Peters, Mary Linton B

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

PURPOSE Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation ( P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

Abstract Background Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. Methods This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. Results Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P &lt; .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P &lt; .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P &lt; .001). Conclusions Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

TPS350 Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) are found in approximately 20-30% of patients with intrahepatic cholangiocarcinoma (CCA), and less commonly in glioma, chondrosarcoma, and other gastrointestinal malignancies. Despite documented clinical activity of mIDH1 inhibition in solid tumors, there are no approved targeted therapies for this patient population. LY3410738 is a potent, selective, and covalent inhibitor of mIDH1 R132. LY3410738 is differentiated from prior mIDH1 inhibitors by 1) its unique covalent binding mode, 2) its increased potency, and 3) its unique binding site outside of the dimer interface, which enables activity in the setting of known common second-site IDH1 mutations. Methods: This is an open-label, multicenter, global phase 1 study with oral LY3410738 currently enrolling patients with advanced CCA and other solid tumor types (NCT04521686). A dose escalation cohort will be followed with 4 exploratory expansion cohorts. The primary objective for dose escalation is determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary objective for dose expansion is to assess the preliminary anti-tumor activity by ORR of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine. Secondary objectives include evaluating safety and tolerability, pharmacokinetics, pharmacodynamics, progression free survival, and overall survival. Key inclusion criteria include any solid tumor with the presence of mIDH1 R132, ECOG performance status ≤1, and adequate organ function. Any prior treatment including an IDH1 inhibitor is allowed in the dose escalation cohort. Exclusion criteria include presence of active central nervous system metastases, leptomeningeal disease, and active or uncontrolled infection. CCA patients must not have had locoregional therapy within 4 weeks prior to the initial study dose, history of hepatic encephalopathy or refractory ascites, ongoing cholangitis, or mixed hepatocellular-CCA histology. Dose escalation will follow a 3+3 design and will allow patient back-fill to dose levels previously cleared for safety. Each cycle will be 28 days (4 weeks). Once the RP2D is determined, LY3410738 will be evaluated as monotherapy in expansion cohorts 1-3, and in combination with cisplatin plus gemcitabine in expansion cohort 4. Cohort 1 will enroll CCA patients with measurable disease who have received prior chemotherapy. Cohort 2 will enroll patients with advanced solid tumors except CCA who have measurable disease and received standard therapies. Cohort 3 will enroll patients with advanced solid tumors who have non-measurable disease and received standard therapies. Cohort 4 will enroll CCA patients with measurable disease who are treatment naïve for advanced disease. Clinical trial information: NCT04521686.

580 Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.