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Background Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Methods We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Findings Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p Interpretation A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. Funding National Institute for Health and Care Research.

Background Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. Methods For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Findings Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00–5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5–78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7–80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89–1·25, p=0·54). The most common grade 3–4 adverse events were hand–foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. Interpretation The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used.

Summary Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. Funding Cancer Research UK.

Purpose Laboratory and case-control studies suggest a pivotal role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis. The purpose of this study was to test whether the COX-2 inhibitor rofecoxib could reduce recurrence and improve survival when administered in the adjuvant setting of colorectal cancer (CRC). Patients and Methods Patients who had undergone potentially curative surgery and completion of adjuvant therapy for stage II and III CRC were randomly assigned to receive rofecoxib (20 mg daily) or placebo. The primary end point was overall survival (OS). Where formalin-fixed paraffin-embedded tumor tissue samples were available, COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome. Results Two thousand four hundred thirty-four patients were entered onto the study. The trial was terminated early because of the worldwide withdrawal of rofecoxib. At this point, 1,167 patients had received rofecoxib and 1,160 patients had received placebo for median treatment durations of 7.4 and 8.2 months, respectively. For the rofecoxib and placebo arms, median follow-up times were 4.84 and 4.85 years, with 241 and 246 deaths and 297 and 329 recurrences, respectively. No difference was demonstrated in OS (hazard ratio [HR] = 0.97; 95% CI, 0.81 to 1.16; P = .75) or recurrence (HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) comparing the two groups. Tumor COX-2 expression by immunohistochemistry was assessed for 871 patients, but neither prognostic nor predictive effects were observed. Conclusion In this study of abbreviated therapy in the adjuvant setting of CRC, rofecoxib did not improve OS or protect from recurrence in unselected patients. In addition, COX-2 expression did not correlate with prognosis overall or predict effectiveness of COX-2 inhibitors.

Background Bevacizumab is an anti-VEGF antibody approved for use in metastatic colorectal cancer (CRC). However 2 trials have suggested lack of efficacy in combination with dual agent chemotherapy in the adjuvant setting and there has been some indication that the spectrum of toxicity may be different compared to that observed in patients with advanced disease. Methods The international phase III trial, QUASAR2, randomised stage III and high risk stage II CRC patients who had undergone potentially curative resection to receive oral Cape (1250mg/m2 bd, days 1-14 q 21d) alone for 6/12 or Cape (6/12) plus intravenous Bev(7.5mg/kg q 21d) for 12/12. This abstract overviews the final toxicity data (15/12 minimum follow up per patient) from the Q2 trial. Results 1952 patients were consented and randomised and, after excluding patients who did not receive at least one cycle of treatment, 963 patients receiving Cape alone and 959 patients receiving Cape plus Bev were analysed. Baseline characteristics (gender / age / stage of disease) were balanced across the 2 arms. See frequency of selected toxicities, as % patients, in table below. Discussion As expected, the rates of hypertension (all grade or high grade) and proteinuria and wound healing (all grade) were significantly higher among patients receiving Bev. Although the addition of Bev did not increase diarrhoea rates, the frequency and severity of HFS was increased. This is not well recognised. Although cardiac chest pain was not increased by the addition of Bev, both arterial and venous thrombo-embolism (ATE/VTE) rates were increased although the difference only reached significance for VTE in this study. This is in contrast to most results in the advanced disease setting and may be a result of an interaction between post-operative risk of VTE and pro-thrombotic potential of Bev. Of note, an excess of ‘possibly treatment-related’ deaths was found in patients receiving Bev (1.9% vs 0.8%:RR2.3:CI 1.0-5.2) and this just reached significance (p = 0.05). All results will be expanded in detail in the presentation / poster. Cape/ Bev Cape RR/CI/p Hypertension (all grades) 33.4 7.8 4.3/3.4-5.4/p Hypertension (g3/4) 3.8 0.6 6.0/2.6-14.2/p Proteinuria (all grades) 20.5 5.1 4.0/3.0-5.4/p Poor wound healing (all grades) 3.1 1.8 1.8/1.0-3.2/p = 0.05 Diarrhoea (g3/4) 10.8 10.6 1.0/0.8-1.3/p = 0.9 Hand-foot syndrome (g3/4) 26.8 20.9 1.3/1.1-1.5/p = 0.002 Cardiac chest pain SAE 2.7 2.6 1.0/0.6-1.8/p = 0.9 Arterial Thromboembolism SAE 1.1 0.6 1.8/0.7-5.0/p = 0.2 Venous Thromboembolism SAE 4.3 2.3 1.9/1.1-3.1/p = 0.01 Disclosure R.S. Midgley: Auther has received no strings attached educational unrestricted grant for clinical research and has sat on advisory boards for Roche. V. Potter: Auther has received a travel grant and has sat on an advisory board for ROche. E. Segelov: Author has sat on an advisory board for Roche Autralia. D.R. Ferry: Auther has received travel grants, research grants and has sat on advisory boards for Roche. S. Grumett: Auther has received traval grants and has sat on advisory boards for Roche. D.J. Kerr: Auther has received no strings attached educational unrestricted grant for clinical research and has sat on Advisory Boards for ROche. All other authors have declared no conflicts of interest.

Aim: The aims of Q2 were to assess whether the addition of BEV 7.5mg/kg q3/52 (12/12) to single agent CAP 1250mg/m2, 14 of every 21/7 (6/12), increases disease-free (DFS) and overall survival (OS) in CRC patients after resection of the primary; and to validate suggested, or discover new, biomarkers of BEV efficacy and toxicity. Methods: A phase III international randomised controlled trial, coordinated by the UK and recruiting in 6 countries. In addition to the collection of data on toxicity, DFS and OS, a biobank comprising 1350 FFPE blocks and 1000 germline DNA samples was established. Hypothesis-driven biomarkers (MSI status and epithelial/stromal ratio) and hypothesis-driven biomarkers (chomosomal instabiity, ras, raf, POLE and an 80-gene ion torrent panel) were analysed to assess their prognostic and predictive (BEV) utility. Results: 1941 patients were randomised in a 1:1 ratio and demographics and disease characteristics were well balanced between the two arms. DFS in the whole trial population demonstrates that BEV does not improve outcome in this setting (3 year DFS 75.2% for CAPBEV vs 78.2% for CAP: HR = 1.06; p = 0.54). Similarly OS was not improved (3 year OS 85.5% for CAPBEV vs 87.2% for CAP; p = 0.38; HR = 1.12). There may be a temporal trend in HRs (HRs: 1 year 0.83[0.61-1.13], 2 year 0.87[0.65-1.17], 3 year 1.32 [0.9-1.98]. Biomarker analyses confirm that high tumour stromal content confers a worse prognosis (3 year DFS HR 1.58 [1.22-2.05]; p = 0.001). MSS positivity was associated with a worse DFS in patients treated with CAP/BEV compared to those treated with CAP alone (n = 840; HR 1.43; p = 0.005) suggesting a negative predictive effect for BEV: For MSI positive patients, there was no significant difference in DFS between the two arms (n = 135; HR 0.74; p = 0.42). Conclusions: Q2 supports data from two other trials suggesting no role for BEV in the adjuvant setting of CRC. The Q2 biobank and linked database allows further collaborative biomarker hypotheses to be tested. There is a rationale for meta-analysis of all BEV adjuvant CRC studies to more fully explore the putative temporal effect of BEV administration on DFS. Disclosure: R.S. Midgley and D.J. Kerr: has received research funding in the form of an unrestricted educational grant from Roche. All other authors have declared no conflicts of interest.

6 Background: There are no randomised trials of 2nd line chemotherapy for esophageal cancer. The phase III COG trial of gefitinib versus placebo in patients with esophageal cancer progressing after chemotherapy did not show significant overall survival (OS) benefit, however the trial incorporated patient reported outcomes (PRO) using validated tools. The PRO data are therefore critical to inform practice and the initial results are presented here. Methods: Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: OS. Secondary outcomes include safety, PFS, PRO (assessed by EORTC QLQ-C30 and EORTC QLQ-OG25 at baseline 4, 8 and 12 weeks until progression) and predictive biomarkers. Pre-specified PRO domains were global quality of life, dysphagia, eating and odynophagia. Analysis by ANCOVA of change in PRO at 4 weeks adjusted for baseline. Results: 450 patients were recruited from 51 UK centres and no difference in OS was detected. There was evidence that PFS was better in the intervention arm (P 35 days, G 49 days; HR=0.795, 95%CI 0.66, 0.96, p=0.017). Questionnaire compliance rates were excellent at baseline (94%) and at 4 weeks (77%). Patients in the gefitinib arm reported significantly better social function (9.26; 95%CI 1.94 to 16.58; p=0.013) and significantly fewer problems with odynophagia (-8.61; 95%CI -14.49 to -2.73; p=0.004), constipation (-15.24; 95%CI -22.83 to -7.65; p=0.0001) and speech (-10.40; 95%CI -16.13 to -4.67; p=0.0004) than patients receiving placebo but more problems with diarrhoea (19.23; 95%CI 11.79 to 26.27; p

Background There is no standard systemic therapy for metastatic esophageal cancer progressing after 1st/2nd line chemotherapy (Thallinger et al, 2011, JCO, 4709-14). High EGFR expression is associated with poor prognosis in esophageal cancer. A phase II trial of the EGFR kinase inhibitor gefitinib showed good tolerance with 11% partial responses and a trend towards improved survival (Ferry et al. Clin Cancer Res 2007, 13: 5869-75). Four other phase II trials showed objective responses with gefitinib or erlotinib. Cancer Research UK funded this pivotal phase III trial with free study drug provided by Astra Zeneca UK. Methods Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status (PS) 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: overall survival (OS) - an increase from 10-18% in 1yr OS is detectable with 450 patients, power 82.5%, significance level 5%, analysed with Kaplan-Meier and log-rank test. Secondary outcomes include safety, PFS, HRQL (EORTC QLQ-C30 and QLQ-OG25) and predictive biomarkers. Results Recruitment of 450 patients from 51 UK centres occurred Mar 2009-Nov 2011. Baseline characteristics were well-balanced - median age 64 years; 83% male; 76% adenocarcinoma; 78% esophageal; PS0 25%, PS1 54%, PS2 21%. Median PFS was P 35 days, G 49 days (HR = 0.795, 95%CI 0.66, 0.96, p = 0.017). Median OS was P 3.60 months, G 3.73 months (HR = 0.90, 95%CI 0.74, 1.09, p = 0.285). No significant safety concerns emerged. PS is a highly significant prognostic factor for both PFS (median PFS: PS0 1.8, PS1 1.4, PS2 1.0 months) and OS (median OS: PS0 6.0, PS1 3.9, PS2 2.0 months). Disease control rate at 8 weeks in patients with measurable disease was P 16.0%, G 25.5% (p = 0.014). HRQL was assessed for the pre-specified outcomes of QoL, dysphagia, eating and odynophagia, the latter of which was improved for gefitinib (p = 0.004). Conclusion COG is the first large randomised trial in the 2nd/3rd line setting in esophageal cancer. Although the primary OS endpoint was not acheived, there was significant PFS improvement and palliation. Durable responses were seen, and the translational study (Trans-COG) is investigating the correlation of benefit with biomarkers. Disclosure D.R. Ferry: Consultant role for Astra Zeneca Honoraria from Astra Zeneca Research funding from Astra Zeneca M. Harrison: Wife has shares in Astra Zeneca. Otherwise no conflicts of interest A. Chatterjee: Received and honoraria for a presentation on gefitinib. otherwise no conflicts of interest A. Garcia-Alonso: A consultant/advisory role for Roche. otherwise no conflicts of interest J. Jankowski: Consultant to AstraZeneca. No other conflicts of interest R.D. Petty: Consultant for Roche and Astra Zeneca (compensated) Honoraria from Roche and Pfizer Research funding from Roche All other authors have declared no conflicts of interest.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.