Longitudinal post-radiotherapy plasma Epstein-Barr virus DNA trends inform on optimal risk stratification in endemic nasopharyngeal carcinoma.

OBJECTIVES: To characterize longitudinal changes in Epstein-Barr virus (EBV) DNA post-radiotherapy in nasopharyngeal carcinoma (NPC) patients, and investigate whether an early (0-2 weeks) or delayed (8-12 weeks) EBV DNA result better predicts for disease-free survival (DFS). MATERIALS AND METHODS: Histologically-confirmed NPC patients with ≥1 EBV DNA test quantified using the harmonized BamHI-W polymerase chain reaction-based assay at 0-2 and 8-12 weeks post-radiotherapy were included. RESULTS: We identified 302 patients with EBV DNA measured at 0-2 weeks post-radiotherapy; of which, 110 (36.4 %) underwent a repeat test at 8-12 weeks post-treatment. Patients harboring a detectable EBV DNA at 0-2 weeks experienced an inferior DFS (adjusted HR1-264 copies 1.72 [95 %CI: 1.05-2.83], P = 0.031; AHR≥265 copies 4.39 [95 %CI: 1.68-11.44], P = 0.002 relative to 0 copies/mL). At 8-12 weeks, we observed substantial shifts in EBV DNA readings from 0 to 2 weeks; 76/110 (69.1 %) and 34/110 (30.9 %) patients at 0-2 weeks versus 90/110 (81.8 %) and 20/110 (18.2 %) at 8-12 weeks recorded undetectable and detectable EBV DNA, respectively. Positive EBV DNA at 8-12 weeks was strongly associated with relapse (73.3 % [11/15] for 1-264; 80.0 % [4/5] for ≥265 subgroups had relapses versus 15.6 % [14/90] for 0 copies/mL). Area under receiver operating curve values for 2-year relapse rates were 0.817 (95 %CI: 0.725-0.909) for stage + EBV DNA8-12w versus 0.654 (95 %CI: 0.542-0.765) for stage + EBV DNA0-2w. CONCLUSION: EBV DNA is dynamic post-radiotherapy, and delayed EBV DNA testing better enriched for higher-risk NPC patients. This implicates trials investigating adjuvant chemotherapy intensification based on early EBV DNA testing.

A Systematic Review and Meta-Analysis of Mapping Biopsy for Primary Extramammary Paget's Disease in Reducing Recurrence Following Surgical Excision.

Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD). Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence. Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported. Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results. Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.

Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma.

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC.

Real world efficacy of osimertinib in second line/beyond in patients with metastatic EGFR+ non-small cell lung cancer and role of paired tumour-plasma T790M testing at tyrosine kinase inhibitor resistance.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the second/subsequent line after resistance to first- and second-generation (1/2G) EGFR-TKI. Methods: We reviewed electronic records of 202 patients who received osimertinib from July 2015 to January 2019 in the second/subsequent line after progression on prior EGFR-TKI. Of these, complete data from 193 patients were available. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use, and survival outcomes were extracted, and results retrospectively analyzed. Results: Of 193 evaluable patients, 151 (78.2%) were T790M+ (T790M positive) with 96 (49.2%) tissue confirmed; 52% of patients received osimertinib in the second line setting. After median follow up of 37 months, median progression-free survival (PFS) of the entire cohort was 10.3 [95% confidence interval (CI): 8.64-11.50] months and median overall survival (OS) was 20 (95% CI: 15.61-23.13) months. Overall response rate (ORR) to osimertinib was 43% (95% CI: 35.9-50.3%); 48.3% in T790M+ vs. 20% in T790M- (T790M negative) patients. OS in T790M+ patients was 22.6 vs. 7.9 months in T790M- patients (HR 0.43, P=0.001), and PFS was 11.2 vs. 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients, however this association was not seen with plasma T790M+. Of the 22 patients with paired tumor/plasma T790M testing, response rate (RR) to osimertinib was 30% for those plasma T790M+/tumour T790M-, compared to 63% and 67% for those who were plasma T790M+/tumour T790M+ and plasma T790M-/tumour T790M+, respectively. By multivariable analysis (MVA), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was associated with shorter OS (HR 2.53, P<0.001) and PFS (HR 2.10, P<0.001), whereas presence of T790M+ was associated with longer OS (HR 0.50, P=0.008) and PFS (HR 0.57, P=0.027). Conclusions: This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity and the advantage with paired tumor-plasma T790M testing at TKI resistance. T790M- disease at resistance remains an unmet treatment need.

Effects of induction chemotherapy on nutrition status in locally advanced nasopharyngeal carcinoma: a multicentre prospective study.

BACKGROUND: Induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) is the standard of care for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This intensive treatment regimen increases acute toxicities, which could negatively impact patients' nutritional status. We conducted this prospective, multicentre trial to investigate the effects of IC and CCRT on nutritional status in LA-NPC patients, so as to provide evidence for further study of nutritional intervention, which was registered in ClinicalTrials.gov (NCT02575547). METHODS: Patients with biopsy-proven NPC and planned for IC + CCRT were recruited. IC entailed two cycles of 3-weekly docetaxel 75 mg/m2 and cisplatin 75 mg/m2 ; CCRT entailed two to three cycles of 3-weekly cisplatin 100 mg/m2 depending on the duration of radiotherapy. Nutritional status and quality of life (QoL) were assessed pre-IC, post-cycles one and two of IC, W4 and W7 of CCRT. Primary endpoint was the cumulative proportion of ≥ 5.0% weight loss (WL5.0 ) by the end of treatment (W7-CCRT). Secondary endpoints included body mass index, NRS2002 and PG-SGA scores, QoL, hypoalbuminaemia, treatment compliance, acute and late toxicities and survivals. The associations between primary and secondary endpoints were also evaluated. RESULTS: One hundred and seventy-one patients were enrolled. Median follow-up was 67.4 (IQR: 64.1-71.2) months. 97.7% (167/171) patients completed two cycles of IC, and 87.7% (150/171) completed at least two cycles of concurrent chemotherapy; all, except one patient (0.6%), completed IMRT. WL was minimal during IC (median of 0.0%), but increased sharply at W4-CCRT (median of 4.0% [IQR: 0.0-7.0%]) and peaked at W7-CCRT (median of 8.5% [IQR: 4.1-11.7%]). 71.9% (123/171) of patients recorded a WL5.0 by W7-CCRT, which was associated with a higher malnutrition risk (NRS2002 ≥ 3 points: 87.7% [WL ≥ 5.0%] vs 58.7% [WL < 5.0%], P < 0.001) and requirement of nutritional intervention (PG-SGA ≥ 9 points: 82.0% [WL ≥ 5.0%] vs 66.7% [WL < 5.0%], P = 0.038). The median %WL at W7-CCRT was higher in patients who suffered from ≥ G2 mucositis (9.0% vs 6.6%, P = 0.025) and xerostomia (9.1% vs 6.3%, P = 0.003). Besides, patients with cumulative WL5.0 also reported a higher detriment on QoL at W7-CCRT compared with patients without, with a difference of -8.3 points (95% CI [-15.1, -1.4], P = 0.019). CONCLUSIONS: We observed a high prevalence of WL among LA-NPC patients who were treated with IC + CCRT, which peaked during CCRT, and had a detriment on patients' QoL. Our data support the need to monitor patient's nutritional status during the later phase of treatment with IC + CCRT and inform on nutritional intervention strategies.

PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer.

AIM: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. METHODS: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method. RESULTS: 455 patients were included (267 EGFR-mutated, EGFR-M+; 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047). At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04-4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72-35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44-13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis. In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. CONCLUSION: PD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.

Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter?

INTRODUCTION: Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. METHODS: Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). RESULTS: Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p = .28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p = .49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p = .66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p = .37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p = .097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p = .32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p = .20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p = .118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). CONCLUSION: Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option.

Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure.

Introduction: To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations. Methods: Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS. Clearance of pEGFR was defined as undetectable levels after a positive baseline result. Results were correlated with time-to-treatment failure (TTF). In exploratory analysis, corresponding change in carcinoembryonic antigen (CEA) levels was evaluated. Results: Between January 1, 2020, and December 31, 2021, 27 patients were recruited. Ex19del comprised 74% (20 of 27) and L858R 26% (seven of 27). Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Sensitivity of ddPCR and NGS in detecting pEGFR mutation at baseline was 70% (19 of 27) and 78% (21 of 27), respectively (p = 0.16). All patients with detectable pEGFR by ddPCR were detected by NGS.At a median of 8 (range 3-24) weeks post-TKI initiation, clearance of pEGFR was achieved in 68% (13 of 19) and 71% (15 of 21) using ddPCR and NGS, respectively. Concordance between ddPCR and NGS was 79% (kappa = 0.513, p = 0.013). Clearance of pEGFR was associated with longer median TTF (not reached versus 6 months, p = 0.03) and median decrease in CEA levels by 70% from baseline.In another cohort of 124 patients, decrease in CEA levels by greater than 70% within 90 days of TKI initiation was associated with doubling of both TTF and overall survival. Conclusions: Plasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.

Adjuvant Capecitabine Following Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Induction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen. Objective: To investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC. Design, Setting, and Participants: This open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm. Interventions: Patients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy). Main Outcomes and Measures: Failure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test. Results: There were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients). Conclusions and Relevance: In this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02143388.

A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma.

Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×1011 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis.

Impact of Immune-Related Adverse Events on Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma.

INTRODUCTION: Development of immune-related adverse events (irAEs) has been associated with enhanced efficacy with the use of immune checkpoint inhibitors (ICIs). It remains unknown whether such an association exists in advanced hepatocellular carcinoma (aHCC). This study aims to evaluate the association between irAEs and ICI efficacy in patients with aHCC. METHODS: We performed a retrospective cohort study on patients with aHCC who received at least one dose of an ICI between May 2015 and November 2019 at the National Cancer Centre Singapore. The primary study objectives were to compare the overall survival (OS) and progression-free survival (PFS) between patients with and without irAEs. Complementary multivariable landmark analyses were performed at the 6-week and 12-week landmarks. Data cutoff was December 31, 2020. RESULTS: One hundred and sixty-eight patients were included. Median age was 69 years, 85.7% were male, 57.7% had hepatitis B infection, 60.7% had ECOG 0, and 78.0% had Child-Pugh A liver cirrhosis. 82.7% received ICI monotherapy, while 17.3% received ICI in combination. Development and severity of irAE were correlated with survival. The median PFS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 8.5 versus 3.6 versus 1.3 mths (p < 0.001). The median OS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 26.9 versus 14.0 versus 4.6 mths (p < 0.001). Patients with ≥2 irAEs had a significantly longer OS on multivariable analysis (adjusted hazard ratio [aHR]0.35, p < 0.001). The presence of grade ≥3 irAEs was associated with a significantly longer OS on the multivariable analysis at the 6-week landmark (aHR0.34, p = 0.030) and 12-week landmark (aHR0.28, p = 0.011). The use of systemic corticosteroids in patients with irAE was associated with a trend toward a longer OS (20.7 vs. 14.3 mths, p = 0.064). CONCLUSION: Our study suggests that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI. Patients with more severe irAEs and multisystem involvement have better prognosis. The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.

Impact of cancer diagnoses on the outcomes of patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: The COVID-19 has caused significant mortality and morbidity across the globe. Patients with cancer are especially vulnerable given their immunocompromised state. We aimed to determine the proportion of COVID-19 patients with cancer, their severity and mortality outcomes through a systematic review and meta-analysis (MA). METHODS: Systematic review was performed through online databases, PubMed, Medline and Google Scholar, with keywords listed in the Methods section (1 November 2019-31 December 2020). Studies with clinical outcomes of at least 10 COVID-19 patients and at least one with a diagnosis of cancer were included. The studies for MA were assessed with PRISMA guidelines and appraised with Newcastle-Ottawa Scale. The data were pooled using a random-effects model using STATA software. The main outcomes were planned before data collection, including proportion of patients with cancer among COVID-19 populations, relative risk (RR) of severe outcomes and death of patients with cancer compared with general COVID-19 patients. RESULTS: We identified 57 case series (63 413 patients), with 230 patients with cancer with individual patient data (IPD). We found that the pooled proportion of cancer among COVID-19 patients was 0.04 (95% CI 0.03 to 0.05, I2=97.69%, p<0.001). The pooled RR of death was 1.44 (95% CI 1.19 to 1.76) between patients with cancer and the general population with COVID-19 infection. The pooled RR of severe outcome was 1.49 (95% CI 1.18 to 1.87) between cancer and general COVID-19 patients. The presence of lung cancer and stage IV cancer did not result in significantly increased RR of severe outcome. Among the available IPD, only age and gender were associated with severe outcomes. CONCLUSION: Patients with cancer were at a higher risk of severe and death outcomes from COVID-19 infection as compared with general COVID-19 populations. Limitations of this study include publication bias. A collaborative effort is required for a more complete database.

Efficacy of targeted therapies for oncogene-driven lung cancer in early single-arm versus late phase randomized clinical trials: A comparative analysis.

There is an expanding number of approved targeted therapies for oncogene-driven lung cancer and many emerging therapies with promising efficacy data. Regulatory approvals are increasingly based on early phase trials (often single-arm phase II trials), in which the primary endpoint is objective response rate (ORR) or progression-free survival (PFS). Efficacy outcomes from early phase trials may not always correlate with those observed in later-phase randomized trials. In the precision oncology era with effective targeted therapies however, there are arguments for greater confidence in the efficacy outcomes from non-randomized single-arm trials. Nevertheless, there remain numerous challenges in understanding and interpreting efficacy outcomes for novel targeted therapies in trials that may have dose finding and safety as the primary objective and lack a standard-of-care control arm. Therefore, we sought to review the efficacy outcomes in early versus late phase clinical trials for approved targeted therapies in lung cancer - to better understand the interpretation of preliminary measures of clinical benefit. Nine pairs of early and late phase trials were identified, according to line of therapy for six targeted therapies in lung cancer (afatinib, ceritinib, crizotinib, dacomitinib, lorlatinib and osimertinib). Key efficacy outcomes, including ORR, PFS and overall survival (OS) were compared. Importantly, we found that in oncogene-driven lung cancer, early phase trial outcomes have historically been consistent with subsequent late phase trials. This suggests efficacy outcomes from early phase trials of targeted therapies in lung cancer may translate reliably to larger randomized trials. This has many potential implications for drug development in lung cancer, with regards to regulatory approvals and the design and conduct of clinical trials.

Clinical Characteristics and Outcomes in Advanced KRAS-Mutated NSCLC: A Multicenter Collaboration in Asia (ATORG-005).

INTRODUCTION: Whereas interpatient heterogeneity in clinical characteristics and treatment outcomes of NSCLC harboring a KRAS mutation is recognized, the characterization of these patients in Asia has been limited. METHODS: A multicenter, retrospective cohort study was conducted in eight academic centers across Asia. Patients diagnosed with advanced NSCLC harboring a KRAS mutation and who had received at least one line of anticancer therapy between January 2014 and December 2018 were included. Modified time to next treatment (TTNT) was adopted as a proxy for progression-free survival. RESULTS: A total of 216 patients were analyzed. The median age at diagnosis of advanced NSCLC was 63.3 years, 70.8% were men and 89.8% had adenocarcinoma. KRAS G12D was the most common subtype (25.5%), followed by G12C (24.5%), and G12V (19.4%) The proportion of current or former smokers was 65.7% in the overall population, with 86.8% in G12C and 58.9% in non-G12C subgroups. For all treatments combined for the total population, the first-line duration of therapy, modified TTNT, and TTNT were 4.5 (95% confidence interval: 3.4-5.9), 6.2 (4.9-8.8), and 9.5 (7.1-11.4) months, respectively. The median overall survival for the total population was 10.3 (6.9-12.4) months and was prolonged in patients ever treated with immunotherapy (14.6 [8.6-19.1] versus 7.0 [5.9-10.6] mo, hazard ratio = 0.54, p < 0.001), with left truncation to account for the time of KRAS testing. CONCLUSIONS: Whereas treatment outcomes with conventional anticancer therapy are reasonable and immunotherapy looks promising, the unmet need remains high for patients with KRAS-mutated NSCLC in Asia, underscoring the need for novel therapeutic approaches.

Prognostication of diffuse large B-cell lymphoma patients with Deauville score of 3 or 4 at end-of-treatment PET evaluation: a comparison of the Deauville 5-point scale and the ΔSUVmax method.

Diffuse large B-cell lymphoma is treated with anti-CD 20 and multi-drug chemotherapy for cure. Positron emission tomography (PET) scans are performed at end of treatment (EOT) to assess response. EOT Deauville scores (DS) are equivocal for treatment response in some situations, requiring physicians to determine the need for further investigations or treatment. Studies have suggested the delta maximum standardised uptake value (ΔSUVmax) to be superior to DS for assessment of metabolic response at interim PET, although its use at EOT PET, especially in cases of equivocal response, has yet to be established. We investigated whether ΔSUVmax could better discriminate prognosis than DS 3 or 4 at EOT. ΔSUVmax did not outperform DS. Combination of DS 3 and International Prognostic Index (IPI) <3 selects for patients with extremely low risk of disease progression (HR 0.06, 95% CI 0.01 to 0.62, p 0.018) compared to DS 4 and IPI ≥3.

Development of a risk classification system combining TN-categories and circulating EBV DNA for non-metastatic NPC in 10,149 endemic cases.

BACKGROUND: The objective of this study was to construct a risk classification system integrating cell-free Epstein-Barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC). METHODS: Clinical records of 10,149 biopsy-proven, non-metastatic NPC were identified from two cancer centers; this comprised a training (N = 9,259) and two validation cohorts (N = 890; including one randomized controlled phase 3 trial cohort). Adjusted hazard ratio (AHR) method using a two-tiered stratification by cfEBV DNA and TN-categories was applied to generate the risk model. Primary clinical endpoint was overall survival (OS). Performances of the models were compared against American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 8th edition TNM-stage classification and two published recursive partitioning analysis (RPA) models, and were validated in the validation cohorts. RESULTS: We chose a cfEBV DNA cutoff of ⩾2,000 copies for optimal risk discretization of OS, disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the training cohort. AHR modeling method divided NPC into six risk groups with significantly disparate survival (p < 0.001 for all): AHR1, T1N0; AHR2A, T1N1/T2-3N0 cfEBV DNA < 2,000 (EBVlow); AHR2B, T1N1/T2-3N0 cfEBV DNA ⩾ 2,000 (EBVhigh) and T1-2N2/T2-3N1 EBVlow; AHR3, T1-2N2/T2-3N1 EBVhigh and T3N2/T4N0 EBVlow; AHR4, T3N2/T4 N0-1 EBVhigh and T1-3N3/T4N1-3 EBVlow; AHR5, T1-3N3/T4 N2-3 EBVhigh. Our AHR model outperformed the published RPA models and TNM stage with better hazard consistency (1.35 versus 3.98-12.67), hazard discrimination (5.29 versus 6.69-13.35), explained variation (0.248 versus 0.164-0.225), balance (0.385 versus 0.438-0.749) and C-index (0.707 versus 0.662-0.700). In addition, our AHR model was superior to the TNM stage for risk stratification of OS in two validation cohorts (p < 0.001 for both). CONCLUSION: Herein, we developed and validated a risk classification system that combines the AJCC/UICC 8th edition TN-stage classification and cfEBV DNA for non-metastatic NPC. Our new clinicomolecular model provides improved OS prediction over the current staging system.

Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Importance: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined. Objective: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence. Design, Setting, and Participants: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021. Exposures: Adjuvant treatment was administered per investigator's discretion. Main Outcomes and Measures: The main outcome was 2-year disease-free survival (DFS). Results: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification. Conclusions and Relevance: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.

Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial.

BACKGROUND: Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. METHODS: Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed. FINDINGS: 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). INTERPRETATION: Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. FUNDING: National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.

Chemoradiation-induced changes in systemic inflammatory markers and their prognostic significance in oesophageal squamous cell carcinoma.

OBJECTIVE: Chemoradiation (CRT) may induce a change in systemic inflammatory state which could affect clinical outcomes in oesophageal cancer. We aimed to evaluate the changes and prognostic significance of systemic inflammatory markers following definitive CRT in oesophageal squamous cell carcinoma. METHODS: A total of 53 patients treated with concurrent CRT were included in this retrospective analysis. We compared neutrophils, lymphocytes, platelets, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) before and after CRT using Wilcoxon signed-rank test. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariable and multivariable survival analysis were performed using Cox regression analysis. Clinical univariable survival prognostic factors with p < 0.1 were included in a multivariable cox regression analysis for backward stepwise model selection. RESULTS: Both NLR (median ∆+2.8 [IQR -0.11, 8.62], p < 001) and PLR (median ∆+227 [81.3-523.5], p < 0.001) increased significantly after CRT. Higher levels of pre-CRT, post-CRT and change (∆) in NLR and PLR were associated with inferior OS and PFS. Post-CRT NLR (HR 1.04, 95% CI 1.02-1.07, p < 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01-1.05, p = 0.005), cT-stage (HR 3.83, 95% CI 1.39-10.60, p = 0.01) and RT dose (HR 0.41, 95% CI 0.21-0.81, p = 0.01) were independent prognostic factors for OS in multivariable analysis. Change in NLR (HR 1.04, 95% CI 1.01-1.06, p = 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01-1.05, p = 0.002), cT-stage (HR 3.98, 95% CI 1.55-10.25, p = 0.004) and RT dose (HR 0.41, 95% CI 0.21-0.80, p = 0.009) were independent prognostic factors for PFS. CONCLUSION: Both NLR and PLR increased following definitive CRT. Post-CRT NLR and ∆NLR were associated with adverse survival in oesophageal SCC. ADVANCES IN KNOWLEDGE: We showed that CRT increased PLR and NLR, possibly reflecting a systemic inflammatory state which were associated with poor clinical outcomes in oesophageal SCC.