes of sarcoma. It is therefore hypothesized that sarcoma may respond to immunotherapy. However, sarcoma is a heterogeneous disease and differences in terms of immunogenicity exist. A multitude of immune-based treatment approaches for sarcoma have been explored. This includes immune checkpoint inhibitors, therapeutic vaccines, and adoptive cell therapy. Single-agent immunotherapy has exhibited efficacy against some sarcoma subtypes, including alveolar soft-part sarcoma, angiosarcoma, and undifferentiated pleomorphic sarcoma. Combination immunotherapy appears superior to single-agent immunotherapy in terms of response, and several ongoing studies of immunotherapy using single/combination immune checkpoint inhibitors and combination with anti-angiogenesis have begun to report beneficial results. Predictive and prognostic biomarkers are also under active investigations, with particular interest in tumor-infiltrating lymphocytes or high tumor mutational burden levels. However, the information is still limited and further studies are needed.

Prophylactic percutaneous endoscopic gastrostomy (PPEG) is widely used for patients with head and neck cancer undergoing concurrent chemoradiation (CCRT). Nevertheless, the necessity of its use in patients with nasopharyngeal cancer (NPC) is uncertain. This study aimed to evaluate the benefits of PPEG on prevention of weight loss and treatment tolerance in patients with NPC receiving CCRT.A retrospective multicenter chart review of 904 patients, 378 in the PPEG group and 526 in the non-PPEG group, was conducted. Baseline characteristics, weight loss, and treatment tolerance were analyzed and compared between the two groups.There was no significant difference in the mean baseline body mass index (BMI) between the groups. At the end of CCRT, no difference in weight loss was found between the 2 groups (non-PPEG group, 6.6%; PPEG group, 5.9%). Nonetheless, the subgroup analysis demonstrated that a baseline BMI 18.5 kg/mAlthough the benefits of PPEG on prevention of weight loss were not observed for the entire cohort, we found a potentially protective effect of PPEG in some subgroups of patients. Additionally, PPEG significantly enhanced chemotherapy tolerance. Therefore, PPEG tube insertion should be strongly considered for patients with NPC receiving CCRT, particularly for underweight patients and those undergoing a non-IMRT technique.

Though concurrent chemoradiotherapy (CCRT) with cisplatin remains a standard of care for patients with locally advanced nasopharyngeal carcinoma (LA-NPC), carboplatin has alternatively been used without sufficient supportive evidences. Thus, we evaluated an efficacy and tolerability of carboplatin CCRT compared with cisplatin in LA-NPC patients.Patients with LA-NPC treated with CCRT were identified through the Thai multicenter head and neck cancer database. Patient tolerability and survival were analyzed and compared between regimens. Survivals were calculated by using the Kaplan-Meier method, and compared by the log-rank test. A p-value of 0.05 was considered statistically significant.A total of 135 of 980 patients (13.8%) were treated with carboplatin. Patients treated with carboplatin were significantly associated with older age (p 0.001), smoking (p = 0.003), more comorbidity (p = 0.014), kidney disease (p = 0.016), and lower baseline creatinine clearance (p 0.001). Intensity-modulated radiation therapy was used significantly more in the cisplatin group than carboplatin group (p 0.001). Patients who received carboplatin were associated with delay (p = 0.049) and hospitalization (p = 0.006), whereas cisplatin CCRT had more dose reduction (p = 0.001). Patients treated with cisplatin had CCRT interruption from grade 3-4 mucositis (p = 0.019) more than carboplatin, whereas carboplatin had more grade 3-4 thrombocytopenia (p 0.001). The 5-year overall survival (OS) of patients treated with cisplatin and carboplatin was 59% and 49%, respectively (p = 0.128). Cisplatin or carboplatin CCRT was not a significant predictor for OS and locoregional recurrence-free survival in multivariate analysis.Carboplatin CCRT provided acceptable efficacy and tolerability profiles in real-world practice. Carboplatin should be considered as an alternative regimen, particularly in cisplatin-ineligible patients with LA-NPC treated with CCRT.

Poor survival of patients with locally advanced head and neck squamous cell carcinoma (LA‐HNSCC) is partly due to early diagnosis difficulties and the lack of reliable biomarkers for predicting treatment outcomes. In the discovery cohort, plasma‐derived extracellular vesicles (EVs) from LA‐HNSCC patients (n = 48) and healthy volunteers (n = 12) were used for profiling for microRNA (miRNA) expression by NanoString analysis. Ten EV‐associated miRNAs were differentially expressed between LA‐HNSCC patients and healthy volunteers. Subsequently, the results were validated in the individual discovery and additional cases (HNSCC, n = 73; control, n = 20) by quantitative RT‐PCR. Among 10 EV‐miRNAs, four (miR‐27b‐3p, miR‐491‐5p, miR‐1910‐5p, and miR‐630) were significantly dysregulated in LA‐HNSCC patients (n = 73) compared with healthy volunteers (n = 20). The miRNA prediction models were developed to discriminate HNSCC patients from healthy volunteers. The model using miR‐491‐5p was selected as a diagnostic biomarker for LA‐HNSCC with a sensitivity and specificity of 46.6% and 100%, respectively (P, We developed a microRNA (miR)‐491‐5p prediction model as a blood‐based biomarker for diagnosis in head and neck squamous cell carcinoma (HNSCC). Importantly, the dynamic changes of the miR‐491‐5p prediction score (ΔmiR‐491‐5p) from pre‐ and posttreatment might be a potential prognostic biomarker for HNSCC, which could help identify HNSCC patients who will eventually show tumor recurrence.

Objectives: Immunotherapies that target the programmed death-1/ programmed death-1 ligand (PD-1/PD-L1) immune checkpoint pathway have shown promise in nasopharyngeal carcinoma (NPC) in early phases clinical studies. Here, we evaluated PD-1 and PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TILs) in NPC patients. Materials and methods: Newly diagnosed NPC patients were identified through the institutional database between January 2007 and December 2012. PD-L1 and PD-1 expression, Epstein-Barr virus (EBV) status, and CD8+ TIL numbers were measured in archival tumor samples at diagnosis and their correlations with clinicopathologic features, including survival, were evaluated. Results: A total of 114 NPC patients were analyzed. Most patients (96%) were EBV positive. PD-L1 was expressed in ≥1% of tumor cells (TCs) in 69% of patients, in ≥50% of TCs in 12% of patients, and in ≥5% of either TCs or infiltrating immune cells in 71% of patients. CD8+ TILs were present in tumors from all patients, whereas only 11% of tumors expressed PD-1. There were no correlations between PD-L1 expression and CD8+ TIL abundance, PD-1 expression, or survival. Conclusions: Approximately 70% of EBV-positive NPC expressed PD-L1, but this did not correlate with patient survival or clinicopathologic features. The findings of this study represent the immune biomarker profile of confirmed EBV-associated NPC in an endemic region. Since the current clinical development of immune checkpoint inhibitor for NPC is mostly focusing on an EBV-associated tumor, differences in immune biomarker profiles and EBV status of endemic and nonendemic regions should be further explored.

AimsRandomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia.MethodsPubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI.Results80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo.ConclusionsOur findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.

IntroductionChemoradiotherapy (CRT) with high cumulative doses (CDs) of cisplatin has been considered the standard of care for locally advanced nasopharyngeal carcinoma (LA-NPC). However, given most patients’ inability to tolerate high CDs due to cisplatin-related toxicities, the optimal CD of cisplatin during CRT remains undetermined.MethodsPatients with LA-NPC who received CRT with cisplatin between 2007 and 2017 were identified through the Thai head and neck cancer multicenter database and then categorized according to cisplatin CD (mg/m2) received. All complications and cisplatin-related toxicities during CRT were recorded.ResultsWe identified 779 LA-NPC patients receiving low (£150; n=97), intermediate (151–250; n=411), and high (>250; n=271) CDs of cisplatin. Low CD patients had significantly lower mean actual radiation dose (pConclusionCD of cisplatin during CRT was not an independent prognostic factor for OS. An intermediate CD induced minimal toxicity without compromising survival and should be considered the optimal CD. Nonetheless, a randomized phase 3 study evaluating the optimal CD of cisplatin is warranted.

An incidence of cisplatin-induced acute kidney injury (AKI) of 34% has been reported in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, delayed cisplatin-induced nephrotoxicity and long-term renal outcomes remain poorly studied. Patients with LA-HNSCC who underwent definitive or postoperative cisplatin-based chemoradiotherapy (CRT) were included. Acute kidney disease (AKD) was defined as newly developed estimated glomerular filtration rate (eGFR) 50% increase in serum creatinine for

Key Clinical Message Systemic treatment of Medullary thyroid carcinoma (MTC) is currently limited to the use of a tyrosine kinase inhibitor. Cytotoxic chemotherapy is not routinely recommended in the earlier lines of treatment due to the lack of efficacy. We describe a patient with locally advanced MTC who had an uncommon response to cisplatin and etoposide.

Key Clinical Message This report presents the results of immediate breast reconstruction with autologous flap in Pregnancy‐associated breast cancer (PABC). There was no obstetrics and surgical complications in our report. Immediate breast reconstruction can be performed in PABC after a careful selection. Multidisciplinary team approach is the key in managing these groups of patients.

No predictive biomarker of immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) has been well established. The impact of programmed death-ligand 1 (PD-L1) expression, CD8+ tumor-infiltrating lymphocytes (TILs), and p16 status in HNSCC is unclear and may vary according to ethnicity.HNSCC patients treated between 2007 and 2013 were reviewed. Archival tissues were retrieved for PD-L1, CD8+ TILs, and p16 analyses. PD-L1 expression was evaluated by using the validated SP142 assay on the VENTANA platform. CD8+ TILs were defined by using semiquantitative scoring.A total of 203 patients were analyzed. PD-L1 expression was observed in 80% of patients and was significantly associated with older age (P 0.001). A high CD8+ TIL score (≥ 6) was significantly associated with never-smoking (P = 0.020), oral cavity cancer (P 0.001), and stage M0 at presentation (P = 0.025). The p16 status was positive in 12% of patients. Patients with a high TIL score had a significantly longer OS (P = 0.032). Patients with PD-L1 expression of 1-49% and ≥ 50% were associated with a significantly shorter OS compared with those with PD-L1 1% (P = 0.027 and P = 0.011, respectively). Multivariate analysis showed that PD-L1 ≥ 50% was significantly associated with a poor OS. (HR 2.98 [95% CI 1.2-7.39]; P = 0.019.) CONCLUSIONS: A high prevalence of PD-L1 expression was observed in HNSCC using the validated SP142 assay. PD-L1 expression was associated with older age, while highly PD-L1 expression (≥ 50%) was an independent prognostic factor for poor OS in anti-PD1/PD-L1 untreated HNSCC patients.

Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS Table.Efficacy in subgroups of patients with PD-L1 CPS Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score

6505 Background: 1L P vs E improved OS in PD-L1 CPS ≥20 and CPS ≥1 populations, and led to noninferior OS in the total population, with favorable safety; 1L P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety in the phase 3 KEYNOTE-048 study (NCT02358031) in patients with R/M HNSCC. Neither P vs E nor P+C vs E improved PFS in the PD-L1 CPS ≥20, CPS ≥1, or total populations. Here, we present the progression after the next line of therapy (PFS2) to assess the effect of 1L P or P+C and subsequent anticancer therapy on patient outcomes. Methods: Patients with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting were randomly assigned 1:1:1 to P, P+C, or E. PFS2 was defined as time from randomization to objective tumor progression on next-line therapy or death from any cause. PFS2 was estimated using the Kaplan-Meier method as an exploratory outcome confined to those receiving subsequent therapy after 1L P. HR and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate (stratified by ECOG performance status [PS], HPV status, and PD-L1 for CPS ≥1 and total populations; by ECOG PS and HPV status for CPS ≥20 population). Data cutoff: Feb 25, 2019. Results: Of 882 (301 [P]; 281 [P+C]; 300 [E]) treated patients,422 (P: 148 [49.2%]; P+C: 115 [40.9%]; E: 159 [53.0%]) received subsequent anticancer therapy after 1L P, most commonly C (P: 135 [44.9%]; P+C: 88 [31.3%]; E: 102 [34.0%]); EGFR inhibitor (P: 59 [19.6%]; P+C: 37 [13.2%]; E: 19 [6.3%]); and immune checkpoint inhibitor (P: 6 [2.0%]; P+C: 12 [4.3%]; E: 50 [16.7%]); patients may have received more than one type of subsequent therapy. Median PFS2 is reported in Table. Conclusions: In patients with R/M HNSCC, longer median PFS2 was observed in the CPS ≥20 and CPS ≥1 populations for P vs E, and in the CPS ≥20, CPS ≥1, and total populations for P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]

6530 Background: In the phase 3 KEYNOTE-048 trial ( NCT02358031 ) in R/M HNSCC (N = 882), 1L P vs E showed superior OS in PD-L1 CPS ≥20 and CPS ≥1 populations, noninferior OS in the total population, no PFS benefit, and favorable safety; 1L P+C vs E showed superior OS in CPS ≥20, CPS ≥1, and total populations, no PFS benefit, and comparable safety. Results of P or P+C vs E in incurable recurrent only, metastatic only, and R/M subgroups are shown. The metastatic only and R/M subgroups were combined and classified as metastatic. Methods: Patients with incurable recurrent (local and/or regional node recurrent disease) or metastatic HNSCC were randomly assigned 1:1:1 to P, P+C, or E. OS and PFS were estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status, HPV status, and PD-L1 status. Data cutoff: Feb 25, 2019. Results: In the incurable recurrent only subgroup (n = 252), median OS was 11.5 vs 12.1 mo (P vs E) and 13.0 vs 11.1 mo (P+C vs E). In the metastatic subgroup (n = 620), median OS was 11.4 vs 9.7 mo (P vs E) and 13.0 vs 10.1 mo (P+C vs E). Median follow-up, OS, and PFS are shown in Table. Treatment-related adverse events (TRAE) in the incurable recurrent only subgroup: 49.4% (P), 94.7% (P+C), and 97.8% (E); grade 3-5 TRAEs rates: 16.0%, 78.7%, and 73.3%, respectively. TRAE rates in the metastatic subgroup: 61.6% (P), 96.4% (P+C), and 96.4% (E); grade 3-5 TRAEs rates: 17.6%, 69.5%, and 67.0%, respectively. Conclusions: P and P+C vs E were efficacious in the metastatic subgroup; in the relatively smaller subgroup of patients with incurable recurrent only HNSCC, the effect was less pronounced. Consistent with the total study population and regardless of disease state, the safety profile was favorable with P vs E and comparable with P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]

Patients with head and neck squamous cell carcinoma are at increased risk of developing a second primary malignancy, which is associated with poor prognosis and early death. To help improve clinical outcome, we aimed to identify biomarkers for second primary malignancy risk prediction using the routinely obtained formalin-fixed paraffin-embedded tissues of the index head and neck cancer. Liquid chromatography-tandem mass spectrometry was initially performed for candidate biomarker discovery in 16 pairs of primary cancer tissues and their matched normal mucosal epithelia from head and neck squamous cell carcinoma patients with or without second primary malignancy. The 32 candidate proteins differentially expressed between head and neck cancers with and without second primary malignancy were identified. Among these, 30 selected candidates and seven more from literature review were further studied using NanoString nCounter gene expression assay in an independent cohort of 49 head and neck cancer patients. Focusing on the p16-negative cases, we showed that a multivariate logistic regression model comprising the expression levels of ITPR3, KMT2D, EMILIN1, and the patient’s age can accurately predict second primary malignancy occurrence with 88% sensitivity and 75% specificity. Furthermore, using Cox proportional hazards regression analysis and survival analysis, high expression levels of ITPR3 and DSG3 were found to be significantly associated with shorter time to second primary malignancy development (log-rank test P = 0.017). In summary, we identified a set of genes whose expressions may serve as the prognostic biomarkers for second primary malignancy occurrence in head and neck squamous cell carcinomas. In combination with the histopathologic examination of index tumor, these biomarkers can be used to guide the optimum frequency of second primary malignancy surveillance, which may lead to early diagnosis and better survival outcome.

Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of pembrolizumab (pembro) or pembro + chemotherapy (chemo) vs EXTREME (E) as first-line therapy for recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). At the second interim analysis, overall survival (OS) was significantly longer with pembro than E in patients with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). Pembro + chemo significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Patients with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to pembro 200 mg Q3W, pembro + chemo (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + chemo) until progressive disease, unacceptable toxicity, 6 cycles of chemo, or 24 months of pembro. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with pembro vs E were 28.6% vs 76.9% in the Asia subgroup and 13.9% vs 67.2% in the non-Asia subgroup; rates with pembro + chemo vs E were 71.9% vs 76.9% in the Asia subgroup and 70.8% vs 67.2% in the non-Asia subgroup. Table: 286O Asia CPS ≥20 Asia CPS ≥1 Asia Tot Pop Non-Asia CPS ≥20 Non-Asia CPS ≥1 Non-Asia Tot Pop HR; 95% CI P vs E 22 v 23 P+C v E 22 v 21 P v E 48 v 46 P+C v E 45 v 43 P v E 56 v 53 P+C v E 57 v 49 P v E 111 v 99 P+C v E 104 v 89 P v E 209 v 209 P+C v E 197 v 192 P v E 245 v 247 P+C v E 224 v 229 OS 0.39; 0.19-0.80 0.80; 0.41-1.58 0.80; 0.51-1.27 1.13; 0.71-1.79 0.74; 0.48-1.13 1.03; 0.68-1.58 0.75; 0.54-1.04 0.68; 0.48-0.96 0.76; 0.61-0.95 0.65; 0.51-0.82 0.87; 0.71-1.06 0.71; 0.57-0.88 PFS 1.16; 0.63-2.11 1.07; 0.58-1.99 1.25; 0.82-1.91 1.14; 0.74-1.76 1.39; 0.94-2.05 1.12; 0.75-1.66 0.95; 0.70-1.28 0.65; 0.47-0.89 1.10; 0.89-1.35 0.74; 0.60-0.92 1.27; 1.05-1.54 0.82; 0.67-1.00 HRs, Kaplan-Meier method; 95% CIs, Cox regression model. Conclusions Pembro vs E showed favorable OS in Asia and non-Asia subgroups, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgroups; safety was favorable. Pembro + chemo vs E showed favorable OS in patients with CPS ≥20 in Asia and non-Asia subgroup regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, CMPP, and Holly Cappelli, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. K. Tanaka: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R-L. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia, MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim (M), Merck Serono (M), Roche (M), Eli Lilly (M), Amgen (M); Speaker Bureau / Expert testimony: Eli Lilly Inc; Research grant / Funding (self): Amgen Inc, MSD, Roche & Genetech, AstraZeneca; Travel / Accommodation / Expenses: Eisai (M), Eli Lilly (M), AstraZeneca (M), MSD Inc, Roche (M), Merck Serono (M), Mundipharma (M), Novartis (M), Pfizer (M), Amgen (M), Menarini (M). V. Sriuranpong: Honoraria (self): MSD; Advisory / Consultancy: MSD. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. N. Nohata: Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: MSD KK. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. B. Gumuscu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. R. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. M. Tahara: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. All other authors have declared no conflicts of interest.

Background Risk factors of cisplatin induced acute kidney injury (AKI) patients has been well described. In HNSCC, an incidence of cisplatin induced AKI was observed in 34.2%. Most studies reported AKI as a surrogate endpoint. However, delayed cisplatin induced nephrotoxicity and long-term renal outcomes were not well studied. Methods Locally advanced HNSCC patients treated between 1/2007 and 12/2018 who underwent definitive or post-operative chemoradiotherapy (CRT) with cisplatin were identified. Patient characteristics, treatments, creatinine at baseline, during, 3, 6, and 12 months after CRT completion were retrospectively reviewed. Acute kidney disease (AKD) was defined by (i) estimated glomerular filtration rate (eGFR) 50 % for Results A total of 509 patients were analyzed. Overall AKD occurred in 27.9% patients. Most patients (95%) had prophylactic feeding. ECOG of 0 was more prominent in AKD patients (p = 0.017) and hypertension (p Conclusions Almost one third of locally advanced HNSCC patients who underwent CRT with cisplatin developed AKD with peak incidence at 3 months after CRT. After 1 year, eGFR of patients with AKD had not recovered, and remained at -30% below baseline. ECOG 0 and hypertension were a predictor for AKD. Hypertension might reflect underlying kidney disease which leads to susceptibility to kidney injury. Moreover, physician’s awareness of AKD and underestimation of potential complications in fit patients might explain these findings. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background HPV induces many alterations in CDK4-Cyclin D-Rb and apoptotic pathways such as up-regulation of p16, loss of Rb and p53 functions in SCCHN carcinogenesis. Loss of p16 expression is known as a poor prognostic marker in SCCHN for survival. Palbociclib is a highly selective inhibitor of CDK4/6 by blocking Rb phosphorylation with radiosensitizing activity in preclinical studies. Addition of palbociclib to cetuximab and IMRT provides a strong rationale to improve efficacy of treatment in locally advanced SCCHN, especially in p16/HPV-negative tumour. Methods This is a phase I study designed to determine the maximum tolerated dose (MTD) and toxicity of palbociclib, cetuximab, and IMRT, using a classical 3 + 3 design (NCT03024489). The study included locally advanced SCCHN of oral cavity, oropharynx, larynx, and hypopharynx. Palbociclib dose was escalated with 3 dose levels (DLs), starting from 75 to 125 mg/d orally for 21 day-on and 7 day-off for 2 cycles. For all DLs, cetuximab was administered at 400 mg/m2IV on day -7 and then 250 mg/m2weekly for 7 weeks. IMRT was delivered 5 day-on and 2 day-off with a total dose of 70 Gy for 33 fractions. MRI and PET scans pre- and post-treatment was used to evaluate preliminary efficacy. Results A total of 13 eligible patients were enrolled in the dose escalation cohort. No MTD was observed. One DLT, febrile neutropenia (FN) was reported in 1 of 7 patients who received 125 mg of palbociclib (DL3) at the 6thweek of IMRT. The FN recovered without G-CSF support within 7 days after discontinuation of palbociclib. Overall, toxicities were related to cetuximab and IMRT. Complete response was observed in 7 of 10 evaluable patients (70%), while overall objective response was demonstarted in 9 of 10 patients (90%). Conclusions The recommended phase 2 dose was palbociclib 125 mg/d for 21 days on and 7 days off with full standard dose of cetuximab and IMRT for locally advanced SCCHN. MTD was not achieved. The combination was well tolerated with promising preliminary efficacy. The expansion cohort of palbociclib 125 mg/d is currently accruing up to 15 locally advanced p16-negative SCCHN patients. Clinical trial identification NCT#03024489. Legal entity responsible for the study The authors. Funding Pfizer. Disclosure N. Ngamphaiboon: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Boehringer Ingelheim; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Taiho. T. Siripoon: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Boehringer Ingelheim. S. Lukerak: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca. N. Sankaseam: Research grant / Funding (institution): Roche; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca. E. Sirachainan: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Sanofi/Aventis; Honoraria (self): Merck; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Mundipharma; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): LF Asia; Honoraria (self): Diethelm Keller Logistics; Honoraria (self): BMS; Honoraria (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of P or P + chemotherapy (C) vs EXTREME (E) as 1L therapy for R/M HNSCC. At 2nd interim analysis, overall survival (OS) was significantly longer with P than E in patients (pts) with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). P+C significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Pts with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to P 200 mg Q3W, P+C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + C) until progressive disease, unacceptable toxicity, 6 cycles of C, or 24 months of P. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with P vs E were 28.6% vs 76.9% in the Asia subgrp and 13.9% vs 67.2% in the non-Asia subgrp; rates with P+C vs E were 71.9% vs 76.9% in the Asia subgrp and 70.8% vs 67.2% in the non-Asia subgrp. Conclusions P vs E showed favorable OS in Asia and non-Asia subgrps, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgrps; safety was favorable. P+C vs E showed favorable OS in pts with CPS ≥20 in Asia and non-Asia subgrps regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Doyel Mitra, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Table: 1136P . Asia, CPS ≥20 Asia, CPS ≥1 Asia, Total Population Non-Asia, CPS ≥20 Non-Asia, CPS ≥1 Non-Asia, Total Population P vs E n = 22 vs 23 P+C vs E n = 22 vs 21 P vs E n = 48 vs 46 P+C vs E n = 45 vs 43 P vs E n = 56 vs 53 P+C vs E n = 57 vs 49 P vs E n = 111 vs 99 P+C vs E n = 104 vs 89 P vs E n = 209 vs 209 P+C vs E n = 197 vs 192 P vs E n = 245 vs 247 P+C vs E n = 224 vs 229 OS: HR (95% CI ) 0.39 (0.19-0.80) 0.80 (0.41-1.58) 0.80 (0.51-1.27) 1.13 (0.71-1.79) 0.74 (0.48-1.13) 1.03 (0.68-1.58) 0.75 (0.54-1.04) 0.68 (0.48-0.96) 0.76 (0.61-0.95) 0.65 (0.51-0.82) 0.87 (0.71-1.06) 0.71 (0.57-0.88) PFS: HR (95% CI) 1.16 (0.63-2.11) 1.07 (0.58-1.99) 1.25 (0.82-1.91) 1.14 (0.74-1.76) 1.39 (0.94-2.05) 1.12 (0.75-1.66) 0.95 (0.70-1.28) 0.65 (0.47-0.89) 1.10 (0.89-1.35) 0.74 (0.60-0.92) 1.27 (1.05-1.54) 0.82 (0.67-1.00) ORR, % 22.7 vs 30.4 45.5 vs 33.3 16.7 vs 37.0 31.1 vs 37.2 14.3 vs 41.5 31.6 vs 40.8 23.4 vs 37.4 42.3 vs 39.3 19.6 vs 34.4 37.6 vs 35.4 17.6 vs 34.8 36.6 vs 35.4 Median DOR, mo 5.7 vs 4.3 6.1 vs 4.3 12.6 vs 4.3 6.1 vs 4.2 12.6 vs 4.1 5.7 vs 4.1 23.4 vs 4.1 8.5 vs 4.1 20.9 vs 4.5 6.9 vs 4.4 20.9 vs 5.0 6.9 vs 5.0 C, chemotherapy; CI, confidence interval; CPS, combined positive score; DOR, duration of response; E, EXTREME; HR, hazard ratio; mo, months; ORR, objective response rate; OS, overall survival; P, pembrolizumab; PFS, progression-free survival. HRs are from product-limit (Kaplan-Meier) method for censored data; 95% CIs are based on Cox regression model with Efron’s method of tie handling with treatment as a covariate. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure M. Tahara: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim, Merck Serono, Roche, Eli Lilly, Amgen; Speaker Bureau / Expert testimony: Eli Lilly; Research grant / Funding (self): Amgen Inc, MSD, Roche, Genentech, AstraZeneca; Travel / Accommodation / Expenses: Eisai, Eli Lilly, AstraZeneca, MSD Inc, Roche, Merck Serono, Mundipharma, Novartis, Pfizer, Amgen, Menarini. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. K. Tanaka: Honoraria (self): AstraZeneca, ONO Pharmaceutical, MSD, Eisai, Merck Serono, Bristol-Myers Squibb. N. Nohata: Shareholder / Stockholder / Stock options: Merck & Co., Inc.; Full / Part-time employment: MSD K.K. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. B. Gumuscu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. R.F. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. All other authors have declared no conflicts of interest.