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Additional description of methods for gene suppression studies, Western blot, immunohistochemistry, flow cytometry and cellular assays

Supplementary Tables S1-5 - PDF filr 185K, Supplementary Table S1: Essentiality of CDKs in CCNE1 amplified cell lines; Supplementary Table S2: GeneGo gene expression pathways enriched in PHA-533533 resistant cell lines; Supplementary Table S3: Copy number changes identified by SNP microarray in PHA-533533 resistant cell lines; Supplementary Table S4: Gene Set Enrichment Analysis (GSEA) of positional gene sets enriched in amplified or deleted genes specific to PHA-533533 resistant cells; Supplementary Table S5: OVCAR-3 cell line and derivative resistant line karyotypes

Change from baseline in tumor burden of target lesions at patient level

PDF file - 191K

Description of additional methods and procedures used in the study. Also includes Supplementary References.

List of shRNAs on the custom reductase library.

Supplementary Figure Legends from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Evaluation of SN30000-induced bystander cell killing in a co-culture system (S1); SN30000 clonogenic survival curves for HT-29, PANC-1 cells and HKO1 (S2); Plating efficiency in HT-29, PANC-1 and HKO2 reductase screens (S3); Density distributions and correlations of reductase screen sequencing data (S4); Log2 enrichment factors of shRNAs significantly selected in the reductase screens (S5); Depletion of POR protein by shRNAs in PANC-1 and HT-29 cells (S6); Replicate SN30000 clonogenic survival assays performed in stably transduced HT-29 and PANC-1 cells (S7); Measurement of plating efficiency in HKO1 and HKO2 whole-genome screens (S8); Coincidence of shRNAs significantly selected (Z > 1.96) in HT-29 and PANC-1 reductase screens and the HKO1 genome-wide screen (S9); Validation of POR shRNAs and clonogenic survival following SN30000 treatment of POR-knockout HCT116 cells (S10); Spatial distribution of POR and CA-IX expression in tongue SCC (S11); Quantitation of POR and CA-IX expression in HNSCC (S12); POR IHC staining in isogenic xenografts used for method development (S13); POR mRNA expression and sequence variation in the TCGA HNSCC dataset (S14).

52-page, 2.4 MB pdf

Gene expression profiling offers a promising new technique for the diagnosis and prognosis of cancer. We have applied this technology to build a clinically robust site of origin classifier with the ultimate aim of applying it to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 primary and metastatic tumors representing 14 tumor types and multiple histologic subtypes. This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy using a 13-class model. Further, we show the translation of a five-class classifier to a quantitative PCR–based platform. Selecting 79 optimal gene markers, we generated a quantitative-PCR low-density array, allowing the assay of both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. Data generated using both quantitative PCR and microarray were subsequently used to train and validate a cross-platform SVM model with high prediction accuracy. Finally, we applied our SVM classifiers to 13 cases of CUP. We show that the microarray SVM classifier was capable of making high confidence predictions in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories.

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.

Background: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. Methods: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. Results: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P

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.

Purpose To examine sexual health, including sexual satisfaction, and perceived changes in relationships and sexual relationships of human papillomavirus (HPV) oropharyngeal cancer (OPC) survivors ≥12 months after (chemo)radiation therapy. Methods and Materials We undertook a cross-sectional study of HPV-OPC survivors who had completed treatment ≥12 months prior. Eligible patients completed the EORTC QLQ-SHQ22, a customized relationship questionnaire, the EORTC QLQ-C30, MDASI-HN, and PROMIS Anxiety and Depression scales. Results We enrolled 136 survivors (median age, 61 years [range, 42-87 years]; male, 84%; currently partnered, 72%). The median time from (chemo)radiation therapy completion was 2.8 years (range, 1.0-5.5 years). Most patients (71/131; 60%) reported an active sex life as important; however, only 20% (26/133) reported significant recent sexual activity (“quite a bit”/“very much”). The mean sexual satisfaction score was 47/100 (interquartile range, 27-67; standard deviation 28). On univariable analysis, greater sexual satisfaction was positively associated with greater importance of sexual activity, stronger libido, greater relationship security, and more erection confidence (males). Lower sexual satisfaction was significantly associated with female sex (P = .04), more medical comorbidities (P = .008), and more time since treatment completion (P = .006). Only a few patients reported a change in their marital status (10/136; 7%). The majority (62/109; 57%) of patients partnered at diagnosis reported no change in their precancer relationship. Among those reporting a change, it was more frequently perceived as positive (29/109; 27%) than negative (16/109; 15%). Regarding their sexual relationship, 54 of 107 (50%) reported no change, 40 of 107 (37%) reported a negative change, and 8 of 107 (7%) reported a positive change. Conclusions Although an active sex life is important to many HPV-OPC survivors, fewer reported significant recent sexual activity. Sexual satisfaction scores were moderate in this cohort. Although recall bias was possible, most patients reported either no change or a positive change in their interpersonal relationship. Prospective studies evaluating sexual health outcomes and addressing informational needs in HPV-OPC survivors are needed.

Background Current international consensus is that ‘early’ referral to palliative care services improves cancer patient and family carer outcomes. In practice, however, these referrals are not routine. An approach which directly addresses identified barriers to early integration of palliative care is required. This protocol details a trial of a standardized model of early palliative care (Care Plus) introduced at key defined, disease-specific times or transition points in the illness for people with cancer. Introduced as a ‘whole of system’ practice change for identified advanced cancers, the key outcomes of interest are population health service use change. The aims of the study are to examine the effect of Care Plus implementation on (1) acute hospitalisation days in the last 3 months of life; (2) timeliness of access to palliative care; (3) quality and (4) costs of end of life care; and (5) the acceptability of services for people with advanced cancer. Methods Multi-site stepped wedge implementation trial testing usual care (control) versus Care Plus (practice change). The design stipulates ‘control’ periods when usual care is observed, and the process of implementing Care Plus which includes phases of planning, engagement, practice change and evaluation. During the practice change phase, all patients with targeted advanced cancers reaching the transition point will, by default, receive Care Plus. Health service utilization and unit costs before and after implementation will be collated from hospital records, and state and national health service administrative datasets. Qualitative data from patients, consumers and clinicians before and after practice change will be gathered through interviews and focus groups. Discussion The study outcomes will detail the impact and acceptability of the standardized integration of palliative care as a practice change, including recommendations for ongoing sustainability and broader implementation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN 12619001703190. Registered 04 December 2019.

This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours. Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a “3 + 3” design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed. Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m2/day. No significant organ toxicity or objective responses were observed, although there were two patients with stable disease lasting up to 7 months. Pharmacokinetic analysis unexpectedly indicated a half-life of 9–19 days, invalidating the CIVI dosing resulting in discontinuation of the study before the RP2D was defined. PENAO was administered by CIVI at dose levels up to 9 mg/m2/day with only one DLT noted. Pharmacokinetic studies invalidated the rationale for continuous dosing and led to discontinuation of the trial without defining a RP2D. Future clinical development of PENAO will use intermittent dosing schedule, alone and in combination with rapamycin.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the safety, patient preference for, and cost of intravenous anti‐cancer therapy (chemotherapy or immunotherapy) delivered at home as an alternative to the same intravenous anti‐cancer therapy regimen delivered in a hospital or community settings, in adults with cancer.

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.

Cemiplimab; Càncer de coll uterí metastàtic; Càncer de coll uterí recurrent Cemiplimab; Cáncer de cuello uterino metastásico; Cáncer de cuello uterino recurrente Cemiplimab; Metastatic cervical cancer; Recurrent cervical cancer Objectives To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). Results Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens ( N = 155), PD-L1 protein expression in tumor and immune cells was negative (

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).

BACKGROUND: Surgery is the primary treatment for patients with recurrent head and neck cutaneous squamous cell carcinoma (cSCC) who have previously been treated by definitive surgery and radiotherapy. There are limited published data to direct management and the role of immunotherapy is currently under evaluation. METHODS: This was a retrospective study of patients with at least stage III recurrent head and neck cSCC previously managed by definitive surgery and radiotherapy. RESULTS: A total of 30 patients met the inclusion criteria. Eighty-seven percent were male and the median age at the time of surgery was 79 years. After salvage surgery, 7% developed local recurrence and 43% regional or distant failure. The 2-year overall survival and disease-free survival were 45% (95% confidence interval 24-64) and 11% (95% confidence interval 1-34), respectively. Advanced age was associated with a higher risk of overall mortality (P

Contains fulltext : 220257.pdf (Publisher’s version ) (Closed access) The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.

Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is increasing rapidly. The younger age, significantly improved prognosis, and relative morbidity of the standard-of-care cisplatin and radiotherapy in this population have led to the popularization of the concept of treatment de-escalation. The recent results of the first 3 randomized de-escalation trials, however, have shown a clear detriment in survival when cisplatin is omitted or substituted. In view of these results, the Head and Neck Cancer International Group identified the need to issue guidance regarding future de-escalation studies for patients with HPV-positive head and neck cancer to avoid the possibility of patients being harmed. We review the current state of the literature regarding HPV de-escalation trials and present a framework and guidance on future and existing clinical trials for treatment de-escalation of HPV-positive OPC. De-escalation paradigms of HPV-positive OPC should be evaluated in phase II studies, and results should be awaited before proceeding to phase III studies. Implementation into clinical practice before high-level evidence is available should not be undertaken in this context. Finally, harm-minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.

Patients with cancer are at increased risk for infection, but the relative morbidity and mortality of all infections is not well understood. The objectives of this study were to determine the prevalence, incidence, time-trends and risk of mortality of infections associated with hospital admissions in patients with haematological- and solid-tumour malignancies over 11 years. A retrospective, longitudinal cohort study of inpatient admissions between 1 January 2007 and 31 December 2017 at the Peter MacCallum Cancer Centre was conducted using administratively coded and patient demographics data. Descriptive analyses, autoregressive integrated moving average, Kaplan-Meier and Cox regression modelling were applied. Of 45,116 inpatient hospitalisations consisting of 3033 haematological malignancy (HM), 18,372 solid tumour neoplasm (STN) patients and 953 autologous haematopoietic stem cell transplantation recipients, 67%, 29% and 88% were coded with ≥ 1 infection, respectively. Gastrointestinal tract and bloodstream infections were observed with the highest incidence, and bloodstream infection rates increased significantly over time in both HM- and STN-cohorts. Inpatient length of stay was significantly higher in exposed patients with coded infection compared to unexposed in HM- and STN-cohorts (22 versus 4 days [p

Summary Background Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma. Methods This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0–1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov , number NCT02760498 . Findings Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1–15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32–55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3–4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia. Interpretation Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care. Funding Regeneron Pharmaceuticals and Sanofi.

Our objective was to determine the negative predictive value (NPV) of preoperative FDG PET/CTfor detecting locoregional nodal disease. The aim was to help inform the decision-making process when identifying patients with early-stage OPSCC that would be suitable for transoral robotic surgery (TORS) as a single-modality treatment.A retrospective cohort study was conducted of adults with primary stage cT1-2 OPSCC with up to one metastatic neck lymph node (cN0-1) planned for TORS. Patients with a preoperative PET/CT and who had undergone staging neck dissection (ND) were included. Clinical and pathological nodal staging was established based on PET/CT and ND, respectively. The primary outcome was the frequency of occult (not seen on PET/CT) nodal disease on ND.Eighty-eight patients were included (N = 88). The rate of occult nodal disease was 28.4 % (n = 25). The NPV of PET/CT in the clinically negative neck was 79 % and 66 % in cases with a single clinical node. Following staging ND, thetreatment plan changed in 27 % of cases overall, 7 % in cN0 and 36.7 % in cN1. Among these, 18 % met criteria for radiotherapy and 9 % for CRT. This represented a decrease in the number of ideal candidates for TORS as single-modality treatment from 88 to 64 (73 %).PET/CT is a useful tool in the workup of patients for primary TORS. However, about one third of patients with early-stage OPSCC might benefit from adjuvant therapy not predicted by preoperative PET/CT. A staging ND helps confirm candidates for single-modality treatment with TORS.

PURPOSE The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies. PATIENTS AND METHODS A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. RESULTS Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1/ 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1/ 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. CONCLUSION ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.

BackgroundThe prognosis for advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains poor for many patients with the disease despite approval of the anti-PD1 antibodies cemiplimab and pembrolizumab.1 2 RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity, which is further improved by combining anti-PD-1 therapy.3 Preliminary results from IGNYTE, a phase I/II clinical study of RP1 in combination with nivolumab showed a high rate of deep and durable responses in patients (pts) with CSCC.4 The objective of this trial is to evaluate the safety and efficacy of cemiplimab + RP1 versus cemiplimab alone in advanced CSCC.MethodsThis global, multicenter, randomized phase 2 study is enrolling pts with metastatic or unresectable, locally advanced CSCC who are not candidates for/refuse surgery and/or radiotherapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial will enroll approximately 180 pts from centers in the EU, Australia, Canada and USA. Pts will be randomized in a 2:1 ratio favoring the RP1 + cemiplimab arm. Pts will receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 will be injected intratumorally at a starting RP1 dose of 1 × 10^6 plaque forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 10^7 PFU/mL Q3W together with cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses. No crossover will be allowed. Pts will be stratified by disease status and prior systemic therapy. Tumor assessments will be performed every 9 weeks. Primary endpoints are overall response rate and complete response rate by blinded independent review. Secondary endpoints include safety, progression free survival, duration of response and overall survival. Exploratory endpoints include viral shedding and biodistribution, and immune biomarker analyses. This trial is currently enrolling pts.Trial RegistrationNCT04050436ReferencesMigden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, Chung CH, Hernandez-Aya L, Lim AM, Chang ALS, Rabinowits G, Thai AA, Dunn LA, Hughes BGM, Khushalani NI, Modi B, Schadendorf D, Gao B, Seebach F, Li S, Li J, Mathias M, Booth J, Mohan K, Stankevich E, Babiker HM, Brana I, Gil-Martin M, Homsi J, Johnson ML, Moreno V, Niu J, Owonikoko TK, Papadopoulos KP, Yancopoulos GD, Lowy I, Fury MG. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379(4):341–351.Grob JJ, Gonzalez R, Basset-Seguin N, Vornicova O, Schachter J, Joshi A, Meyer N, Grange F, Piulats JM, Bauman JR, Zhang P, Gumuscu B, Swaby RF, Hughes BGM. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol 2020;38(25):2916–2925.Thomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, Smith H, Kaufman HL, Harrington KJ, Coffin RS. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer 2019;7(1):214.Middleton M, Aroldi F, Sacco J, Milhem M, Curti B, VanderWalde A, Baum S, Samson A, Pavlick A, Chesney J, Niu J, Rhodes T, Bowles T, Conry R, Olsson-Brown A, Earl Laux D, Kaufman H, Bommareddy P, Deterding A, Samakoglu S, Coffin R, Harrington K. 422 An open-label, multicenter, phase 1/2 clinical trial of RP1, an enhanced potency oncolytic HSV, combined with nivolumab: updated results from the skin cancer cohorts. J Immunother Cancer 2020; 8 (3).Ethics ApprovalThe study was approved by institutional review board or the local ethics committee at each site. Informed consent was obtained from patients before participating into the trial.

Introduction/Background* There is no standard of care regimen in the second-line setting for women with recurrent/metastatic (R/M) cervical carcinoma. Cemiplimab was recently shown to significantly improve overall survival (OS) compared with investigator’s choice (IC) chemotherapy in patients with R/M cervical cancer after first-line platinum-based chemotherapy (NCT03257267; ESMO-VP-2021). We present a pre-planned exploratory subgroup analysis comparing cemiplimab to individual IC chemotherapy options. Methodology EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 is an open-label, randomised (1:1), multi-centre, Phase 3 clinical trial of anti-programmed cell death (PD)-1 cemiplimab vs IC single agent chemotherapy in R/M cervical cancer that has progressed after first-line platinum-based treatment. The selection of single-agent chemotherapy by the investigator (gemcitabine, pemetrexed, vinorelbine, topotecan or irinotecan) was not protocol-defined, but the regimen had to be chosen prior to randomisation. Adult females (age ≥18 years) were enrolled regardless of PD-ligand 1 expression and received cemiplimab 350 mg intravenously every 3 weeks or IC chemotherapy for up to 96 weeks; and were stratified by histology (squamous cell carcinoma/adenocarcinoma or adenosquamous), geographic region (North America/Asia/rest of world), prior bevacizumab, and ECOG performance status (0/1). Primary endpoint was OS. Additional endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response, quality of life and safety. Data cutoff was 4 January 2021. Result(s)* A total of 608 patients were randomised: 304 to cemiplimab and 304 to IC chemotherapy (gemcitabine, n=121; premetrexed, n=111; vinorelbine, n=32; topotecan, n=21; irinotecan, n=19) across geographic regions and histologies. Median duration of study follow-up (range) was 4.8 months (0.0–25.9) for the overall population. At second interim analysis, the trial was stopped early for efficacy. OS, PFS and ORR (table 1) demonstrated improvements with cemiplimab vs each IC chemotherapy treatment similar to those observed with cemiplimab vs pooled IC chemotherapy. Conclusion* Improvements in OS, PFS and ORR with cemiplimab trended consistently with the results for the overall population regardless of IC chemotherapy drug.

PURPOSE: We aimed to develop an accurate prognostic model to identify suitable candidates for definitive radiation therapy (DRT) in addition to palliative chemotherapy (PCT) among patients with de novo metastatic nasopharyngeal carcinoma (mNPC). METHODS AND MATERIALS: Patients with de novo mNPC who received first-line PCT with or without DRT were included. Overall survival for patients who received PCT alone versus PCT plus DRT was estimated using inverse probability of treatment weighting–adjusted survival analyses. We developed and validated a prognostic model to predict survival and stratify risks in de novo mNPC. A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores obtained from the prognostic model and to identify suitable DRT candidates. Dominance analysis was used to determine the relative importance of each predictor of receiving DRT. RESULTS: A total of 460 patients were enrolled; 244 received PCT plus DRT and 216 received PCT alone. The 6-month conditional landmark, inverse probability of treatment weighting–adjusted Cox regression analysis showed that PCT plus DRT was associated with a significant survival benefit (hazard ratio: 0.516; 95% confidence interval, 0.403–0.660; P < .001). A prognostic model based on 5 independent prognostic factors, including serum lactate dehydrogenase, number of metastatic sites, presence of liver metastasis, posttreatment Epstein–Barr virus DNA level, and response of metastases to chemotherapy was developed and subsequently validated. Prognostic scores obtained from the prognostic model were used for risk stratification and efficacy estimation. High-risk patients identified using the proposed model would not benefit from additional DRT, whereas low-risk patients experienced significant survival benefits. Socioeconomic factors, including insurance status and education level, played an important role in receipt of DRT. CONCLUSIONS: Additional DRT after PCT was associated with increased overall survival in patients with de novo mNPC, especially low-risk patients identified with a newly developed prognostic model.

Purpose This study examined the clinical outcomes and prognostic factors of patients with metastatic cutaneous SCC metastatic to the axilla and groin when managed with curative-intent lymphadenectomy and received (neo)adjuvant treatment. Methods and materials We conducted a single institution retrospective review. Patients who had nodal disease without distant spread were 18 years or older with no non-cutaneous primary identified. Results From January 2000 to July 2015, 78 patients were treated for axilla (64, 82%) or inguinal (14, 18%) involvement with cSCC. The median age was 75.5 years (range: 29-95), and 8 patients (11%) were immunosuppressed. The median size of the largest node was 45 mm (range: 8-135), and extracapsular extension was found in 63 (81%) cases. A majority of patients were treated with surgery alone (21, 26.9%) and surgery with adjuvant radiation therapy (54, 69%). The 2-year OS and PFS were 50% (95% CI: 40%-63%) and 43% (95% CI: 33%-56%), and 5-year OS and PFS were 33% (95% CI:23%-47%) and 32% (95% CI:22%-46%) respectively in the entire cohort. On univariable analysis, factors associated with longer OS were as follows: younger age (HR 1.1, 95% CI: 0.9-1.3 P = 0.021), improved performance status (HR 1.5, 95% CI:1.0-2.3 P = 0.026), lack of immunosuppression (HR 3.3, 95% CI: 1.5-7.3 P = 0.001), lower lymph node ratio (HR 1.2, 95% CI:1.0-1.3 P = 0.007), lower number of positive nodes (HR 1.1, 95% CI:1.0-1.2 P = 0.004) and the use of radiation therapy (HR 0.5, 95% CI:0.3-0.9 P = 0.012). Conclusion Metastasis to the axilla and groin with cSCC has poor outcomes with standard treatment. The addition of immunotherapy warrants investigation.

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.

BackgroundTo provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL).MethodsPatients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks).ResultsMedian duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (pConclusionsThis is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement.Trial registration numberClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.

Lessons Learned Background Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti–PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). Methods Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. Results Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3–67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7–4.7). Conclusion The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti–PD-1 inhibitor monotherapy for R/M HNSCC.

Purpose The excellent prognosis of patients with low-risk human papillomavirus (HPV)- associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiation therapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an epidermal growth factor receptor targeting antibody, when combined with radiation therapy would result in a decrease in symptom burden and toxicity with similar efficacy compared with weekly cisplatin. Methods and Materials TROG12.01, a randomized, multicenter trial involving 15 sites in Australia and New Zealand enrolled patients with HPV-associated oropharyngeal squamous cell carcinoma, American Joint Committee on Cancer 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomized (1:1) to receive radiation therapy (70 Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40 mg/m2, or cetuximab, loading dose of 400 mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks postcompletion of radiation therapy using the area under the curve. Trial was registered on ClinicalTrials.gov: NCT01855451. Results Between June 17, 2013, and June 7, 2018, 189 patients were enrolled, with 92 in cisplatin arm and 90 in cetuximab included in the main analysis. There was no difference in the primary endpoint of symptom severity; difference in area under the curve cetuximab-cisplatin was 0.05 (95% confidence interval [CI], –0.19, 0.30), P = .66. The T-score (mean number of ≥grade 3 acute adverse events) was 4.35 (standard deviation 2.48) in the cisplatin arm and 3.82 (standard deviation 1.8) in the cetuximab arm, P = .108. The 3-year failure-free survival rates were 93% (95% CI, 86%-97%) in the cisplatin arm and 80% (95% CI, 70%-87%) in the cetuximab arm (hazard ratio = 3.0 [95% CI, 1.2-7.7]); P = .015. Conclusions For patients with low-risk HPV-associated oropharyngeal cancer, radiation therapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared with radiation therapy and weekly cisplatin. Radiation therapy and cisplatin remain the standard of care.

Patient understanding of medicines information and adherence to medication instructions are important variables for ensuring optimal cancer care. This randomised controlled trial (RCT) aimed to evaluate the impact of an outpatient clinical pharmacy service on medication adherence and symptom burden in cancer patients.In this single-centre RCT, 115 patients were randomised 1:1 to a pharmacist-led pharmaceutical care program (intervention, n = 59) versus standard of care (control, n = 56) within an outpatient multidisciplinary radiotherapy clinic. The primary endpoint was medication adherence as assessed by Medication Understanding and Use Self-Efficacy (MUSE) scale and Teach-Back assessment. Secondary endpoints were patient-reported symptom burden assessed by the Edmonton Symptom Assessment Scale (ESAS). Patients were assessed at baseline (weeks 1-2) and at discharge from radiotherapy (weeks 5-7).Polypharmacy (use of five or more medications) was observed in 26% of patients at baseline compared to 97% at discharge. Patient self-efficacy and medication adherence was higher in the intervention arm compared to the control arm, with a mean MUSE score difference of 2.70 (95% CI 1.24, 4.17) after adjustment for baseline, and a higher proportion of patients with average Teach-Back score of four or more (86% vs 14%; odds ratio (OR) 46.09, 95% CI 14.49, 146.56). The mean (SD) scores for aggregate ESAS (0-100) at discharge were 26.2 (14.0) in the intervention arm and 32.0 (15.8) in the control arm demonstrating lower overall symptom burden associated with the intervention (mean score difference adjusted for baseline - 0.52; 95% CI - 1.03, - 0.01).A structured outpatient clinic pharmacy service significantly improved medication adherence and reduced overall symptom burden in patients receiving radiotherapy.

Since the initial reports of activity of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), investigation of the role of immune therapies has been the major focus of clinical trials in R/M HNSCC. Randomised trials initially with nivolumab and later with pembrolizumab established overall survival benefit in patients with R/M HNSCC previously treated with platinum compared to physicians choice of 2nd line therapy, and have led to regulatory approval around the world. More recently the Keynote-048 trial has compared both pembrolizumab monotherapy and pembrolizumab + platinum/5FU to the Extreme regimen of platinum/5FU/cetuximab in the first-line R/M setting. The key findings from this trial are that pembrolizumab monotherapy compared to Extreme improved overall survival in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1, and that pembro/chemotherapy improved OS in CPS ≥ 20, CPS ≥ 1 and the total population. Relative to Extreme there was less toxicity in the monotherapy arm and comparable toxicity in the pembro/chemo arm. Based on this trial use of pembrolizumab as part of first-line treatment for R/M HNSCC is appropriate for the majority of patients, and represents a new standard of care. The focus has now moved to identifying combinations that may be superior to pembrolizumab monotherapy or to chemotherapy + pembrolizumab. Some of the more promising approaches under investigation in HNSCC are discussed in this chapter. In summary, immune therapies are now the cornerstone of management of R/M HNSCC with the approval of pembrolizumab in the first-line R/M setting.

Highlights • Unilateral radiotherapy is utilised in T1-2, N0-N1 lateralised tonsillar tumours. • The role of unilateral radiotherapy in more advanced nodal disease is less clear. • Higher symptom burden and lower QoL was reported by patients treated with bilateral radiotherapy. • In the IMRT era, bilateral treatment for tonsillar cancer may have an enduring impact on the patient. • Prospective evaluation of unilateral radiotherapy with lateralised tumours and N2-3 is needed., Purpose The purpose of this study was to compare self-reported health-related quality of life (QoL) and symptom burden in early stage tonsillar carcinoma patients treated with unilateral (URT) and bilateral radiotherapy (BRT). Methods and materials This is a secondary analysis of a larger study assessing patient reported outcomes in human papillomavirus (HPV) oropharyngeal cancer (OPC) patients. Recruited patients were ≥12 months from completion of radiotherapy. This analysis included only patients with T1-2, N1-2b tonsil cancer and excluded patients with base of tongue involvement or recurrent disease. QoL and patient reported toxicity was measured using the EORTC QLQ-C30 module and the MDASI-HN. Results Patients were enrolled from November 2018 to May 2019. Of the 136 patients recruited to the main study, 43 were eligible for this substudy (22 URT, 21 BRT), with a median age and follow up of 58.2 and 3.0 years respectively. The two groups were balanced with respect to patient, tumor and treatment factors with the exception of higher rates of T2 disease (27% v 71%, p = 0.006) and more extensive GTV nodal volumes (11.0 v 25.5cc, p = 0.006) in the BRT group. BRT patients had lower global health status/QoL (84 v 69, p = 0.0005) and social functioning scores (93 vs 78, p = 0.033) on the EORTC QLQ-C30, and higher symptom severity (0.6 vs. 2.0, p = 0.001) and symptom interference scores (0.8 vs. 2.0, p = 0.010) on the MDASI-HN. Four of the six largest differences observed on MDASI-HN items were attributable to radiotherapy technique (dry mouth, mucous, difficulty swallowing/chewing and taste), with corresponding dose differences to the respective organs (contralateral parotid, oral cavity and pharyngeal constrictors). In every instance, severity of symptoms was worse on average for patients treated with BRT. Conclusions In the highly conformal radiotherapy era, BRT in early HPV tonsillar cancer survivors has an enduring impact on long-term QoL and toxicity.

Immune checkpoint inhibitors have changed the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, only a minority of patients respond, hence the search for predictive biomarkers. Potential predictive biomarkers for immune checkpoint inhibitors discussed in this chapter include (1) Immune checkpoint ligand expression e.g., PD-L1, (2) biomarkers of a T-cell inflamed tumour microenvironment (TME) such as gene expression profiles of activated T cells, (3) biomarkers of tumour neoepitope burden such as tumour mutation burden (TMB) and (4) multidimensional quantitative techniques. At present only PD-L1 expression has been shown to have clinical utility in head and neck cancer. It enriches for populations more likely to respond, but the false positive predictive value remains high. In the pivotal Keynote−048 trial that established a role for pembrolizumab (anti-PD1) monotherapy and pembrolizumab + chemotherapy as treatment options in first-line R/M HNSCC, primary endpoints included overall survival in defined subgroups based on PD-L1 expression. In this trial the combined positive score (CPS) was used which takes into account PD-L1 expression in tumour and immune cells. Based on this trial regulatory approvals for first-line pembrolizumab in R/M HNSCC require assessment of PD-L1 expression using the CPS. Finally we discuss emerging evidence that locoregionally advanced HPV-associated oropharyngeal cancers that have high expression of CD103 positive CD8 T cells have an excellent prognosis and features that suggest increased probability of responding to anti-PD1/PD-L1, raising the possibility of incorporating these immune therapies as part of a de-escalation trial strategy.

TPS9592 Background: CSCC is the second most common skin cancer with an estimated incidence of 1 million cases per year in the US. While the surgical cure rate for CSCC is > 95%, some pts have high risk of recurrence as assessed by immune status, primary disease stage, extent of nodal involvement, presence of extracapsular extension (ECE), and prior treatment. Postoperative RT is recommended for these pts but relapse with locoregional recurrence or distant metastases may still occur. C-POST is evaluating the efficacy of cemiplimab as adjuvant therapy for pts with high-risk CSCC. Here, we provide summary of the most recent study protocol amendment. Methods: C-POST is a randomized, placebo-controlled, double-blind, multicenter Phase 3 study to evaluate cemiplimab as adjuvant treatment for pts with high-risk CSCC, based on surgical and clinicopathologic findings, who completed surgery and postoperative RT (minimum total dose 50Gy, within 10 weeks before randomization) (NCT03969004). Pts with at least one of the following high-risk features are eligible: (1) nodal disease with (a) ECE and at least one node ≥20 mm or (b) at least three lymph nodes positive on surgical pathology report, regardless of ECE; (2) in-transit metastases; (3) T4 lesion; (4) perineural invasion; and (5) recurrent CSCC with at least one other risk factor. Pts with CSCC involvement in at least three lymph nodes (feature 1b) were added to the eligibility criteria, as this group was found to be at similar risk of CSCC recurrence as the initially planned study population. Protocol amendment now allows patients with chronic lymphocytic leukemia (CLL) who are not on active treatment to be enrolled. The study has two parts. In Part 1 (blinded), pts are randomly assigned 1:1 to receive cemiplimab 350 mg or placebo intravenously every 3 weeks for 12 weeks, followed by cemiplimab 700 mg or placebo every 6 weeks for 36 weeks. In optional Part 2 (unblinded), pts in the placebo arm who experience disease recurrence and pts in the cemiplimab arm who experience disease recurrence ≥3 months after completion of 48-week treatment in Part 1 are eligible to receive open-label cemiplimab for up to 96 weeks. The trial is expected to enrol 412 pts from about 100 sites in North and South America, Europe, and Asia-Pacific regions. Key primary objective is to compare disease-free survival; secondary objectives include evaluating overall survival, freedom from locoregional relapse, and distant relapse with adjuvant cemiplimab versus placebo in patients with high-risk CSCC. This study is once again open for enrolment following interruptions owing to the COVID-19 pandemic. Clinical trial information: NCT03969004.

BACKGROUND: The objective was to determine the incidence of, and factors associated with contralateral neck failure (CNF) in oral tongue squamous cell carcinoma (OTSCC). METHODS: Consecutive patients with OTSCC between 2007 and 2016 were included. The predefined policy of the contralateral neck included neck dissection (ND) where the primary tumor extended/crossed midline or the contralateral neck was involved; and elective nodal irradiation (ENI) where the primary tumor was ≤1 cm from midline/2 cm from tip. RESULTS: This study included 258 patients. ND was ipsilateral 169 (66%) and bilateral 33 (13%). Fifty-five patients (21%) received ENI to the undissected contralateral neck. CNF occurred in 19 patients (7%) and was similar by treatment received. Utilizing this approach, we observed higher rates of CNF with increasing N classification, perineural invasion, extracapsular extension, and depth of invasion ≥6 mm. CONCLUSIONS: Using our institutional policy of treatment to the contralateral neck, a low rate of CNF (≤10%) was observed.