Citations

93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P < 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.

92 Background: Since the publication of the MOSAIC trial, stage III CC has been treated with a six-month (mo) regimen of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Recently, the IDEA collaboration challenged this practice by demonstrating that the 3-year rate of disease-free survival (DFS) was non-inferior to 6mo of treatment (Rx) when given for low risk CC (83.1 vs. 83.3%) and resulted in significantly lower rates of grade 2 and higher neuropathy. In high risk (T4, N2) patients (pts) the DFS of 3mo of CAPOX was equivocal to 6mo (64.1 vs. 64.0%), while 3mo of FOLFOX was inferior to 6mo (61.5 vs. 64.7%). We hypothesized that trends in prescribing would favor shorter courses of Rx with a preference towards CAPOX given its efficacy across both high and low risk CC. Methods: We performed a retrospective analysis of stage III CC pts from 4 institutions. We evaluated prescribing patterns of 3mo or 6mo of Rx and CAPOX vs. FOLFOX over a period of 5 years from Jan 2016 to Jan 2021, a time period that traverses before and after the release of IDEA. Logistic and multinomial logistic regression models, with a linear time trend, were used to estimate the percentage of pts receiving CAPOX vs. FOLFOX and the combination of Rx and duration, respectively, while adjusting for baseline characteristics. The prescribing patterns in important subgroups were examined by incorporating the interaction term in the models. Results: A total of 366 pts met inclusion criteria. From 2016-2021, there was a significant increase per quarter in patients treated with CAPOX when compared to FOLFOX (OR 1.16 95% CI 1.11 – 1.21, p <.001). Prior to IDEA, 78.3% of pts received 6mo FOLFOX and 7.4% received 3mo CAPOX. Two years after IDEA, only 17.3% of pts were on 6mo FOLFOX compared to 67.5% of pts on 3mo CAPOX (Table). At present, high risk pts are more likely to receive 6mo FOLFOX (47.8%) than 3mo of FOLFOX (3.9%), 3mo CAPOX (25.8%), or 6mo CAPOX (22.4%). Low risk pts are more likely to receive 3mo of CAPOX (67.9%) than other Rx. Conclusions: Our findings suggest that since IDEA, physician practice has significantly changed in favor of CAPOX and shorter courses of Rx. The use of CAPOX has significantly increased overall, presumably due to its efficacy across all risk groups and relatively reduced toxicity.[Table: see text]

Purpose Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase ( IDH)-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH-mutated CCA. METHODS We conducted a multicentric, retrospective analysis of patients with IDH-mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH). RESULTS Sixty-five patients with IDH-mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non–gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%. CONCLUSION CCA with m IDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup.

Abstract Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

Abstract Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a &gt;80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. Prevention Relevance: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

AbstractLiposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN‐38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI‐1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two‐compartment model with first‐order elimination, with SN‐38 formed directly by a first‐order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN‐38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN‐38 clearance. Model evaluation was satisfactory for both irinotecan and SN‐38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN‐38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN‐38 concentrations. In summary, the PKs of total irinotecan and SN‐38 after administration of liposomal irinotecan were well‐described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.