tbuckley/cabot-search huggingface dataset:
Overall survival of adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line treatment for extensive-stage small cell lung cancer.
Authors: Dawei Chen, Aiqin Gao, Bing Zou, Wei Huang, Qian Shao, Xiangjiao Meng, Pinliang Zhang, Xiaoyong Tang, Xudong Hu, Yan Zhang, Jun Guo, Wei Zhao, Lei Fu, Changhong Zhao, Jiajia Yuan, Jinming Yu, Linlin Wang
Journal: Journal of Clinical Oncology (2024)

8014 Background: The phase 3 trial (CAPSTONE-1) showed that adebrelimab (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival (OS) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC). Previous studies have shown that radiotherapy can enhance the immunogenicity of tumors, indicating the great potential of combining radiotherapy with immunotherapy. The purpose of this study was to explore the efficacy and safety of adebrelimab combined with chemotherapy and sequential thoracic radiotherapy (TRT) as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts received 4~6 cycles of adebrelimab (20mg/kg, D1, q3w) combined with EP/EC (etoposide, 100mg/m 2 , D1-3, q3w and cisplatin, 75mg/m², D1, q3w or carboplatin, AUC = 5, D1, q3w). Pts with response sequentially received adebrelimab combined with consolidate TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation). Pts then entered the maintenance treatment stage with adebrelimab until disease progression or intolerable side effects. The primary endpoint was OS. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to April 2023, 67 pts with ES-SCLC were enrolled. Most patients were male (83.6%), current or former smokers (65.7%) with an ECOG performance status of 1 (95.5%). 22 (32.8%) patients were diagnosed with brain metastasis and 21 (31.3%) patients had liver metastasis at baseline. 45 patients received sequential TRT as planned. All patients were included in the safety and efficacy analysis population. At data cutoff (December 22, 2023), the median follow-up duration was 17.7 months. The median OS was 21.4 months (95% CI: 17.2–not reached months). 1-year and 2-year OS rate were 74.1% (95% CI: 63.6-86.4%) and 39.7% (95% CI: 25.5-61.9%). The median PFS was 10.1 months (95% CI: 6.9–15.5 months). The confirmed ORR was 71.6% (95% CI: 59.3-82.0%) and DCR was 89.6% (95% CI: 79.7-95.7%). The most common grade 3 or higher treatment-related adverse events included neutrophil count decreased (41.8%), white blood cell count decreased (19.4%) and lymphocyte count decreased (13.4%). No unexpected adverse events were observed. Conclusions: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Clinical trial information: NCT04562337 .
Health-related quality of life (HRQoL) with tepotinib in patients with <i>MET</i> exon 14 (<i>MET</i>ex14) skipping non-small cell lung cancer (NSCLC) with brain, liver, adrenal, or bone metastases in the phase II VISION trial.
Authors: Niels Reinmuth, Julien Mazieres, Sanjay Popat, Luis G. Paz-Ares, Emma S Hook, Anthony Hatswell, Soetkin Vlassak, Andreas Johne, Helene Vioix, Paul K. Paik
Journal: Journal of Clinical Oncology (2024)

8575 Background: Tepotinib, a highly selective MET inhibitor, showed robust and durable activity in patients with METex14 skipping NSCLC in the VISION trial (NCT02864992) (1). Systemic and intracranial activity was seen in patients with brain metastases. Secondary endpoints in the overall population showed stability in overall HRQoL, dyspnea and chest pain, with clinically meaningful improvement in cough. We analyzed HRQoL in patients with brain, liver, adrenal or bone metastases. Methods: Eligible patients (including patients with brain metastases if asymptomatic or neurologically stable on a stable steroid dose) received oral tepotinib 500 mg (450 mg active moiety) once daily. HRQoL was assessed at baseline and during follow-up using the EORTC QLQ-C30 Global Health Score (GHS), EQ-5D-5L visual analog scale (VAS), and EORTC QLQ-LC13 cough, dyspnea, and chest pain scores. Subgroup analyses evaluated patients with brain, liver, adrenal or bone metastases at baseline per independent review (data cut-off: November 20, 2022). Mean change from baseline across all visits was evaluated by linear mixed model regression in patients with baseline and ≥1 post-baseline score. Results: Of 313 enrolled patients, change from baseline in HRQoL was evaluable in 52 patients with brain (16.6%), 56 with liver (17.9%), 54 with adrenal (17.3%), and 86 with bone metastases (27.5%). At baseline, mean ± standard error (SE) EORTC QLQ-C30 GHS was worst in patients with bone metastases (49.90 ± 2.03), followed by patients with adrenal (51.85 ± 2.51), liver (58.33 ± 2.77), or brain metastases (59.94 ± 2.53). A similar pattern was observed for baseline EQ-5D-5L VAS (bone: 60.42 ± 1.94; adrenal: 63.06 ± 2.45; liver: 65.30 ± 2.46; brain: 66.75 ± 2.57). During tepotinib treatment, overall HRQoL (i.e. EORTC QLQ-C30 GHS and EQ-5D-5L VAS) remained stable in patients with brain, liver, adrenal or bone metastases (Table). Symptom scores in these patients showed trends for improvement in cough, with stability in dyspnea and chest pain. Conclusions: In the VISION trial in METex14 skipping NSCLC, patients with brain, liver, adrenal or bone metastases maintained overall HRQoL during tepotinib treatment, with trends for improvement in cough, consistent with results for the overall population. 1. Mazieres et al. JAMA Oncol 2023;9:1260–66. Clinical trial information: NCT02864992 . [Table: see text]
Sacituzumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study.
Authors: Wenfeng Fang, Qiming Wang, Ying Cheng, Yongzhong Luo, Xiujuan Qu, Haibo Zhu, Zhenyu Ding, XingYa Li, Lin Wu, Yan Wang, Sheng Hu, Enwen Wang, Anwen Liu, Yuping Sun, Yun Fan, Feng Ye, Kaihua Lu, Yalan Yang, Junyou Ge, Li Zhang
Journal: Journal of Clinical Oncology (2024)

8502 Background: Sacituzumab Tirumotecan (SKB264/MK-2870)is a TROP2 ADC developed with novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the initial results from a phase II study of SKB264 combined with KL-A167 in patients (pts) with advanced NSCLC (OptiTROP-Lung01, NCT05351788). Methods: Pts with treatment naive advanced NSCLC without actionable genomic alterations were enrolled to receive SKB264 5 mg/kg Q3W + KL-A167 1200 mg Q3W (cohort 1A) or SKB264 5 mg/kg Q2W + KL-A167 900 mg Q2W (cohort 1B) in a non-randomized manner until disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Results: As of 02 Jan 2024, 40 and 63 pts have been enrolled in cohort 1A and 1B. Median ages were 63/63 years; 97.5%/85.7% had ECOG PS of 1; 30.0%/33.3%, 32.5%/30.2% and 37.5%/36.5% of pts had PD-L1 expression &lt; 1%, 1%–49% and ≥ 50% of tumor cells by IHC 22C3 pharmDx assay, respectively. In cohorts 1A/1B, the most common Grade ≥ 3 treatment-related adverse events (TRAEs) were neutrophil count decreased (30.0%/30.2%), white blood cell count decreased (5.0%/17.5%), anemia (5.0%/15.9%), rash (5.0%/6.3%) and drug eruption (7.5%/0). TRAE leading to discontinuation of SKB264 occurred in 1 pt of cohort 1B due to drug hypersensitivity, and there were no treatment-related deaths. After median follow up of 14.0 mos and 6.9 mos for cohort 1A and 1B, the ORR was 48.6% (18/37, 2 pending confirmation), DCR was 94.6% and median PFS was 15.4 mos (95% CI: 6.7, NE) with 6-mo PFS rate of 69.2% for cohort 1A ; the ORR was 77.6% (45/58, 5 pending confirmation), DCR was 100% and median PFS was not reached with 6-mo PFS rate of 84.6% for cohort 1B. Additional subgroup analyses are shown in the Table. Conclusions: SKB264 in combination with KL-A167 demonstrated promising efficacy results in treatment naive advanced NSCLC with manageable safety profile. SKB264 Q2W was recommended for further investigation. A Phase 3 study of SKB264 Q2W plus pembrolizumab vs pembrolizumab in 1L metastatic NSCLC with PD-L1 TPS ≥ 50% (NCT06170788) is ongoing. Clinical trial information: NCT05351788 . [Table: see text]
A real-world study on biomarker retesting among patients with non-small cell lung cancer and disparity in outcomes.
Authors: Samuel Crawford, Charu Aggarwal, Sophia Ng, Qingqing Xu, Archana Simmons, Ashish Gulati, Mary Beth Beasley
Journal: Journal of Clinical Oncology (2024)

8590 Background: Prior studies revealed sociodemographic disparities in biomarker testing among patients (pts) with advanced/metastatic non-small cell lung cancer (a/mNSCLC). However, the association of testing disparities with clinical outcomes among real-world pts requires further characterization. Methods: This retrospective study used ConcertAI Patient360™ US dataset to assess biomarker testing disparities and their association with median overall survival (mOS) among adults with a/mNSCLC (2017–2022) who received ≥1 line of therapy with ≥90-day follow-up. Analyses were conducted in pts who initiated first-line (1L) treatment and stratified by setting (community vs academic) and race. Biomarker testing is a curated data element in this database, leveraging structured and unstructured electronic medical record data and includes the following biomarkers ALK, BRAF, EGFR, KRAS, MET amp, MET exon 14, NTRK, PD-L1, RET, and ROS1. Biomarker testing to inform 1L decision was defined as testing before 1L start. Testing to inform second-line (2L) decision was defined as testing after 1L start and before 2L start. Variables were compared using chi-square or ANOVA tests. Unadjusted and adjusted OS using multivariate Cox proportional hazards are reported. Results: Of 3678 pts included in the 1L cohort, 3127 (85%) received 1L testing. In community settings, 22% of Black pts vs 15% of White pts did not receive 1L testing (P=0.002), whereas 1L testing rates between races were similar in academic settings (Table). In 2L community setting among pts who received 1L but not 2L testing, mOS was 5.9 vs 9.9 months in Black (n=54) vs White (n=529) pts, respectively (P=0.35). In 2L community setting among pts who were and were not tested prior to 1L and not tested at 2L, mOS was 5.9 vs 10.1 months in Black (n=62) vs White (n=613) pts, respectively (P=0.27). Accounting for recorded sociodemographic and clinical characteristics at baseline, differences in OS by testing setting and status start to normalize to the reference group. Disparities within groups appear to potentially exist despite no statistical significance (except for ECOG score of 2+). Conclusions: Despite small 2L sample sizes and lack of significance, disparities in testing rates and outcomes were observed, which may be overcome by normalizing testing across race and treatment setting to potentially improve pt outcomes. Further analysis can be performed across census regions. Further research is needed to confirm the impact of lack of biomarker testing on pt outcomes on a broader scale, particularly around characteristics that may impact outcomes but were undetected in this dataset. [Table: see text]
Gene expression correlates of adagrasib response in KRAS<sup>G12C</sup> mutated non-small cell lung cancer (NSCLC).
Authors: Eejung Kim, Xinyuan Tong, Ayushi Patel, Shengwu Liu, Julien Dilly, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, James G Christensen, Peter Olson, Andrew Aguirre, Kwok Wong, Hongbin Ji
Journal: Journal of Clinical Oncology (2024)

8529 Background: KRAS G12C inhibitors such as adagrasib and sotorasib have shown clinical promise in targeting KRAS G12C -mutated lung cancers; however, most patients develop primary or secondary resistance. A biomarker of response to KRAS G12C inhibitor is needed for better patient stratification and to understand the resistance mechanism. Methods: We analyzed transcriptional correlates of adagrasib treatment outcome in 68 patients in the KRYSTAL-1 trial, a phase 1/2 clinical trial of adagrasib monotherapy in the second line and beyond treatment for NSCLC. We also treated KRAS-mutated lung cancer mouse models and organoids with a KRAS inhibitor for the long term and characterized the resistant tumors’ transcriptional profile to identify resistance mechanisms. We also performed serial gene expression analysis of Kras G12D mutated lung organoids undergoing squamous transformation to identify transcription factor involved in the resistance process. Results: In patients with lung adenocarcinoma with KRAS G12C and STK11/ LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRAS G12C and Kras G12D lung cancer mouse models and organoids, treated with KRAS inhibitors adagrasib and MRTX1133, respectively, reveal that tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. We identify TP63 to be a transcription factor whose expression correlated with squamous transformation. The analysis of lineage plasticity program, adagrasib resistant tumors, and p63 regulon revealed KRT6A to be a common biomarker whose expression correlated with overall survival in the KRYSTAL-1 cohort. Conclusions: KRAS G12C mutated lung adenocarcinoma patients with a higher expression of squamous cell carcinoma gene expression signature respond poorly to adagrasib treatment. Expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
DeLLphi-301: Tarlatamab phase 2 trial in small cell lung cancer (SCLC)—Efficacy and safety analyzed by presence of brain metastasis.
Authors: Anne-Marie C. Dingemans, Myung-Ju Ahn, Fiona Helen Blackhall, Martin Reck, Horst-Dieter Hummel, Suresh S. Ramalingam, Melissa L. Johnson, Hiroaki Akamatsu, Juergen Wolf, Jacob Sands, Taofeek K. Owonikoko, Hossein Borghaei, Sujoy Mukherjee, Shuang Huang, Pablo Martinez, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2024)

8015 Background: Brain metastases affect 40%–70% of patients with SCLC. Tarlatamab, a BiTE (bispecific T-cell engager) immunotherapy targeting delta-like ligand 3, demonstrated durable responses and promising survival outcomes in patients with previously treated SCLC (10 mg Q2W) (DeLLphi-301; NCT05060016; Ahn M-J, N Engl J Med 2023). Here, tarlatamab efficacy and safety in patients with baseline brain metastases from DeLLphi-301 are reported. Methods: The DeLLphi-301 study design has been published. Patients with treated, stable, asymptomatic brain metastases were included. Subgroup analyses for efficacy (blinded independent central review [BICR] assessments) and safety by presence or absence of baseline brain metastases were performed. Intracranial activity was assessed. Post enrollment, brain imaging was performed if clinically indicated. Results: As of 27 June 2023, 186 patients had received tarlatamab (ECOG PS: 0–1; median prior lines of therapy: 2; median follow-up: 13.6 months). 29% of patients (54/186) had treated and stable brain metastases at baseline. Most patients (91%) with brain metastases had received prior local radiotherapy; 6% each had received surgery only or both radiotherapy and surgery. Overall systemic objective response rate (ORR; RECIST 1.1) was 45.3% in patients with brain metastases and 32.6% in patients without brain metastases (Table). Any grade immune effector cell associated neurotoxicity syndrome and associated neurological events occurred in 24.1% of patients with brain metastases and in 13.6% of patients without brain metastases; grade ≥ 3 events occurred in the 100 mg group only: 9.4% and 1.8%, respectively, and did not lead to tarlatamab discontinuation in any patient with brain metastases. Analysis of intracranial activity will be presented. Conclusions: Tarlatamab showed promising efficacy and a favorable benefit-risk profile in patients with previously treated SCLC and stable brain metastases. Clinical trial information: NCT05060016 . [Table: see text]
Phase I trial of aurora kinase A (AURKA) inhibitor VIC-1911 plus osimertinib for TKI-resistant, EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: Shen Zhao, Hongyun Zhao, Li Zhang, Yuping Sun, Wu Zhuang, Xiaorong Dong, Jianying Zhou, Mingjun Li, Xiaoyan Li, yuqin xi, Jintao Zhang, Wen Xu, Ao Li, Qianrong Chen, Linda J. Paradiso, Thomas J. Myers, Lei Zhang
Journal: Journal of Clinical Oncology (2024)

8077 Background: ARUKA has been implicated in the emergence of resistance to osimertinib. VIC-1911 is a highly selective ARUKA inhibitor that has minimal activity in EGFR-mutant (mt) cell lines as a monotherapy. Preclinical data show synergy of VIC-1911 with osimertinib across in vitro and in vivo osimertinib-resistant models. Sustained tumor control after drug withdrawal is observed in both osimertinib-naïve and -resistant xenograft models. This trial evaluated the safety and efficacy of VIC-1911 plus osimertinib in patients with TKI-resistant, EGFRmt NSCLC (NCT05489731). Methods: This is a phase I trial with a 3+3 dose escalation stage and a dose expansion stage. Eligible patients should have advanced NSCLC with EGFR 19del/L858R and failure after ≥1 lines of EGFR-TKIs. Patients enrolled into the dose escalation stage were treated with VIC-1911 150mg or 200mg BID intermittently (4 days on, 3 days off) plus osimertinib 80 mg QD consecutively. Patients enrolled into the dose expansion stage were treated with VIC-1911 at the recommended phase 2 dose (RP2D) plus osimertinib 80 mg QD. Toxicity was assessed by the NCI CTCAE V5. Efficacy was evaluated per RECIST v1.1. Results: As of 18 December 2023, a total of 24 patients were treated. Median lines of prior treatment were 3 (range,1-8). Seven patients were enrolled during the dose escalation stage (150mg = 4, 200mg = 3). No DLT was observed and 200mg was selected as the RP2D. The most common AEs related to VIC-1911 at RP2D were diarrhea (52.3%), leucopenia (38.1%), neutropenia (33.3%), and thrombocytopenia (28.6%). Efficacy was evaluable in 23 patients. Among them, 10 patients were osimertinib-naïve (T790M-negative = 8,T790M-positive = 2) and 13 were osimertinib-resistant. For osimertinib-naïve patients, confirmed objective response rate (ORR) was 50% (5PRs, T790M-negative = 4, T790M-positive = 1) and disease control rate (DCR) was 80% (3SDs). For osimertinib-resistant patients, ORR was 0% and DCR was 53.8% (7SDs). Among patients with disease control, 66.7% (10/15) stayed on treatment as of data cutoff. The median follow-up duration was 5.5 months. Median duration of response (DOR) was not reached. The 6-month (6m) DOR rate was 50%. Median progression-free survival (PFS) was not reached and 4.3months for osimertinib- naïve and -resistant patients, respectively. The 6m PFS rate was 70.0% and 38.5%, respectively. Updated DOR and PFS data will be presented. Conclusions: VIC-1911 in combination of osimertinib is well-tolerated in previously-treated EGFRmt NSCLC. The combination demonstrates sustained antitumor activity, which indicates the potential of AURKA blockade in delaying the emergence of resistance to osimertinib. Clinical trial information: NCT05489731 .
Two years of teaching close to home: Lessons learned from a near-peer model for an introductory lecture series for hematology-oncology fellows.
Authors: Anthony Iacoviello, Barbara Lam, Rushad Patell, Jonathan L Berry, Deepa Rangachari
Journal: Journal of Clinical Oncology (2024)

9027 Background: First-year hematology-oncology fellows face a large initial knowledge gap due to limited disease-specific content exposure during residency training. To facilitate their transition, we introduced a near-peer lecture series during academic year (AY) 2021-22, featuring near-peers (2 nd and 3 rd year [“senior”] fellows) as the primary instructors guided by content experts (disease specific faculty) [Berry, et al. JCO OP 2023]. This follow-up study’s primary aim was to assess the lectures’ continued impact on learning for 1 st year fellows, as well as the impact on the educational skills of senior fellows. We also sought to assess the continued support of this format by faculty. Methods: For AY 2023-24, each rising senior fellow attended a one-hour preparatory workshop on active learning techniques in Spring 2023. They were then assigned 2-3 topics to teach and paired with ≥1 expert faculty. Lectures were conducted from July to September 2023. We administered anonymous surveys immediately post-lecture to attendees and at end-of-series to senior fellows and faculty. Results are summarized as proportions with binomial 95% confidence intervals (CI). Results: We received 109 immediate post-lecture responses for 26 lectures (66% of total lectures). Of 1 st year fellow respondents (82.5% of all responses), 80% (95% CI [72-88%]) found the lectures very engaging, 82% (95% CI [76-90%]) found them relevant, 54% (95% [CI 46-62%]) felt very confident in disease diagnosis and staging, and 43% (95% CI [37-49%]) felt very confident in disease treatment following the lectures. All responding senior fellows (N=7) endorsed the lecture format. The majority of senior fellows (67%, 95% CI [50-84%]) found the one-hour workshop only somewhat helpful, and 71% (95% CI [50-92%]) felt only somewhat well equipped to give their lecture. Over half (57%, 95% CI [41-73%]) of senior fellows reused previous slide decks and did not meet with faculty in person to prepare for their sessions. On qualitative review of senior fellow feedback, common themes included time constraints and lack of structured format during the preparation phase. Of faculty respondents (N=9), 78% (95% CI [50-99%]) supported continuation of the format, but only 44% (95% CI [38-50%]) met in-person with their assigned senior fellow in advance of the teaching session. Conclusions: Our near-peer lecture series has broad support for its continuation and is meeting the needs of 1 st year fellows. To better help senior fellows improve their education skills, future iterations will focus on optimizing the pre-session coaching and preparatory phase. This will include structured coaching with an expert educator for content planning and development, an augmented process for pre-session meetings between senior fellows and faculty, and greater focus on defining the optimal timeline for session preparation.