IMPORTANCE Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H).OBJECTIVE To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. DESIGN, SETTING, AND PARTICIPANTSA randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease.INTERVENTIONS We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. MAIN OUTCOMES AND MEASURESThe primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). RESULTSOf 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). CONCLUSIONS AND RELEVANCEThis phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted.

481 Background: D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Targeting both PD-L1 and CTLA-4 may have additive/synergistic activity as the mechanisms of action of CTLA-4 and PD-L1 inhibition are non-redundant. This study evaluated whether combining PD-L1 and CTLA-4 inhibition would lead to improved pt survival vs BSC alone in rCRC. Methods: Pts with rCRC were randomized 2:1 to D+T vs BSC . Pts were eligible if they failed all standard regimens; containing a fluoropyrimidine, irinotecan and oxaliplatin (and an EGFR inhibitor if Ras wild type). Prior treatment (Tx) with anti-VEGF agents or TAS-102 was permitted but not mandatory. Tx consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and all appropriate supportive measures. Primary endpoint was overall survival (OS) and a two-sided p-value < 0.10 was considered statistically significant. Results: Between August 2016 and June 2017, 180 pts were enrolled and 179 treated as randomized. Pt baseline characteristics were balanced. 85% of pts received ≥ 90% of planned doses of D and T. No pts with known defective mismatch repair (dMMR) tumors were enrolled. With a median (med) follow-up of 15.2 months (mo), the med OS was 6.6 mo for D+T and 4.1 mo for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54–0.97). Med progression free survival was 1.8 mo and 1.9 mo respectively (HR 1.01, 90% CI 0.76–1.34; p=0.97). Disease control rate was 22.7% for D+T and 6.6% for BSC (p = 0.006). Grade 3/4 abdominal pain, fatigue, lymphocytosis and eosinophilia were significantly higher in D+T. At 16 weeks, there was significantly less deterioration on EORTC QLQ-C30 physical function for D+T. Confirmation of MMR status is ongoing. Conclusions: D+T significantly prolonged OS in pts with rCRC and preserved quality of life. Adverse events were more frequent with D+T. This is the first study showing that combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with advanced refractory CRC not selected for dMMR. Clinical trial information: NCT02870920.

3512 Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p < 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values > 0.7). Using a minimum p-value approach, pts with TMB >28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5-7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics:■ Follow-up and survivorship of patients with resected colorectal cancer ■ Indications for liver metastasectomy ■ Treatment of oligometastases by stereotactic body radiation therapy ■ Treatment of borderline resectable and unresectable pancreatic cancer ■ Transarterial chemoembolization in hepatocellular carcinoma ■ Infectious complications of antineoplastic agents

3545 Background: Nutritional stress is one of the mechanisms used by tumour cells to evade the immune system. Arginine (ARG), an amino acid involved in several cellular functions including immunomodulation, is important in regulating T-lymphocyte cell activity and the anti-tumour response. ARG deficiency in the tumour microenvironment has been shown to impair T-cell response while ARG supplementation may promote anti-tumour immune activity. In this exploratory post-hoc analysis of the Phase II CO.26 trial (NCT02870920), we investigated the role of plasma ARG in predicting response to ICI in patients (pts) with refractory mCRC. Methods: CO.26 was a phase II trial which randomized pts with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from blood samples pre-treatment using HPLC-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying pts into ARG-high (≥10650 ng/ml) versus ARG-low ( < 10650 ng/ml) groups. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard models were used to analyze prognostic and predictive impacts of ARG on PFS and OS. Results: Of 180 pts enrolled in CO.26, 162 pts (N = 115 treated with D+T and 47 BSC) had pre-treatment blood samples for baseline ARG analysis. There were no significant differences in baseline characteristics between pts included in this analysis and the total study pts, or between ARG-high and ARG-low pts. In pts treated with D+T, ARG-high was associated with more favourable prognosis (ARG-high median OS 7.62 months vs. ARG-low 5.49 months, multivariable hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.40-0.91, p = 0.016). In ARG-high pts, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.61 months BSC; HR 0.61, 95% CI 0.37-0.99, p = 0.04). In ARG-low pts there was no OS benefit with D+T (median OS 5.49 months D+T vs 4.27 months BSC; HR 0.84, 95% CI 0.50-1.41, p = 0.51. Interaction p = 0.037). Baseline ARG values had no association with PFS or disease control rate. Conclusions: Baseline plasma ARG was prognostic in pts with mCRC treated with D+T, and high ARG was predictive of improved OS with ICI. Prospective studies should be done to validate ARG as a biomarker identifying mCRC pts likely to derive benefit from ICI. Therapeutic approaches targeting the ARG pathway should be investigated in future studies.

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood. Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC. Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial. Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints. Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline ( p = 0.0030) and progression ( p = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints ( p < 0.05). Conclusion: While increasing panel breadth beyond two tracked variants improved variant re-detection in ctDNA samples from patients with treatment refractory mCRC, increases beyond four tracked variants yielded no significant improvement in variant re-detection.

Background: Facing the deadly COVID-19 pandemic, health care providers especially those on the frontline and directly involved in the management of COVID patients faced severe mental health problems as compared to general population. Objective: To evaluate the factors associated with mental health outcomes among health care providers working in Mayo Hospital, Lahore. Methods: Out of 200, 100 participants working in different departments of Mayo Hospital completed the survey by filling an online questionnaire comprising 23 questions during period of one month June 01, 2020 to July 01, 2020. Participants were assessed for symptoms of anxiety, depression, hopelessness, poor concentration on work and indecisiveness. Particular COVID-19 related risk factors were also studied. Results: Among the respondents, 68.5% were females and 31.5% were males. 87.6% were doctors and remaining 12.4% belonged to other departments of health care system. 65.2% participants reported symptoms of anxiety, 41.6% reported deterioration in performance, 50% hopelessness, 61.8% symptoms of depression, 41.6% lack of concentration at work and 30.3% reported studying COVID related information in free time. Severe symptoms were reported in frontline workers, female gender, young age and having a close friend or relative infected. Conclusions: This study analyses the impact of COVID-19 on mental health of health care providers either directly or indirectly involved in managing patients categorizing the health care providers as high risk population. It also highlights the measures which need to be taken to reduce these psychological effects.

183 Background: In response to energetic stress, colorectal cancer cells secrete creatine kinase brain-type (CKB). CKB converts creatine and ATP from the extracellular matrix to PC, which is imported intracellularly to sustain survival and metastatic spread. In addition, PC modulates immune cell functions and may play a role in mediating responses to immune checkpoint inhibition. CO.26 was a phase II trial (NCT02870920) that randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). In an exploratory, post-hoc analysis, we investigated the role of plasma PC as a predictive biomarker for response to D+T. Methods: PC concentrations were determined from pre-treatment blood samples with HPLC-tandem mass spectrometer. A minimum p-value approach was used to select an optimum cut-off value which dichotomized patients into low (< 95.6 ng/ml) versus high (≥ 95.6 ng/ml) groups predictive for benefit. Cox proportional hazard models were used to analyze predictive impacts of PC on progression free survival (PFS) and overall survival (OS). Results: Of 180 pts enrolled, pre-treatment blood samples were available for 162 pts (N =115 for D+T; 47 BSC). Pre-treatment PC was low in 15% (N=24) and high in 85% (N=138). There were no differences in baseline characteristics between pts included in this analysis and the total study pts, or PC low and high pts. D+T improved OS significantly in PC low pts (median OS 4.7 months vs 2.3 months; Hazard Ratio (HR) 0.32, 95% confidence interval (CI): 0.11 – 0.95, p = 0.03). There was no improvement in PC high pts with D+T (median OS 6.8 vs 5.2 months; HR 0.80, 95% CI: 0.55 – 1.17, p = 0.24. Interaction p < 0.0001). Plasma PC values had no impact on PFS and rates of disease control. Conclusions: Pts with low plasma PC derived more benefit from immune checkpoint inhibition with D+T in pts with refractory mCRC. Further prospective validation studies are needed. Predictive analysis for OS with pre-treatment PC levels dichotomized by minimum p approach. [Table: see text]