tbuckley/cabot-search huggingface dataset:
Efficacy and safety of MCLA-129, an EGFR/c-MET bispecific antibody, in advanced non-small cell lung cancer (NSCLC).
Authors: Jie Wang, Jia Zhong, Lin Wu, Bolin Chen, Zhe-Hai Wang, Yu Yao, Xiaorong Dong, Wei Li, Xiubao Ren, Xiaoming Hou, Ai-min Zang, Xiujuan Qu, Guojun Zhang, Yongsheng Wang, Yuansong Bai, Linlin Liu, Guohua Yu, Xingwu Chen, Lieming Ding
Journal: Journal of Clinical Oncology (2024)

8604 Background: MCLA-129 is a common light chain, Biclonics, bispecific antibody targeting EGFR and c-MET with enhanced antibody-dependent cellular cytotoxicity. Here we describe the ongoing first-in-human phase 1/2 study of MCLA-129 in patients with NSCLC, including patients with MET exon 14 skipping (METex14) mutation (cohort A), EGFR exon 20 insertion (exon20ins)-mutated (cohort B) and sensitized EGFR-mutated disease (cohort C). Methods: Patients received MCLA-129 (100–2000 mg) IV biweekly or 1000-1500 mg IV weekly in a 28-day cycle in dose escalation. Doses at 1500 and 2000 mg IV biweekly are being explored in dose expansion. The primary endpoint was safety and tolerability. Objective response rate by investigator assessment per RECIST v1.1 of patients with NSCLC treated at 1500 and 2000 mg IV biweekly in three cohorts is reported. Results: As of 26 May 2023, 217 enrolled patients received MCLA-129 in China. The data cut-off was 24 Nov 2023. The most common treatment-emergent adverse events (TEAEs) were infusion related reaction (71.9%), hypoalbuminemia (54.8%), decreased neutrophil count (46.1%), and decreased white blood cell count (40.1%). TEAEs mostly were grade 1-2. Grade ≥3 TEAEs and drug-related TEAEs were reported in 51.6% and 39.2% of patients, respectively. 176 of the 215 NSCLC patients were evaluable. The confirmed objective response rates (ORR) in Cohort A, B and C were 43.5%, 28.6% and 21.8%, respectively. Especially, for patients in Cohort A receive prior MET TKI, the ORR was 37.5% and disease control rate (DCR) was 93.8%. Overall efficacy is shown (Table). Conclusions: MCLA-129 demonstrates robust and durable antitumor activity in patients with NSCLC harboring METex14, EGFR exon20ins and sensitized EGFR mutations, with a manageable safety profile; enrollment in dose expansion is ongoing. Clinical trial information: NCT04930432 . [Table: see text]
A randomized phase II study of toripalimab consolidation or observation after concurrent chemoradiotherapy in limited-stage small cell lung cancer.
Authors: PengXin Zhang, FangJie Liu, DaQuan Wang, ShiYang Zheng, JinYu Guo, YingYi Zou, Ying Liang, Yuanyuan Zhao, Bo Qiu, Hui Liu
Journal: Journal of Clinical Oncology (2024)

8098 Background: In recent years, the use of immune checkpoint inhibitors has led to significant progress in the treatment of extensive-stage small cell lung cancer. However, there is limited data on the efficacy of immunotherapy in patients with limited-stage disease (LS-SCLC). Therefore, we conducted a phase II randomized study to verify the efficacy and safety of Toripalimab consolidation following definitive concurrent chemoradiotherapy (CCRT) in patients with LS-SCLC (ClinicalTrials.gov ID: NCT04418648). Methods: Patients with LS-SCLC who had achieved complete or partial response after definitive CCRT (including four to six cycles of etoposide and cisplatin , and curative-intent thoracic radiotherapy) were randomly assigned (1:1) to receive Toripalimab consolidation (240mg intravenously, every 3 weeks for 6 months) or observation. Prophylactic cranial irradiation (PCI) was recommended but not mandatory. The primary endpoint was progression-free survival (PFS) calculated from randomization, and secondary endpoints included overall survival (OS) and toxicity. Results: As of data cutoff (November 30, 2023), a total of 64 eligible patients (intent-to-treat population) were randomly assigned to the Toripalimab group (n = 31) or the observation group (n = 33), respectively. With the median follow-up of 25 months, PFS was significantly improved with Toripalimab (hazard ratio [95% CI]: 0.47 [0.22-1.02]; P = 0.04). The median PFS in observation group was 12.3 months (95% CI, 0.04-24.50), while the median PFS in the Toripalimab group has not been reached. The 24-month PFS rate was 61.6% (95% CI, 43.0%-88.3%) in the Toripalimab group and 34.8% (95% CI, 21.5%-56.3%) in the observation group. The 24-month OS was 82.7% (95% CI, 65.2%-100%; P = 0.23) in the Toripalimab group and 59.1%(95% CI, 44.2%-79.1%) in the observation group. There were 5(16.1%) and 3 (9.1%) patients in the Toripalimab group and observation group experiencing G2+ pneumonitis respectively. No G4+ toxic events occurred in either group. Conclusions: Our preliminary results suggested Toripalimab consolidation following definitive CCRT was effective and tolerable in LS-SCLC. Clinical trial information: NCT04418648 . [Table: see text]
Therapeutic manipulation of the microbiome in liver disease
Authors: Gopanandan Parthasarathy, Harmeet Malhi, Jasmohan S. Bajaj
Journal: Hepatology (2024)

Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.
Real-world outcomes of osimertinib (Osi) vs. afatinib or erlotinib in patients with classical vs. atypical <i>EGFR</i>-mutated metastatic non-small cell lung cancer (mNSCLC).
Authors: Adam Barsouk, Omar Elghawy, Alec Heidlauf, Connie Yu, David Yang, Martin Kurian, Keshav Goel, Lynn Rushkin, Anran Huang, Teja Voruganti, Lova Sun, Aditi Puri Singh, Roger B. Cohen, Charu Aggarwal, Melina Elpi Marmarelis, Corey J. Langer
Journal: Journal of Clinical Oncology (2024)

8566 Background: Limited data are available on the efficacy of osi for mNSCLC with atypical EGFR mutations (AM) such as L861Q, G719X, S768I, and exon20 insertions. Afatinib is FDA approved for mNSCLC harboring L861Q, G719X, and S768I. Real-world analyses comparing osi to afatinib and erlotinib for AM have yielded mixed results. Methods: We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007-2023 with EGFRTKIs. Clinical trial patients were excluded. Patients with classical EGFRmutations (CM) were compared to those with AM. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the EMR. Median PFS and OS were estimated and compared via Kaplan-Meier log-rank analysis. Independent sample t-tests and chi-square analyses were used for univariate comparisons. P-values&lt;0.05 were considered statistically significant. Results: Among 355 patients with 1L EGFR-mutated mNSCLC, 315 (90%) had CM (exon19 del [N=182; 51%] and L858R [N=119; 34%]), while 36 (10%) harbored AM in G719X (N=21; 6%), Exon 20 (N=11; 3%), L861Q (N=7; 2%), and S768I (N=4; 1%). Patients with CM vs AM had similar median age at diagnosis (63, p=0.406), gender (65% F; p=0.213), racial composition (p=0.653), and history of smoking (44%, p=0.167). At diagnosis, 45% vs 48% of patients had CNS involvement (p=0.434). 52% vs 41% received osi, 36% vs 20% patients received erlotinib, and 11% vs 37% received afatinib (p&lt;0.001). Patients with CM had superior mPFS (29 vs 15m; p=0.021) and mOS (49 vs 13m; p&lt;0.001) vs AM (Table). In AM patients (N=36), osi had superior mPFS (15m [7-23]) vs afatinib (11m [8-15]; p=0.005) or erlotinib (8m [6-10]; p=0.001). mOS was likewise superior for osi (29m [6-50]) vs afatinib (13m [9-17]; p&lt;0.001) or erlotinib (14m [6-21]; p&lt;0.001). 121 CM and 7 AM patients were rechallenged with a TKI; mPFS2 for AM was 13m for osi (N=4) vs 4m for afatinib (N=3; p=0.114). Dose-reduction due to AE was lower for osi (19%) vs afatinib (24%; p=0.003) or erlotinib (23%; p=0.002). Discontinuation due to AE was lower for osi vs afatinib (1% vs 2%; p&lt;0.001) or erlotinib (2%; p=0.004). Conclusions: Retrospectively, AM were associated withinferior PFS and OS compared to CM. Osi demonstrated superior survival and tolerability compared to afatinib or erlotinib for AM. [Table: see text]
Prospective validation of in silico clinical trials prediction using an EGFR-mutated NSCLC mechanistic computational disease model.
Authors: Michaël Duruisseaux, Perrine Masson, Arnaud Nativel, Nicolas Girard, Jacques Cadranel, Aurélie Swalduz, Matthieu Coudron, Guillaume Bouchard, Riad Kahoul, Evgueni Jacob, Jim Bosley, Jean-Louis Palgen, Adèle L'Hostis, Claudio Monteiro
Journal: Journal of Clinical Oncology (2024)

8614 Background: Advanced lung adenocarcinoma (aLUAD) is divided into multiple molecularly defined subsets, each with specific biological characteristics and responses to targeted therapy. Consequently, conducting practice-changing and cost-effective randomized trials is challenging. In silico clinical trials, utilizing mechanistic computational models, offer a potential solution, yet their ability to predict clinical trial results has not been proven. Methods: We updated a previously published version of the computational mechanistic model of EGFR-mutated aLUAD, notably by incorporating metastases. Disease model was integrated with physiologically based pharmacokinetic (PBPK) models of cisplatin, pemetrexed, and osimertinib, offering a more comprehensive understanding of the disease's dynamics. These models are founded on causal connections between biological entities and phenomena, establishing a link between the specific biological behaviors of EGFR-mutated aLUAD and the evolution of tumor size and progression over time. We have independently and prospectively simulated the outcomes of the FLAURA2 and MARIPOSA randomized trials dedicated to EGFR-mutated aLUAD. This was achieved by replicating the experimental protocols and generating cohorts of virtual twins of patients using publicly available data. Results: In silico results were released before the actual outcomes of the FLAURA2 and MARIPOSA trials were publicly available. The simulations yielded predictions with overlapping confidence intervals, similar hazard ratios, median survivals, and shapes of curves compared to the actual trial data. Bootstrapped weighted log-rank tests were used to compare the simulated and observed Kaplan-Meier curves for the two arms of FLAURA2 and for the osimertinib arm of MARIPOSA. Between 94 and 98% of the tests were statistically non-significant (α=0.05), confirming the accuracy of the predictions. Conclusions: This first-of-its-kind prediction of clinical trial outcomes demonstrates that in silico trials, when based on robust mechanistic models, can be a reliable tool for enhancing the design of actual trials, particularly for EGFR-mutated aLUAD. They offer a promising avenue for overcoming the challenges of comparator arms in single-arm trials and may serve as a new standard for formulating statistical hypotheses in future studies.
Association of combination tumor texture and vessel tortuosity with progression free survival across PD-L1 subgroups in durvalumab treated non-small cell lung cancer (NSCLC): Blinded validation results from CP1108.
Authors: Mohammadhadi Khorrami, Pushkar Mutha, Vidya Sankar Viswanathan, Amit Gupta, Vamsidhar Velcheti, Anant Madabhushi
Journal: Journal of Clinical Oncology (2024)

8600 Background: Immunotherapy (IO) has shown a durable response with minimal toxicity in the treatment of metastatic NSCLC. However, only 30-50% of these patients (pts) actually respond. Despite initial optimism surrounding PD-L1 expression as a potential biomarker, IO provides benefit across PD-L1 low (&lt;25%) and high (≥25%) status. This highlights a critical need for more effective biomarkers to guide treatment decisions. Here, we present blinded validation results of a CT-based biomarker of change in quantitative vessel tortuosity (1) (Δ-QVT) and texture radiomics (2) (Δ-Rad) between baseline (B) and 6 weeks post-treatment (TP1) for predicting response, overall survival (OS) and progression free survival (PFS) in CP1108 (NCT01693562). Methods: CT scans at B and TP1 were retrospectively analyzed from two studies (a) a multi-center training set (S tr , N=110) of metastatic NSCLC pts treated with first line IO and (b) a blinded NSCLC cohort of N = 151 pts treated with Durvalumab in CP1108 study (S v ). In S v , N=75 pts were PD-L1 high (S v + ) whereas N=65 pts were PD-L1 low (S v - ). An in-house MATLAB based algorithm was used to extract intra-tumoral, peri-tumoral texture and QVT features from up to two largest measurable tumors in each CT. A classifier (M Combo ) was trained on S tr to predict best overall response defined as per the RECIST v1.1 criteria using combination of Δ-QVT and Δ-Rad features. Area under the receiver operating characteristic (AUC) was used to evaluate M Combo against RECIST response whereas univariable and multivariable Cox regression models with log-rank test, hazard ratio (HR) with confidence interval (CI) and concordance index (C-index) were used to study the association of M Combo with OS and PFS in S v , S v + , and S v - . Results: M Combo predicted objective response with an AUC of 0.78 in S v and was statistically significantly associated with PFS (Table) in S v , S v + , and S v - . M Combo was associated with OS in S v , S v + , but not in S v - . Multivariable analysis with PD-L1 status, histological subtype, ECOG status, liver metastasis, line of therapy and sex showed independent association of M Combo across OS and PFS. Conclusions: Our results indicate that combination of radiomics and vessel tortuosity biomarker from CT is independently prognostic of response and PFS across PD-L1 levels. Prospective validation of this biomarker is needed. 1. Alilou et al. Sci Adv 2022. 2. Khorrami et al. Cancer Immunol Res 2020. [Table: see text]
Sotorasib plus carboplatin and pemetrexed in <i>KRAS</i> G12C advanced NSCLC: Updated analysis from the international CodeBreaK 101 trial.
Authors: Bob T. Li, Jeffrey Melson Clarke, Enriqueta Felip, Jose Carlos Ruffinelli, Pilar Garrido, Jon Zugazagoitia, Sarah B. Goldberg, Suresh S. Ramalingam, Iván Victoria, Sonam Puri, David R. Gandara, William Kormany, Sophie Edmonds, Kerry Palmer, Ravi G. Gupta, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2024)

8512 Background: The combination of platinum doublet chemotherapy with sotorasib may improve anti-tumor activity and overcome therapeutic resistance in KRASG12C-mutated advanced non-small cell lung cancer (NSCLC). We report updated efficacy and safety of sotorasib plus carboplatin and pemetrexed from the international CodeBreaK 101 phase 1b trial (NCT04185883). Methods: Patients (Pts) with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg QD plus carboplatin AUC 5 IV Q3W and pemetrexed 500 mg/m 2 IV Q3W for up to 4 cycles followed by sotorasib plus pemetrexed maintenance until disease progression/unacceptable toxicity. Data were analyzed by prior therapy in the locally advanced/metastatic setting (1L and 2L+). Primary endpoints were safety/tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) according to RECIST v1.1 per investigator, and overall survival (OS). Results: As of December 1, 2023, 58 pts (median age, 65.5 yrs; 45% male; ECOG status 0/1, 38%/62%) were treated with sotorasib plus carboplatin and pemetrexed; 37 (64%) pts in the 1L and 21 (36%) in the 2L+ setting. In 2L+, 18/21 (86%) pts had received prior anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 54 (93%) pts; grade 3–4 in 30 (52%) pts and fatal in 1 (2%) (Table). In 1L, ORR was 65% (95% CI, 46.5–80.3), DCR was 100%, median DOR was 9.1 mo (95% CI, 4.4–12.5), and median PFS was 10.8 mo (95% CI, 5.4–NE; median follow-up [f/u], 9.2 mo). Median PFS was 11.9 mo (95% CI, 5.3–NE) in the PD-L1 &lt;1% subgroup (n=19). For 2L+, ORR was 42% (95% CI, 20.3–66.5), DCR was 84%, median DOR was NE, and median PFS was 8.3 mo (95% CI, 4.1–NE; median f/u, 4.4 mo). OS data remained immature. Conclusions: Sotorasib plus platinum doublet chemotherapy conferred robust and durable responses with a manageable safety profile in CodeBreaK 101, supporting evaluation of this regimen in the ongoing CodeBreaK 202 phase 3 trial in treatment naïve, PD-L1 negative, KRAS G12C-mutated advanced NSCLC (NCT05920356). Clinical trial information: NCT04185883 . [Table: see text]
Exploring gut microbiome markers in predicting efficacy of immunotherapy against lung cancer.
Authors: Wenjie Han, Junnan Xu, Tao Sun, Yuhang Zhou, Yun Feng, Li Han, Xiaolin Liu
Journal: Journal of Clinical Oncology (2024)

8525 Background: Immunotherapy has profoundly changed the treatment landscape for lung cancer (LC) due to its tolerable safety profile and longer sustained therapeutic response. However, only about 20% of patients with locally advanced and metastatic disease can derive long-term clinical benefit from ICIs. Previous studies have suggested that the microbiome is involved in the development of LC in some way. We aimed to use the gut microbiome (GM) to model the benefit of immunotherapy and to mine the biomarkers with a global impact on immune response. Methods: We performed human gut metagenomic analysis on the responder patients and non-responder patients with immunotherapy. A total of 296 fecal samples, including baseline samples (71 responders, 98 non-responders and 72 healthy controls), and 55 samples during treatment were enrolled in our study, the taxonomic and functional features of these samples also were excavated. A machine-learning model was developed to identify responders and non-responders. At the same time, we also explored the influence of antibiotic use on the above results. Results: Specific species, Bacteroides caccae and Bacteroides uniformis, were positively correlated with responders. In non-responders, Prevotella copri was the main enrichment species. The α diversity of microbiota in responding patients was significantly higher than that in non-responding groups, and antibiotic use increased this trend. There was no significant difference in β diversity between the two groups, but LEFSE analysis also could obtain biomarkers of biological significance between the two groups. We used the biomarkers from the above analysis to construct a random forest model, and the area under the receiver operating characteristic curve (AUC) (species level: 82.10%; genus level: 79.4%). In addition, our studies suggested that metabolism such as amino acid metabolism, valine, leucine might be important in regulating the immunotherapy response that warrants further investigation. Conclusions: Overall, our study explored the relationship between microbial composition and immunotherapy efficacy in LC patients and mined relevant markers, and further research is needed to investigate the mechanisms of action of these key strains in influencing immunotherapy in the future.
Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).
Authors: Ernest Nadal, Paloma Martín-Martorell, Jose Carlos Benítez, Maria Angeles Sala, Susana Cedres Perez, Carlos Álvarez Fernandez, Manuel Domine, Elia Sais, Maria Saigi, Rafael Lopez Castro, Laia Vilà, Bartomeu Massuti, Rosario Garcia Campelo, Mariano Provencio, Begona Campos
Journal: Journal of Clinical Oncology (2024)

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m 2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .