Jin, Zhaohui

Hepatocellular carcinoma (HCC) is an aggressive malignancy accounting for 90% of primary liver malignancies. Therapeutic options for HCC are primarily based on the baseline functional status, the extent of disease at presentation and the underlying liver function that is clinically evaluated by the Barcelona-Clinic Liver Cancer system and Child–Pugh score. In patients with advanced HCC, the United States Food and Drug Administration (US-FDA) approved systemic therapies include the combination of atezolizumab–bevacizumab, sorafenib, and lenvatinib in the first line setting while cabozantinib, regorafenib, ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL), pembrolizumab, nivolumab, and nivolumab-ipilimumab combination are reserved for patients who progressed on sorafenib. European Medical Agency (EMA) approved the use of atezolizumab–bevacizumab, sorafenib, and lenvatinib in the first line setting, while cabozantinib, regorafenib, and ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL) are approved for use in patients that progressed on first-line therapy. In the first line setting, sorafenib demonstrated a median overall survival (OS) benefit of 3 months as compared to that of best supportive care in randomized phase III trials, while lenvatinib was shown to be non-inferior to sorafenib. Recently, phase 3 studies with immunotherapeutic agents including atezolizumab plus a bevacizumab combination and tremelimumab plus durvalumab combination demonstrated a better OS and progression free survival (PFS) compared to sorafenib in the first-line setting, making them attractive first-line options in advanced HCC. In this review, we outlined the tumorigenesis and immune landscape of HCC in brief and discussed the role and rationale of combining immunotherapy and anti-VEGF therapy. We further expanded on potential limitations and the future directions of immunotherapy in combination with targeted agents in the management of advanced HCC.

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti–programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.

TPS213 Background: Regorafenib (R) is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis; it has a survival benefit in refractory metastatic colorectal cancer (mCRC). The current standard (std) treatment in patients (pts) with RAS wildtype (WT) mCRC is sequential treatment with an anti-EGFR antibody (AEA) followed by R. However, R, which is orally administered once daily, may be more convenient and thus preferable for pts than AEA. REVERCE, a Japanese trial, demonstrated a significant 5.8 month (mo.) survival benefit with regorafenib administered prior to AEA compared to the std sequence. Based off these findings, the proposed phase II trial is to confirm the observed survival benefit from regorafenib sequencing prior to anti-EGFR monoclonal antibody therapy in REVERCE in a US patient population. Methods: REVERCEII is an Academic and Community Cancer Research United (ACCRU) network-led randomized phase II study of R (dose escalation from 80mg to 160mg based on tolerance) prior to AEA (R+AEA) compared to standard sequencing (AEA+R) in pts with refractory RAS WT mCRC. Patients are randomized 1:1 to receive R (Arm A) vs. AEA (with or without irinotecan per investigator choice) (Arm B). At the time of disease progression or intolerance, patients will receive sequential treatment until disease progression. Eligibility criteria include histologically confirmed mCRC, ECOG ≤ 2, acceptable organ function, and patients must have had prior fluoropyrimidine, oxaliplatin and irinotecan, and no prior AEA nor R. The primary objective is to compare the overall survival (OS), the primary endpoint, between evaluable patients (eligible, consented, started protocol treatment) who were randomized to R+AEA (arm A) and AEA+R (arm B). With 83 OS events, we have 87% power to detect an improvement in median OS from 9 months to 14.5 mo., assuming 1-sided significance level of 0.15, and exponential distribution. The total sample size is 124 patients. Secondary endpoints include progression-free survival, objective response, and adverse events. The total study duration is expected to be 3 years. Clinical trial information: NCT04117945. Clinical trial information: 04117945.

344 Background: ICI with anti-PD-1 therapy was approved by the US FDA as 1st/2nd-line treatment of advanced GEC regardless of PD-L1 status. It is argued that patients (pts) with PD-L1-low GEC do not benefit from ICI. To avoid spurious exclusion of pts, we systematically reviewed phase 3 trials to assess the magnitude and consistency of PD-L1 to predict benefit from ICI. We also examined other potential predictive factors to understand their magnitude and consistency in comparison with PD-L1 status. Methods: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register were searched for all randomized clinical trials (RCT; 2000-2021) in advanced GEC comparing ICI, alone or with chemotherapy, vs standard of care (SOC). The primary endpoint was overall survival (OS). Study screening, data abstraction, and bias assessment were done independently by two reviewers per PRISMA guidelines. The mean HR for ICI vs SOC was calculated by random effects model. The predictive value of a factor was quantified using relative magnitude and consistency (table). Results: 14 RCTs at low risk of bias were included (N = 9,210 pts; KN62, CM649, CM648, ESCORT1st, KN590, ATT4, JAV100, KN181, KN61, ATT3, ESCORT, RATIONALE302, JAV300, ATT2). 6 trials were 1st-line, 8 were after 1st-line. Treatment comparisons were ICI + chemo vs chemo (6 trials), ICI vs chemo (9 trials), and ICI vs placebo (1 trial). ICI was always anti-PD-1/-L1 (1 trial also had anti-CTLA-4). Table shows primary results. To enable head to head comparisons, subgroup analyses of trials containing both levels of a factor or having similar design were done and generally yielded consistent results. Conclusions: PD-L1 CPS is the strongest predictive biomarker, after MSI, for OS benefit from ICI-containing therapy vs SOC. Additional research on gender is warranted.[Table: see text]

248 Background: Esophageal carcinoma is the 6th most common cause of death worldwide. While squamous cell carcinoma (SCC) was the most common among the histologic subtypes in the 20th century, recent reports have demonstrated an increased incidence of adenocarcinoma in both Eastern and Western world. With this changing paradigm of esophageal carcinoma, it is important to estimate the future burden of esophageal carcinoma by histology, age, sex, and race, that could help plan prevention, control, and treatment strategies for this cancer. Methods: We used Surveillance, Epidemiology, and End Results (SEER) 14 registries to obtain incidence data from 2000 to 2016. We applied age-period-cohort models to estimate future esophageal carcinoma incidence rates and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: Our estimate suggests that the incidence (per 100,000 persons) of esophageal adenocarcinoma is increasing in people within the age group of 40-65 years. Our prediction showed that the incidence will increase from 2.12 in 2021 to 2.82 in 2030 (3.2% per year, 95% CI –2.3% to 9.1%, p=0.26). Notably, we noticed a similar marginal increase in incidence among Asians, Black, and Whites in the 40-65 years age group (3.1%, 3.2%, and 4.2%, per year, respectively). White males aged >65 years had the highest incidence of esophageal adenocarcinoma (17.34 in 2021), and incidence decreased 1.3% per year. We noticed a marginally decreased incidence in Black male (-1.1% per year, p=0.71) and Asian male (-3.9% per year, p=0.17) population aged >65 years. Interestingly, we found a decrease in the incidence of SCC in the current age groups 40-65 (-2.7% per year, p=0.31) and >65 years (-4.6% per year, p=0.081). We observed that Asians had the greatest decrease in incidence (-4.3% per year) as compared to that of Blacks (-4.2% per year) and Whites (-2.9% per year), although there was no statistically significant difference in the annual decrease among races. Conclusions: In our study of esophageal cancer, we predict an increased incidence of adenocarcinoma histology subtype in the younger age group (40-65 years) while the SCC subtype will have a decreased trend. Strategies to prevention esophageal adenocarcinoma, including dietary changes, should preferentially target patients <65 years of age.[Table: see text]

192 Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p<0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p<0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p<0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p<0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]

Abstract Background Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusions Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

PURPOSECholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort.METHODSThis is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020.RESULTSOur group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038).CONCLUSIONFGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.