bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of long-term survivors in the TOPAZ-1 study of durvalumab or placebo plus gemcitabine and cisplatin in advanced biliary tract cancer.
Authors: Bouattour Mohamed , Valle Juan W. , Vogel Arndt , Kim Jin Won , Kitano Masayuki , Chen Jen-Shi , Burris III Howard A. , Zaucha Renata , Qin Shukui , Evesque Ludovic , Zhen David Bing , Gupta Vineet Govinda , Park Joon Oh , Żotkiewicz Magdalena , Rokutanda Nana , Cohen Gordon , Oh Do-Youn
Published: January 2023

531

Background: At the primary analysis of TOPAZ-1 (NCT03875235; data cut-off [DCO] Aug 11, 2021), durvalumab (D) + gemcitabine and cisplatin (GC) significantly improved overall survival (OS) vs placebo (PBO) + GC in participants (pts) with advanced biliary tract cancer (BTC), with OS curves that separated over time (Oh et al. NEJM Evid 2022), that persisted with further follow-up (DCO Feb 25, 2022; HR, 0.76 [95% CI, 0.64–0.91]; 18-month OS, 34.8% [D + GC] vs 24.1% [PBO + GC]; Oh et al. Ann Oncol 2022 Abs 56P). We characterized long-term survivors (LTS) in TOPAZ-1. Methods: Pts untreated for unresectable locally advanced, recurrent or metastatic BTC received D (1500 mg every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on days 1 and 8 Q3W, up to 8 cycles, followed by D (1500 mg Q4W) or PBO. Characteristics and outcomes of LTS (pts who survived ≥18 months after randomization; DCO Feb 25, 2022) were assessed. Results: There were more LTS with D + GC vs PBO + GC (Table). Characteristics of LTS were consistent with the full analysis set (FAS, all randomized pts) including age, sex, region, primary tumor location, disease classification (metastatic vs locally advanced) and PD-L1 expression. Recurrent disease was more common than initially unresectable disease in LTS vs FAS. Median exposure to study treatment was 11.3 months (mo; D), 9.7 mo (PBO) and 5.5 mo (GC, both arms) in LTS and 7.3 mo (D), 5.8 mo (PBO) and 5.1 mo (GC, both arms) in FAS. The objective response rate in LTS was greater with D + GC vs PBO + GC (44.3%, D + GC; 33.8%, PBO + GC), and greater for both groups vs FAS (26.7%, D + GC; 18.7%, PBO + GC). A higher proportion of LTS in the PBO + GC group received subsequent anticancer therapy, including immunotherapy, than LTS in the D + GC group. The frequency of treatment-related adverse events leading to discontinuation in LTS was consistent with FAS. Conclusions: In TOPAZ-1, characteristics of LTS were generally consistent with the FAS. Overall, LTS were more common with D + GC; LTS in the PBO + GC group appear to be associated with higher frequency of subsequent treatments, including immunotherapy. Clinical trial information: NCT03875235 . [Table: see text]
A multicenter study to investigate the role of sarcopenia as a prognostic factor in patients with hepatocellular carcinoma treated by trans-arterial radioembolization.
Authors: Nam Heechul , Yang Hyun , Seo Yeon Seok , Kim Do Young , Kim Yoon Jun , Bae Si Hyun
Published: January 2023

532

Background: Trans-arterial radioembolization (TARE) is a form of radiation therapy performed by selective intra-arterial injection of microspheres loaded with Yttrium-90 in hepatocellular carcinoma (HCC). The aim of this study is to identify prognostic factors for overall survival (OS) and progression free survival (PFS) in patients with HCC undergoing TARE. Methods: This is a multi-center retrospective study on consecutive HCC patients undergoing TARE from Jul 2009 to May 2019. Using pre-treatment plain computed tomography imaging, the total cross-sectional area (cm2) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI) was calculated by normalizing muscle area to patient height. Results: A total of 347 patients were included in the study (mean age 66 years, 284 male patients). 107 patients (30.8%) had portal vein tumor thrombus (PVTT). 126 patients (36.3%) were classified as sarcopenia. Median 5-year OS was 31.3 months (95% CI 24.7–37.9) and median 12-month PFS was 9.7 months (95% CI 8.0–11.4). Sarcopenia (HR, 1.44; 95% CI, 1.01-2.04, p=0.04), PVTT (HR, 1.70; 95% CI, 1.13-2.56, p=0.01), hypoalbuminemia (≤3.5 g/dL) (HR 1.64; 95% CI 1.17-2.30, p<0.01), and prior treatment experience (HR 1.61; 95% CI 1.00-2.57, p=005) were independently associated with poor 5-year OS by multivariate Cox regression analysis. Sarcopenia, PVTT, multifocal tumor, and prior treatment experience were independent predictors of PFS in multivariate analysis. Conclusions: TARE is an effective therapy for patients with advanced HCC. In patients undergoing TARE, Sarcopenia and PVTT are independent predictors of both OS and PFS.
IMbrave150: Exploratory analysis to examine the association between bevacizumab (bev) ever being skipped and bev never being skipped in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bev in a global phase 3 study.
Authors: Kudo Masatoshi , Tsuchiya Kaoru , Shao Yu Yun , Finn Richard S. , Galle Peter R. , Ducreux Michel , Cheng Ann-Lii , Yamashita Tatsuya , Koga Hironori , Aoki Kenichi , Yamada Kyoko , Asakawa Takashi , Nakagawa Yuki , Ikeda Masafumi
Published: January 2023

538

Background: Treatment with atezo + bev has been approved globally for patients with unresectable HCC who have not received prior systemic therapy, based on results from the Phase 3 IMbrave150 study (NCT03434379, Finn NEJM 2020 and Cheng J Hepatol 2022). According to Phase 1b study data (Lee Lancet Oncol 2020), when combined with atezo, bev has a clinically relevant contribution in terms of immune enhancement and normalization of tumor blood vessels. However, it is unknown if bev being skipped due to bev adverse events of special interest (AESIs) has an impact on the efficacy of atezo + bev. Here, we conducted an exploratory efficacy analysis examining patients who had skipped bev vs those who never skipped bev using IMbrave150 study data. Methods: In Arm A of IMbrave150, patients were assigned to receive atezo + bev. Group A-1 included patients whose bev was ever skipped due to bev AESIs. Group A-2 included the patients who were not included in group A-1. Landmark analyses of overall survival (OS) and progression-free survival (PFS) were performed in patients who received atezo + bev for ≥6 months to minimize immortal time bias. Results: Of 210 patients who received ≥6 months of atezo + bev, 69 were assigned to group A-1 and 141 were assigned to group A-2. No obvious differences between groups were observed in the distribution of baseline characteristics. Of the group A-1 patients, 75.4% were BCLC stage C and 76.8% were Child-Pugh A5, while group A-2 patients were 80.1% BCLC stage C and 77.0% were Child-Pugh A5. At the data cutoff (Aug 20, 2020), median OS was 25.8 vs 26.2 months (HR, 1.04; 95% CI: 0.64, 1.69) and median PFS per independent review facility-assessed RECIST 1.1 was 15.5 vs 10.0 months (HR, 1.07; 95% CI: 0.74, 1.55) for groups A-1 and A-2, respectively. Conclusions: The patients who had ever skipped bev did not show different efficacy compared with those who had never skipped bev in this post hoc analysis. Although limitations due to the non-randomized and exploratory nature of this comparison should be acknowledged, the results suggest that skipping bev did not have considerable impact on the efficacy of atezo + bev. Clinical trial information: NCT03434379 .
The efficacy of capecitabine as a salvage treatment in metastatic colorectal cancer after prior 5-fluorouracil–included chemotherapies.
Authors: Jang Jae Yeon , Bang hyun-Jin , Bae Woo Kyun , Lee Seung-Shin , Lee Soonil , Shim Kwang Yong , Kong Jee Hyun , Kim Yundeok , Lim Seungtaek
Published: January 2023

54

Background: We aimed to retrospectively analyze the efficacy and toxicity of capecitabine, as a salvage treatment, in metastatic colorectal cancer (mCRC) that progressed after prior standard 5FU included chemotherapies. Methods: From January 1, 2008, to December 31, 2017, patients with mCRC, age ≥ 18, who received capecitabine as third- or fourth-line treatment at five different centers in South Korea, were included. All had disease progression on prior palliative chemotherapies including 5FU, oxaliplatin, and/or irinotecan. Results: A total of 131 patients were analyzed with a median age of 62 (range, 35-87). Almost all patients were exposed to prior 5FU (100%), irinotecan (100%), and oxaliplatin (98.5%). Patients were treated with cetuximab (26.7%), or bevacizumab (45.8%) before capecitabine. The median and mean duration from the last 5FU exposure to capecitabine start were 21 and 67.3 days, respectively (range, 5-1322). The objective response rate (ORR) of capecitabine was 3.6%, and the disease control rate was 30.4%. The median progression free survival (mPFS) and median overall survival (mOS) was 2.77 (95% CI, 2.495-3.045) and 9.60 months (95% CI, 7.625-11.575), respectively. There was a significant difference in efficacy according to the duration from the last 5FU exposure to the time of starting capecitabine. Compared to patients who started capecitabine earlier than 67 days after the last 5-FU administration, those who started capecitabine later than that time showed higher ORR (11.1% vs 1.2%; p-value = 0.043), mPFS (4.430 (95% CI, 2.274-6.586) vs 2.570 months (95% CI, 2.326-2.814); p-value = 0.011), and mOS (14.070 (95% CI, 5.627-22.513) vs 9.500 months (95% CI, 7.370-11.630, p-value = 0.021) (Table). 68.7% patients experienced any grade of adverse events, but only 4.6% complained grade 3 or higher. There was no treatment related death. Conclusions: Capecitabine showed modest antitumor activity with good tolerability in mCRC patients whose disease progressed after oxaliplatin and/or irinotecan. It could be considered as an alternative treatment option for mCRC patients, especially for those who have longer treatment free interval after 5FU based chemotherapies. [Table: see text]
Pertuzumab plus trastuzumab (P+T) in patients (pts) with biliary tract cancer (BTC) with ERBB2/3 amplification (amp), overexpression (oe), or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Cannon Timothy Lewis , Rothe Michael , Garrett-Mayer Elizabeth , Chiu Vi Kien , Hwang Jimmy J. , Vijayvergia Namrata , Alese Olatunji B. , Dib Elie G. , Duvivier Herbert Leon , Klute Kelsey , Sahai Vaibhav , Ahn Eugene R , Behl Deepti , Sinclair Sarah , Thota Ramya , Urba Walter John , Yang Eddy Shih-Hsin , Grantham Gina N. , Halabi Susan , Schilsky Richard L.
Published: January 2023

546

Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with BTC with ERBB2/3 amp, oe, or mut treated with P+T are reported. Methods: Eligible pts had advanced BTC, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was done in CLIA-certified, CAP-accredited labs. Dosing of P was 840 mg IV over 60 minutes (m), then 420 mg IV over 30-60 m Q3 weeks (wks); T was 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m Q3 wks until disease progression. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) at 16+ wks (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, cohort is closed for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from start of tx to PD. Results: 29 pts with BTC (15 gallbladder (GB), 11 biliary duct (BD), 3 ampulla of Vater) and ERBB2/3 amp, oe, or mut were enrolled from Feb 2017 to Jan 2022. Median (med) age was 66 years (yrs) (range, 34-83 yrs). 66% of pts were female; 52% were White, 21% were Black/African American, 10% were Asian/Asian American; 83% were not Hispanic or Latino. 83% of pts had ECOG PS 0-1 and 48% had ≥3 prior systemic regimens. 1 pt was not evaluable and excluded from efficacy analysis. The table shows efficacy outcomes. 1 pt had CR (GB; ERBB2 amp; DOR: 71.1 wks), 8 pts had PR (6 GB/2 BD; 5 ERBB2 amp; 2 ERBB2 mut; 1 ERBB3 mut/ ERBB2 amp; med DOR: 30.4 wks (4.4 to 68.9 wks)) and 2 pts had SD16+. 4 pts with a KRAS mut did not achieve OR or SD16+. 4 pts had a Grade 3 drug-related adverse or serious adverse event (SAE): anemia, diarrhea, infusion related reaction (SAE), and fatigue. Conclusions: P+T demonstrated antitumor activity in pts with advanced BTC with ERBB2/3 alterations. These data, along with results previously reported by other studies, support continued study of P+T in pts with ERBB2 amplified BTC tumors. Clinical trial information: NCT02693535 . [Table: see text]
Comparison of clinical features by primary sites in patients with biliary tract cancer who received gemcitabine-based chemotherapy: An exploratory analysis of JCOG1113.
Authors: Suzuki Yuko , Morizane Chigusa , Mizusawa Junki , Sano Yusuke , Kobayashi Satoshi , Imaoka Hiroshi , Terashima Takeshi , Ikeda Masafumi , Okano Naohiro , Sugimori Kazuya , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Sekimoto Mitsugu , Sano Keiji , Tobimatsu Kazutoshi , Katanuma Akio , Okusaka Takuji , Ozaka Masato , Ueno Makoto
Published: January 2023

548

Background: Biliary tract cancers (BTCs) include gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AV). Although it was previously reported that there were differences in clinical features individually, the reported data were limited to data from some subgroup analyses of recent randomized controlled trials. JCOG1113 (UMIN000010667) showed the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin in terms of overall survival (OS) in patients (pts) with advanced BTCs. We aimed to compare clinical features among the primary sites of BTCs using JCOG1113 data. Methods: Among the 354 pts enrolled in JCOG1113, 352 pts were included in this analysis except for 2 pts without BTCs. We compared the patient characteristics and treatment outcomes, such as OS, progression-free survival (PFS), and objective response rate (ORR), among the four primary sites. Results: Of the 352 pts, 137 pts (38.9%), 94 pts (26.7%), 108 pts (30.7%) and 13 pts (3.7%) had GBC, IHCC, EHCC, and AV, respectively. GBC was more common in females (58.4%) than males, in contrast to the other primary sites. The percentage of pts with metastatic disease for GBC was the highest (78.1%) and involved multiple metastatic organs (41.6%), in contrast with the other primary sites. The median OS for GBC, IHCC, EHCC and AV were 12.6 months (reference), 15.7 months (hazard ratio [HR]; 0.749, 95% confidence interval [CI], 0.559-1.005), 16.3 months (0.704, 0.532-0.934) and 11.5 months (1.148, 0.633-2.080), respectively. The median PFS for GBC, IHCC, EHCC and AV were 5.7 months (reference), 6.2 months (0.843, 0.644-1.104), 8.7 months (0.636, 0.489-0.826) and 4.1 months (1.506, 0.851-2.665), respectively. The ORRs for GBC, IHCC, EHCC and AV were 34.4%, 28.9%, 34.4%, and 0.0%, respectively. Conclusions: Except for AV which included a few patients in this trial, GBC showed a poorer prognosis compared with the other primary sites. Furthermore, it was more likely to include metastatic disease and multiple metastases, and this is likely one of the causes of the poorer prognosis. [Table: see text]
Presence and impact of antidrug antibodies (ADAs) to tremelimumab (T) or durvalumab (D) in the phase 3 HIMALAYA study of unresectable hepatocellular carcinoma (uHCC).
Authors: Crysler Oxana V. , Yarchoan Mark , Furuse Junji , Galle Peter R. , Sukeepaisarnjaroen Wattana , Thinh Nguyen Tien , Masi Gianluca , Lim Ho Yeong , Varela Maria , Gupta Charu , Makowsky Mallory , Negro Alejandra , Abou-Alfa Ghassan K.
Published: January 2023

551

Background: ADAs to immune checkpoint inhibitors may decrease antitumor activity in HCC. Reported rates of treatment-emergent ADAs (TE-ADAs) vary from 1.5% for pembrolizumab and 8.6% for nivolumab to 54.1% for atezolizumab across indications (Enrico et al. Clin Cancer Res 2020). In the global, Phase 3 HIMALAYA study (NCT03298451) in uHCC, the STRIDE regimen (Single T Regular Interval D) significantly improved overall survival vs sorafenib (S); D monotherapy was noninferior to S (Abou-Alfa et al. NEJM Evid 2022). Here, we analyzed ADAs to T and D in HIMALAYA. Methods: Prespecified secondary analyses assessed the presence of ADAs to D and T before the first study dose (baseline), once during treatment and once after treatment discontinuation. For participants (pts) who were ADA-positive at any visit (ADA+), presence of neutralizing antibodies (nAbs) was also assessed. TE-ADA+ was defined as pts with a positive post-baseline sample only or pts with an ADA titer that increased ≥4-fold following treatment. ADA negative (ADA-) was defined as pts with no positive sample at any visit, at baseline or post-baseline. Objective response rate (ORR; RECIST v1.1, inc. unconfirmed), overall survival (OS) and treatment-related adverse events (TRAEs) were evaluated in ADA subgroups. Results: The frequency of ADAs to D was similar in the STRIDE (T+D) and D arms: 8.2% (24/294) and 7.1% (20/282) of pts, respectively, were ADA+ to D; 3.1% (9/294) and 2.8% (8/282) of pts, respectively, were TE-ADA+ to D; and 1.7% (5/294) and 0.7% (2/282) of pts, respectively, had nAbs to D. In the STRIDE arm, 15.9% (29/182) of pts were ADA+ to T, 11.0% (20/182) of pts were TE-ADA+ to T, and 4.4% (8/182) of pts had nAbs to T. Although the number of pts was small, in the STRIDE arm, ORR was 11.1% (1/9) in pts TE-ADA+ to D, 35.0% (7/20) in pts TE-ADA+ to T and 23.9% (94/393) in the full analysis set (FAS). In the D arm, ORR was 25.0% (2/8) in pts TE-ADA+ to D and 18.5% (72/389) in the FAS. OS for pts TE-ADA+/nAb+ to D or T in the D and STRIDE arms was consistent with the FAS. In both arms, TRAE and Grade 3/4 TRAE rates were not increased in the ADA+ vs ADA- groups (Table) and were generally consistent with the overall population. Conclusions: In HIMALAYA, the rates of TE-ADAs and nAbs to D and T were low (≤11%). The presence of ADAs did not appear to impact clinical efficacy or safety of STRIDE or D monotherapy in the small number of ADA+ pts. These results support a low risk of ADAs for STRIDE or D in uHCC. Clinical trial information: NCT03298451 . [Table: see text]
Efficacy of nivolumab and ipilimumab in patients with hepatocellular carcinoma with prior immune-checkpoint inhibitor treatment.
Authors: Cheon Jaekyung , Kang Beodeul , Jung Sang-Hoon , Kim Chan , Chon Hongjae
Published: January 2023

554

Background: Nivolumab plus ipilimumab (NIVOIPI) demonstrated promising efficacy in patients with unresectable hepatocellular carcinoma(uHCC) in the phase 1/2 CheckMate 040 trial. However, as atezolizumab plus bevacizumab (Ate/Bev) is a new first-line standard systemic therapy, it is necessary to evaluate the role of NIVOIPI after treatment with Ate/Bev. Methods: Patients with uHCC who received NIVOIPI after previous systemic treatment were included. Patients received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks (four doses), followed by nivolumab (240 mg) every 2 weeks. Patients with Child B/C class and BCLC D stage uHCC were excluded. Patients who had at least one follow-up visit after the start of NIVOIPI were included. Results: A total of 47 patients were included with characteristics as follows: median age of 60 years (range, 37–79); hepatitis B (n = 40, 85.1%), hepatitis C (n = 2, 4.3%), non-viral (n = 5, 10.5%); BCLC B/C (n = 2, 4.3%; n = 45, 95.7%); macrovascular invasion (n = 12, 25.5%); extrahepatic metastasis (n = 41, 87.2%); and AFP ≥ 400 ng/ml (n = 26, 55.3%). Thirty-five (74.5%) patients had a history of prior immune-checkpoint inhibitor (ICI) treatment (n = 35, 74.5%), including Ate/Bev (n = 23, 48.9%). According to the RECIST 1.1, 12 patients achieved a partial response, resulting in an overall response rate (ORR) of 25.5% and disease control rate (DCR) of 42.6%. The ORR and DCR were 41.7% and 58.4% in ICI-naïve patients and 20.0% and 37.1% in patients with prior ICI treatment. The median follow-up duration was 5.7 months (95% confidence interval [CI], 5.4–6.1), the median progression-free survival was 1.4 months (95% CI, 1.1–1.7) in all patients, 1.3 months (95% CI, 0.1–1.1) in prior ICI-treated patients and was not reached in ICI-naïve patients. The median overall survival was not reached. The most common grade 3–4 toxicities were aspartate aminotransferase elevation (n = 4, 8.5%), neutropenia (n = 4, 8.5%), skin toxicity (n = 3, 6.4%), alanine transaminase elevation (n = 2, 4.3%) and pneumonitis (n = 2, 4.3%). There was one treatment-related death due to toxic epidermal necrolysis. Conclusions: NIVOIPI demonstrated clinical meaningful efficacy in patients with uHCC, with and without prior ICI treatment.
Multisite institutional study of efficacy and safety of cabozantinib following immunotherapy in patients with advanced hepatocellular carcinoma.
Authors: Palmer Mathias Earl , Storandt Michael H. , Gile Jennifer , Zemla Tyler J. , Bekaii-Saab Tanios S. , Jin Zhaohui , Tran Nguyen H. , Mahipal Amit
Published: January 2023

559

Background: Cabozantinib, a multikanase inhibitor, is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) following progression on sorafenib. The CELESTIAL study which demonstrated benefit from cabozantinib following sorafenib included only patients with Child Pugh class A liver function. Recently, bevacizumab plus atezolizumab has replaced sorafenib as the first line treatment for HCC. It is unclear whether there is benefit from using Cabozantinib following progression on immunotherapy as CELESTIAL trial included very few patients who received prior immunotherapy. We describe the outcomes of individuals with advanced stage HCC treated with Cabozantinib following progression on immunotherapy. Methods: This was a multicenter, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic Arizona, Florida, and Minnesota. Progression free survival (PFS) and median overall survival analysis were performed using Kaplan-Meier method. Results: We identified a total of 26 patients with advanced stage HCC who received cabozantinib following progression on immunotherapy. The median age of patients was 61 years (range, 39 – 81) and the majority were male (85%). Eighteen (72%) patients had Child Pugh A at initiation of cabozantinib therapy. Four (15%) patients received cabozantinib as second line therapy, the rest received it as third line or later. PFS on cabozantinib was 2.1 months (95% CI: 1.3 – 3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3 – 14.9). PFS was shorter with Child Pugh Class B, 1.3 months (95% CI: 0.9 – NE) compared to those with Child Pugh Class A, 2.1 months (95% CI: 1.5 – 4); although this difference was not significant (p=0.55). Common adverse events included fatigue (50%), anorexia (35%), aspartate aminotransferase (AST) elevation (35%), and diarrhea (31%); 7 (26%) patients experienced Grade 3 or greater adverse events including hypertension, diarrhea, anorexia, and bowel obstruction. Two patients discontinued cabozantinib due to side effects including one for uncontrolled blood pressure elevations and the other due to fatigue. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy is unknown. Treatment with cabozantinib may improve clinical outcomes following progression on immunotherapy with similar adverse event profile. This study included patients with Child Pugh class B liver disease (28%) and heavily pretreated population and demonstrated mPFS and mOS similar to other work examining outcomes of cabozantinib in real world setting after progression on sorafenib. Further studies to determine optimal treatment sequencing for this patient population are needed.
Real-world use of biologics and its association with outcomes in RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) in Canada.
Authors: Cheung Winson Y. , Boyne Devon J. , Brenner Darren R. , Martinez Daniel , Wani Rajvi J. , Ngan Elaine
Published: January 2023

56

Background: The use of biologics in combination with chemotherapy early in the course of treatment in mCRC improves outcomes, but whether this approach is uniformly adopted in clinical practice is unclear. This study aims to describe biomarker testing, treatment patterns, and survival of RAS WT, left-sided mCRC patients in a real-world population. Methods: We performed deterministic linkages with population-based data sources, including the cancer registry, pharmacy data, electronic medical records, and vital statistics to identify all patients who were diagnosed with RAS WT, left-sided mCRC, and treated with first-line (1L) combination systemic therapy from 2014 to 2019 in Alberta, Canada. Patients were followed until December 31, 2020. Results: Of 2,721 patients with left-sided mCRC, 1,375 were referred and received systemic therapy, 977 underwent RAS testing prior to or within 30 days of initiating 1L treatment, and 420 were found to be RAS WT. Among them, 320 were treated with 1L combination systemic therapy: FOLFOX/CAPOX/FOLFIRI (n=204), panitumumab (pani) with doublet chemotherapy (n=64), or bevacizumab (bev) with doublet chemotherapy (n=52). The interval from diagnosis to RAS test results was 38 (IQR 24-61) days. Only 207 (65%) and 125 (39%) of the 320 1L-treated patients reached 2L and 3L therapy, respectively. Median overall survival based on the different 1L regimens are summarized. Conclusions: Many real-world patients with mCRC were not exposed to biologics as part of their front-line treatment. There is a need to enhance RAS testing in 1L as 29% of patients were not tested, despite recommendations from guidelines. Because attrition across lines of therapy is high in mCRC, the opportunity to receive and benefit from biologics in later lines of therapy may be importantly reduced. [Table: see text]
A phase II clinical trial to study the use of cabozantinib (cabo) in patients with hepatocellular carcinoma (HCC) post immunotherapy treatment.
Authors: Chan Stephen Lam , Ryoo Baek-Yeol , Mo Frankie , Cheon Jaekyung , Li Leung , Wong Kwan H. , Yim Nicole , Kim Hyeyeong , Yoo Changhoon
Published: January 2023

571

Background: There has been a lack of prospective clinical trial data on subsequent treatment after immune checkpoint inhibitor (ICI)-based treatment in HCC. To address this question, we designed and completed a phase II multicentred study to evaluate the use of cabo in HCC after prior ICI-based treatment. Methods: This is an investigator-initiated clinical trial involving 3 academic centres in Hong Kong and Korea. Key eligibility criteria include confirmed diagnosis of HCC; refractoriness to prior ICI-based treatment; duration of prior ICI-based treatment ≥2 months; Child's A liver function; ECOG performance status 0-2; maximal 2 lines of therapy. All patients (pts) were started cabo at 60mg once daily to progressive disease or intolerable toxicity. The primary endpoint is progression-free survival (PFS). Other secondary endpoints including response rate (RR) according to the RECIST, overall survival (OS) and treatment-related adverse event (TRAE). Total sample size is 48 (one-sided alpha 0.05; power 80%). Results: Total 48 pts were recruited from Oct 2020 to May 2022. Data were frozen on 1 Aug 2022 for analyses. The median follow-up was 11.2m. Seven (14.9%) pts remained on treatment; 1pt was found to ineligible and excluded from the analysis. The median age is 61 (Range 36-83). Aetiology of HCC: HBV 34 (72.3%); HCV 2 (4.3%); alcoholic 8 (17%); Most pts have BCLC stage C (93.6%). All pts have Child’s A liver function. Total 39 (83%) pts receive ICI-based first-line therapy, and 19 (40.4%) pts have prior atezolizumab-bevacizumab (AB) treatment. The median PFS is 4.1m (95% CI 3.3-5.3). Regarding RR, PR and SD occurs in 3 (6.4%) and 36 (76.6%) pts, respectively. The median OS is 9.9m (95% CI 7.3-14.4) and the 1-year survival rate is 45.3%. Amongst the 19 pts receiving prior AB treatment, the median OS is 14.3m (95% CI: 5.5-14.4) with 1-year survival rate of 50.7%. For non-AB regimen, the median OS is 8.9m (95% CI 6.1-NR) with 1-year survival rate of 42.0%. Commonest G3-4 TRAE is thrombocytopenia (6%); hypertension (4%) and ALT elevation (4%).The median dose of cabo is 41.6mg per day (range: 24.3-60.0 mg). Conclusions: Post-ICI use of cabo is associated with a median PFS of 4.1m and median OS of 9.9m. AB-cabo sequence appears to have more favourable outcome than non-AB-cabo sequence. No new safety signals were observed. This clinical trial reports the first prospective post-ICI survival data on TKI. Clinical trial information: NCT04588051 .
Tislelizumab in combination with anlotinib as first-line treatment for unresectable hepatocellular carcinoma: A single-arm, phase II clinical trial.
Authors: Laoguo Shi-xue , Huang Huasheng , Zeng Jie , Jiang Yangfeng , Liu Cuizhen , Mo Ning , Zhu GuangZhi , Ma Fuchao , Peng Tao , Zeng Zhiming , Ma Jie
Published: January 2023

576

Background: The inability to perform liver resection is an important cause of high mortality in Hepatocellular carcinoma (HCC) patients. Based on the clinical data of anlotinib (a multi-targeted tyrosine kinase inhibitor) and tislelizumab (anti‐PD‐1 antibody) in HCC pts, we therefore evaluated the safety and efficacy of tislelizumab plus anlotinib as first-line therapy for patients with unresectable HCC. Methods: Patients aged 18-75 years, with unresectable HCC, ECOG PS 0-3, BCLC stage A-D, Child-Pugh score A-C, and CNLC stage Ia-IV were enrolled. Patients who met the inclusion criteria received tislelizumab(intravenous drip, 200 mg/d1, Q3W) and anlotinib(oral, 8-12 mg/d1-14, Q3W). The primary endpoint was objective response rate (ORR). The secondary endpoints included disease control rate (DCR),overall survival (OS), progression-free survival (PFS), adverse events (AEs), and serious adverse events (SAEs). Results: Between Sep-2020 until Sep-2022, 37 patients were enrolled, and 25 patients’ clinical data were available to assess clinical efficacy. The median age of the pts was 62 years (ranged 31-72 years), 15 pts (60%) ECOG PS 1, 14 pts (56%) BCLC stage C, 17 pts (68%) Hepatitis B Virus Infection and 13 pts (52%) had received prior local regional therapy. The ORR per mRECIST was 32% (95% CI, 12.3%-51.7%) and DCR was 72% (95% CI, 53.1%-90.9%). The best clinical response was CR in 2 pts (8%), 6 pts (24%) PR and 10 pts (40%) SD. With a median follow-up of 12.7 months, the estimated median PFS was 11.8 months, and the median OS was not reached. The most common AEs during follow-up were AST increased (52%), γ-GT increased (48%), and hypoalbuminemia (48%). Conclusions: Tislelizumab combined with anlotinib showed high antitumor activity and good tolerability in the treatment of unresectable HCC, which may be an effective and safe treatment option.
Phase 2 trial of pembrolizumab (pembro) and bavituximab (bavi) in advanced hepatocellular carcinoma (HCC).
Authors: Hsieh David , Kainthla Radhika , Zhu Hao , Beg Muhammad S.
Published: January 2023

584

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for more than 500,000 deaths annually. Bavi, a monoclonal antibody designed to inhibit the immunosuppressive effects of phosphatidylserine through interaction with TIM and TAM receptor family members in the tumor microenvironment (TME), is being evaluated in combination with pembro, a monoclonal antibody designed to inhibit Programmed cell death protein 1 (PD-1), in patients with advanced HCC. Methods: This phase 2, open-label, multi-site trial included patients with histologically confirmed locally advanced or metastatic HCC who have not received prior systemic therapy. Patients were treated with pembro (200 mg Q3W) in combination with bavi (3 mg/kg QW) until disease progression. The primary endpoint of the trial is confirmed ORR by RECIST 1.1. A minimax two-stage method to analyze ORR after 15 patients and enroll an additional 13 patient if 3 or more responses observed in first 15 patients (NCT03519997). Results: Three out of 15 evaluable patients responded during Stage 1, allowing for enrollment to continue with a planned 13 additional patients in Stage 2. The study completed enrollment after a total of 28 patients were determined to be evaluable. The confirmed ORR based upon data from 28 patients evaluable for response was 32% (9 confirmed, partial responses). The disease control rate was 61% (9 partial responses, 8 stable disease). The safety profile of pembro plus bavi was consistent with the established profiles of individual drugs and updated adverse events will be reported at the time of presentation along with correlative studies. Conclusions: The combination of bavi and pembro appears to be well tolerated in this patient population and has a toxicity profile comparable to monotherapy immune checkpoint inhibitor. Preliminary analyses suggests that bavi and pembro may have promising anti-tumor activity in advanced HCC. Clinical trial information: NCT03519997 .
A glimpse into the future of cholangiocarcinoma: Predicting the future incidence based on the current epidemiological data.
Authors: Tella Sri Harsha , Wieczorek Mikolaj , Hodge David , Mahipal Amit
Published: January 2023

616

Background: Cholangiocarcinoma (CCA) is an aggressive, heterogenous group of neoplasms that arise from the epithelial lining of bile ducts that have dismal poor prognosis. A recent epidemiological study in the United States demonstrated a steady increase in the incidence of cholangiocarcinoma from 2001 to 2017 with a predominant increase in the intrahepatic sub-type (iCCA). We sought to evaluate the future incidence of cholangiocarcinoma stratified based on the subtype, age, sex, and race, that could possibly help plan prevention, control, and treatment strategies for this cancer. Methods: We obtained histologically confirmed cases of cholangiocarcinoma (ICD-0-3 Site: C220, C21, and C240) from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) 18 registries between 2000 to 2017 and predicted the incidence between the years 2018-2029. We applied age-period-cohort models to estimate future cholangiocarcinoma incidence rates (per 100, 000) and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: A total of 12,737 and 8,395 patients with iCCA and extra-hepatic cholangiocarcinoma (eCCA) were included in the final analysis. The median age of iCCA cohort was 64 (range: 20-79) years and 46.4% were females whereas in eCCA the median age was 66 (range: 20-79) years and 43.8% were females. The overall observed age-adjusted incidence of iCCA between 2000-2017 was 1.07, which is predicted to increase to 2.13 by 2029 (99% increase) with a predominant increase in incidence rate observed in the age groups 70-79 and White males and females. Interestingly, incidence rate remained stable in Black and Asian males and in Asian females. Similarly, as compared to 2001-2017, the incidence of eCCA is projected to increase from 0.74 to 1.01 by 2029 (36.5% increase) with predominant increase noted in Black and Hispanic cohorts. In contrast, we noticed a relatively stable and decreasing incidence rate in White and Asian females, respectively. Conclusions: We predict an overall increased incidence of both iCCA and eCCA over the next decade especially in certain subgroups warranting the urgent need for preventive strategies. Further epidemiological studies are needed to determine the etiological factors contributing to predicted increase in incidence rate.
Quality-of-life outcomes after total neoadjuvant short course radiotherapy, chemo-immunotherapy, and total mesorectal excision for locally advanced rectal cancer.
Authors: Shamseddine Ali , Chehade Laudy , Kattan Joseph Gergi , Temraz Sally Naji , Amarin Rula , Awabdeh Tala , Charafeddine Maya , Al Darazi Monita , Turfa Rim
Published: January 2023

63

Background: A growing body of evidence supports total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC), however the optimal regimen is yet to be determined and little is known on the quality-of-life (QOL) implications of these therapies. We report QOL data from the Averectal study, which assessed the efficacy and safety of neoadjuvant short course radiotherapy (SCR) plus chemo-immunotherapy for patients with LARC. Methods: Between July 2018 and October 2020, patients enrolled in the Averectal study were invited to fill the Functional Assessment of Cancer Therapy for colorectal cancer (FACT-C) throughout their treatment. We analyzed results at baseline (T0), at completion of SCR and chemo-immunotherapy (T1), and at last-follow up after total mesorectal excision (TME) (T2). Paired sample t-test was used to compare mean scores for individual patients. Results: 39 patients completed the FACT-C form at the specified points. Median follow-up duration was 25.7 months. Median age was 58 years (range 31-74 years), 25 (64.1%) were males, 1 (3.1%) had stage II disease and the rest (96.9%) had stage III. All patients received SCR then 6 cycles of mFOLFOX-6 plus avelumab followed by TME. The mean score differences of the FACT-C subscales at different time-points are summarized. At the end of TNT, the social (SWB), emotional (EWB), functional well-being (FWB) and colorectal cancer subscale (CCS) scores improved compared to baseline (not significant) but physical well-being score (PWB) worsened (21.05 vs 22.94 p=0.025). After TME, all scores except EWB and FWB improved compared to T1, and all scores improved compared to baseline. The CCS, which assesses colorectal cancer specific concerns, significantly improved between T0 and T2 (19 vs 21.06, p=0.003). Overall, trial outcome index (TOI), reflecting functional status, improved after TME compared to baseline. Conclusions: Adopting neoadjuvant chemo-immuno-radiotherapy followed by TME for LARC does not result in QOL deterioration compared to baseline, and can improve colorectal cancer specific concerns. Clinical trial information: NCT03503630 . [Table: see text]
Clinical and radiological response to locoregional and systemic treatments in well-differentiated gastroenteropancreatic neuroendocrine tumors with liver metastases treated at a reference center in Mexico.
Authors: Arce Sandoval Cesar , Meneses Medina Mónica Isabel , Cisneros Cordero Miriam Heidi , Hernandez-Felix Jorge Humberto , Rosas Camargo Vanessa , Torres Valdiviezo Lucero Itzel , Ramirez Rixci , Gabutti Thomas Jesus Alejandro , Huitzil Melendez Fidel David David
Published: January 2023

644

Background: liver metastases (LM) from well-differentiated gastroenteropancreatic neuroendocrine tumors (wd-GEP-NET) can develop in 28-77% of patients (pts) in their lifetime. Multiple treatments can provide radiological and symptomatic response. Our aim was to evaluate responses to locoregional (LRT) and systemic (SYST) treatments in wd-GEP-NET with LM. Methods: we included consecutive records of pts with confirmed histological diagnosis of wd-GEP-NET and radiological LM, treated at our institution between 2008-2019. Relevant variables were retrospectively extracted from electronic records. Radiological response was assessed with RECIST 1.1 by radiological independent review. Results: 55 pts, 45.5% male. Median age at LM diagnosis 49 years (IQR 41-63). Primary tumor sites: 49% pancreatic, 27.3% small intestine, 11% unknown, 12.7% others. WHO 2019 grade 1, 2 and 3 in 52.7, 41.8 and 1.8%, respectively. Twentynine tumors (52.7%) were functional, with carcinoid syndrome in n20. At LM diagnosis, 91% of pts had symptomatic disease: hormonal n8, local n4, systemic n4, hormonal + local n4, local + systemic n22, hormonal + systemic n5, hormonal + local + systemic n5. LM tumoral burden was <10% in 22%, 11-50% in 43.6, > 50% in 30.9% of pts. 49.1% of pts had extra hepatic metastatic disease. LRT to LM was administered to 32 pts: TAE/TACE n26, ablation n8. SYST to 22 pts: somatostatin analog n15, Lutetium-177 n4, chemotherapy n2, everolimus n1. 1 pt did not receive treatment. Response to treatments is shown. In the LRT group, -- pts developed complications: n16 postembolization syndrome, n2 infections, n3 liver failure, n7 others. There was 1-procedure-related death. Conclusions: Patients treated with LRT at our institution achieved similar efficacy and safety results compared to those reported by previous studies.[Table: see text]
Evaluating surgical treatment options for small nonfunctional pancreatic neuroendocrine tumors in the NCDB.
Authors: Sugawara Toshitaka , Rodriguez Franco Salvador , Kirsh Michael , Colborn Kathryn , Ishida Jun , Grandi Samuele , Al-Musawi Mohammed , Gleisner Ana , Schulick Richard D. , Del Chiaro Marco
Published: January 2023

645

Background: The role of surgery for small (≤2 cm), nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial due to the wide range of tumor aggressiveness. Consensus guidelines of the US, Europe, and Japan offer different recommendations for treatment of small NF-PNETs. The objective of this study is to evaluate the survival benefit of surgical resection for small NF-PNETs. Methods: Patients with NF-PNETs were identified in the National Cancer Database from 2004 to 2018. Small NF-PNETs were divided into two groups: group 1a (tumor ≤1 cm) and group 1b (tumor 1.1 – 2.0 cm). Cox regression models were used to compare the overall survival between resected and unresected small NF-PNETs patients. Interactions between preoperative factors and surgery were estimated using subgroup analyses. Results: We identified 1,278 patients in group 1a and 3,363 patients in group 1b. After adjusting for preoperative factors, surgery was associated with longer survival for patients in group 1b (HR, 0.58; 95% CI, 0.42–0.80; P <0.001), but not for patients in group 1a (HR, 0.68; 95% CI, 0.41–1.11; P = 0.122). Interaction analysis found that age younger than 65 years, fewer comorbidities, treatment at academic institutions, distal pancreatic tumors, and clinical lymph node metastasis were factors associated with longer survival in group 1b by surgery. Conclusions: Findings from this large study support surgical resection for some patients with NF-PNETs (1.1 – 2.0 cm). This, of course, must be taken in context with the patient’s clinical situation. Based on data available for analysis in this study, resection for subcentimeter NF-PNETs does not appear to be of general benefit, but should also be investigated in the context of Ki-67 index.[Table: see text]
Proteomic profiling of antibody-drug conjugate (ADC) biomarkers in pancreatic cancer.
Authors: Thyparambil Sheeno P. , Liao Wei-Li , Heaton Robert , Strasbaugh Amanda , Melkie Marya Abebe , Ling Xuefeng
Published: January 2023

671

Background: Pancreatic cancer (PaC) is a highly fatal disease with a 5-year survival rate of 5-10%. Effective screening is not available, and most patients (50-55%) present with metastatic (50%-55%) disease at diagnosis. For patients with advanced PaC, the standard chemotherapy combinations include FOLFIRINOX and/or gemcitabine/nab-paclitaxel which has results in a overall survival of 7-11 months. The lack of effective therapies underscores the importance of exploring other agents. We propose that quantitating therapy-associated protein biomarkers including markers of antibody-drug conjugates (ADC) can improve treatment personalization for PaC. Methods: FFPE tumor tissues from 185 clinical PaC patients were microdissected and solubilized for mass spectrometry-based targeted proteomic analysis. We quantified biomarkers for ADCs simultaneously from 2-3 section of FFPE. These biomarkers include antibody targets such as EGFR, HER2, HER3, FRalpha, and Trop2 and payload biomarkers of sensitivity (TOPO1) and resistance (TUBB3). The multiplexed assay also quantified additional 65 clinically relevant protein biomarkers for chemotherapy, immunotherapy and targeted therapy. Results: Expression of EGFR was observed in majority of samples (88%) while only overexpressed ( > 1000 amol/µg) in 3% of samples. HER2 was expressed in half of patients (52%) and overexpressed ( > 750 amol/µg) in 5% of cases while the rest of HER2 protein expression ranged from 300 -750 amol/µg which corresponds to low Her2 expression. Trop2 was expressed in majority of patients (91%) with a 25x distribution between lowest and highest expressor. Other ADC biomarkers include HER3(55%, 5x), Axl (24%, 12x), Mesothelin (65%, 58x), Folate receptor alpha (10%, 17x). Expression of TUBB3 (77%, 8x) and TOPO1 (92%, 8x) in antibody target-positive subset may suggest resistance or response for several known payloads, such as taxanes and irinotecan/deruxtecan/govitecan, respectively. Conclusions: There is currently no approved ADC for pancreatic cancer, but several ADC clinical trials are underway. Quantitative proteomics identified antibody targets as well as markers of resistance or response to payloads for a variety of approved and investigational ADC therapies, which could aid in patient stratification in ADC clinical trials.