tbuckley/cabot-search huggingface dataset:
High PD-L1 expression among patients with ALK rearranged non–small cell lung cancer and response to first line ALK tyrosine kinase inhibitors.
Authors: Yunan Nie, Alyse Staley, Trista Hinz, Dan Merrick, Michael Yang, Erin L. Schenk, Paul A. Bunn, David Ross Camidge, Lynn Heasley, Tejas Patil
Journal: Journal of Clinical Oncology (2024)

8626 Background: Patients with ALK rearrangements are highly responsive to ALK tyrosine kinase inhibitors (TKIs). Negative prognostic markers to ALK TKIs include TP53 alterations and ALK Variants 3a/b. The prognostic role that PD-L1 expression plays in first line ALK TKI outcomes is less clear. Methods: Retrospective review of patients with metastatic ALK-rearranged NSCLC seen between 2015 - 2022 at the University of Colorado who received first line ALK TKIs was performed. PD-L1 expression was denoted as high (≥50%) or low (&lt; 1% or 1-49%) based on pre-treatment biopsies. Clinicopathologic features, treatment outcomes, and genomic data were collected. Survival outcomes were assessed using Kaplan Meier methods. Multivariate modeling adjusted for brain metastases, TP53 mutations, ALK variant status, and ALK TKI. PD-L1 was overexpressed in EML4-ALK murine cell lines with lentiviruses. In vitro and in vivo response to ALK TKIs were compared to non-infected cell lines. Neutrophils and lymphocytes were quantified on pre-treatment H&amp;E slides. Results: Baseline characteristics of 130 patients are shown. Median PFS was significantly (p &lt; 0.001) longer in the PD-L1 low cohort than the PD-L1 high cohort (21 vs 11 mos, HR 0.44, 95% CI 0.29 – 0.66). There was no difference in OS between the PD-L1 low and PD-L1 high cohort (p = 0.4, 107 vs 91 mos, HR 0.86, 95% CI 0.46 – 1.61). In an alectinib sub-group analysis (n = 89), PD-L1 high expressers had a higher rate of CNS progression (93.0 vs 73.9%, p = 0.022). Forced overexpression of PD-L1 in murine EML4-ALK cell lines exerted no difference to in vitroor in vivo response to alectinib. Pre-treatment biopsies from the PD-L1 high cohort (n = 19) revealed significantly more neutrophils (p = 0.021), but not lymphocytes (p = 0.904). Conclusions: High PD-L1 expression (≥50%) is associated with worse PFS and higher intracranial progression rate among those receiving ALK TKIs. Induced PD-L1 expression in ALK cell lines did not alter in vitro or in vivo ALK TKI sensitivity. Higher neutrophil counts track with high PD-L1 expression (≥50%), suggesting that differences within the immune tumor microenvironment may be relevant. [Table: see text]
Tifcemalimab combined with toripalimab and chemotherapy as 1st line treatment for extensive-stage small cell lung cancer (ES-SCLC): A phase Ib/II, open-label study.
Authors: Yongfeng Yu, Yan Yu, Yan Zhang, Wei Zhang, Dongqing Lv, Yuan Chen, Dingzhi Huang, Mingjun Zhang, Yongsheng Li, Dairong Li, Junzhen Gao, Lin Wu, Zhiyong He, Jianhua Shi, Mingfang Zhao, Anwen Liu, Chunyue Wang, Hui Zhu, Shun Lu
Journal: Journal of Clinical Oncology (2024)

8089 Background: Tifcemalimab, a humanized IgG4 monoclonal antibody against B and T lymphocyte attenuator (BTLA), has shown preliminary anti-tumor activities in combination with toripalimab (anti-PD-1) as a later line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC). We further conducted a multi-cohort phase Ib/II study (NCT05664971) to evaluate the safety and efficacy of tifcemalimab combined with toripalimab and chemotherapy as a 1 st line treatment for patients with advanced lung cancer. Here, we report the preliminary results from the ES-SCLC cohort. Methods: Patients without previous systemic anti-tumor therapy for ES-SCLC were eligible. Patients received tifcemalimab 200mg in combination with toripalimab 240mg and standard chemotherapy (etoposide + carboplatin/cisplatin) intravenously once every three weeks (Q3W) for 4 cycles, then followed by tifcemalimab plus toripalimab maintenance therapy until disease progression, intolerable toxicity, or completion of 2 years treatment. Primary endpoints included safety and objective response rate (ORR) by investigators per RECIST v1.1. Results: From 7/12/2023 to 12/6/2023, a total of 44 ES-SCLC patients were enrolled. As of Dec 28, 2023, the median follow-up duration was 8.3 weeks. The median age of the patients was 65.5 (range 48-73) years, and 84.1% (37/44) were males. Forty-one (93.2%) patients experienced treatment-emergent adverse events (TEAEs), and 26 (59.1%) experienced ≥ grade 3 TEAEs. The most common TEAEs included leukopenia (65.9%), neutropenia (63.6%), anemia (40.9%) and thrombocytopenia (40.9%). No treatment-related adverse events led to discontinuation of tifcemalimab and toripalimab. Four (9.1%) patients experienced immune related AE (irAEs), and 1 experienced ≥ grade 3 irAE. Among 37 evaluable patients, 32 PR and 5 SD were observed. The ORR was 86.5% (32/37) and the DCR was 100% (37/37). By the data cut-off date, 94.6% of the responses were ongoing and the median duration of response was not reached. The preliminary biomarker analysis of tumor tissue suggested 100% ORR was observed among patients with either PD-L1 or HVEM positive expression. Further biomarker analysis will be updated. Conclusions: Tifcemalimab in combination with toripalimab and chemotherapy showed a promising objective response rate with a manageable safety profile as a 1 st line treatment for patients with ES-SCLC. Continued follow-up is ongoing for additional safety and efficacy (PFS and OS) evaluation after extended exposure. Clinical trial information: NCT05664971 .
Metabolic profile and therapeutic vulnerabilities of multi-omic characterization of<i>KRAS/STK11/KEAP1</i> co-mutant non–small cell lung cancer (NSCLC).
Authors: Triparna Sen, Utsav Sen, Charles Coleman, Andrew Elliott, Dan Hasson, Ari M. Vanderwalde, Patrick C. Ma, Nishant Gandhi, Balazs Halmos
Journal: Journal of Clinical Oncology (2024)

8576 Background: KRAS-mutant NSCLC with co-occurring loss-of-function mutations in STK11 and KEAP1(KSK) are remarkably aggressive and poorly responsive to chemo- and immunotherapy. Novel therapeutic strategies are urgently needed to improve outcomes for patients with KRAS/STK11/KEAP1co-mutant NSCLC (KSK). We interrogated the transcriptomic landscape using a large real-world dataset of NSCLC to identify therapeutic vulnerabilities that may help guide treatment selections in KSK. Methods: KRAS mutant NSCLC clinical samples (N=7210) were tested with NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). Specimens were stratified into KRAS MUT /STK11 MUT /KEAP1 MUT (KSK; N=698), KRAS MUT /STK11 MUT /KEAP1 WT (KS; N=786), KRAS MUT /STK11 WT /KEAP1 MUT (KK; N=466), and KRAS MUT /STK11 WT /KEAP1 WT (K; N=4536). Real-world overall survival (OS) data was obtained from insurance claims and investigated using Kaplan-Meier estimates. Additionally, an in vitro CRISPR screen, bulk RNA sequencing, and phospho-kinase arrays were performed in KRAS/STK11/KEAP1 co-mutant, single mutant, and wild-type cell lines to better characterize these models. Results: KEAP1mutations (median OS: KK=7.83 months, KSK=7.23 months) were strongly associated with poor OS compared to STK11 mutations (median OS: KS=17.6months). Pathways significantly upregulated in KSK clinical samples included fatty acid metabolism and redox pathways. When compared to single mutant or wild-type conditions, KSK clinical samples had significant up-regulation of genes involved in ferroptosis evasion and metabolism like SLC7A11(KSK/KK=1.28, KSK/KS=4.82, KSK/K=10.24; all q&lt;0.01) and SCD1(KSK/KS=1.19, KSK/K=1.24; both q&lt;0.01). To confirm our clinical findings, CRISPR/Cas9-based genetic screening identified SCD1, and SLC7A11 master regulators of fatty acid metabolism and ferroptosis, as a potential therapeutic target in the KSK cell lines. SCD1 inhibition augmented the effect of ferroptosis inducer, erastin. Targeting SCD1 led to global metabolomic changes in KSK cells, including key pathways involved in lipid and glucose metabolismas compared to single mutants or wild-type cells. Finally, pharmacological inhibition of SCD1 caused significant tumor regression and augmented the anti-tumor response of SLC7A11 inhibitor, imidazole ketone erastin (IKE), in KSK syngeneic mouse models. Conclusions: Our study is the first to highlight the importance of the ferroptosis regulators, SCD1-SLC7A11,in regulating unique metabolic and ferroptosis evasion pathways in KSK patient tumor and preclinical models. The study data furthers the understanding of ferroptosis in NSCLCand the potential to translate SCD1 inhibitors and ferroptosis inducers in KRAS NSCLC clinical trials.
Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA.
Authors: Martin Reck, Tudor-Eliade Ciuleanu, Michael Schenker, Stephanie Bordenave, Manuel Cobo, Oscar Juan-Vidal, Niels Reinmuth, Eduardo Richardet, Enriqueta Felip, Juliana Menezes, Ying Cheng, Hideaki Mizutani, David Paul Carbone, Shun Lu, Tom John, Takekazu Aoyama, Javed Mahmood, Nan Hu, Laura Eccles, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2024)

8560 Background: InCheckMate 9LA (NCT03215706), 1L N + I + C demonstrated long-term, durable survival benefit vs C alone in pts with mNSCLC, regardless of tumor PD-L1 expression or histology. Here, we report updated efficacy and safety data with a 5-y follow up (f/u) and outcomes in 5-y survivors. Methods: Adults with stage IV or recurrent NSCLC, ECOG PS ≤ 1, and EGFR/ALK wild-type were randomized 1:1 to N 360 mg Q3W + I 1 mg/kg Q6W + C Q3W (2 cycles; n = 361) or C alone Q3W (4 cycles; n = 358). Maintenance pemetrexed was allowed for pts with non-squamous (NSQ) NSCLC (C arm only). Assessments were OS, PFS, ORR, DOR, treatment (tx)-free interval (TFI; time from last study tx dose to start of subsequent systemic tx or death), and safety. Exploratory analyses included quantifying the number of ipilimumab doses received by 5-y survivors, as well as PFS and TFI in these pts. Results: With a median f/u of 64.5 mo (database lock, 15 Dec 2023), clinical benefit continued to be seen with N + I + C vs C in all randomized pts (Table); 5-y OS rates were 18% vs 11%, respectively. Of pts treated with N + I + C, 11% were tx-free at 5 y. Clinical outcomes favored N + I + C vs C across tumor PD-L1 expression and histology subgroups (Table). In pts with tumor PD-L1 &lt; 1%, 5-y OS and PFS rates with N + I + C were both ~3-fold higher than with C, and 5-y DOR rates were 25% vs 0% in the respective tx arms. Among pts who discontinued N + I + C due to tx-related adverse events (TRAEs; n = 61), 37% were alive at 5 y, and the TFI rate was 22%. In analyses of 5-y survivors, PFS favored N + I + C (n = 48) vs C (n = 30; HR, 0.52 [95% CI, 0.26–1.02]), and 5-y TFI rates were 72% vs 35%, respectively. Of 5-y survivors in the N + I + C arm, 21/48 (44%) received ≥ 17 doses of ipilimumab; of those who received &lt; 17 doses, most had discontinued ipilimumab due to TRAEs. The extended f/u revealed no new safety signals. Conclusions: 1L N + I + C maintained long-term, durable survival benefit vs C in pts with mNSCLC at this 5-y f/u, particularly in pts with tumor PD-L1 expression &lt; 1% or squamous (SQ) histology. N + I + C increased 5-y survivorship, with improved PFS and TFI in 5-y survivors over C. These data further underscore 1L N + I + C as an efficacious tx option for pts with mNSCLC. Clinical trial information: NCT03215706 . [Table: see text]
EGFR-TKI as neoadjuvant treatment in patients with NSCLC with EGFR sensitive mutation: A retrospective real-world analysis.
Authors: Sangtian Liu, Wenhua Liang, Jianxing He
Journal: Journal of Clinical Oncology (2024)

8081 Background: This study aimed to evaluate the efficacy and outcome of Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as preoperative neoadjuvant treatment in patients with NSCLC and EGFR sensitive mutation. Methods: A retrospective analysis was conducted. Patients with resectable stage I-III NSCLCs and received neoadjuvant treatment with any generation of EGFR-TKI before surgical resection were enrolled. The primary endpoint were major pathological response (MPR) and objective response rate (ORR), the second endpoints included diseases down staging, surgical outcomes, disease-free survival (DFS) and overall survival (OS). Results: A total of 58 patients were enrolled. Female accounted for 62.1% and most of them (77.6%) were never-smoker. Forty-five (77.6%) patients received the first generation of EGFR-TKI and 11 received the third. The median duration of EGFR-TKI before surgery was 3.6 months (0.7-19.5m). Nine (15.5%) patients achieved MPR and one patient (1.71%) achieved pathological complete response (pCR). The ORR was 60.3% (35/58) according to RECIST v1.1. Eighteen patients achieved TNM downstaging with T downstaging occurred in 44.8% of patients and N downstaging was about 32.8%. Majority of patients (96.6%) underwent thoracoscopic surgery and the rate of R0 resection was 82.8% (48/58). The DFS and OS of the whole cohort was 25.7months and not reached respectively. Patients with MPR had statistically improved outcomes than those without. What noticeable was that patients with tumor regression grade 3 (13/58) (residual viable tumor cells counts for 10% to 50%) also demonstrated a significant benefit from EGFR-TKI preoperative treatment than those with TRG4 or 5 (residual viable tumor cells&gt;50%) (p = 0.01). We define patients with TRG1 to TRG3 as deep pathological regression (DPR) and the rest as non-DPR, and the DPR cohort showed significantly prolonged DFS than those with non-DPR (median DFS, 60.9 vs 16.7 months; HR, 0.29 (95%CI: 0.11-0.74), p = 0.006), the data of OS was not mature. Subgroup analysis validated DPR was an independent predictive factor for DFS. Conclusions: EGFR-TKI as neoadjuvant therapy had good effect on tumor pathological regression and disease downstaging, DPR patients were more likely to achieve long-term disease-free survival. Patients with NDPR should be closely followed up and appropriate adjuvant therapy was necessary after surgery due to the high risk of reccurence.
Optimizing hematology/oncology (H/O) curricula for internal medicine (IM) residents: A two-institution Delphi survey.
Authors: Jordyn Silverstein, Laura Ann Huppert, Matthew Schwede, Sarah Goglin, Tyler Paul Johnson, Jennifer Babik, Sam Brondfield
Journal: Journal of Clinical Oncology (2024)

9033 Background: Although H/O topics are essential for primary care physicians, internists and subspecialists, the H/O curriculum is not standardized across IM residency programs. We aimed to identify the most important H/O topics for IM residents to learn, according to IM generalists and H/O specialists. Methods: We used a modified Delphi approach to conduct a 2-round cross-sectional survey of IM generalists and H/O specialists at the University of California, San Francisco and Stanford University. Participants rated the importance of H/O curricular topics gathered from national H/O and IM organizations on a 1-5 scale (very unimportant to very important). Participants then viewed their own ratings compared to the group mean and standard deviation (SD) for each topic from round 1 and could change their ratings in round 2 if they wished. We used a content validity index (CVI, the percentage of respondents who rated the topic ≥4) of &gt;75% to identify the most important topics. We compared the effect sizes of the differences between mean generalist and specialist ratings for each topic using Cohen’s d. Results: The survey included 239 topics (75 classical hematology, 52 malignant hematology, 112 solid oncology). The round 1 survey was sent to 132 clinicians (68 generalists, 64 H/O specialists), with 92 round 1 responses (response rate [RR] 69.7%) and 77 round 2 responses (RR 83.7%). The average variance decreased from round 1 to round 2 (1.00 to 0.86), indicating increasing agreement. Ninety-two topics met the CVI threshold: 41 from classical hematology, 15 from malignant hematology, and 36 from solid oncology. The Table shows the highest rated topics as examples. Most effect sizes were small (58.6%), indicating agreement between generalists and specialists across most topics. Conclusions: With input from both generalists and H/O specialists, we identified the most important H/O topics for IM residents, which can guide curriculum development for IM residency programs. [Table: see text]
Factors influencing career choices and post-fellowship perspectives in adult hematology/oncology fellows: A nationwide cross-sectional study.
Authors: Luis Gonzalez Mosquera, Nino Balanchivadze, Faria Ali, Matthew Meranda, Oscar Hinojosa Castro, Philip Kuriakose
Journal: Journal of Clinical Oncology (2024)

9016 Background: The aim ofour study was to explore the characteristics, aspirations, and factors influencing career choices among adult Hematology/Oncology (HO) fellows, as well as their post-fellowship perspectives. Methods: An anonymous 25-question survey was distributed online to adult HO fellowship programs in the United States. The survey collected data on demographics, educational background, career plans, and specific factors influencing career choices. Results: Of the 56 fellows completing the survey, 54% identified as male, and 46% as female. The majority were White (40%), followed by Asian (34%), Middle Eastern (12%), Hispanic (7%), and Black (3%). Most fellows (79%) were aged 30-34 years, and 68% were MD graduates of US/Caribbean schools. A significant proportion expressed certainty (80%) during residency about pursuing adult HO as a career. Thirty eight percent of the respondents planned to practice both hematology and Oncology. While 39% hoped to work in an academic/university setting, 41% planned to stay within the community. Geographically, 45% preferred suburban, and 39% urban areas. Only 3% of respondents had plans to pursue a career in classical hematology. Factors influencing career choice included clinical interest in the field (98%), previous research experience in HO (54%), career mentorship (70%), lifestyle considerations (66%), and perceived job market (60%) (Table). Almost all respondents (97%) expressed a high likelihood of pursuing adult HO fellowship if they had to choose again. Fellows were confident about finding positions aligned with their interests, including clinical (72%), providing research opportunities (43%), and those offering intellectual stimulation (73%). While the majority were confident in achieving work-life balance (84%), 16% expressed some concerns. Conclusions: This study offers valuable insights into the factors influencing career choices among adult HO fellows. The findings emphasize the necessity of adjusting strategies to align with the evolving needs and aspirations of prospective fellows. Key initiatives could include fortifying career mentorship programs, providing increased support for those interested in classical hematology, fostering research experiences during residency training, and actively promoting a diverse and inclusive environment. Understanding these aspects and results is crucial for program directors, educators, and policymakers to optimize training programs and support the diverse needs of future practitioners in the field. [Table: see text]
Implementing a research methods curriculum for first year hematology oncology fellows.
Authors: Noha Sharafeldin, Jori E. May, Grant Richard Williams, Inas Abuali
Journal: Journal of Clinical Oncology (2024)

9034 Background: The Hematology/Oncology Fellowship Program at the University of Alabama at Birmingham is an ACGME accredited, three-year academic training program. Fellows are expected to participate in at least one mentored research project during their second and third years of training. The program, however, did not provide formal training in research methods. Here, we provide the results of implementing a research methods curriculum for first year fellows to fulfill that educational need and to facilitate engagement in research projects throughout their fellowship training. Methods: We developed a structured curriculum composed of 10 didactic sessions covering the fundamental concepts of epidemiology and biostatistics. Based on the core competencies of research methods, learning objectives integrated concepts of 1) study design; 2) identifying bias and confounding; 3) exploratory data analysis, statistical inference, hypothesis testing; and results interpretation; and 4) critical appraisal of research evidence. The course was designed to promote self-directed learning and build on individual experiences and interests. One-on-one meetings between curriculum faculty and fellows facilitated identification of fellow research interests and pairing with mentors with aligned expertise. The didactic sessions were evaluated using a 21 question pre- and post- knowledge assessment. Fellows also self-rated on a 10-point scale their level of confidence performing research related activities. Following the course, fellows were expected to complete at least i) one research project, present it at a scientific meeting and submit for publication in peer-reviewed journal; and/or ii) one research proposal grant application. Results: To date, 13 first-year fellows across three cohorts have participated in the course, two of which have been completed, and the third will conclude in March 2024. Complete pre- and post- assessment scores were available for 8 fellows. Mean score difference was statistically significant comparing pre- to post- knowledge scores (3.79 points (SD= 4.43), paired t-test p-value=0.02). Self- ratings improved across all components on average from 3.7 pre- to 6.5 post-course (p&lt;0.001). The largest change in self-ratings were in understanding study design concepts, basic principles of research and critical appraisal, followed by interpreting statistical outputs. All fellows are leading at least one mentored research project and 7 out of 8 fellows have presented abstracts at national meetings including the American Society of Clinical Oncology and the American Society of Hematology. Conclusions: Implementing a dedicated research methods curriculum to clinical fellows is feasible, and improved learner knowledge, skills, and engagement in research activities. Research methods principles can be effectively incorporated into the first year of clinical fellowship training.