tbuckley/cabot-search huggingface dataset:
Exploring young-onset colorectal cancer sex difference incidence rates by race and ethnicity: A SEER database analysis (2000-2020).
Authors: Sharon Hechter, Jennifer Appiah, Anish Kumar Kanukuntla, Ibrahim Alnaser, Christina Eliachevsky, Sophia Ji, Ambica Nair, David B. Greenberg
Journal: Journal of Clinical Oncology (2024)

e15529 Background: Since 1994, there has been a 51% increase in young onset colorectal cancer incidence rates, as reported by the National Cancer Institute. Recently, the U.S. Preventative Task Force revised its guidelines, recommending colorectal cancer screening to commence at age 45 rather than 50. This study aimed to explore sex differences in cancer incidence across various race and ethnicities, aiming to discern whether these differences are rooted in biological factors or environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology and End Result (SEER) program (2000-2020) was used to calculate male-to-female incidence rate ratios (MF IRR) for colon and rectal cancer, stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic), and age-standardized to the 2000 U.S. population for individuals under the age of 50 diagnosed with colon or rectal cancer. Results: A total of 82,238 patients with colorectal cancer under the age of 50 were identified in the study period. Of these, 43,255 (52.6%) were males and 38,983 (47.4%) were females. The incidence trends over the years were analyzed, revealing a steady increase, with the highest incidence found in 2019 (4,819, 5.8%) and the lowest in 2000 (3,189, 3.8%). Non-Hispanic Whites comprised 57.2% of the cases, while the second and third largest groups were Non-Hispanic Black (13.2%) and Hispanic (17.9%). Incidence rates were highest among the non-Hispanic American Indian/Alaskan Native population (8.6 per 100,000 cases), followed by the non-Hispanic Black population (8.4 per 100,000 cases), and lowest in the Hispanic population (5.7 per 100,000 cases). Young-onset colorectal cancer incidence rates exhibited a male predominance, with the MF IRR consistently &gt; 1 every year across race and ethnicity. Non-Hispanic Asian/Pacific Islander had the highest MF IRRs (7 per 100,000 cases in males vs. 5.8 per 100,000 cases in females), while Non-Hispanic American Indian/Alaskan Native had the lowest MF IRRs throughout the years, with the lowest being in 2019 (5.1 per 100,000 cases in males vs. 12.6 per 100,000 cases in females). Conclusions: The MF IRR for young onset colorectal cancer showed no significant variation by race, implying a potential influence of biological factors. Notably, disparities in incidence rates were observed among different racial and ethnic groups, with the highest rates among non-Hispanic Black and non-Hispanic American Indian/Alaskan Native populations. Further research is warranted to pinpoint specific factors driving young onset colorectal cancer, facilitating targeted interventions for at-risk populations.
Botensilimab plus balstilimab in microsatellite stable metastatic colorectal cancer: Assessing efficacy in non-liver metastatic sites.
Authors: Marwan Fakih, Andrea J. Bullock, Benjamin L. Schlechter, Apostolia Maria Tsimberidou, Wells A. Messersmith, Agustin Pimentel, Ani Sarkis Balmanoukian, Rachel E. Sanborn, Neil Howard Segal, Bruno Bockorny, Sunil Sharma, Brian S. Henick, Ian Chau, Joseph Elan Grossman, Jaymin M. Patel, Wei Wu, Benny Johnson, Heinz-Josef Lenz, Steven O'Day, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2024)

3556 Background: Botensilimab (BOT) is an Fc-enhanced, multifunctional anti-CTLA-4 antibody with unique mechanisms of action. In microsatellite stable colorectal cancer (MSS CRC), previous I-O combinations have shown poorer responses in metastatic sites of disease outside of the lungs and lymph nodes, even in non-liver metastases (NLM) populations. Here we present updated efficacy data with longer follow-up from an expanded phase 1b study (NCT03860272) in patients with NLM MSS CRC treated with BOT and balstilimab (BAL; anti-PD-1). Methods: As of Nov 29, 2023, 77 patients with NLM MSS CRC (median follow-up 13.0 months [range 0.6–42.6]) with ≥6 months follow-up were included (intention to treat [ITT]; all treated); of these, 70 had ≥1 post-baseline scan (efficacy evaluable [EE]). Patients received BOT 1 or 2 mg/kg every 6 weeks (Q6W) and BAL 3 mg/kg every 2 weeks. Endpoints included RECIST 1.1 confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). Results: Median age was 56 years (range 36–82), 48% male, and median prior lines of therapy was 4 (range 1–10). ORR was 22% (17/77) and DCR was 73% (56/77), with the median DOR not reached (NR; 95% CI 5.7–NR). An additional response confirmed after the data cutoff (18/77; ORR 23%), with 11/18 responses ongoing. Subgroup analyses revealed that BOT and BAL showed comparable activity (ORR 18–33%) across metastatic sites outside of the lungs, including the peritoneum, soft tissue, pleura, and the brain (Table). One responder with an occult brain metastasis experienced pseudoprogression, followed by a complete systemic response to treatment in target lung lesions. No new safety signals were observed and updated safety and translational data will be presented. Conclusions: In summary, for MSS CRC, BOT and BAL is differentiated from previous I-O combinations by producing deep and durable responses even in difficult-to-treat metastatic sites. In NLM patients, responses were observed in 18–33% of sites of disease including the peritoneum, soft tissue, pleura, and the brain. These compelling results support further investigation in the fully enrolled, randomized, global phase 2 trial in MSS CRC (NCT05608044) and a planned global phase 3 trial. Clinical trial information: NCT03860272 . [Table: see text]
Efficacy of FOLFIRI plus bevacizumab versus FOLFIRI plus cetuximab in RAS-mutant metastatic colorectal cancer: Final update on patients with RAS-mutant metastatic colorectal cancer treated in FIRE-3.
Authors: Lena Weiss, Sebastian Stintzing, Dominik Paul Modest, Ludwig von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian A. Lerchenmuller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Markus H. Moehler, Werner Scheithauer, Swantje Held, Lisa Miller-Phillips, Arndt Stahler, Andreas Jung, Volker Heinemann
Journal: Journal of Clinical Oncology (2024)

3550 Background: Doublet chemotherapy plus bevacizumab is a well-established standard of care in the first-line treatment of RAS-mutant (RASmut) metastatic colorectal cancer (mCRC). The FIRE-3 trial was the first randomized study to compare FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC. Since this trial initially included patients irrespective of RAS mutation status, the present analysis performs an updated evaluation of therapeutic efficacy of targeted therapy with bevacizumab versus cetuximab in RASmut mCRC. Methods: FIRE-3 trial included 752 patients. Initially, pyrosequencing (PSeq) was used to identify RAS mutations. In a subsequent investigation next-generation sequencing (NGS) was applied in 373 available tumors. A 5% mutant allele cutoff was used for both PSeq and NGS both of which were done centrally. Results: Of the 224 RASmut and BRAF wild-type patients, 187 were identified by polymerase chain reaction (PCR) and PSeq, 122 by NGS. 86 tumors were PCR positive and NGS positive (PCR+/NGS+), 36 tumors PCR negative and NGS positive (PCR-/NGS+). In the overall RASmut cohort of 224 patients, no overall survival (OS) benefit was observed when cetuximab was compared to bevacizumab (20.3 months vs 21.1 months; HR 1.028; 95% CI, 0.547-1.583; P=.842). This effect was observed independent of sidedness of primary tumors (PT) for left-sided (21.5 months vs 22.1 months; HR 1.054; 95% CI, 0.763-1.456) and right-sided PT (19.2 months vs 19.5 months; HR 0.931; 95% CI, 0.547-1.583). Conclusions: While cetuximab notably is not effective in RASmut mCRC, this randomized comparison does not provide an indication for superior efficacy of bevacizumab in the first-line treatment of this patient group. Trial identification number: NCT00433927 [clinicaltrials.gov]
Phase Ib/II trial of hepatic arterial infusion chemotherapy in combination with fruquintinib for refractory unresectable colorectal cancer liver metastases.
Authors: Aiwei Feng, Song Gao, Jianhai Guo, Fuxin Kou, Shaoxing Liu, Xin Zhang, Baojiang Liu, Xiaodong Wang, Hui Chen, Haifeng Xu, Peng Liu, Guang Cao, Qinzong Gao, Xu Zhu
Journal: Journal of Clinical Oncology (2024)

3561 Background: Hepatic arterial infusion chemotherapy (HAIC), a highly efficient local therapy for patients with colorectal liver metastases (CRLM), is supposed to have a synergetic effect when it is in combination with a systemic therapy. The aim of this study was to determine the recommended phase 2 dose (PR2D) of fruquintinib combine with HAIC and evaluate efficacy and safety in expansion cohort of patients with CRLM. Methods: This open-label, single-arm, phase Ib/II study (NCT05406206) enrolled patients with CRLM who had received at least two prior lines of treatment. In the dose-finding phase, based on a standard 3+3 design, patients were treated with HAIC involving oxaliplatin (85 mg/m 2 ) and 5-FU (2000 mg/m 2 ) on day 1 and 2 every 4 weeks, alongside fruquintinib (3mg, 4mg, 5mg, d3-23, q4w, respectively) until unacceptable toxicities, progressive disease, or death occurred. In the dose-expansion phase, patients received HAIC and RP2D of fruquintinib determined in the dose-escalation phase. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included RP2D, objective response rate (ORR; RECIST 1.1), disease control rate (DCR), overall survival (OS) and safety. Results: As of data cutoff date on January 30, 2024, a total of 30 patients were enrolled. 9 (30.0%) patients were female, and the mean age was 56 years, 22 (73.3%) patients were RAS/BRAF mutant. During the dose-escalation phase, 15 patients were enrolled, with 3, 6, and 6 patients receiving doses of 3 mg, 4 mg, and 5 mg, respectively. Only one dose-limiting toxicity occurred in a patient of 4 mg level (G3 hypertension failed to control with antihypertensive treatment within 7 days). RP2D of fruquintinib was established as 5 mg. Fifteen patients were evaluable for efficacy, with best response of pathological complete response in 1 patient, partial response in 5 patients and stable disease in 6 patients, yielding an ORR of 40.0% and DCR of 80.0%. Median hepatic-PFS and median PFS was 6.8 months (95% CI, 5.890-7.710) and 5.9 months (95% CI, 3.576-8.224), respectively. The median OS reached 15.0 months (95% CI, 8.671-21.329). 7 (23.3%) patients experienced G3/4 treatment-related adverse events (TRAEs). The most common TRAEs of all grades were voice alteration, hypertension, abdominal pain and hand-foot syndrome. Conclusions: The combination of HAIC and fruquintinib showed a manageable safety profile and survival benefit of heavily treated CRLM patient. Clinical trial information: NCT05406206 .
Effect of p16 immunohistochemical expression (exp) on irinotecan in metastatic colorectal cancer (mCRC): A translational analysis of the TRIBE and TRIBE2 studies.
Authors: Marco Maria Germani, Roberto Moretto, Veronica Conca, Francesca Signorini, Agnese Proietti, Mirella Giordano, Daniele Rossini, Vittorio Studiale, Sabina Murgioni, Giacomo Di Paolo, Filippo Pietrantonio, Alessandra Russo, Ada Taravella, Alessandro Passardi, Alberto Zaniboni, Tiziana Pia Latiano, Alessandro Cappetta, Clara Ugolini, Chiara Cremolini
Journal: Journal of Clinical Oncology (2024)

3562 Background: CDKN2A encodes the inhibitor of the cyclin-dependent kinases p16 and is frequently methylated in colorectal cancer, thus reducing the exp levels of p16 protein. In pre-clinical models of colorectal cancer cells, the demethylation of CDKN2A gene induces topoisomerase I upregulation increasing the sensitivity to irinotecan. In metastatic colorectal cancer (mCRC) pts, the role of p16 expression has been poorly investigated. Methods: Tumour samples of pts randomized in the phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab (bev) versus (vs) FOLFOX/bev were assessed for p16 immunohistochemical exp. A validation analysis in patients treated with FOLFIRI/bev in the TRIBE study was conducted. Results: Out of 679 patients enrolled in the TRIBE2 study, 231 tumours were assessed for p16 exp. Overall, 152 (66%), and 79 (34%) were classified as positive (pos) (IHC 2+ and 3+) and negative (neg) (IHC 0 and 1+), respectively. In the p16 pos group, 69 (45%) and 83 (55%) pts received FOLFOXIRI/bev and FOLFOX/bev, respectively, while in the p16 neg cohort, FOLFOXIRI/bev was administered in 37 (47%) and FOLFOX/bev in 42 (53%) cases. Pts with p16 neg tumours had more frequently an ECOG-PS of 1-2 (16% vs 6%, p=0.0098) and a BRAF mut tumour (26% vs 7%, p=0.0002). No PFS difference was observed between p16 neg and pos patients, while a trend for a longer OS was shown in favour of p16 pos pts (25.5 vs 21.3 months; HR: 0.74, 95%CI: 0.53-1.02, p=0.068) that was not confirmed at the multivariate analysis (p=0.61). Among patients with p16 pos tumours, those treated with FOLFOXIRI/bev reported longer PFS (12.8 vs 9.4 months, HR: 0.55, 95%CI: 0.39-0.78, p=0.0008) and OS (30.0 vs 21.4 months, HR: 0.66, 95%CI: 0.46-0.95, p=0.026) than those receiving FOLFOX/bev. On the other hand, no significant difference was observed among p16 neg patients in terms of both PFS (9.0 vs 9.4 months, HR: 0.91, 95%CI: 0.57-1.46, p=0.69) and OS (21.3 vs 19.5 months, HR: 0.95, 95%CI: 0.58-1.57, p=0.85), thus suggesting a differential treatment effect according to p16 exp (p interaction for PFS =0.12; p interaction for OS =0.19). Among patients treated with FOLFIRI/bev in the TRIBE study (N=58) patients with p16 pos tumours reported longer PFS and OS than those with p16 neg. (HR for PFS: 0.45, 95%CI: 0.22-0.92, p=0.026; HR for OS: 0.41, 95%CI: 0.20-0.85, p=0.013). Conclusions: In mCRC, p16 pos exp seems associated with higher benefit from irinotecan. Prospective confirmation in independent randomized series is warranted.
A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.
Authors: Meredith McKean, Thomas E. Hutson, Sarina A. Piha-Paul, Ida Micaily, Mingxiang Liao, Robin Humphreys, Graham Brock, Natasha Sahr, Vian Amber, Alexander I. Spira
Journal: Journal of Clinical Oncology (2024)

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .
Real-world use of anti-EGFR therapy in metastatic colorectal cancer.
Authors: Hannah Ruth Robinson, Junxiao Hu, Nicole Baranda Balmaceda, Robert William Lentz, Emily Baiyee Toegel, Alexis Diane Leal, Sunnie S. Kim, Wells A. Messersmith, Christopher Hanyoung Lieu, S. Lindsey Davis
Journal: Journal of Clinical Oncology (2024)

3552 Background: Anti-EGFR therapies including cetuximab and panitumumab are recommended in frontline or later-line treatment regimens for left-sided metastatic colorectal cancer (mCRC) lacking mutations in RAS or BRAF. Here we report patterns of anti-EGFR therapy use in patients with mCRC diagnosed between 2013 and 2023. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, which contains patient-level data originating from approximately 280 cancer clinics in the United States (~800 sites of care).Adult patients diagnosed with mCRC from January 1, 2013 to April 28, 2023 who received at least 1 line of treatment were included. The percentage of patients who received anti-EGFR agents based on biomarker indication and primary tumor sidedness (PTS) was determined. PTS was assessed by ICD codes, with left-sided disease defined as tumors originating from the splenic flexure to the rectum. Univariate and multivariable analyses were performed to evaluate for factors associated with utilization of biomarker-directed anti-EGFR therapy. Results: A total of 25,937 patients were included in this analysis. Among these, 3,425 (13.2%) had a confirmed indication for anti-EGFR therapy, based on the presence of left-sided disease and documented KRAS, NRAS,and BRAFwildtype status (Cohort 1). In contrast, 15,015 (57.9%) patients had a documented RASor BRAF mutation and/or right-sided disease (Cohort 2). Anti-EGFR therapy was included in frontline treatment for 19.7% of patients in Cohort 1 versus 3.3% of patients in Cohort 2. Anti-EGFR therapy was included in any-line treatment for 56.6% of patients in Cohort 1 versus 12.1% of patients in Cohort 2. Patients in Cohort 1 were less likely to receive anti-EGFR therapy in any treatment line if they were ≥ 75 versus &lt; 45 years old at diagnosis (odds ratio [OR] 0.72, p = 0.027), had a primary rectal versus colon cancer (OR 0.87, p = 0.045), or were diagnosed at a later timepoint. For instance, while 72.4% of Cohort 1 patients diagnosed between 2013-2015 received anti-EGFR therapy, only 63.9% (OR 0.68, p = 0.05), 59.5% (OR 0.57, p &lt; 0.001), and 46.7% (OR 0.34, p &lt; 0.001) of patients diagnosed between 2016-2017, 2018-2019, and 2020-2023 received anti-EGFR therapy, respectively. Patient sex, race, ethnicity, practice setting, socioeconomic index, and performance status were not associated with anti-EGFR therapy use. Conclusions: Based on results from the Flatiron Health database, use of anti-EGFR therapy is enriched among patients with biomarker-based indications for treatment. Notably, anti-EGFR therapy was employed in only 56.6% of patients with RAS and RAF wildtype, left-sided mCRC, with decreased use observed from 2013 to 2023.
Phase 1/2 study of FMC-376 an oral KRAS G12C dual inhibitor in participants with locally advanced unresectable or metastatic solid tumors (PROSPER).
Authors: Anne Therese Keating, Kyriakos P. Papadopoulos, Eleni Hloros, Alexander I. Spira, William Bennion McKean, Andrew Peter Krivoshik
Journal: Journal of Clinical Oncology (2024)

TPS3184 Background: FMC-376 is a highly selective, orally bioavailable, dual (ON/OFF) irreversible covalent inhibitor that rapidly and effectively blocks signaling via ON (GTP-bound) mutant KRAS G12C and prevents OFF (GDP-bound) KRAS G12C from being activated. This prevents downstream KRAS G12C signaling without affecting wild-type KRAS protein. Nonclinical pharmacology studies demonstrate that FMC-376 inhibits tumor cell growth and viability in cells harbouring KRAS G12C mutation and results in tumor regression in multiple mouse models including PDX models of NSCLC, PDAC and CRC. FMC-376 demonstrated the ability to overcome mechanisms associated with innate and acquired resistance to the first generation KRASG12C (off) only inhibitors. [1]. Methods: This clinical study is global and is designed to evaluate the safety, tolerability, PK/PD and anti-tumor activity of FMC-376. Phase 1A (Dose Escalation) may enroll ~83 participants, Phase 1B (Dose Expansion) in tumor specific cohorts may enroll ~120 participants to optimize dosing and Phase 2 (Cohort Expansion) may enroll multiple tumor specific cohorts. Phase 1A includes participants who have progressed on or are ineligible for available standard approved therapies including KRAS G12C inhibitors. Participants will be enrolled into 1 of 5 escalating dose levels. BOIN design will be employed with a single Cohort, accelerated titration. Key eligibility criteria include histologically or cytologically confirmed locally advanced/unresectable or metastatic solid tumors with KRAS G12C mutations, ECOG 0-1 and adequate hematologic, hepatic and renal function. Participants with stable treated brain metastases may be eligible, but participants with leptomeningeal disease or carcinomatous meningitis are not eligible. FMC-376 will be administered PO QD for 21-day cycles until PD. Key objectives include establishing doses, based on incidence of DLTs, identifying SAEs/AEs and changes in ECG parameters, characterizing the PK profile and evaluating the clinical activity of FMC-376 via RECIST v1.1. In addition, FMC-376 target engagement and changes in expression of RAS pathway genes will be evaluated. A dose escalation and safety committee will be established to oversee the dose escalation portion of the study. The study is open to enrollment as of February 2024, NCT06244771. 1. AACR 2023 Annual Meeting Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRAS G12C Kevin Webster, April 16, 2023. Clinical trial information: NCT06244771 .