bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective analysis of adherence and persistence of encorafenib in combination with cetuximab among patients with BRAF metastatic CRC in the United States (US).
Authors: Parikh Aparna Raj , Vieira Maria Cecilia , Silver Michelle , Rava Andrew , Rau Reina , Li Benjamin 
Published: January 2024

64 Background: The BRAF V600E mutation (BRAF-m) occurs in approximately 7% of patients with metastatic CRC (mCRC). Encorafenib (enco) in combination with cetuximab (cetux) was approved in April 2020 as the first targeted regimen for the treatment of adult patients with mCRC with BRAF-m. The purpose of this study is to analyze the post-approval real-world persistence and adherence to treatment with enco in combination with cetux or with panitumumab (pani), an alternative EGFR, in mCRC, based on a claims database in the US. Methods: This was a retrospective cohort study in the IQVIA PharMetrics Plus claims database (2013-2022). Adults ≥18 years old with ≥1 claim for enco (first claim for enco on/after 4/1/2020) with concurrent EGFR (cetux or pani), ≥2 ICD-9/10 codes for malignancy of the colon or rectum ≥30 days apart in the 1 year before index date, and ≥1 day of pharmacy and medical continuous enrollment during the index date were included. Patients were excluded if they had a record of melanoma or non-small cell lung cancer during the year before index date, were enrolled in a clinical trial any time after the CRC diagnosis date or did not have a treatment regimen starting on or after CRC diagnosis date. Index date was the date of first treatment of enco + EGFR during the identification period (4/1/2020-3/31/2022). Patient demographics and disease characteristics were assessed at baseline, adherence (measured as at least 80% of days covered) and persistence (measured as time to discontinuation by Kaplan-Meier method) were estimated during the follow-up period. Results: 125 patients were included. Median (Q1 [1st quartile], Q3 [3rd quartile]) age at index was 58 (49, 63) years and 52.0% were female. Metastases were present in 3 or more sites in 60.8% of the patients, in 1 or 2 sites in 37.6%. The 2011 Modified Quan Charlson Comorbidity Index was 0 for 44.8% of the patients, 1-2 for 39.2%, and 3 or more for 16.0%. Most patients received cetux as their EGFR combined with enco (77.6%). Adherence to enco + EGFR was high (85.6%); enco + cetux vs. enco + pani: 89.7% vs. 74.1%. Median (Q1, Q3) proportion of time on cetux while on enco was 87.9% (77.9%, 94.3%) and median (Q1, Q3) proportion of time on pani while on enco was 79.9% (70.0%, 90.0%). Median (95% confidence interval) time to enco regimen discontinuation during follow-up was 6.2 (4.9–8.8) months. Conclusions: This up-to-date study provides current real-world evidence on the use of enco + EGFR in mCRC BRAF-m patients in the US. The results show high levels of adherence to the treatment, suggesting high tolerability to encorafenib, and persistence consistent with clinical trial evidence.
Real-world effectiveness and safety of pembrolizumab in mismatch repair-deficient (dMMR) gastrointestinal non-colorectal tumors.
Authors: Martinez Lago Nieves , Gonzalez Villarroel Paula , Cousillas Castiñeira Antia , Grana Suarez Begona , Gallardo Martin Elena , Agraso Busto Sara , Carral Maseda Alberto , Fernandez Montes Ana , Vazquez Maria Francisca , Reboredo Lopez Margarita ,   Galician Research Group on Digestive Tumors (GiTUD)
Published: January 2024

733 Background: The KEYNOTE-158 trial demonstrated durable clinical efficacy with pembrolizumab in long-term follow-up of previously treated unresectable or metastatic MSI-H/dMMR non-colorectal cancer. Our study, the GAIN study, aims to evaluate effectiveness and safety of pembrolizumab in dMMR Gastrointestinal Non-Colorectal Tumors in real-world clinical practice. Methods: We conducted a multicenter, retrospective, observational study on patients with Mismatch Repair-Deficient (dMMR) Gastrointestinal Non-Colorectal Tumors treated with pembrolizumab in real-world practice at six university hospitals affiliated with the Galician Research Group on Digestive Tumors (GiTUD) in Northwest Spain. Results: Between January 2018 and April 2023, 35 patients were enrolled. The median age was 66 years (range 33-88), with 54.3% being male. Tumor locations included 23 (65.7%) gastroesophageal adenocarcinomas, 3 (8.6%) pancreatic adenocarcinomas, 2 (5.7%) duodenal adenocarcinomas, 2 (5.7%) intrahepatic cholangiocarcinoma, 2 (5.7%) jejune adenocarcinomas, 2 (5.7%) esophageal squamous cell carcinomas, and 1 (2.8%) tumor of unknown origin. 54.3% of tumors were poorly differentiated. The most frequent alteration was the loss of MLH1-PMS2 expression (71.4%). By tumor location, 100% of gastroesophageal, jejune, and unknown origin tumors showed MLH1-PMS2 loss; while 100% of duodenal, pancreatic, and biliary tumors exhibited MSH2-MSH6 loss. All patients received pembrolizumab, with 57.1% having no prior metastatic disease treatment, 80% having ECOG PS0-1, and 31.4% having hepatic metastases. Among 33 evaluable patients, the overall response rate (ORR) was 81.8% (including 30.3% complete response) and the disease control rate (DCR) was 90.9%. Specifically, in gastroesophageal adenocarcinomas, the ORR was 81%, and the DCR was 90.5%. In the overall population, the median progression-free survival (PFS) was 34.76 months (95% CI 5.33 – 64.19 months), and the median overall survival (OS) was 39.75 months (95% CI 4.33-75.18 months). Treatment was well-tolerated; only 3 patients discontinued treatment due to nephritis, sarcoidosis-like symptoms, or diarrhea. No treatment-related deaths occurred. Conclusions: Our study underscores the real-world effectiveness of pembrolizumab in patients with dMMR Gastrointestinal Non-Colorectal Tumors. The high ORR, DCR, and favorable safety profile support its use in this challenging patient group, providing valuable real-world evidence for clinical decision-making.
Durable efficacy of selpercatinib in patients with RET fusion+ solid tumors, with a focus on GI tumors: LIBRETTO-001.
Authors: Subbiah Vivek , Drilon Alexander E. , Sukrithan Vineeth , Spira Alexander I. , Robinson Bruce , Deschler-Baier Barbara , Barker Scott , Lin Yan , Szymczak Sylwia , Ohe Yuichiro 
Published: January 2024

746 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. This update includes more patients (pts, n=52) and 16 months (mo) longer follow-up (data cut-off: 13Jan2023) in RET fusion+ solid tumors other than lung/thyroid with a focus on GI histologies. Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET fusion+ solid tumors. 51/52 pts received the recommended dose of 160 mg orally. The efficacy analysis set consisted of pts enrolled ≥6 months prior to the cut-off date. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Of the 52 pts with RET-activated solid tumors other than lung or thyroid, 51.9% were female with a median age of 54.0 years. The majority (31/52) of patients had GI RET fusion+ tumor types, with pancreatic (N=13) and colorectal (N=13) as the most common (Table). 47 pts received prior systemic therapy (median prior lines: 2, range 0-9); 28.8% received ≥3 lines. In 52 efficacy-evaluable pts, confirmed ORR by IRC was 44.2% (23/52, 95% CI: 30.5, 58.7). ORR by IRC for pts with pancreatic tumors was 53.8% and for colorectal tumors was 30.8%. Clinical benefit (complete response + partial response + stable disease ≥16 weeks) was observed in 67.3% (35/52) of pts. Median DoR was 37.2 mo (95% CI: 13.3, NE) for overall pts (Table). No new safety signals were identified compared to previous reports. 4 grade 5 AEs were observed (unrelated to treatment by INV), and 2 pts discontinued due to treatment-related AEs per INV. Conclusions: Selpercatinib continued to demonstrate durable antitumor activity and tolerable safety in pts with RET fusion+ cancers across multiple tumor types and fusion partners, including difficult-to-treat GI cancers with poor results in standard-of-care options, such as pancreatic and colorectal. These results emphasize the importance of comprehensive genomic profiling across all tumor types in order to identify actionable oncogenic drivers, including RET fusions. Clinical trial information: NCT03157128 .[Table: see text]
Alteration of metabolic syndrome and the risk of colorectal cancer in individuals younger than 50 years.
Authors: Jin Eun Hyo 
Published: January 2024

81 Background: Colorectal cancer (CRC) is a significant global health concern, with a rising incidence of early-onset cases in individuals under 50. This trend may be influenced by various factors, including metabolic syndrome (MetS), obesity, dietary habits, and lifestyle choices. However, the impact of changing MetS status on the risk of early-onset CRC remains understudied. Methods: A total of 3,340,635 Korean national insurance beneficiaries that received two consecutive biennial mandatory health exams (2009–2011) were followed-up until 2019. Participants were categorized into MetS-free, recovered, developed, or persistent groups. The study assessed CRC risk patterns associated with these MetS dynamics, considering factors like age, sex, smoking, alcohol consumption, exercise, and income status. Results: Among 20-39-year-olds, those with persistent MetS had a 16% higher risk of CRC (adjusted hazard ratio [aHR] 1.16; 95% CI, 1.00–1.33) compared to MetS-free individuals. Furthermore, persistent MetS was associated with a 29% higher risk of rectal cancer in this age group, while recovery from MetS also increased rectal cancer risk by 28%. Among 40-49-year-olds, the MetS-persistent group had a 22% higher risk of CRC (aHR 1.22; 95% CI, 1.14-1.30), with a 34% higher risk of distal colon cancer, while those who developed MetS showed a 26% higher risk of CRC compared to the MetS-free group. Conclusions: This study highlights that the persistence of MetS in young adults is associated with an increased risk of early-onset CRC. The findings suggest that managing MetS in young individuals through lifestyle modifications, such as weight reduction and regular exercise, could be beneficial in reducing the risk of early-onset CRC.
Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study.
Authors: Andre Thierry , Elez Elena , Van Cutsem Eric , Jensen Lars Henrik , Bennouna Jaafar , Mendez Guillermo , Schenker Michael , De La Fouchardiere Christelle , Limon Maria Luisa , Yoshino Takayuki , Li Jin , Lenz Heinz-Josef , Manzano Mozo Jose Luis , Tortora Giampaolo , Garcia-Carbonero Rocio , Cela Elvis , Yang Yingsi , Lei Ming , Jin Lixian , Lonardi Sara 
Published: January 2024

LBA768 Background: Patients (pts) with MSI-H/dMMR mCRC have poor outcomes with standard chemo ± targeted therapies. NIVO ± IPI are approved in previously treated pts with MSI-H/dMMR mCRC in many countries, based on the phase 2 CheckMate 142 study. CheckMate 8HW (NCT04008030) is a randomized phase 3 study comparing NIVO + IPI with NIVO or chemo in pts with MSI-H/dMMR mCRC. We report progression-free survival (PFS) by blinded independent central review (BICR) at a prespecified interim analysis for NIVO + IPI vs chemo in the 1L setting. Methods: Pts ≥ 18 years with recurrent or mCRC not amenable to surgery and MSI-H/dMMR status per local testing were enrolled across different lines of therapy. Previously untreated pts were randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). For pts with BICR-documented progression with chemo, optional crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. Results: In the 1L setting, 303 pts were randomized to NIVO + IPI (n = 202) or chemo (n = 101); of these pts, 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32]; P < 0.0001) (Table). No new safety signals were identified (Table). Conclusions: NIVO + IPI demonstrated superior PFS vs chemo in previously untreated pts with MSI-H/dMMR mCRC. NIVO + IPI had a different safety profile compared to chemo, with fewer grade 3–4 treatment-related adverse events (TRAEs). These results support 1L NIVO + IPI as a standard-of-care option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]
Zanzalintinib (XL092) plus atezolizumab versus regorafenib in previously treated MSS/MSI-low metastatic colorectal cancer (mCRC): The randomized phase 3 STELLAR-303 study.
Authors: Saeed Anwaar , Tabernero Josep , Wang Guan , Ma Xia , Smith Robina , Hecht J. Randolph 
Published: January 2024

TPS229 Background: Patients with microsatellite stable/microsatellite instability-low (MSS/MSI-low) mCRC account for ~95% of mCRC cases, and there is a significant unmet need in patients with treatment-refractory MSS/MSI-low mCRC. Although immune checkpoint inhibitors (ICIs) have shown limited activity in this patient population, the addition of tyrosine kinase inhibitors (TKIs) may increase sensitivity to ICIs by promoting an immune-permissive tumor microenvironment. Furthermore, TKI-ICI combinations have demonstrated encouraging clinical activity in patients with mCRC, particularly in subgroups of patients without liver metastases (LM). Most recently, in the phase 3 LEAP-017 study of patients with non–MSI-high/mismatch repair deficient (dMMR) mCRC, although pembrolizumab + lenvatinib did not improve overall survival (OS) vs standard of care, subgroup analysis suggested the potential for clinical benefit in patients without LM (Kawazoe et al, ESMO-WCGI 2023). Zanzalintinib is a novel multi-kinase inhibitor targeting VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). In a phase 1 study, zanzalintinib alone and in combination with atezolizumab (an anti–PD-L1 ICI) showed preliminary anti-tumor activity and a manageable safety profile across multiple tumor types (Sharma et al, ESMO 2022). Methods: STELLAR-303 (NCT05425940) is a global, randomized, open-label phase 3 study to assess the efficacy and safety of zanzalintinib + atezolizumab versus regorafenib in adult patients with MSS/MSI-low mCRC. Patients must have documented MSI/MMR status (non–MSI-high/dMMR) and RAS status by tissue-based analysis, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and radiographic progression during/after or intolerance to standard of care treatments for mCRC. Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed. Patients with or without active LM at baseline are eligible; those with definitively treated LM (includes surgical resection, microwave/radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) are considered to have non-active LM if treated ≥6 months before enrollment with no evidence of radiologic progression on subsequent imaging. Patients are randomized 1:1 to receive zanzalintinib + atezolizumab or regorafenib. Planned enrollment is 874 patients; number of patients with LM will be capped to ensure results of the study are relevant to the real-world mCRC population. Primary endpoint is OS in patients without LM. The key secondary efficacy endpoint is OS in all randomized patients. A hierarchical testing strategy will be employed for primary and key secondary endpoints. Safety will also be assessed. Enrollment is ongoing in the US, Europe, and Asia-Pacific region. Clinical trial information: NCT05425940 .
Phase II clinical study evaluating the efficacy and safety of disitamab vedotin combined with sintilimab and S-1 in the conversion treatment of HER2-overexpression unresectable gastric cancer.
Authors: Liang Han , Wang Xiaona , Shang Liang , Chen Xiaodong , Cheng Xiangdong , Li Ziyu , Wei Bo , Zheng Zhichao , Li Guoxin , Ji Gang , Zhang Zizhen , Tian Yantao , Zhao Qun , Yang Lin , Liu Heli , Chen Hao , Liu Yanliang ,   RC48 Gastric cancer
Published: January 2024

TPS428 Background: Gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA) is the fifth commonest cancer and the fourth leading cause of cancer deaths worldwide. In about 30% to 40% of patients with advanced gastric cancer have lost the opportunity for radical surgery at the first diagnosis, and the overall 5-year survival rate is less than 50%. In recent years, conversion therapy has shown great promise. Disitamab vedotin is an antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, In previous study C008, RC48 showed a good safety profile and promising activity towards GC, and showed equivalent efficacy for HER2 IHC 2+ or HER2 IHC 3+ tumors. Methods: This study is a single-arm, phase II trial carry out at 16 academic hospitals in China, and will evaluate DV combined with Sintilimab and S-1 in patients with HER2-expressing unresectable gastric cancer. Eligible patients are at ≥ 18 to ≤ 75 years old; histologically confirmed, unresectable stage IV GC or GEJA; Single initial unresectable factor. For example, peritoneal metastasis (P1), Intraperitoneal free cancer cells positive (CY1), Paraaortic lymph node metastasis, liver metastasis (≤ 3 lesions, and ≤ 5 cm for a single lesion), ovarian metastasis; and documented histologically confirmed HER2 IHC 3+ or 2+; ECOG 0-1; at least one unresectable, measurable tumor lesion according to the RECIST version 1.1; adaptable function of the heart, liver, and kidney. 30 patients will be enrolled in this trial and receive Disitamab Vedotin(2.5mg/kg, IV, Q3W), Sintilimab (200 mg, IV, Q3W) and S-1 (twice daily on D1-14 are given at a dose calculate according to the body surface area and repeated every 3 weeks), until patients assessed by MDT to meet the criteria for surgical resection undergo gastrectomy. And the patients with peritoneal dissemination will combine with intraperitoneal administration of paclitaxel (60mg / m2, Q3W). The primary endpoint is R0 resection rate, Secondary endpoints include cORR, OS, RFS and safety. Seven patients have been enrolled in this study. Clinical trial information: NCT05627414 .
Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer
Authors: Slamon Dennis J. , Diéras Véronique , Rugo Hope S. , Harbeck Nadia , Im Seock-Ah , Gelmon Karen A. , Lipatov Oleg N. , Walshe Janice M. , Martin Miguel , Chavez-MacGregor Mariana , Bananis Eustratios , Gauthier Eric , Lu Dongrui R. , Kim Sindy , Finn Richard S. 
Published: January 2024

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. PALOMA-2 demonstrated statistically and clinically significant improvement in progression-free survival with palbociclib plus letrozole versus placebo plus letrozole in estrogen receptor–positive/human epidermal growth factor receptor 2–negative (ER+/HER2–) advanced breast cancer (ABC). Here, we report results for the secondary end point overall survival (OS). Postmenopausal women (N = 666) with ER+/HER2– ABC without previous systemic therapy for ABC were randomly assigned 2:1 to palbociclib plus letrozole or placebo plus letrozole. After a median follow-up of 90.1 months, 405 deaths were observed and 155 patients were known to be alive. The median OS was 53.9 months (95% CI, 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI, 43.7 to 58.9) with placebo plus letrozole (hazard ratio [HR], 0.96 [95% CI, 0.78 to 1.18]; stratified one-sided P = .34). An imbalance in the number of patients with unknown survival outcome between the treatment arms (13.3% v 21.2%, respectively) limited interpretation of OS results. With recovered survival data, the median OS was 53.8 (95% CI, 49.8 to 59.2) versus 49.8 months (95% CI, 42.3 to 56.4), respectively (HR, 0.92 [95% CI, 0.76 to 1.12]; one-sided P = .21). OS was not significantly improved with palbociclib plus letrozole compared with placebo plus letrozole.
Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers
Authors: Schenk Kara M. , Deutsch Julie Stein , Chandra Sunandana , Davar Diwakar , Eroglu Zeynep , Khushalani Nikhil I. , Luke Jason J. , Ott Patrick A. , Sosman Jeffrey A. , Aggarwal Vikram , Schollenberger Megan D. , Sharfman William H. , Bibee Kristin P. , Scott Jeffrey F. , Loss Manisha J. , Wang Hao , Qi Hanfei , Sharon Elad , Streicher Howard , Chen Helen X. , Woodward Robert N. , Bagnasco Serena M. , Taube Janis M. , Topalian Suzanne L. , Brennan Daniel C. , Lipson Evan J. 
Published: January 2024

PURPOSE Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.