tbuckley/cabot-search huggingface dataset:
Updated safety, efficacy, pharmacokinetics, and biomarkers from the phase 1 study of IMC-002, a novel anti-CD47 monoclonal antibody, in patients with advanced solid tumors.
Authors: Ho Yeong Lim, Jin Seok Ahn, Joon Oh Park, Jung Yong Hong, Sung Young Lee, Haeun Jeong, Hwi-yeol Yun, Seunghwan Shin, Chan-Young Ock, Heung Tae Tae Kim
Journal: Journal of Clinical Oncology (2024)

2642 Background: Preliminary safety and efficacy data from the phase 1a dose escalation study of IMC-002 has been reported, showing no dose limiting toxicity (DLT) across 4 dose levels. Here we present updated insight into safety, efficacy, optimal dose determination through pharmacokinetics (PK) modeling, and CD47 expression. Methods: Eligible pts had metastatic or locally advanced solid tumors that progressed following at least 1 prior systemic therapy and an ECOG PS ≤1. A traditional 3+3 design was employed to evaluate DLT over 21 days, administering 4 doses of IMC-002 (5, 10, 20 and 30 mg/kg) every 2 weeks (Q2W). Tumor assessments were performed Q6W using RECIST 1.1. Optimal dosing was determined through target-mediated drug disposition (TMDD) PK modeling, incorporating FcRn recycling. CD47 immunohistochemistry (IHC) images were analyzed with an AI analyzer (Lunit SCOPE) that can distinguish staining positivity and cell type at the single cell level. Results: A total of 12 refractory patients (hepatocellular carcinoma 9, breast cancer 2, gallbladder cancer 1) were received IMC-002 with a median follow-up of 11 months (max 19 months). All treatment related adverse events (TRAEs) were grade 1-2 (92%) and TRAEs observed with over 20% incidence included skin rash, transient floaters and anemia. After the initial exposure, there was a decrease in hemoglobin levels, but these levels subsequently recovered without the evidence of hemolytic anemia. Among the 12 efficacy evaluable patients, the disease control rate was 50.0% and the clinical benefit rate (CBR, stable disease ≥ 6 months of treatment) was 33.3% with a median treatment duration of 10 months. Based on PK modeling, 20 mg/kg Q3W was selected as optimal RP2D. In the AI analysis of CD47 IHC, the density of CD47 positive macrophages tended to be higher in case with CBR compared to non-CBR cases (mean CD47+ macrophage density: 71.0 vs 44.3/mm 2 ), while the percentage of tumor cells expressing CD47 was similar between the two groups (mean CD47+ tumor cells: 54.5 vs 59.8%). Conclusions: IMC-002 has an excellent safety profile when administered intravenously at a dose of up to 30 mg/kg every 2 weeks intravenously for max 12 months treatment. IMC-002 monotherapy demonstrates meaningful clinical benefits in refractory HCC. The density of CD47+macrophages analyzed by AI is higher in CBR patients. Clinical trial information: NCT05276310 . [Table: see text]
PD-L1 immunohistochemistry in gastric cancer: Comparison of combined positive score and tumor area positivity across 28-8, 22C3, and SP263 assays.
Authors: Samuel J. Klempner, Eric S Cowden, Samuel Louis Cytryn, Matteo Fassan, Hisato Kawakami, Hideaki Shimada, Laura H. Tang, Daniel-Christoph Wagner, Yasushi Yatabe, Alexander Savchenko, Jennifer Salcius, Dorhyun Johng, Lauren Fairchild, Jing Chen, Giuliana Montenegro, Markus H. Moehler
Journal: Journal of Clinical Oncology (2024)

2625 Background: The clinical application of programmed death-ligand 1 (PD-L1) immunohistochemistry is complicated by multiple available assays and different testing platforms, scoring algorithms, and cut-offs applied. This study assessed the analytical comparability of three commercially available PD-L1 assays (28-8, 22C3, and SP263) and two scoring algorithms used in gastric cancer (GC). Methods: Serial sections of 100 commercially procured GC samples, selected by the 28-8 assay to represent the dynamic range of PD-L1 expression, were stained with the three in vitrodiagnostic (IVD)-grade PD-L1 assays. Stained slides were blindly and independently evaluated by three trained pathologists for intra- and inter-reader assessment. Scoring was performed using the combined positive score (CPS) and tumor area positivity (TAP) methods, followed by statistical analysis. Digital image analysis (DIA) was used to objectively assess the technical performance of each assay by simulating CPS and TAP scoring methods using the HALO platform. Results: Comparable, specific, staining patterns were observed with the three PD-L1 assays. Pathologist assessment of PD-L1 positivity was reproducible in GC sample cohorts despite discernible variability in the observed staining intensity. When the same PD-L1 cut-offs were applied, inter- and intra-assay assessments of all three assays, using either CPS or TAP scoring methods, demonstrated moderate to almost-perfect (inter-assay Cohen’s kappa [κ] ranged from 0.47 to 0.83) and substantial to almost-perfect (intra-assay κ ranged from 0.77 to 1.00) agreement, respectively. Moreover, inter-pathologist evaluation showed a significant level of reproducibility (intraclass correlation coefficient (ICC) ≥0.92). DIA confirmed no difference in technical performance when specific digital algorithms were applied. Conclusions: This GC study highlights analytical concordance in PD-L1 testing among three major PD-L1 assays when TAP and CPS scoring algorithms are prospectively applied. Independently, DIA further supports the comparability of the technical performance of the assays. These observations support flexibility in cross-application of the different PD-L1 assays and scoring algorithms currently used to characterize PD-L1–positive GC samples.
AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer.
Authors: Craig E. Devoe, Shubham Pant, Zev A. Wainberg, Vincent Chung, Thomas J. George, Pashtoon Murtaza Kasi, Haley VanWyk, Amy Tavares, James Perry, Thian Kheoh, Lisa McNeil, Esther Welkowsky, Peter DeMuth, Christopher M. Haqq, Eileen M. O'Reilly
Journal: Journal of Clinical Oncology (2024)

2636 Background: Diverse KRAS mutations occur in 25% of solid tumors with G12D, V and R most frequent. ELI-002 7P is an expanded spectrum vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D, V, R, C, S, A, and G13D mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Earlier ELI-002 2P showed high rates of T cell and tumor biomarker response (both 21/25, 84%), with median relapse-free survival not reached versus 4.01 months (HR 0.14; p=0.0167) comparing patients (pts) above versus below T cell median (12.75X). Methods: This multicenter phase IA trial assessed safety, immunogenicity and preliminary antitumor activity of ELI-002 7P in pancreatic (PDAC) and colorectal pts with minimal residual disease (MRD) following standard locoregional treatment. Pts with elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), and KRAS mutation were enrolled and treated with subcutaneous fixed dose Amph-CpG-7909 and 1.4 mg or 4.9 mg of Amph-Peptides 7P (Table). Safety, T cell change, and preliminary antitumor activity including biomarker reduction/clearance are reported. Results: No dose-limiting toxicities, no treatment related SAEs or cytokine release syndrome were observed, no maximum tolerated dose was identified, and the recommended phase 2 dose (RP2D) was 10.0 mg Amph-CpG-7909 with 4.9 mg Amph-Peptides 7P. Safety: all grade 1, fatigue (29%), malaise (21%), and injection site reaction (7.1%). At data cutoff Dec 18, 2023, polyfunctional mKRAS-specific T cells were observed in 100% (n=11/11). Both CD8+ and CD4+ responses were induced in 63.6% of pts (7/11), with higher median fold-change from baseline at RP2D and durable responses post-booster immunization in 100% of pts (7/7). Biomarker reductions were observed in 2/5 (40%) at the 1.4 mg Amph-Peptides 7P dose level and in 5/7 (71%) at the RP2D 4.9 mg dose level in pts with all the common G12X (D, V, R) and G13 (D) KRAS mutations; MRD clearance was observed in 1 G12V PDAC pt at 4.9mg. Conclusions: ELI-002 7P was safe with median RP2D T cell responses exceeding the prior formulation (7P median 109.2; 2P 12.75), and early indications of antitumor activity. The randomized phase II is now open in patients with pancreas cancer. Clinical trial information: NCT05726864 . [Table: see text]
Impact of body mass index (BMI) on survival outcomes in patients with cancer treated with immune checkpoint inhibitors (ICPI): A systematic review and meta analysis.
Authors: Rahul Mishra, Mahnoor Sukaina, Nitya Batra, Madhan Srinivasan Kumar, Kamalpreet Singh Walia, Rutvi Chahal, Atulya Aman Khosla, Rohit Singh, Shahid Sattar Ahmed, Karan Jatwani
Journal: Journal of Clinical Oncology (2024)

2624 Background: With the increased adoption of ICPI in treating various cancers, there is active exploration of individual-level factors that could predict treatment responses. A high-body mass index (BMI) induces a chronic inflammatory state and could drive T-cell dysfunction through high leptin levels, which may confer better outcomes with ICPI usage. However, there are conflicting outcomes in different studies. We performed this systematic review and meta-analysis to evaluate survival outcomes with ICPI in patients with BMI ≥25 vs &lt;25 Kg/m 2 . Methods: A comprehensive search was conducted across PubMed, Embase, Scopus, and web of science databases. The original studies evaluating response [overall survival (OS) and progression free survival (PFS)], to ICPI-based therapies among adult cancer patients, stratified by BMI groups (high, BMI ≥25Kg/m 2 or low, BMI &lt;25Kg/m 2 ), were included. RevMan version 5.4.1 was used for statistical analysis. A random effect model with inverse variance as the statistical method was used for hazard ratio (HR) and 95% confidence interval (CI). Results: Of 1215 identified studies, 22 observational studies, comprising 5859 patients (60.3% males) met the inclusion criteria. ECOG performance score was reported as 0-1 for 40.3% patients, and ≥2 for 7.1% patients. In 12-studies only PD-1 and/or PD-L1 inhibitors were administered, but no CTLA-4 inhibitor. Most frequently reported cancers were non-small cell cancer of lung (40.9%), melanoma (36.6%), and renal cell cancer (31.8%) in advanced/metastatic stages. Higher BMI, compared to low BMI, favored significant improvement in PFS [HR 0.86; 95% CI (0.76, 0.99), P= 0.03, I 2 47%], and OS [ HR 0.73; 95% CI (0.62, 0.85), P&lt; 0.0001, I 2 53%] with any ICPI-based regimens. Similar findings were noted for patients treated with PD-1/PDL1 inhibitors [Table]. Conclusions: This study contributes to the evidence that BMI of 25 kg/m 2 or higher exerts a beneficial impact on PFS and OS among cancer patients treated with ICPI. The favorable impact underscores the significance of considering BMI as a potential prognostic factor in ICPI therapy. However, the precise underlying mechanisms responsible for this observation warrant further investigation to deepen our understanding and potentially optimize therapeutic strategies in this patient population. [Table: see text]
Tislelizumab first-line (1L) gastric/gastroesophageal junction cancer (G/GEJ) treatment efficacy on patient-reported outcome (PRO)-based symptom endpoints adjusting for informative missing data bias: Results from RATIONALE 305.
Authors: Daniel Serrano, Hui Xu, Tao Sheng, Liyun Li, Gisoo Barnes, Do-Youn Oh
Journal: Journal of Clinical Oncology (2024)

2605 Background: PRO-based symptom endpoints are rarely associated with treatment efficacy in oncology trials. PRO analyses emphasize early treatment cycles to avoid bias arising from study dropout (SDO; eg, due to death or other intercurrent events). SDO is thought to induce data missing not at random (MNAR), thereby biasing estimates and inference. However, separation between arms on other efficacy endpoints (eg, overall survival [OS]) typically occurs at cycles subsequent to the analysis period cutoff for PRO-based endpoints. This research examined treatment efficacy in PRO-based symptom endpoints in treatment cycles occurring later than typically analyzed. To protect against MNAR bias associated with later cycles, joint models (JMs) were employed. Methods: RATIONALE 305 was a randomized, double-blind, placebo-controlled, phase 3 trial comparing efficacy and safety of tislelizumab + chemotherapy (tislelizumab) with placebo + chemotherapy (chemo) as 1L treatment for patients with locally advanced, unresectable, or metastatic G/GEJ adenocarcinoma. EORTC-STO22 symptom domain scores were analyzed. Change from baseline (CFBL) in each domain was analyzed for up to 21 cycles between baseline and Cycle 38 (cycle with no less than 10% of baseline surviving). Treatment efficacy for STO22 endpoints was analyzed using JMs. The JM linked a linear mixed model (LMM) for STO22-domain CFBL to a Cox proportional hazards model for OS, adjusting LMM estimates for the potential MNAR bias arising from OS-based SDO. The LMM and Cox model were adjusted for study randomization factors of region (East Asia vs Rest of World), PD-L1 status (positive vs. negative), and peritoneal metastases (present vs. absent). All analyses were conducted using JMBayes2 package in R version 4.3.2. Results: STO22 pain results are reported; all domains will be presented. For tislelizumab (n=465) vs. chemo (n=467), subjects remaining at Cycle 38 were 46 (10%) and 28 (6%), respectively. Tislelizumab was associated with a constant lower level of pain compared with chemo (-2.08; P=0.0109). Tislelizumab was associated with a 21% reduction in risk of death ( P=0.0269). Conclusions: In this analysis, compared with chemo, tislelizumab + chemo was associated with lower pain and longer survival. Joint models for PRO-based symptom endpoints may illuminate patient-centric therapeutic benefits. [Table: see text]
A phase 2a study of NT-I7 (efineptakin alfa), a long-acting IL-7, and pembrolizumab to evaluate efficacy, including overall survival, in hard-to-treat gastrointestinal tumors.
Authors: Richard D. Kim, Hirva Mamdani, Minal A. Barve, Melissa Lynne Johnson, Julie A. Murphy, Lauren Trogun, Sara Ferrando-Martinez, Byung Ha Lee, Se Hwan Yang, Marya F. Chaney, Aung Naing
Journal: Journal of Clinical Oncology (2024)

2621 Background: Microsatellite-stable colorectal (MSS-CRC) and pancreatic cancer (PDAC) are immunologically cold tumors with null response to checkpoint inhibitors (CPI). NT-I7, a long-acting IL-7, in combination with pembrolizumab (pembro) has shown to significantly increase intratumoral T cell infiltration and elicit some tumor control in these hard-to-treat gastrointestinal indications. The original MSS-CRC and PDAC cohorts, enrolling 25 patients (pts) each, were expanded to 50 pts per indication. Here, we provide an updated analysis including the original and expansion cohorts. Methods: Open-label Phase 2a study in subjects with relapsed/refractory CPI-naïve MSS-CRC and PDAC; NT-I7 1200 µg/kg IM every 6 weeks (Q6W), pembro 200 mg IV Q3W. Antitumor activity assessed by RECIST v1.1/iRECIST. Results: As of 02OCT2023, 98 subjects were efficacy-evaluable (50 MSS-CRC, 48 PDAC); median age 61.0 years, all with baseline ECOG status 0-1. 95.9% (94/98) received study treatment ≥3 rd line, with a median follow -up of 6.1 months. Safety profile for NT-I7 was similar to previous reports. In MSS-CRC pts, 1 pt and 3 pts achieved confirmed partial responses per RECIST and iRECIST, respectively; median duration of response (DOR/iDOR) was 13.1/13.0 months (mo) and 2 responders were alive with no progression at data cutoff. Disease control rate (DCR/iDCR) was 36.0% (18/50) / 38.0% (19/50), with a duration of response and stable disease (DORSD/iDORSD) of 3.2/14.5mo. Interestingly, iDCR was 71.4% (5/7) in MSS-CRC pts with primary tumor in the rectum, versus 30.8% (12/39) in pts with primary tumor in the colon. With 11 pts on follow up, progression free survival (PFS/iPFS) was 1.5/3.8 mo. Among PDAC pts, 2 and 3 pts achieved confirmed PR and iPR, with DOR/iDOR of NE/9.7 mo; 1 responder was alive with no progression at data cutoff. DCR/iDCR was 25.0% (12/48) / 27.1% (13/48), and DORSD/iDORSD was 2.9/9.8mo. With 11 pts on follow up, PFS/iPFS was 1.4/2.1 mo. Clinical benefit in MSS-CRC and PDAC was most evident by a notable median overall survival (mOS); 13.2 mo in MSS-CRC [95% CI 8.9 – 18.6 mo] and 11.1 mo in PDAC [95% CI 4.1 – 13.3 mo], compared to historical mOS for standard of care, 10.8 mo (MSS-CRC) and 6.1 mo (PDAC). Conclusions: NT-I7 and pembro treatment was associated with longer mOS relative to historical studies. Identification of predictive biomarkers that may define pts with higher likelihood of clinical benefit would be a promising step to maximizing potential of the NT-I7 + pembro treatment combination for pts with these indications. Research in this area is ongoing. Clinical trial information: NCT04332653 .
A phase 1 study of the small-molecule PD-L1 inhibitor INCB099280 in select advanced solid tumors: Updated safety, efficacy, and pharmacokinetics (PK) results.
Authors: Hans Prenen, Jeannie Daniel, Victoria Ebiana, Jason Howe, Xiaohua Gong, Susan Spitz, Antoine Italiano
Journal: Journal of Clinical Oncology (2024)

2608 Background: INCB099280 has shown preliminary efficacy and acceptable safety in an ongoing phase 1, open-label, multicenter study in patients (pts) with advanced solid tumors (1). Here we present updated results and PK data. Methods: Eligible pts were ≥18 years of age with ECOG PS ≤1 and disease progression after available treatment (tx) or were ineligible for/without access to standard tx. Study started with dose escalation (100 mg qd to 800 mg bid), followed by dose expansion in 3 cohorts (IO-naive; IO-naive, MSI-H/dMMR tumors; anti–PD-1 previously treated). Primary endpoints are safety, tolerability, and determination of pharmacologically active dose/MTD. PK, objective response rate (ORR) per RECIST v1.1, and pharmacologic biomarkers were also analyzed. Results: As of January 14, 2023, 179 pts had received INCB099280 at doses from 100 mg qd to 800 mg bid (median age, 63 years [range, 21-86]; ≥2 prior lines of tx, 65.4%; prior IO, 16.2%). MTD was not reached. Overall, 96.6% of pts had ≥1 tx-emergent adverse events (TEAEs). Immune-related (ir) TEAEs occurred in 23.5% of pts. Best antitumor activity was noted with 400 mg bid (ORR, 17.8%) in pts with mixed tumor types. Updated clinical data will be presented. PK exposures increased proportionally as dose increased up to 800 mg bid (Table). Steady-state PK was achieved by cycle 1 day 8, with an accumulation ratio of 2-3. Inter-individual PK variability was high, but similar to that of healthy participants. Steady-state trough concentrations exceeded IC 90 across 300-800 mg bid doses. In preliminary analyses correlating exposure with clinical outcomes, increased exposure was associated with a moderate trend of higher ORR and incidence of serious and/or ir-TEAEs. Preliminary electrocardiogram data suggested that large QTc effects (&gt;20 ms) can be excluded at doses up to 800 mg bid. No association was detected between PK exposure and ctDNA change at cycle 4 day 1 or end-of-tx vs baseline, but decreased ctCNA was seen in all complete responders (n=2) and 6 partial responders (n=11). Conclusions: INCB099280 was generally well tolerated at all doses tested and showed promising antitumor activity. INCB099280 PK was dose proportional up to 800 mg bid, with high variability; steady-state trough exposure exceeded IC 90 for ≥300 bid doses. These data support further development of INCB099280 as monotherapy and in combination regimens for solid tumors. Phase 2 studies are ongoing. 1. Prenen, ESMO-IO 2023; NCT04242199. Clinical trial information: NCT04242199 . [Table: see text]
Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors.
Authors: Jiajian Liu, Caicun Zhou, Wei Li
Journal: Journal of Clinical Oncology (2024)

2639 Background: LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&amp;L Biopharma Co., Ltd, which blocks the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways, and showed better T/DC cell activity and in vivo anti-tumor efficacy compared to TIM-3 and PD-1 antibody combination in preclinical studies. Here we report the results of the first-in-human, multicenter, open-label, phase I trial of LB1410 monotherapy in pts with advanced solid tumors ( Keyplus-001 ). Methods: Eligible pts were ≥ 18 yr old with ECOG PS 0-1 and previous treatment. Dose escalation cohorts ranged from 0.001 mg/kg to 20 mg/kg IV Q2W: 0.001mg/kg-1mg/kg in an accelerated titration design, and 3 mg/kg-20 mg/kg using traditional 3+3 design. The primary objective is safety, including dose-limiting toxicities (DLTs). Secondary/exploratory objectives include efficacy, pharmacokinetics (PK), and immunogenicity. Data cutoffs were January 5, 2024 for safety, and January 25, 2024 for efficacy. Results: In total, 52 pts received LB1410 from 0.001 mg/kg to 20 mg/kg as of Jan 5, 2024, median age 58 yr, 69% male. All of patients enrolled had multiple organ metastases or multiple metastases in a single organ, and were heavily treated with anti-tumor treatment, 36/52 (69.2%) were resistant to or refractory to PD-1/PD-L1 inhibitors, and 16/52 (30.8%) were MSS CRC. Treatment related AEs (TRAEs) occurred in 65.4% of pts. The most common TRAE was anemia (19.2%). 2 patients developed Gr3 hypokalemia. There were no DLTs. Tumor response evaluation were available in 40 pts: 14 had stable disease, 25 had progression, and 1 was not evaluable. Target lesion shrinkage was observed in 9 pts, including one patient's sum of target lesion reduced by 48.7% from baseline. Of 14 pts who had stable disease, there were 2 pts with stable disease lasting for more than 6 months. PK was generally dose proportional within 1 mg/kg~15 mg/kg, with t 1/2 ~4.12 days in 10 mg/kg, and t 1/2 ~4.77 days in 15 mg/kg. Of the 22 subjects tested for ADA, only one produced ADA for LB1410, the positive rate was 4.5%. Antidrug antibodies had limited impact on PK. As of Jan 5, 2024, 39 pts remained on the study; updated data will be presented. Conclusions: LB1410 has manageable safety and shows preliminary efficacy. Additional dose and efficacy expansion study is ongoing in immunotherapy-naive pts with MSS CRC and pts who are resistant to immunotherapy. Clinical trial information: NCT05357651 .