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Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I–IV patients (hazard ratio: 1.57; 95% CI: 1.23–1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48–2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.

Background Several systemic agents have been approved for use in advanced hepatocellular carcinoma (aHCC). However, it is unclear which treatment is superior in either the first- or second-line settings due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods Randomized clinical trials evaluating systemic agents in first and second line settings in aHCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and the annual ASCO and ESMO conferences from 2017 to 2020. Studies in English reporting clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. The primary outcomes of interest were pooled hazard ratios (HR) of OS and pooled odds ratios (OR) of ORR in first line studies and pooled HR of PFS and OR of ORR for second line studies. Additionally, OS for second line agents were reported in the qualitative analysis. Results Overall, first line studies comprised 8335 patients (13 studies) and second line studies comprised 4612 patients (11 studies). In the first line setting, atezolizumab plus bevacizumab was associated with the highest OS benefit over sorafenib (HR 0.58, 95% CI, 0.42-0.80; P-score 0.993). Additionally, lenvatinib was associated with the greatest ORR benefit (OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) in the first line setting. In the second line setting, cabozantinib was associated with the highest PFS benefit over placebo (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest ORR benefit (OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusion Atezolizumab plus bevacizumab appears to have superior efficacy among first line agents whereas cabozantinib appears to be superior in the second line setting. Further studies are warranted to determine whether the type of prior therapy received affects the efficacy of subsequent second line therapy.

Background: Given the inconclusive evidence behind the safety and efficacy of immune checkpoint inhibitors re-challenge, herein, we have conducted a systematic review and meta-analysis to synthesize available data. Results/methodology: PubMed, Embase, Cochrane Database, and ASCO and ESMO were searched for studies published from conception to March 2020. Pooled incidence of recurrent immune-related adverse events (irAEs), objective response rates, and odds ratios for irAEs at initial versus re-treatment were calculated. Overall, 437 patients (ten studies) were included. Incidence of any grade, grade 3/4, and steroid-requiring recurrent irAEs were 47%, 13.2%, and 26% respectively. Objective response rate in previous non-responders was 12.5% (5.8–24.8%). Odds ratio for severe irAEs was 0.28 (0.11–0.72) and steroid-requiring irAEs 0.19 (0.06–0.56). Discussion/conclusion: This analysis suggests that immune checkpoint inhibitors re-challenge is safe and potentially efficacious.

BackgroundPARP inhibitors (PARPi) have recently been approved for various malignancies based on the results of several clinical trials. However, these trials have mostly recruited patients with germline BRCA mutations, and it is unclear whether PARPi have similar efficacy in patients with somatic BRCA mutations. Our study aimed to determine the efficacy of PARPi in patients with somatic BRCA mutations.MethodsWe performed a meta-analysis comparing overall response rate to PARPi in patients harboring somatic versus germline BRCA mutations. We looked at studies including somatic and germline mutations in BRCA patients that received PARPi.ResultsAfter screening and removing duplicates, 18 studies met our criteria for including both somatic and germline BRCA mutations. Only 8 studies reported response rates for both somatic and germline BRCA mutations.In those studies, 24 out of 43 patients with somatic BRCA mutations (55.8%), and 69 out of 157 (43.9%) patients with germline BRCA patients had a response to therapy to PARPi. This difference was not statistically significant (p = 0.399).In all five studies that reported progression-free survival, there was no obvious difference in outcomes between somatic versus germline BRCA patients, however a precise statistical analysis could not be performed.ConclusionOur meta-analysis and systematic review of the literature indicates similar response rates of PARPi therapy in patients with somatic and germline BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of somatic BRCA mutations in further clinical trials is paramount in improving therapeutic options for our patients.

The developing countries are still starving for the betterment of health sector. The disease commonly found among the women is breast cancer, and past researches have proven results that if the cancer is detected at a very early stage, the chances to overcome the disease are higher than the disease treated or detected at a later stage. This article proposed cloud-based intelligent BCP-T1F-SVM with 2 variations/models like BCP-T1F and BCP-SVM. The proposed BCP-T1F-SVM system has employed two main soft computing algorithms. The proposed BCP-T1F-SVM expert system specifically defines the stage and the type of cancer a person is suffering from. Expert system will elaborate the grievous stages of the cancer, to which extent a patient has suffered. The proposed BCP-SVM gives the higher precision of the proposed breast cancer detection model. In the limelight of breast cancer, the proposed BCP-T1F-SVM expert system gives out the higher precision rate. The proposed BCP-T1F expert system is being employed in the diagnosis of breast cancer at an initial stage. Taking different stages of cancer into account, breast cancer is being dealt by BCP-T1F expert system. The calculations and the evaluation done in this research have revealed that BCP-SVM is better than BCP-T1F. The BCP-T1F concludes out the 96.56 percentage accuracy, whereas the BCP-SVM gives accuracy of 97.06 percentage. The above unleashed research is wrapped up with the conclusion that BCP-SVM is better than the BCP-T1F. The opinions have been recommended by the medical expertise of Sheikh Zayed Hospital Lahore, Pakistan, and Cavan General Hospital, Lisdaran, Cavan, Ireland.

Background/aim Previous association studies have linked the functional miR-146a SNP rs2910164 with risk of digestive system cancer; however, the results of these studies are inconclusive and inconsistent. The objective of the following study is to provide an up-to-date and comprehensive meta-analysis of the association of miR-146a rs2910164 and digestive system cancer risk. Patients and methods We searched the PUBMED/MEDLINE and Cochrane/EBM databases. The following inclusion criteria were used for the study selection: i) Case-control studies; ii) studies with reported allelic frequency/genotype data; and iii) studies with reported association with risk of a digestive system cancer. The following exclusion criteria were used: Review article, meta-analysis, case report and case series; studies evaluating relationships of miR-146a rs2910164 with outcomes other than cancer incidence, such as cancer morbidity or mortality. Study quality was assessed using the Newcastle-Ottawa Scale and publication bias assessed graphically and numerically using Begg's funnel plot and Egger's regression test and rank test. Outcome measure was the pooled odds ratios under the allelic frequency, dominant, recessive, and over-dominant models. Subgroup analysis was conducted for country of study origin. Results No association of miR-146a rs2910164 with overall risk of digestive system cancer was identified. However, subgroup analysis showed an association with overall risk in the European population in the over-dominant model. Furthermore, miR-146a rs2910164 was associated with reduced risk of gastric cancer in the dominant model (pooled odds ratio=0.91, 95% confidence intervaI=0.83-0.99), increased risk of colorectal cancer under the recessive model and reduced risk of colorectal cancer under the over-dominant model in the European population. No significant within-study or publication biases were detected. Conclusion miR-146a rs2910164 was not associated with overall risk of digestive system neoplasms. However, the GG genotype and the CC genotype may be linked to higher risk of gastric cancer and colorectal cancer, respectively; and the CG genotype may be protective against digestive system neoplasms overall in the European population, especially for colorectal cancer.

BackgroundImmune checkpoint inhibitors (ICIs) are approved by the U.S. Food&Drug Administration in over 17 tumor types. Older adult patients make up about a quarter of all cancer patients but are historically understudied in cancer clinical trials. ICIs are associated with immune-related adverse events (irAEs), which may be particularly morbid for older adult patients with underlying comorbidities and impaired functional status. In this study, we provide insight into the real-world safety and efficacy of ICIs among older adult patients (≥80 years) with cancer.MethodsThis is a multicenter, international retrospective study of tumor-agnostic older adult patients with cancer treated with single-agent ICIs between 2010–2019 from 18 academic centers in the U.S. and Europe. A cohort of 928 patients aged ≥80 years during treatment with ICI was assembled and analyzed to evaluate clinical outcomes and irAE patterns in older adult patients treated with single-agent ICIs.ResultsMedian age at ICI initiation was 83.0 years (range 75.8–97.0). Most patients (86.9%) were treated with anti-PD-1 therapy. Among the full cohort, the three most common tumors were non-small cell lung cancer (NSCLC, 37.2%,n=345), melanoma (35.5%,n=329), and genitourinary (GU) tumors (16.5%,n=153). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median progression-free survival (PFS) was 6.7 months (95%CI, 5.2–8.6) for patients with NSCLC, 11.1 months (95%CI, 8.9–16.0) for patients with melanoma, and 6.0 months (95% CI, 5.0–10.7) for patients with GU malignancy. Median overall survival (OS) was 10.9 months (95%CI, 8.6–13.1) for patients with NSCLC, 30.0 months (95%CI, 23.6–46.4) for patients with melanoma, and 15.0 months (95%CI 9.1–25.4) for GU patients (Figure 1A-C). Within histology-specific cohorts (NSCLC, melanoma and GU), clinical outcomes were similar across age subgroups (90). Among all patients (N=928), 41.3% experienced ≥1 irAE(s), including 12.2% reported to be grade (G)3–4. No irAE-related deaths occurred. The median time to irAE onset was 9.8 weeks; 57% occurred within the first 3 months after ICI initiation. ICI was discontinued due to irAEs in 16.1% patients. There was no significant difference in the rate of irAEs among patients age ConclusionsICIs are effective and generally well-tolerated among older patients with cancer. However, ICI discontinuation due to irAE is more frequent with increasing age.

In real time scenarios, the single image encryption schemes are not that efficient when a bunch of color images is to be encrypted. This problem should be addressed due to computational cost incurred by multiple executions of single color-image encryption scheme. The objective of this research work is to provide a new and efficient multiple color images cipher scheme. This cipher is based on chaotic system, circular shift operations and SHA-384 hash codes. First of all, an arbitrary number of RGB images are input. They are combined in a rectangular fashion to get their hash code. Then this big color-image is decomposed into its three basic components, i.e., red, green and blue. To scramble the pixels of these components, they are shifted circularly both the row-wise and column-wise. Further, XOR operation has been performed to realize the effects of diffusion in these components. Lastly, these components are joined together to get the final RGB cipher image. Apart from the 384-hash codes, a salt key of 384-bit has also been used in the proposed cipher to heighten the security effects. The SHA-384 hash codes render the required key space and plaintext sensitivity. The simulation results and the performance analyses carried out at the end clearly prove the efficiency, effectiveness, robustness and the real-world applicability of the proposed multiple RGB images cipher. Besides, the encryption throughput 7.716 Mb/s of the proposed scheme outperforms many of the existing ones.

A 54-year-old Caucasian male with history of hypertension, hyperlipidemia, insulin-dependent diabetes mellitus, and chronic skin rash of 4 years presented to the emergency department with worsening rash and weight loss. Physical examination revealed diffuse erythematous rash, skin ulceration, bullae with associated paresthesia in the lower extremities, trunk, bilateral upper extremities, and palms and soles. A computed tomography (CT) scan with contrast showed a large, heterogenously enhancing pancreatic mass measuring 9.4 × 3.8 cm with surrounding low-attenuation soft tissue thickening. Blood tests showed hemoglobin A1C of 10.0%. Glucagon level was elevated to 2,178 (normal < 80 pg/dl). Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) from the pancreatic mass was suggestive of pancreatic endocrine tumor. The tumor cells were positive for synaptophysin, chromogranin, CD56, and pan-cytokeratin with focal positivity for glucagon, suggestive of glucagonoma. The patient underwent distal pancreatectomy along with splenectomy and cholecystectomy. The glucagon level normalized to 25 pg/dl within a week of tumor resection, and during his 6-week outpatient follow up, skin rash had completely resolved.

Gemcitabine plus cisplatin remains the standard first-line systemic therapy for advanced cholangiocarcinoma and offers a median survival of approximately 1 year. No standard regimens beyond the first line and no targeted or immunotherapy agents are approved yet in this disease. Development of molecular targeted therapy in this heterogenous and relatively rare malignancy continues to be a challenging area. The rapidly growing precision medicine efforts have uncovered the underlying mutational landscape of this lethal disease and paved the way for molecularly oriented clinical trials. The early results from such trials like those exploring IDH and FGFR2 derangements have highlighted its promising potential as alternative therapeutic options. Additionally, advances in cancer immunology have identified certain correlates as biomarkers of response to immune modulatory approaches. For instance, the presence of tumor DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI), in 5% to 10% of cholangiocarcinoma, is associated with high rates and durability of responses to immune checkpoint blockade. Beside checkpoint inhibitors, other types of immune therapeutics like peptide and dendritic cell-based vaccines and adoptive cell therapies have been developed and are undergoing active evaluation in cholangiocarcinoma. With further research effort, the integration of tumor molecular profiling in trials exploring targeted immunotherapy will lead to better understanding of the predictive role of various molecular and immune biomarkers and ultimately shine the horizon for this patient population.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

4010 Background: Bema is a first-in-class humanized IgG1 monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b). Results from the FIGHT study showed an improvement in progression-free survival (PFS), overall survival (OS), and overall response rate with the addition of bema to mFOLFOX6 in FGFR2b+, non HER2+ GC. This report provides updated analyses of patient (pt) subgroups, additional data on ocular adverse events (AEs), and the median OS result for the bema+mFOLFOX6 combination. Methods: Pts were treated with mFOLFOX6 and randomized 1:1 to bema (15 mg/kg) or placebo (pbo) every 2 weeks (wks) with an additional 7.5 mg/kg bema/pbo dose on cycle 1 day 8. Eligible pts had unresectable locally advanced or metastatic GC not known to be HER2+, and had FGFR2b overexpression (any 2+/3+ staining) by centrally performed immunohistochemistry (IHC+) or FGFR2 amplification by circulating tumor DNA (ctDNA+). Results: Of the 155 pts who were randomized, 149 (96%) were FGFR2b+ by IHC, 26 (17%) by ctDNA, and 20 (13%) by both. 96 pts (62%) had tumors with FGFR2b IHC 2+/3+ in ≥10% of tumor cells. The proportion of pts with ctDNA+ or with ≥5% or ≥10% tumor cells FGFR2b+ by IHC was similar across geographic regions. Bema showed a benefit vs pbo across pre-specified subgroups including age, gender, geographic region, and prior adjuvant therapy. Patients with FGFR2b overexpression irrespective of ctDNA gene amplification benefited from bema: IHC+/ctDNA- PFS hazard ratio (HR) 0.63 (95% CI 0.4, 0.99), OS HR 0.66 (95% CI 0.39, 1.12); IHC+/ctDNA+ PFS HR 0.15 (95% CI 0.02, 1.18), OS HR 0.10 (95% CI 0.01, 0.83). Frequency and severity of ocular AEs were similar for the overall enrolled population and for pts with ≥5% or ≥10% FGFR2b+ by IHC. Corneal AEs in the bema arm increased in frequency and severity over time; 10.5% (0% G3) wk 1-8 vs 44.1% (15.3% G3) wk ≥25. Following discontinuation of study treatment, subsequent anti-cancer therapy was balanced in the 2 arms (bema 53%; pbo 49%). With a median follow-up of 12.5 months (mo), the bema arm had a median OS of 19.2 mo (95%CI: 13.6, not reached) vs 13.5 mo (95%CI: 9.3, 15.9) for placebo (HR:0.60 95%CI: 0.38, 0.94) for the intent-to-treat population; for the subset of pts with ≥10% FGFR2b+ by IHC, the median OS for bema was 25.4 mo (95%CI: 13.8, not reached) vs 11.1 mo (95% CI: 8.4, 13.8) for placebo (HR: 0.41 95%CI: 0.23, 0.74). Conclusions: The addition of bema to mFOLFOX6 improved the OS of 1L FGFR2b+ GC pts vs mFOLFOX6 alone. Outcomes favored bema across pre-specified subgroups. Pts with overexpression of FGFR2b even without ctDNA amplification demonstrated a benefit from the addition of bema to mFOLFOX6, supporting further evaluation of bema in tumors with FGFR2b overexpression without the requirement for gene amplification. Clinical trial information: NCT03694522.

Simple Summary Biomarker research for immunotherapy in gastroesophageal cancer has been rapidly developing in parallel with the growing use of immune checkpoint inhibitors. Although several biomarkers have been approved for use in the clinical setting they are imperfect in predicting responses. Several novel biomarkers are currently being studied and demonstrate potential for application in the clinical setting. Future research should determine the ability of immunotherapy biomarkers to predict response and synergy in combination therapy. Abstract Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.

The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received >10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p

Several targeted agents including multi-tyrosine kinase inhibitors (mTKIs) and immunotherapy (IO) agents have been approved for use beyond the frontline setting in patients with advanced hepatocellular carcinoma (HCC). Due to lack of prospective head-to-head comparative trials, there is no standardized way for alternating those agents beyond frontline. Therefore, we performed a retrospective review of the Kansas University (KU) cancer registry to determine whether IO may be superior to non-IO therapy. Patients with advanced HCC were divided into two groups based on the second-line systemic regimen received (IO vs. non-IO). Progression-free survival (PFS) and overall survival (OS) were calculated under the Kaplan&ndash, Meier and Cox proportional hazards models. No statistically significant differences in PFS and OS were found, although a non-significant delayed separation in the survival curve favoring IO was identified (median PFS 3.9 months vs. 3 months, median OS 10 months vs. 10 months respectively for IO vs. non-IO). This retrospective analysis is one of the earliest and largest studies comparing second-line IO and non-IO therapies thus far reported. Future studies should aim to define specific biomarkers for response prediction and treatment optimization based on individual patient and tumor characteristics. Furthermore, combinatorial therapeutic strategies is an evolving approach showing early promising signal.

BackgroundNivolumab is Food and Drug Administration approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking.Patients and methodsWe performed an international, multicenter observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from eight centers in North America, Europe and Asia.ResultsPatients received nivolumab for Barcelona Clinic Liver Cancer stage C (n=191, 92.0%) and Child-Pugh (CP) A (n=158, 67.8%) or B (n=75, 32.2%) HCC as first (n=85, 36.5%) or second to fourth systemic therapy line (n=148, 63.5%). Objective response rate (ORR) was 22.4% and disease control rate was 52.1%. Median overall survival (OS) was 12.2 months (95% CI 8.4 to 16.0) and median progression-free survival was 10.1 months (95% CI 6.1 to 14.2). Treatment-related adverse events of grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months vs 16.3 months, p=0.05). Achievement of an objective response predicted for improved OS (25.4 months vs 13.2 months, pConclusionsThis study confirms safety and efficacy of nivolumab in advanced HCC across various lines of therapy and degrees of liver dysfunction. Despite equal ORR and toxicity to nivolumab, patients with CP-B functional class have shorter survival than the patients with CP-A.

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p &lt, 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57&ndash, 0.74) versus 0.63 (95% CI 0.54&ndash, 0.72). ALBI grade at ICI cessation independently predicted for PIOS (p &lt, 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p &gt, 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.

e15060 Background: Despite increasing clinical experience with immune checkpoint inhibitors and the recent publication of clinical practice guidelines for managing treatment-related adverse events, precise and nuanced checkpoint inhibitor data in the setting of combination therapy is lacking. Herein we have conducted a systematic review and meta-analysis of treatment-related adverse event data from clinical trials evaluating combination immune checkpoint inhibitors. Methods: Studies published in PubMed, Embase, and Cochrane Database from conception to September 28, 2019 were included in the meta-analysis. Studies were eligible for inclusion if combination immune checkpoint inhibitor therapy was evaluated in advanced unresectable cancer and treatment-related adverse event data were available. For comparison of severity of adverse events in combination versus monotherapy, only the studies containing monotherapy arms as a control population were included, while all were included for calculation of pooled incidence of selected adverse events. Pooled risk ratio (RR) was used for the comparison of combination versus monotherapy and the logit transformed proportion for calculation of pooled incidence. Between-study risk of bias was evaluated using the Begg's funnel plot and Egger's regression test. Subgroup analysis was conducted by combination regimen, cancer type, and dosing regimen. Results: A total of 18 studies comprising 2767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment type (PD-1+CTLA-4 and PD-L1+CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1 and D20T1). Incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945] and grade 3 or higher events/all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusions: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.

Systemic chemotherapy is the mainstay of therapy in patients with advanced gastric and esophageal cancer, but has multiple drawbacks including lack of durable efficacy and dose limited toxicities. Recent clinical trials data on the efficacy of immune therapy in this patient group have shed light on its potential as an alternative treatment option. Checkpoint inhibitors, specifically the anti-PD-1/PD-L1 inhibitors, seem to be beneficial for a subgroup of patients with advanced gastric or esophageal cancer who have progressed on multiple systemic chemotherapies. As clinical trials results mature, it will become apparent whether checkpoint inhibitors are effective in other treatment settings such as in first-line therapy or adjuvant therapy. Although the toxicity of checkpoint inhibitors is generally unpredictable, they tend to be more manageable and better tolerated than the toxicities of systemic chemotherapy. Furthermore, recent research in molecular subtyping of esophageal and gastric cancer are paving way for better treatment response prediction and patient selection for checkpoint inhibitor therapies. Compared to checkpoint inhibitors, other types of immune therapies such as cancer vaccines, and adoptive cell therapies have yet to be proven effective in esophageal and gastric cancer and are further away from clinical use. Immune therapy seems poised to take a firm position as part of the therapeutic armamentarium for advanced gastric and esophageal cancer and future clinical trials will show the extent of its application in different treatment settings in this patient population.

To evaluate the expression of programmed cell death-ligand 1 (PD-L1) in anal cancer. In a retrospective cohort analysis, subjects with squamous cell carcinoma of the anal canal were tested for PD-L1 expression, then followed for recurrence and survival. Crude recurrence rates (CRRs), crude mortality rates (CMRs), and crude event rates (CERs) were assessed for PD-L1-dependent differences using Poisson regression. All 3 types of crude rate were expressed as the number that occurred per hundred person-years (hPY) of follow-up. Samples from 41 subjects were evaluated for PD-L1 expression; 23 (56%) were positive. Subjects with PD-L1-expressing versus PD-L1-negative tumors respectively had CRRs of 30.8 versus 12.1 recurrences/hPY (P=0.082), CMRs of 16.7 versus 12.0 deaths/hPY (P=0.47), and CERs of 39.2 versus 16.9 events/hPY (P=0.069). PD-L1 positivity was associated with worse CRR and CER, and marginally worse CMR. The effect on progression-free and overall survival needs to be validated in a study with a larger sample size.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti–programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non–small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged

BackgroundCabozantinib is a multi-tyrosine kinase inhibitor primarily targeting VEGFR, MET, and AXL. These targets promote a tumor immune permissive microenvironment. Cabozantinib has demonstrated immunomodulatory properties & clinical synergy when paired with PD-L1 inhibitors such as durvalumab. Here, we present final results of phase Ib of the Camilla trial assessing cabozantinib plus durvalumab in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), and hepatocellular carcinoma (HCC). This is an investigator-initiated trial funded by Exelixis & Astrazeneca.MethodsPatients were administered cabozantinib + durvalumab in a dose escalation (3+3) then expansion to find the Dose Limiting Toxicities (DLTs), Recommended Phase 2 Dose (RP2D), ORR, PFS, and OS. Subgroup analysis was conducted to assess efficacy in patients with PD-L1 Combined Positive Score (CPS) ≥ 5. Dosing of cabozantinib was 20mg QD, 40mg QD, and 60mg QD PO in the 1st, 2nd, and 3rd cohorts. Dosing of durvalumab was 1500mg IV Q4W in all cohorts. DLT window was 28 days. Treatment beyond progression was allowed following modified RECIST v1.1 criteria.Results35 patients (14F, 21M), median age 53 years (range 27–79) were enrolled. 10 patients had GEA, 20 had CRC, and 5 had HCC; none had MMR deficiency. Median number of prior systemic therapies was 3 (range 0–3). No DLTs were observed during dose escalation. Per mature tolerability data, 11/14 patients receiving cabozantinib 60mg required dose-reduction post cycle 2 to 40mg. RP2D was determined to be cabozantinib 40mg QD plus durvalumab 1500mg Q4W. Of the 247 observed Treatment-Related Adverse Events (TRAEs), 10% (24) were grade≥3. Most common TRAEs were grade 1–2 fatigue (57%), nausea (43%), anorexia (40%), diarrhea (37%), transaminitis (34%), hand-foot syndrome (23%), & weight loss (23%). 2 patients each developed grade≥3 fatigue, weight loss, & abdominal pain. Overall, 30 pts were evaluable for efficacy. ORR 26.7%; DCR 83.3%; median PFS 4.5 months; 6-month PFS 36.7%; and median OS 9.1 months. 12 patients had PD-L1 CPS ≥5. In this subgroup, ORR 33.33%; DCR 91.67%; median PFS 6.13 months; 6-month PFS 50%; and median OS was not reached.ConclusionsCabozantinib plus durvalumab demonstrated promising efficacy and was fairly tolerated without new safety signals. High PD-L1 expression defined as CPS ≥ 5 was associated with improved efficacy & survival. The phase II multi-cohort part of the trial is currently ongoing.Trial RegistrationNCT03539822Ethics ApprovalThe study was approved by the participating site’s local IRB.ConsentAll study participants granted a written informed consent prior to treatment initiation.

Introduction. Ampullary cancers represent a subset of periampullary cancers, comprising only 0.2% all gastrointestinal cancers. Localized disease is primarily managed by a surgical intervention, called pancreaticoduodenectomy (PD), followed in many cases by the administration of adjuvant chemotherapy (CT) or chemoradiation therapy (CRT). However, there are no clear evidence-based guidelines to aid in selecting both the modality and regimen of adjuvant therapy for resected Ampullary carcinoma. Methods. We retrospectively analyzed 54 patients at KU Cancer Center, who had undergone endoscopic resection or pancreaticoduodenectomy (PD) for Ampullary cancer from June 2006 to July 2016. We obtained patients’ baseline characteristics, clinical presentation, pathology, treatment modality, recurrence pattern, and survival outcomes. The time-to-events data were compared using Kaplan-Meier methods. A univariate and multivariate Cox proportional hazards regression was performed to evaluate factors associated with overall survival (OS) and generate hazard ratios (HR). Results. The mean age of the 54 patients was 68 (37-90). 38 (70%) were males and 16 (30%) were females. Most of the patients were Caucasian (76%). Approximately half of all patients had a history of smoking, 20% had alcohol abuse, and 13% had pancreatitis. Among the 54 patients with localized cancers, 9 (16%) were treated definitively with nonoperative therapies, usually due to a prohibitive comorbidity profile, performance status, or unresectable tumor. 45 out of 54 patients (83%) underwent surgery. Of the 45 patients who underwent surgery, 18 patients (40% of the study cohort) received adjuvant therapy due to concerns for advanced disease as determined by the treating physician. 13 patients (24%) received adjuvant CT and 5 patients (9.2%) received CRT. The remaining 27 patients (50%) underwent surgery alone. The median OS for the entire study cohort was 30 months. When compared to surgery alone, adjuvant therapy with either CT or CRT had no statistically significant difference in terms of progression-free survival (p=0.56) or overall survival (p=0.80). In univariate Cox proportional hazards regression analysis, high-risk features like peripancreatic extension (16%) and perineural invasion (26%) were found to be associated with poor OS. Lymph node metastasis (29%) did not significantly affect OS (HR 1.42, 95% CI [0.73-1.86]; p=0.84). Lymphovascular invasion (29%) was not associated with poor OS (HR 1.22, 95% CI [0.52, 2.96]; p=0.76). In multivariate Cox regression analysis, only age group>70 years was significantly associated with OS , while other factors, including the receipt of adjuvant therapy, lymph nodes, positive margin, and lymphovascular, perineural, and peripancreatic involvement, were not significantly associated with OS. These results are likely due to small sample size. Conclusions. Despite numerous advances in both cancer care and research, efforts in rare malignancies such as Ampullary cancer remain very challenging with a clear lack of an evidence-based standard of care treatment paradigm. Although adding adjuvant therapies such as chemotherapy or chemoradiotherapy is likely to improve survival in high-risk disease, there is no standardized regimen for the treatment of Ampullary cancer. More research is required to elucidate whether statistically and clinically relevant differences exist that may warrant a change in the current adjuvant treatment strategies.

PURPOSE OF REVIEW: Gut microbiota has the ability to modify the metabolism of wide array of therapeutic drugs. Current treatment modalities used in colorectal cancer have a narrow therapeutic index with a side effects profile that decreases tolerance to these treatments and adversely affects treatment outcome. Harnessing the gut microbiota ability to modify oncotherapeutic drugs metabolism and hence efficacy, could be potentially used to improve treatment outcomes in colorectal cancer patients. This review will shed lights on important findings from recent microbiome interaction studies which would hopefully serve as a useful tool to guide future translative colorectal cancer research. RECENT FINDINGS: Recent advances in microbiome studies have revealed an interesting aspect of gut microbes carcinogenic properties in dysbiotic gut environment. Microbiota niche in colorectal cancer can also modify efficacy and toxicity profile of different oncotherapeutic treatment modalities from chemoradiotherapy to immunotherapy. Conversely, each of these treatment modalities has numerous effects on the gastrointestinal flora, causing changes in the gut microbial community that affects host morbidity and mortality. SUMMARY: Symbiotic gut microbiota is an incredible functioning organ that maintains essential aspects of our homeostasis and immunity. According to the recent body of literature, they also can modify efficacy of many therapeutic drugs including oncotherapy. Considering that unexplainable variable treatment outcomes as well as variable tolerance to treatment have been observed in colorectal cancer patients, studying gut microbiota modulatory effects on oncotherapy might be a feasible approach to explain this phenomenon.

e15613 Background: Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are commonly used chemotherapies for solid tumors, and essential for curative intent treatment of colorectal cancer. But sometimes, their use may be limited by cardiac toxicity limiting the possibility of cure in some patients. Cardiotoxicity could be asymptomatic (EKG changes) or manifested as chest pain, arrhythmias, acute coronary syndrome or death. Rechallenging may be daunting and it may result in interruption or even discontinuation of planned chemo. Traditionally, nitrates and/or IV/oral calcium channel blockers (CCB) have been used for management of fluoropyrimidine-induced cardiotoxicity but without much benefit. Ranolazine, an oral antianginal drug approved for chronic angina, diminishes myocardial ischemia by reducing calcium overload caused by inhibition of late sodium current and it does not affect heart rate or blood pressure. Our objective was to evaluate the efficacy of our novel approach using ranolazine with other traditional drugs. Methods: 8 patients (median age 49.5 yrs) with fluoropyrimidine induced cardiotoxicity were retrospectively analyzed. They were rechallenged with the planned fluoropyrimidine regimen with our 3 drug cardioprotective regimen (KU protocol). This included oral Ranolazine 1000mg BID and Amlodipine 2.5 mg daily to start the day before starting 5FU infusion/oral capecitabine and to continue it until the day after completion of infusion/treatment, and Nitroglycerin paste 1 inch every 6 hours starting before infusion and continue until it was completed. These meds were discontinued upon completion of chemo. Results: 8 patients were rechallenged with fluoropyrimidine utilizing KU protocol, 6 patients (75%) were able to complete previously planned fluoropyrimidine regimen. One pt (*) discontinued capecitabine due to recurrent chest pain and treatment was switched to 5FU based regimen with KU protocol, which pt was able to complete without chest pain. Another pt (**), 5FU was stopped due to severe diarrhea, not due to cardiotoxicity. All pts tolerated KU protocol well. Conclusions: In our small, single center experience, we were able to safely and effectively rechallenge pts with fluoropyrimidines and complete curative intent treatment with our KU protocol. This protocol uses FDA approved oral and transcutaneous drugs without requiring a healthcare personnel to administer an IV CCB that can cause precipitous bradycardia and/or hypotension. Our results need validation in a larger cohort. [Table: see text]

4085 Background: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI), however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). This retrospective multi-center study aimed to examine whether trAEs are prognostic in HCC. Methods: We established an international consortium of 10 tertiary-care referral centers located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to test whether the development of clinically significant trAE (i.e. graded >2, trAE2) predicted for improved overall (OS), progression-free survival (PFS), and overall response rates (ORR) following ICI, and subsequently validated this association in a separate cohort of 406 HCC patients receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. Results: In a multi-institutional cohort of 357 patients, 274 (77%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 304, 85%), trAE were reported in 146 patients (41%). Development of trAE2 were associated with longer OS (23.3 versus 12.2 months) and PFS (8.6 months versus 3.7 months). After adjusting for viral aetiology, gender, presence of cirrhosis, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy, trAE2 were confirmed predictors of improved OS (HR 0.55; 95%CI:0.34-0.88) and PFS (HR 0.51; 95%CI: 0.35-0.74). TrAE2 were associated with higher ORR (27% versus 16%) from ICI. The association between trAE2 and patients’ OS (HR 0.49; 95%CI:0.34-0.70) and PFS (HR 0.43; 95%CI:0.32-0.59) was also observed in the FDA dataset. After a 6-weeks landmark selection, trAE2 were confirmed to be associated with improved PFS (HR 0.59; 95%CI:0.39-0.87); the additional analysis adjusted for tumour response and duration of treatment within the FDA cohort further confirmed the association with longer PFS (HR 0.67; 95%CI: 0.47-0.94). Conclusions: Development of trAE2 may correlate with response and survival in patients with HCC receiving ICI, a clinical setting where the lack of biomarkers still represents an unmet need. Prospective studies aimed at understanding the underlying immunologic foundations of such relationship are warranted to identify predictive biomarkers of toxicity and response.

3557 Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]

e16194 Background: Hepatocholangiocarcinoma (HCC-CC) is a rare form of cancer with a poor prognosis. Of all primary liver cancers, the incidence of HCC-CC ranges from 0.4 to 14.2%. HCC-CC is a mixed carcinoma with findings of both hepatocellular carcinoma and cholangiocarcinoma. Immune checkpoint inhibitors are a potent first line treatment in hepatocellular carcinoma with multiple clinical trial showing effectiveness in cholangiocarcinoma. HCC-CC has limited proven treatment options as patients are generally excluded from clinical trials. In this study we reviewed outcomes of patients with HCC-CC who received immune checkpoint inhibitor in a single center. Methods: Records of patients who had a pathological confirmed HCC-CC by a subspecialized hepatic pathologist at the University of Kansas medical center were reviewed. We identified 6 patients with locally advanced unresectable or metastatic HCC-CC that received immune checkpoint inhibitor between February 2017 and January 2021. Baseline characteristics were obtained, as well as best response, line of therapy, and duration of response. Results: Of the six patients 4 (66%) received PD-1 inhibitor alone and 2 (34%) received combination therapy with CTLA-4 inhibitor for the treatment of HCC-CC. There were 3 (50%) females and 6 (100%) with prior hepatitis C infection. four (66%) patients had metastatic disease and 2 had locally unresectable advanced disease. Objective response rate was 83.3%. One patient achieved complete response and had a treatment holiday after receiving treatment for 2 years, and restarted immunotherapy upon relapse. Four patients had a partial response, of which two passed away after disease progression. One patient had stable disease on 2 different lines of immunotherapy then progressed. Of those who responded, one patient received immunotherapy, 3 (50%) received liver directed therapy and two received chemotherapy or Lenvatinib as first line treatment (Table). Conclusions: Immune checkpoint inhibitors demonstrate potential activity in patients with HCC-CC without unexpected side effect in this unmet need high-risk population. Larger studies are needed to confirm activity and efficacy in this setting.[Table: see text]

293 Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.

TPS153 Background: The clinical benefit of approved therapies in patients (pts) with metastatic colorectal cancer (mCRC) who progress on first- and second-line chemotherapy (FOLFOX and FOLFIRI) is limited. In pts with chemotherapy-refractory RAS wild type mCRC, antibodies targeting EGFR offer a monotherapy response rate of approximately 20% and a progression-free survival (PFS) of 4 months (Price 2014). HER2 is a validated target in gastric and breast cancers, with HER2 amplification occurring in ~3–5% of pts with mCRC. Tucatinib (TUC), recently approved for HER2+ metastatic breast cancer, is a tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR. In pt-derived xenograft models of HER2+ mCRC, the combination of TUC + trastuzumab (TRAS) showed significantly greater antitumor activity compared with either agent alone (Kulukian 2020). The MOUNTAINEER trial was initiated to evaluate the efficacy and safety of TUC in combination with TRAS in pts with HER2+ RAS wild-type mCRC. Interim analysis of the initial 26 pts enrolled in MOUNTAINEER demonstrated an objective response rate (ORR) of 52.2% (12 partial responses [PRs] in 23 evaluable pts), median duration of response of 10.4 months, with a median PFS of 8.1 months and a median overall survival (OS) of 18.7 months (Strickler 2019). Based on these results, the trial was expanded to enable better estimation of ORR and safety. Methods: MOUNTAINEER (NCT03043313) is an open-label, pivotal phase 2 trial that initially consisted of a single cohort of up to 45 pts (Cohort A) treated with TUC (300 mg BID) and TRAS (8 mg/kg IV followed by 6 mg/kg IV every 3 weeks). The trial was expanded to include an additional 70 pts randomized 4:3 into 2 cohorts: Cohort B (N = 40) who will receive TUC + TRAS, and Cohort C (N = 30) who will receive TUC monotherapy. Pts in Cohort C will be treated with TUC (300 mg orally twice daily) with the option to crossover to TUC + TRAS if an objective response is not achieved by 12 weeks, or if progressive disease develops at any time. Eligible pts have RAS wild-type and HER2+ mCRC, and must have previously received regimens that include fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and an anti-PD-1 if the tumor has dMMR proteins or is MSI-H. Pts who have received prior HER2-directed therapies are not eligible. Additionally, pts must have measurable disease and ECOG PS of 0 to 2. The primary endpoint of this trial is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, PFS, OS, and safety and tolerability. Enrollment is ongoing in the US and planned for the EU. Clinical trial information: NCT03043313.

Background: Antibiotic exposure has been associated with worse outcomes with immune checkpoint inhibitors (ICIs) in cancer patients, likely due to disruption of the gut microbiome. Other commonly prescribed medications, such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs), are also known to disrupt the microbiome, but data on their association with ICI outcomes are conflicting. Methods: We conducted a retrospective, multicenter, international cohort study including 314 hepatocellular carcinoma (HCC) patients treated with ICIs from 2017 to 2019 to assess the association between PPI or H2RA exposure (up to 30 days before ICI) and overall survival. Secondary outcomes included overall response rate (ORR) and development of any treatment-related adverse events (AEs). Results: Baseline PPI/H2RA exposure was not associated with overall survival in univariable (HR 1.01, 95% CI 0.75–1.35) or multivariable analysis (HR 0.98, 95% CI 0.71–1.36). Baseline PPI/H2RA exposure was not associated with either ORR (OR 1.32, 95% CI 0.66–2.65) or AEs (OR 1.07, 95% CI 0.54–2.12) in multivariable analysis. Conclusions: Our results suggest that exposure to PPI/H2RA prior to ICIs does not adversely affect outcomes in HCC patients.

Advanced pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with an abysmal prognosis. Beyond the first-line setting, treatment for advanced PDAC is limited and suboptimal. Also, the efficacy of epidermal growth factor receptor (EGFR) targeted therapy alone in the chemo-refractory setting in PDAC tumors harboring druggable EGFR mutations is unclear. Here we describe the case of a patient with chemo-refractory advanced PDAC with an activating exon-19 EGFR mutation who had an exceptional response to erlotinib monotherapy.

Importance Standard therapy for locally advanced rectal cancer includes concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A). An alternative strategy known as total neoadjuvant therapy (TNT) involves administration of CRT plus neoadjuvant chemotherapy before surgery with the goal of delivering uninterrupted systemic therapy to eradicate micrometastases. A comparison of these 2 approaches has not been systematically reviewed previously. Objective To determine the differences in rates of pathologic complete response (PCR), disease-free and overall survival, sphincter-preserving surgery, and ileostomy between patients receiving TNT vs standard CRT plus A. Data sources MEDLINE (via PubMed) and Embase (via OVID) were searched from inception through July 1, 2020, for the following terms: anal/anorectal neoplasms OR anal/anorectal cancer AND total neoadjuvant treatment OR total neoadjuvant therapy. Only studies in English were included. Study selection Randomized clinical trials or prospective/retrospective cohort studies comparing outcomes in patients with locally advanced rectal cancer who received TNT vs CRT plus A. Data extraction and synthesis Data regarding the first author, publication year, location, sample size, and rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival were extracted using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and pooled using a random-effects model. Main outcomes and measures Rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival. Results After reviewing 2165 reports, 7 unique studies including a total of 2416 unique patients, of whom 1206 received TNT, were selected. The median age for the patients receiving TNT ranged from 57 to 69 years, with 58% to 73% being male. The pooled prevalence of PCR was 29.9% (range, 17.2%-38.5%) in the TNT group and 14.9% (range, 4.2%-21.3%) in the CRT plus A group. Total neoadjuvant therapy was associated with a higher chance of achieving a PCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98). No statistically significant difference in the proportion of sphincter-preserving surgery (OR, 1.06; 95% CI, 0.73-1.54) or ileostomy (OR, 1.05; 95% CI, 0.76-1.46) between recipients of TNT and CRT plus A was observed. Only 3 studies presented data on disease-free survival, and pooled analysis showed significantly higher odds of improved disease-free survival in patients who received TNT (OR, 2.07; 95% CI, 1.20-3.56; I2 = 49%). Data on overall survival were not consistently reported. Conclusions and relevance The findings of this systematic review and meta-analysis suggest that TNT is a promising strategy in locally advanced rectal cancer, with superior rates of PCR compared with standard therapy. However, the long-term effect on disease recurrence and overall survival needs to be explored in future studies.

Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome with lifetime CRC risks of up to 70%.1 Conventionally, CRC specimens are screened for LS postoperatively but preoperative diagnosis of LS could impact decisions, such as the extent of resection and the need for additional risk-reducing surgeries for uterine and ovarian cancers. Few studies have addressed this issue2-5 and surveys indicate that most gastroenterologists are unsure that LS can be screened for preoperatively.6 We compared the yield of preoperative versus postoperative screening of LS by immunohistochemistry (IHC) and microsatellite instability (MSI) in unselected patients with newly diagnosed CRC who underwent testing under real-life laboratory conditions to mimic clinical practice.

Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.

e16802 Background: PARP inhibitor (PARPi) has recently been approved for various cancers. However, trials have mostly recruited pts with germline BRCA (gBRCA) mutations, and it is unclear whether PARPi have similar efficacy in pts with somatic BRCA (sBRCA) mutations. We aimed to determine the efficacy of PARPi in pts with sBRCA mutations. Methods: Per PRISMA guidelines, systematic review of PubMed, Embase, Cochrane RCT, and Web of Science Collection was performed from inception thru Jan 2020 to identify studies. Our inclusion criteria were clinical trials and retrospective studies that reported use of PARPi in pts with both s and g BRCA mutations. We performed a meta-analysis comparing overall response rate and PFS with PARPi in pts with s versus g BRCA mutations. Results: After screening, 18 studies met our criteria for including both s and g BRCA mutations. Only 8 studies reported response rates for both s and g BRCA mutations (Table). In those studies, 24 out of 43 pts with sBRCA mutations (55.8%), and 69 out of 157 (43.9%) pts with gBRCA had a response to PARPi (pooled OR 1.13, p value = 0.399, I2 = 0). In all five studies that reported PFS, there was no obvious difference in outcomes between sBRCA (HR in these studies ranged 0.23 to 0.27) versus gBRCA (HR ranged 0.17 to 0.27), however a precise statistical analysis could not be done. Conclusions: Our meta-analysis and systematic review of the literature indicates similar outcomes of PARPi therapy in pts with s and g BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of sBRCA mutations in future clinical trials is essential. [Table: see text]

e16677 Background: Nivo is FDA-approved in sorafenib-experienced, advanced HCC. Post-registration data to portray treatment in a real-world setting is lacking. Methods: We describe safety and efficacy of nivo in patients (pts) from 8 centres (USA n = 181, Asia n = 47, Europe n = 5), documenting overall (OS), progression-free survival (PFS), overall response (ORR) and disease control rates (DCR) (RECIST). Results: We analysed 233 pts, mostly cirrhotic (n = 176, 75%) due to hepatitis C (n = 95, 54.0%) with Barcelona Clinic Stage (BCLC) C HCC (n = 178, 76.4%), Child-Pugh class (CP) A (n = 158, 67.8%) or B (n = 75, 32.2%), and AFP > 400 IU/mL (n = 132, 56.7%). Nivo was given as first (1L, n = 85, 36.5%), second line (2L, n = 130, 55.8%) or > 2L (n = 18, 7.7%), after local (n = 191, 82%) and systemic therapy (n = 148, 63.5%), mostly sorafenib (n = 142, 60.9%). Median duration of nivo was 6.0 months (mo, interquartile range [IQR] 2.6-11.9) and stopped due to progression (n = 109, 46.8%) or toxicity (n = 8, 3.4%). After median follow up of 7 mo (IQR 3.0-12.3), ORR was 22.4% and DCR was 52.1%. Best responses (n = 219, 94%) included complete and partial responses in 18 (7.7%) and 31 (13.3%) pts respectively, stable disease in 65 (27.9%) and progressive disease in 105 (45.1%), not dissimilar by CP (p = 0.26). Median OS was 12.2 mo (95%CI 8.4-16.0) and predicted by CP (CPA 16.3 mo 95%CI 11.7-20.8; CPB 7.3 mo 95%CI 4.2-10.4; hazard ratio [HR] 1.9, p = 0.01), nivo line (1L 16.3 mo 95%CI 8.0-24.5; > 1L 10.4 mo 95%CI 7.4-13.5; HR 0.68, p = 0.05), and PVT (PVT- 13.8 mo 95%CI 11.7-16.0; PVT+ 10.4 mo 95%CI 7.8-13.0; HR 1.8, p = 0.015) but not cirrhosis, AFP, BCLC or steroid use (p > 0.05). Median PFS was 10.1 mo (95%CI 6.1-14.2), predicted by BCLC (A-B 19.0 mo 95%CI 7.1-30.8; C 8.2 mo 95%CI 4.9-11.4; HR 2.8, p = 0.002) and line (1L 18.2 mo 95%CI 10.4-25.9; > 1L 8.2 mo 95% CI 6.2-10.2; HR 0.60, p = 0.021), but not cirrhosis, AFP, or steroid use (p > 0.05). 26 pts (11.2%) suffered > = Grade 2 toxicities, most commonly fatigue (n = 29, 24.7%). Conclusions: Real-world use of nivo in advanced HCC across line of therapy suggests reproducible clinical efficacy and safety compared to prospective trials.

e16787 Background: Identifying novel biomarkers for early detection and prognosis would allow for improved survival outcomes in pancreatic cancer (PC). Arginase has been implicated in tumorigenesis through its production of L-ornithine. Its aberrant expression provides metabolites for tumor proliferation. Methods: In our study, 47 patients with metastatic PC, 29 with localized PC, and 50 healthy controls were enrolled at KU Cancer Center from 2000 to 2019. Overall survival (OS) was retrospectively assessed and correlated to serum protease levels at diagnosis. Protease expression was analyzed using nanobiosensors, which utilized fluorescent nanoparticles read by Spectra Scan to measure arginase, matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA), neutrophil elastase (NE), cathepsin B (CTSB), and cathepsin E (CTSE). Survival analysis was completed by Kaplan-Meier method. Results: Protease expression in localized vs. healthy cases was significant for (CTSB [p = 1.33E-10], MMP1 [p = 6.66E-21], MMP3 [p = 1.39E-13], MMP9 [p = 2.77E-08], NE [p = 0.00015], uPA [p = 2.55E-11]) and borderline significant for arginase [p = 0.05082]. Protease expression in metastatic vs. healthy cases was significant for (CTSB [p = 7.06E-06], MMP1 [p = 3.08E-12], MMP3 [p = 2.51E-14], MMP9 [p = 1.73E-08], NE [p = 0.01430], uPA [p = 0.00024]). Further, metastatic vs. localized cancer was significant for (arginase [p = 0.00034], CTSB [p = 0.00584], MMP1 [p = 2.03E-13], NE [p = 2.29E-10], and uPA [p = 6.58E-07]. Characteristics of 21 localized PC patients are illustrated in Table. Median OS was 25m in localized PC with low Arginase expression (mean < 215) vs 17.5m in high Arginase expression (p = 0.0477). Conclusions: Expression pattern of CTSB, MMP, NE, arginase, uPA proteases showed statistical significant difference for detection of localized PC vs metastatic PC vs healthy cases. In localized PC, lower arginase expression showed a statistically significant improvement in survival vs high arginase expression. Arginase expression was borderline significant for detection of localized PC vs healthy controls, likely due to small sample. Arginase as a potential biomarker for early detection and prognosis of PC warrants validation in a larger cohort. [Table: see text]

e16738 Background: A phase II trial has shown improved efficacy of neoadjuvant therapy when combined with losartan (by remodeling desmoplasia) in locally advanced pancreatic ductal adenocarcinoma (PDA). However, role of losartan is unknown in metastatic PDA. We examined the relationship between the use of the angiotensin II receptor antagonist, losartan, at time of diagnosis with clinical outcomes in metastatic PDA pts that received chemo. Methods: We retrospectively evaluated 114 metastatic PDA pts treated at our center between Jan 2000 and Nov 2019. We compared OS, PFS, objective response rate (ORR), and disease control rate (DCR) between pts using losartan at time of cancer diagnosis and a control group of pts not on losartan. A subanalysis was performed based on losartan dose: 100mg dose versus control pts. and based on chemo: FOLFIRINOX or gemcitabine+abraxane. Results: Table shows baseline demographics. No significant difference was found in OS [p = 0.455] or PFS [p = 0.919] in pts on losartan (median 274d, 83d) vs control (median 279d, 111d) [p = 0.466]. No significant difference was found in ORR [p = 0.621] or in DCR [p = 0.497]. No significant difference was found in OS [p = 0.771] or PFS [p = 0.064] in losartan pts (median 347d, 350d) vs control (median 333d, 101d) treated with FOLFIRINOX. No significant difference was found in OS [p = 0.916] or PFS [p = 0.341] in losartan (median 312d, 69d) vs control (median 221d, 136d) [p = 0.916] treated with gemcitabine+abraxane. No significant difference was found in OS [p = 0.727] or PFS [p = 0.790] in 100mg losartan pts (median 261d, 84d) vs control (median 279d, 111d). Conclusions: Pts on losartan at time of diagnosis had no significant difference in OS, PFS, ORR, DCR than control pts. However, a subanalysis of pts treated with FOLFIRINOX revealed a longer PFS with losartan than control but did not meet statistical significance, likely due to small sample size. To confirm if the benefit of losartan + FOLFIRINOX seen in neoadjuvant setting for locally advanced cancer also applies to metastatic cancer, our findings need to be validated in a larger cohort. [Table: see text]

4563 Background: Cabo targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-L1 inhibitors like durva. We conducted a phase Ib GI basket trial to evaluate the safety & efficacy of this regimen in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), & hepatocellular carcinoma (HCC). Methods: Patients received cabo and durva in 3+3 dose escalation then expansion to determine the dose limiting toxicity (DLT), Recommended Phase 2 Dose (RP2D), ORR, PFS & OS. Cabo was dosed at 20mg QD, 40mg QD, and 60mg QD in the first, second, and third cohorts respectively. Durva was dosed at 1500mg IV Q4W in all cohorts. DLT window was 28 days. Scans were obtained every 8 wks. Treatment beyond progression was allowed. Results: 23 Pts (16 M, 7 F), median age 60 yrs (range 33-79) were currently enrolled. 12 in the dose escalation cohort with cabo 20mg (6 pts), or 40mg (3 pts), or 60mg (3 pts). 11 pts enrolled in the dose expansion cohort with cabo 60mg. 8 pts had GEA, 13 pts had CRC, and 2 pts had HCC. Median number of prior chemotherapies was 3 (range 1-3). 3 pts were not evaluable for DLT due to missing ≥30% of DLT window doses, not related to DLT. No DLTs were observed. Drug-related Grade (G) 1&2 AEs included fatigue (83%), abnormal LFTs (39%), anorexia (26%), diarrhea (26%), nausea (13%), & hand foot syndrome (13%). One pt each developed drug related G3 hypertension, hyperthyroidism, thrombocytopenia, & thromboembolic event, all occurring outside the DLT window. 19 pts were evaluable for response: 4 PR (2 GEA & 2 CRC), 12 SD, 3 PD; ORR 21%; clinical benefit rate 84%; median time to PD 16 wks (range 8-40+). Conclusions: RP2D was determined to be Cabo 60mg QD and Durva 1500mg Q4W. Enrollment to phase I dose expansion is ongoing. RP2D may be adjusted based on additional experience & long-term tolerability. Early efficacy data was encouraging. This is an investigator-initiated trial funded by Exelixis & Astrazeneca. Clinical trial information: NCT03539822 .

e16803 Background: Pancreatic cancer has a dismal 5 year survival of 5-10%. Deaths commonly occur in-hospital as they present with acute complications. The purpose of this study is characterize this population compared to all pancreatic deaths, identify causes for admission, trends in palliative care utilization and its effect on costs and patient stay. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of pancreatic cancer were identified using the National Inpatient Sample. Annual trends in death were compared to overalls deaths using SEER data. Trends in hospital length of stay (LOS) and total charges (TC) were assessed, as well as utilization of palliative care. The effect of palliative care utilization on hospital LOS and TC were also identified. Results: 97,389 (weighted) patient deaths occurred from 2002 to 2014, with 7,634 in 2002, compared to 7,200 in 2014. Compared to total overall deaths of 38,026 and 42,047 respectively. Signifying 25% (2002) to 21% (2014) total patients expiring in an in-patient setting. The most common billed primary diagnosis was sepsis at 15.5%, followed by acute renal failure and fluid disorder (12.5%) and liver failure (5.3%). Overall length of stay trended down from 9.0 days to 7.5 days (p < 0.001). And total charges for admission increased from $36,704 to $88,063 (p < 0.001). Palliative care consults increased from 12% in 2002 to 45% in 2014. In 2014, the TC for deaths among those who received palliative care consults was $52,612 (p < 0.001 when compared to all deaths). LOS among these patients also decreased from 7.5 days to 6.2 days. When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $86,738 to $74,544 (p < 0.001). LOS was not significantly different at 8.8 days compared to 8.5 days (p = 0.15). Conclusions: A quarter of patients with pancreatic cancer die in an in-hospital setting. Palliative involvement decreased health care resource utilization. In reviewing patients who developed sepsis without in-hospital mortality, a palliative care consult decreased total charges of admission.

e16673 Background: Liver cancer and bile duct cancer remain among of the most deadly cancers with a dismal 5 year survival of 2-15%. Patients often end up dying in an in-hospital setting as a result of acute complication of cancer progression. The purpose of this study is to identify annual trends in this sub-population, including cause of admission, palliative care utilization and economic impact on healthcare. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of liver and bile duct cancer were identified using the National Inpatient Sample. Annual trends in incidence were compared to overall deaths via the SEER database. Trends were identified in hospital length of stay (LOS), total charges (TC), as well as utilization of palliative care. The effect of palliative care utilization on hospital length of stay and costs were also studied. Results: 73,833 (weighted) patient deaths were recorded from 2002 to 2014, 4,577 in 2002, compared to 6,595 in 2014. Signifying 33% (2002) to 32% (2014) of total deaths related to these cancers. The most common billed primary diagnosis was liver failure at 16.9%, sepsis (15.3%) and renal failure (6.7%). Overall LOS trended down from 5.9 days to 4.8 days (p < 0.001). Palliative consults increased from 8.2% in 2002 to 39.4% in 2014. In 2014, the mean TC for those who received palliative consults versus those who did not was $52,612 and $64,388 respectively (p < 0.001). LOS among these patients did not significantly change at 5.9 and 5.6 days (p = 0.13). When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $87,564 to $75,223 (p < 0.001). LOS was not significantly different at 8.8 days to 8.5 days (p = 0.15). Conclusions: A third of patients with liver and bile duct cancers die in an in-hospital setting. More effort needs to be undertaken to identify these patients and establish appropriate goals of care prior to such an event. Nonetheless, palliative involvement decreased health care resource utilization. Even among patients with sepsis who did not die, a palliative care consult decreased total charges of admission.

e15129 Background: Recent studies have observed an association between immune-related adverse events (irAE) and favorable clinical outcomes in the setting of cancer treatment with immune checkpoint inhibitors (ICI). However, results have been variable and inconclusive. Therefore, we have conducted a pan-cancer meta-analysis evaluating the relationship between irAEs and clinical outcomes. Methods: The search included PubMed, Embase, and Web of Science from conception to 12.28.2019 as well as abstracts published in the ASCO and ESMO meetings from 2015 to 2019. Studies were included if ICI was used in advanced or metastatic cancer settings and excluded if data contained only combination therapy regimens or contained anti-CTLA-4. Pooled sensitivity (SN), specificity (SP), positive (PPV) and negative predictive values (NPV), and odds ratios (ORs) were calculated using the 2 x 2 table and logit transformed proportions; and summary receiver operating curve (sROC) was generated using the bivariate approach for ORR. Pooled HRs were calculated using the means weighted by inverse of the variance for OS and PFS. Heterogeneity was assumed and random effects model was used throughout analyses. Results: Final analysis included 32 studies encompassing non-small cell lung cancer, melanoma, gastric cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancer. With respect to ORR, pooled SN, SP, PPV and NPV, and OR were 0.522 [0.423-0.619], 0.810 [0.771-0.844], 0.516 [0.413-0.618], 0.819 [0.764-0.864], and 4.59 [3.24-6.50] respectively. The area under the curve (AUC) derived from the sROC was 0.773. HR for OS and PFS were 0.47 [95% CI 0.37-0.60] and 0.46 [95% CI 0.37-0.56] respectively. Between-study publication bias was present for ORR, OS, and PFS but results remained significant after trim-fill analysis. Conclusions: irAEs predict OR, OS, and PFS across different types of cancer and may represent useful biomarkers in the clinical setting. [Table: see text]

531 Background: The impact of corticosteroid treatment (CT) on the efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) is undefined. We evaluated whether CT administered at baseline (bCT) or concurrently to ICI (cCT) influences clinical outcomes of HCC patients treated with ICI. Methods: This retrospective, multi-center observational study was conducted across 9 tertiary academic referral centers collected 341 HCC patients who received ICI across 3 continents between January 1, 2016 and April 1, 2019. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of ICI commencement and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1) on 6-8 weekly periodic restaging. Results: Of 331 eligible patients, 254 (76%) had BCLC-C stage HCC and received mostly PD(L)-1 ICI monotherapy (n=250, 85%). Median OS was 12.1 months (95%CI 9.2-15.0 months) and median PFS was 8.1 months (95%CI 6.3-10 months). In total 81 patients (24%) received >10 mg prednisone equivalent daily either as bCT (n=15, 4%) or cCT (n=66, 20%). Indications for CT included procedure/prophylaxis (n=37, 45%), management of irAE (n=31, 37%), cancer-related symptoms (n=5, 2%) or comorbidities (n=8, 3%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in uni- and multi-variable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (2.4 vs. 11.3 months, p=0.01), OS (4.5 vs. 12.8 months, p=0.05) and reduced ORR (p=0.03) compared to cancer-unrelated indications. Conclusions: This is the first study to demonstrate that neither bCT nor cCT appear to influence response and OS following ICI in HCC. Worse survival and ORR in CT recipients for cancer-related indications appears driven by the poor prognosis associated with symptomatic HCC.