tbuckley/cabot-search huggingface dataset:
Promising first-line immuno-combination therapies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.
Authors: Feng Wen, Peng Huang, Qiuji Wu, Yang Yang, Qiu Li
Journal: Journal of Clinical Oncology (2024)

469 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death all over the world, bringing a heavy social economic burden especially in China. Several immuno-combination therapies have shown promising efficacy in the first-line treatment of unresectable HCC and are widely used in clinical practice. However, which combination is the most affordable is unknown. The current study assessed the cost-effectiveness of the immuno-combinations as first-line treatment for patients with unresectable HCC from the Chinese payers' perspective. Methods: A Markov model was built based on five global, multicenter, open-label, phase III randomized trials (Himalaya, IMbrave150, ORIENT-32, CARES-310, LEAP-002) to investigate the cost-effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A+B), sintilimab plus bevacizumab biosimilar (IBI305) (S+B), camrelizumab plus rivoceranib (C+R) and pembrolizumab plus lenvatinib (P+L). Three disease states were included: progression free survival (PFS), progressive disease (PD), and death. Medical costs were searched from the Red Book, published literatures, and West China Hospital. Cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. Results: The total cost and quality-adjusted life years (QALYs) of C+R, S+B, P+L, A+B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73 respectively, resulting in the most cost-effective strategy of C+R with CER of $13,306.89 per QALY followed by S+B with CER of $24,072.86 per QALY. The S+B strategy would become the most cost-effective when the willing-to-pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap-002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. Conclusions: As one of the promising immuno-combination therapies in the first-line systemic treatment for unresectable HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost-effective strategy, which warranted further studies to best inform the real-world clinical practices.
Clinical impact on treatment effectiveness of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.
Authors: Keito Suzuki, Yutaka Yasui, Kaoru Tsuchiya, Hiroaki Matsumoto, Yudai Yamazaki, Naoki Uchihara, Yuki Tanaka, Haruka Miyamoto, Michiko Yamada, Taisei Keitoku, Risa Okada, Mayu Higuchi, Kenta Takaura, Shohei Tanaka, Chiaki Maeyashiki, Nobuharu Tamaki, Hiroyuki Nakanishi, Yuka Takahashi, Masayuki Kurosaki, Namiki Izumi
Journal: Journal of Clinical Oncology (2024)

479 Background: Immune checkpoint inhibitors (ICIs) have emerged as the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, their administration poses the risk of immune-related adverse events (irAEs). Recent data suggests that the occurrence of irAEs may be associated with a favorable prognosis. Nevertheless, limited studies have explored the relationship between irAE severity or specific symptoms and clinical outcomes. Therefore, the objective of this study was to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable HCC treated with immune checkpoint inhibitors. Methods: We enrolled 130 patients with unresectable HCC treated with atezolizumab plus bevacizumab between November 2022 and January 2023 at a single center. We investigated the relationship between irAEs and both response rate and post-treatment outcomes. Results: Out of the 130 patients, 36 (27.7%) developed irAEs. Patients with irAEs exhibited a significantly longer progression-free survival (PFS) compared to the non-irAE group, with a median PFS of 8.9 months compared to 4.6 months (p &lt; 0.01). There was no difference in overall survival with or without irAEs. The irAE group demonstrated significantly higher disease control rate (DCR) compared to the non-irAE group (97.0% vs 65.5%, p &lt; 0.01). The analysis by the severity of irAE revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 months vs 4.6 months, p =0.007) and higher DCR (100% vs 65.5%, p &lt; 0.01) compared to the non-irAE group. Furthermore, hypothyroidism was correlated with a favorable PFS (8.9 months vs 5.4 months, p = 0.02), DCR (100% vs 71.3%, p = 0.03) and overall response rate (58.3% vs 18.5%, p = 0.005). Conclusions: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (Grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.
Phase I trial of short-course chemoradiotherapy followed by chemotherapy as total neoadjuvant therapy for patients with potentially resectable gastric cancer.
Authors: Brian D. Badgwell, Prajnan Das, Naruhiko Ikoma, Mariela A. Blum Murphy, Jenny Jing Li, Jeannelyn Estrella, Bruce D. Minsky, Paul F. Mansfield, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2024)

362 Background: The purpose of this phase I trial was to evaluate the safety and toxicity of preoperative short-course chemoradiotherapy (CXRT) in patients with potentially resectable gastric or gastroesophageal adenocarcinoma as part of a total neoadjuvant therapy (TNT) approach. Methods: Patients with potentially resectable gastric or gastroesophageal adenocarcinoma received CXRT consisting of 30 Gy in 10 fractions with concurrent capecitabine or fluorouracil, followed by systemic therapy for 2 months and then surgery. The primary objective was safety of CXRT with secondary endpoints of pathologic complete response, perioperative complications, and overall survival (OS). Results: A total of 24 patients were treated between March 2021 and December 2022. Ten patients (42%) presented with bleeding and 3 (13%) presented with gastric outlet obstruction. Two patients (8%) had cirrhosis. Clinical nodal involvement was reported in 12 patients (50%). Twenty patients (83%) had poorly differentiated tumors, and 13 (54%) had signet ring cell histology. All patients completed CXRT. CXRT treatment-related toxic effects included grade 3 lymphopenia in 7 patients (29%), grade 4 lymphopenia in 1 (4%), and grade 3 anemia in 1 (4%). After CXRT, 22 patients (92%) completed 2 months of chemotherapy, 1 patient (4%) with a microsatellite-high tumor completed immunotherapy, and 1 patient (4%) underwent resection without systemic therapy. All patients underwent attempted resection, and gastrectomy was performed in 20 (83%). R0 resection rate was 95%. Pathologic complete response was observed in 2 patients (8%), and ≤ 1% viability was observed in an additional 4 (17%). Three patients had surgical complications (grade I in 1 patient [4%], grade IIIb in 1 [4%], and grade IVa in 1 [4%]); there were no deaths within 90 days. The median follow-up time was 20 months, and median OS was not reached. One- and 3-year OS rates from the date of diagnosis were 96% and 80%, respectively. Conclusions: Short-course CXRT (30 Gy in 10 fractions) may be safely used as part of a planned TNT approach. Rates of treatment completion, pathologic response, and survival were promising, supporting further research into TNT for gastric cancer. Clinical trial information: NCT04523818 .
Preoperative endoscopic biliary drainage procedures may affect intrahepatic recurrence of cholangiocarcinoma after surgical resection.
Authors: Jin-Oh Kim
Journal: Journal of Clinical Oncology (2024)

468 Background: To determine the impact of preoperative endoscopic nasal biliary drainage (ENBD) and/or endoscopic retrograde biliary drainage (ERBD) procedures on intrahepatic recurrence rate in patients with cholangiocarcinoma after surgical resection. Methods: Between January 2005 and January 2023, 143 patients diagnosed cholangiocarcinoma and received surgical resection. Among 143 patients, 99 patients were treated with preoperative ENBD and/or ERBD. We retrospectively analysed prognostic factors (age, gender, preoperative ENBD and/or ERBD, tumor differentiation, pT factor, lymph node metastasis, surgical margin, lymphovascular invasion, preoperative maximal total bilirubin, postoperative chemoradiation/chemotherapy/radiation therapy, CA19-9) for recurrence after surgical resection. Results: Intrahepatic recurrence after surgical resection was detected in 22 /99(22.2%) patients with preoperative ENBD and/or ERBD, and 5/44(11.4%) patients without preoperative ENBD and/or ERBD for median period of 12 months (range 0-48). On univariate analysis, intrahepatic recurrence rate of patients who underwent ENBD and/or ERBD (n=99) was higher than that of patients who did not (n=44) ( P=0.090) and and that of patients who had T3/T4 factor (n=74) was higher than that of who had T1/T2 factor (n=69) (P=0.168). Intrahepatic recurrence rateof patients who had elevated CA19-9 (&gt; 200) (n=49) was higher than that of patients who had not (n=94) ( P=0.002). In multivariate analyses, preoperative ENBD and/or ERBD and elevated serum CA19-9 level (&gt;200 ng/mL) were prognostic factors for intrahepatic recurrence, with hazard ratios (HR) of 2.154 (95% confidence interval (CI) 0.893-7.626, P = 0.080) and 3.647, (95% confidence interval (CI) 1.660-8.011, P = 0.001). Conclusions: Preoperative preoperative endoscopic nasal biliary drainage (ENBD) and/or endoscopic retrograde biliary drainage (ERBD) procedures may affect the intrahepatic recurrence of tumor in patient with cholangiocarcinoma after surgical resection. And serum elevated CA 19-9 level affected intrahepatic recurrence of tumor in patients with cholangiocarcinoma after surgical resection.
A phase I clinical trial of riluzole in combination with mFOLFOX6 and bevacizumab in treating patients with metastatic colorectal cancer.
Authors: Chunjie Li, Anne M. Noonan, John L. Hays, Sameek Roychowdhury, Pannaga G. Malalur, Rifat T. Elkhatib, Ashish Manne, Arjun Mittra, Shafia Rahman, Mitch A. Phelps, Beiyuan Liang, Hadyen Storts, Misbah Khan, Evan Zhang, Xinru Zheng, Wayne Miles, Jing Wang, Ning Jin
Journal: Journal of Clinical Oncology (2024)

101 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU) based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. It is essential to develop new treatment strategies in metastatic CRC patients with microsatellite stable disease, in whom immune checkpoint blockade is ineffective. Our preclinical studies showed riluzole, an oral medicine for amyotrophic lateral sclerosis, can increase intratumoral CD8 + T cells and suppress tumor growth in a syngeneic colon cancer mouse model. Riluzole-mediated tumor growth inhibition depends on the presence of CD8 + T cells and activation of cGAS/STING/IFNβ signaling. Methods: This was a single-arm phase I trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC. The dose of riluzole started from 50 mg twice daily with dose escalation to 100 mg twice daily or dose de-escalation to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Then patients either continued mFOLFOX/bevacizumab or switched therapy. The primary objective was adverse events (AE). The secondary objectives were objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). Results: Fourteen patients were enrolled, and twelve patients were evaluable. All patients received FOLFOX in the past; two patients received 2 lines of chemotherapies; one patient received 3 lines and eight patients had ≥ 4 lines before the study. Five patients (41.7%) had disease resistance to FOLFOX. During the study, two patients received only 2 cycles of treatment due to poor PS. Two patients received 7 cycles, and nine patients completed 8 cycles of treatment. The common grade 3 &amp; 4 AEs included neutropenia (46.2%), lymphopenia (30.8%), and abdominal pain (15.4%). No complete response was observed; two patients obtained partial response; nine patients had stable disease, and only one patient had progressive disease. The ORR was 16.7%, and DCR was 91.7%. The median DoR was 5.1 (95% CI 3.2-7.0) months. The maximum tolerated dose for riluzole is 100 mg twice daily. Conclusions: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX. Further study is necessary to confirm the immunomodulation effect of riluzole. Clinical trial information: NCT04761614 .
Phase II trial of cabozantinib (cabo) plus durvalumab (durva) in chemotherapy refractory microsatellite stable (MSS) patients with advanced gastric and esophageal (G/E) adenocarcinoma: CAMILLA G/E cohort results.
Authors: Anwaar Saeed, Robin Park, Junqiang Dai, Anup Kasi, Lori Barbosa, Kelly Mulvaney, Jordan Rarden, Milind A. Phadnis, Azhar Saeed, Ibrahim Halil Sahin, Joaquina Celebre Baranda, Stephen K. Williamson, Weijing Sun, Raed Moh'd Taiseer Al-Rajabi
Journal: Journal of Clinical Oncology (2024)

373 Background: Cabo is a multi-tyrosine kinase inhibitor harboring anti-VEGFR2, MET, AXL, MER and TYRO3 activity. Immunomodulatory and synergistic anti-tumor activity of cabo in combination with PD-1/L1 inhibitors have been demonstrated preclinically and in prior studies in various solid tumors. The phase Ib gastrointestinal (GI) basket CAMILLA trial evaluating cabo + durva confirmed manageable toxicity and anti-tumor activity, leading to the expansion into a multi-cohort phase 2 study. Herein, we report the results of the phase II G/E adenocarcinoma cohort. Methods: Patients (Pts) enrolled in the phase II G/E adenocarcinoma cohort were administered cabo + durva at the RP2D of 40mg QD and 1500mg IV Q4W respectively. Enrolled pts must have progressed on &gt;1 line(s) of systemic therapy. Prior exposure to PD-1/L1 inhibitors was allowed. Those with HER2 positive disease must have progressed on anti-HER2 therapies. The primary outcome was objective response rate (ORR). Secondary outcomes were treatment-related adverse events (TRAEs), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Exploratory subgroup analyses were conducted in PD-L1 CPS &gt;5. Results: 31 patients were enrolled, with 29 patients evaluable for efficacy. The median age was 61 years (range 32-79). 86% had an ECOG performance status of one. 48% had ≥ 2 prior lines of systemic therapies (range 1-4). Of the 29 pts evaluable for efficacy, 6 pts had confirmed objective responses (5 PR + 1 CR = ORR 20.69%). The most common TRAEs were fatigue (65%), anorexia (58%), elevated liver enzymes (39%), and diarrhea (35%). Grade &gt;3 TRAEs occurred in 19% of pts. Grade &gt;3 immune-related adverse events (irAE) rate was 6%. DCR was 86.2% (25/29). Median PFS and OS were 4.4 (95% confidence interval (CI) 2.2-5.4) and 5.6 months (95% CI 3.6-8.3) respectively. In patients with PD-L1 CPS &gt;5 (12/29), ORR was 25%, and median PFS and OS were 5.5 months (95% CI 1.8-12.4) and 19.3 months (95% CI 2.3-28.2) respectively. Conclusions: Cabo + durva showed anti-tumor activity and manageable toxicity in advanced chemotherapy refractory G/E adenocarcinoma. Further evaluation in patients with high PD-L1 CPS ≥ 5 is warranted in a future randomized trial. Clinical trial information: NCT03539822 .
First-line pembrolizumab (pembro) plus chemotherapy (chemo) for advanced esophageal cancer: 5-year outcomes from the phase 3 KEYNOTE-590 study.
Authors: Manish A. Shah, Jong-Mu Sun, Lin Shen, Ken Kato, Peter C. Enzinger, Antoine Adenis, Toshihiko Doi, Takashi Kojima, Zhigang Li, Sung-Bae Kim, Byoung Chul Cho, Wasat Mansoor, Shau-Hsuan Li, Patrapim Sunpaweravong, Maria Alsina Maqueda, Gary L Buchschacher, Jimin Wu, Sukrut Shah, Pooja Bhagia, Jean-Philippe Metges
Journal: Journal of Clinical Oncology (2024)

250 Background: First-line (1L) pembro + chemo significantly improved survival versus placebo (pbo) + chemo in patients (pts) with advanced esophageal cancer after a median follow-up of 22.6 mo in the randomized phase 3 KEYNOTE-590 study (NCT03189719). We report 5-yr follow-up data. Methods: Eligible pts had locally advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus (ESCC), or Siewert type I gastroesophageal junction adenocarcinoma; measurable disease per RECIST v1.1; and ECOG PS 0 or 1. Pts were randomized 1:1 to receive pembro 200 mg or pbo IV every 3 weeks for ≤35 cycles both with chemo (5-fluorouracil [≤35 cycles] and cisplatin [≤6 cycles]). Primary end points were OS in pts with ESCC and PD-L1 CPS ≥10 and OS and PFS per RECIST v1.1 by investigator in all pts, pts with ESCC regardless of PD-L1, and pts in the ITT population with CPS ≥10. Secondary end points included ORR and DOR per RECIST v1.1 by investigator and safety. Pt-reported outcomes will also be presented. Data cutoff was July 10, 2023. Results: Overall, 749 pts were randomized to receive pembro + chemo (n = 373) or pbo + chemo (n = 376). Median time from randomization to data cutoff was 58.8 mo (range, 49.2-70.6). A total of 701/740 pts (94.7%) discontinued treatment; most commonly due to progressive disease (n = 449; 60.7%). ORR and DOR by pt population are provided (Table). In the ITT population, median OS was 12.3 mo for pembro + chemo and 9.8 mo for pbo + chemo (HR 0.72 [95% CI 0.62-0.84]); 5-yr OS rates were 10.6% and 3.0%, respectively. Median PFS was 6.3 mo for pembro + chemo and 5.8 mo for pbo + chemo (HR 0.64 [95% CI 0.54-0.75]); 5-yr PFS rates were 5.5% and 0%, respectively. Grade 3-5 treatment-related AEs occurred in 266 (71.9%) pts in the pembro + chemo arm and 250 (67.6%) pts in the pbo + chemo arm. Treatment-related AEs led to death in 9 (2.4%) and 5 (1.4%) pts in the pembro + chemo and pbo + chemo arms, respectively. Conclusions: After 5 yrs, use of pembro + chemo showed durable efficacy versus pbo + chemo, with no new safety concerns in pts with untreated advanced esophageal cancer. Long-term results continue to support 1L pembro + chemo for advanced esophageal cancer. Clinical trial information: NCT03189719 . [Table: see text]
First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): 64-month (mo) follow-up from CheckMate 142.
Authors: Heinz-Josef Lenz, Michael J. Overman, Eric Van Cutsem, Maria Luisa Limon, Ka Yeung Mark Wong, Alain Hendlisz, Massimo Aglietta, Pilar Garcia-Alfonso, Bart Neyns, Fabio Gelsomino, Dana Backlund Cardin, Tomislav Dragovich, Usman Shah, Stephen McCraith, Rui Wang, Ming Lei, Jin Yao, Lixian Jin, Sara Lonardi
Journal: Journal of Clinical Oncology (2024)

97 Background: NIVO + IPI demonstrated robust, durable clinical benefit and was well tolerated as a 1L therapy in pts with MSI-H/dMMR mCRC in the phase 2 CheckMate 142 study (NCT02060188), leading to the inclusion of NIVO + IPI in the NCCN guidelines as an initial therapy option for these pts. At 52-mo median follow-up, 1L NIVO + IPI continued to demonstrate durable clinical benefit, and no new safety signals were identified. Here we report longer follow-up results. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV; overall survival (OS); and safety. Results: In total, 45 pts received 1L NIVO + IPI. With median follow-up of 64.2 mo (range, 59.4–68.9 mo), ORR by INV was 71% (95% CI, 56–84%). The proportion of pts with a best overall response of complete response (CR) was 20%, partial response (PR) was 51%, stable disease (SD) was 13%, and progressive disease was 16%. Median DOR (mDOR) was not reached, and the 60-mo DOR rate was 72%. Median PFS (mPFS) by INV and median OS (mOS) were not reached, with 60-mo PFS and OS rates of 55% and 67%, respectively (Table). Among pts alive at the data cutoff (n = 31), 30 remained treatment-free after initial study treatment without receiving any subsequent systemic therapy, with a median treatment-free interval of 34.7 mo (range, 1.6–61.4 mo). Exploratory analysis by tumor mutational burden status will be presented. Safety data are shown in the Table. Conclusions: At 64-mo follow-up, NIVO + IPI continued to demonstrate clinically meaningful survival and durable responses, with mPFS, mOS, and mDOR still not reached, suggesting the potential for long-term clinical benefit. Safety remained consistent with previous data. These findings further support current recommendations for NIVO + IPI as a 1L treatment for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188 . [Table: see text]
One of these is not like the others: A descriptive study of the attenuated phenotype of <i>PMS2</i>.
Authors: Edward D. Esplin, Brandie Heald, Sarah M. Nielsen, Rachel Ellsworth, Emily M. Russell, Daniel Esteban Pineda Alvarez
Journal: Journal of Clinical Oncology (2024)

76 Background: Data from Lynch syndrome (LS) registries reveal that patients (pts) with PMS2 pathogenic germline variants (PGVs) have the lowest cancer risk. This retrospective study of pts undergoing germline genetic testing (GGT) for any indication compared the phenotypes of PMS2 carriers to other LS pts. We hypothesized that PMS2 pts were more likely to have no cancer or non–LS associated cancers than other LS pts. Methods: All Pts with a single PGV in any LS gene were identified from a commercial laboratory database. Demographics and personal and family cancer history data were clinician-reported on the test requisition form. Data from PMS2 pts were compared to MSH6 and MLH1/MSH2/EPCAM pts using descriptive statistics, unpaired two-samples t tests, Chi-square tests, and multivariate logistic regression analyses that also included patients with no PGVs, with p&lt;0.05 defining significance. Results: 17,711 pts met inclusion criteria (5,189 PMS2, 5,182 MSH6, and 7,340 MLH1/MSH2/EPCAM). PMS2 pts were significantly older at testing (mean 55.1±16.0y) than MLH1/MSH2/EPCAM (48.7±15.7y) and had significantly less family cancer history (84.9%) than both MSH6 (86.8%) and MLH1/MSH2/EPCAM (86.6%) pts. PMS2 pts had lower odds of any colorectal and uterine cancers than the MSH6 and MLH1/MSH2/EPCAM cohorts (Table). All LS-related PGVs were significantly associated with lower odds of breast, pancreatic, and prostate cancer. Conclusions: Pts with PMS2 PGVs were older at the time of testing and had lower odds of any and LS-related cancers than other LS pts. These data are consistent with prior registry studies and can aid in counseling and management of PMS2 pts. [Table: see text]