tbuckley/cabot-search huggingface dataset:
Nivolumab plus ipilimumab (N+I) in patients (pts) with solid tumors with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: John K Chan, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Timothy Lewis Cannon, Eugene R. Ahn, Paul Swiecicki, Evthokia Hobbs, Reza Nazemzadeh, Maria C Bell, Peter Joel Hosein, Funda Meric-Bernstam, Dominique C. Hinshaw, Abby Gregory, Gina N. Grantham, Susan Halabi, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2024)

3130 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]
A multi-centre, single arm, phase 2 trial of pembrolizumab in treatment-naïve patients with carcinoma of unknown primary site.
Authors: Jose Gerard Monzon, Hatim Karachiwala, John WT Walker, Rakesh Goel, Paul Wheatley-Price, Timothy R. Asmis, Vishal Navani, Patricia A. Tang, Michael M. Vickers
Journal: Journal of Clinical Oncology (2024)

2659 Background: Cancer of unknown primary (CUP) represents a heterogeneous group of cancers that present with metastatic epithelial disease with no identifiable primary lesion at the time of diagnosis. Patients with poor prognostic features have limited effective systemic therapy options. Researchers hypothesize that these primary lesions are occult, in part, due to anti-cancer immune surveillance. We hypothesize, pembrolizumab will have activity in this setting. Methods: This single arm phase 2 study evaluated the use of pembrolizumab in treatment naïve patients with poor prognosis CUP. Patients ≥18 years of age with ECOG PS 0-1 and histologically proven, measurable metastatic carcinoma with no primary site identified were eligible. Pembrolizumab was administered at 200 mg intravenously every 3-weeks for up to 24 months. The primary endpoint was safety and objective response rate (ORR) per RECIST 1.1. Secondary objectives included progression free survival (PFS) and overall survival (OS). The study used a Simon’s two stage design based on a one-sided test with a type 1 error rate of 0.1, null hypothesis for ORR ≤ 20% yielding a power of 0.8 with an alternate hypothesis of ≥40%. The null hypothesis will be rejected if 8 or more responses are observed in 25 patients. Mismatch repair (MMR) and microsatellite instability (MSI) testing was not mandatory for patients. Results: There were 27 evaluable and 6 unevaluable (no response assessment, included in adverse event analysis) patients. The median age was 64 (range 21-80) and the majority were male (57.6%) and ECOG 1 (84.8%). Four patients experienced grade 3 treatment related adverse events (pain, anorexia, fatigue, confusion, and anemia). There were no treatment related deaths or new signals of toxicity. Of the evaluable patients, the ORR was 18.5% (4 partial responses and 1 complete response), disease control rate was 51.9% (9 stable disease) and thus the null hypothesis could not be rejected. For evaluable patients, the median PFS and OS were 2.56 (95% CI 2.10 – 7.46) and 9.79 (95% CI 3.84 – 16.03) months respectively. The one patient who developed a CR had MMR deficiency and has completed 2 years of therapy. Of the 4 patients with a partial response, one had an MMR proficient tumour, while the remaining 3 had unknown MMR status. Conclusions: Although not meeting the primary endpoint, pembrolizumab has some activity in CUP patients. Patients with CUP should be screened for MMR or MSI. Future studies should evaluate combination therapies with the addition of pembrolizumab. Clinical trial information: NCT03391973 .
Hydroxyethyl starch-based self-reinforced nanomedicine inhibits both glutathione and thioredoxin antioxidant pathways to boost reactive oxygen species-powered immunotherapy
Authors: Yuxuan Xiong, Zhengtao Yong, Qingfu Zhao, Ao Hua, Xing Wang, Xiang Chen, Xiangliang Yang, Zifu Li
Journal: Biomaterials (2024)
Evaluation of mixed response in tumor size and survival in patients with rare cancers treated with dual checkpoint inhibitor therapy (DART SWOG S1609).
Authors: Young Kwang Chae, Eliana Dietrich, Megan Othus, Liam IL Young Chung, Hye Sung Kim, Christopher W. Ryan, Charles D. Blanke, Sandip Pravin Patel, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2024)

2514 Background: RECIST criteria evaluate changes in tumor burden and have been utilized in cancer research for decades. Changes in the sum of maximum diameters of “target” lesions are used to designate patients into response categories, including complete response, partial response, stable disease, and progressive disease. However, not much is known about the implications of mixed response, where lesions within a patient show contrasting responses to systemic treatment. Here we evaluate the data from the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609 to investigate the association between mixed response and survival among patients treated with dual checkpoint inhibitor therapy. Methods: A total of 796 patients were enrolled on the S1609 DART trial, a basket trial evaluating ipilimumab plus nivolumab across solid rare tumor subtypes. All patients had RECIST-measurable disease at the study entry. Patients were excluded from the analyses due to: ineligibility, n=47; not receiving any protocol therapy, n=23; death before day 65 (landmark for analysis based on first scan), n=86; 1 target lesion, n=153. Thus, 487 patients were analyzed. A 5mm cut-off for increase/decrease in lesions was used to define a mixed response. Cox regression models were used to evaluate associations between survival (landmarked at day 65, stratified by basket) and response category (reference of Stable Disease). Results: 6 groups were identified among the 487 patients: no lesions changed more than 5 mm (n = 105), all lesions increased more than 5mm (n = 69), all lesions decreased more than 5mm (n = 39), one+ lesion increased more than 5mm and one+ lesion decreased more than 5 mm (n = 24), one+ lesion increased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =155), one+ lesion decreased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =95). Hazard ratios and median survival (mOS) are shown (Table). Conclusions: This is the first evaluation of the association between mixed response and survival outcomes among patients with various tumors receiving dual checkpoint therapy. Our results suggest that survival outcomes are driven by the “worst” performing lesion; in other words, having an increase in any lesion is associated with worse outcomes, even if not all lesions increase. [Table: see text]
A first-in-human trial of selective CDK7 inhibitor Q901, in patients with advanced solid tumors: Interim results of a phase I study (QRNT-009).
Authors: Hao Xie, Anthony B. El-Khoueiry, Angela Tatiana Alistar, Hani M. Babiker, Devalingam Mahalingam, Minal A. Barve, Joohyuk Sohn, Mitesh J. Borad, Jae Cheol Lee, Jiye Ahn, Dayoung Lee, Jinho Choi, Jeongjun Kim, Dong-Hoon Yu, Seung-Joo Lee, Borami Jeon, Stefan Proniuk, Jaeseung Kim, Kiyean Nam
Journal: Journal of Clinical Oncology (2024)

3078 Background: Q901 is a potent, covalently binding CDK7 inhibitor with excellent specificity for CDK7 against other protein kinases. Transcriptional regulation by CDK7 inhibition in cancer cells leads to DNA damage repair response inhibition and increased genomic instability. Q901 also regulates cell cycle checkpoints by inhibiting T-loop phosphorylation and transcriptionally downregulating CDK1, 2 and 4. In preclinical in vivo models, intravenous (iv) administration of Q901 once a week and once every three-week dosing regimen was well tolerated and showed significant antitumor activity. The safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy data for 18, 36 and 60 mg/m 2 are presented. Methods: QRNT-009 (NCT05394103) is an ongoing Phase 1/2 multicenter, open-label, dose escalation and expansion study. Q901 is administered iv once weekly for four weeks, then once every two weeks thereafter in patients with advanced or metastatic ovarian cancer, castration-resistant prostate cancer (CRPC), breast cancer, endometrial cancer, colorectal cancer, small cell lung cancer (SCLC), or pancreatic cancers. Results: As of data cutoff (12Jan2024), 17 patients received Q901 across 3 dose levels: 5 patients at 18 mg/m 2 , 4 patients at 36 mg/m 2 , and 8 patients at 60 mg/m 2 . The median prior lines of systemic therapy were 4 (range 2 - 17). Of 17 patients who received Q901 across all doses, there were no treatment related SAEs, treatment discontinuations, or dose reductions. Most common TRAEs ≥ 15% were nausea (29.4%), anemia (23.6%) and fatigue (23.5%). As of data cutoff, no DLTs were observed. All plasma PK analyses across dose levels showed dose dependent increase of AUC 0-last and C max . No major metabolite was observed. POLR2A, which is a CDK7 target engagement marker showed biologically effective change starting from 18 mg/m 2 . 1 patient with pancreatic cancer who received 18 mg/m 2 had a partial response with CA19-9 reduction from 4,632 to 219. 2 patients at 18 mg/m 2 and 2 patients at 36 mg/m 2 had stable disease. Additional safety and efficacy data will be presented. Conclusions: Preliminary data from QRNT-009 study showed that selective CDK7 inhibitor Q901 is well tolerated. Preliminary antitumor activity and pharmacodynamic observations are encouraging. Dose escalation is ongoing to identify MTD or recommended dose for further studies. Clinical trial information: NCT05394103 .
Comprehensive analysis of TMB, TNB, and HLA via NGS sequencing in a large cohort of Chinese pan-cancer patients.
Authors: Chunhui Jin, Xu Wang, Yanlin Liao, Minxiao Guan, Huijia Wu, Jiaxing Zhao, Zeyu Jiang, Yafei Zhang, Ying Long
Journal: Journal of Clinical Oncology (2024)

2656 Background: Evidence suggests that patients with high tumor mutational burden (TMB) and tumor neoantigen burden (TNB) are more likely to benefit from Immune checkpoint inhibitors (ICIs). Furthermore, loss of heterozygosity (LOH) in human leukocyte antigen (HLA) alleles, particularly HLA class I, impairs neoantigen presentation and contributes to resistance against ICIs. This study provides real-world insights into the distribution of TMB, TNB, and HLA variations within a large cohort of Chinese patients with various cancers. Methods: From 2021 to 2023, we performed a retrospective analysis on 1603 cancer patients, examining genetic mutations and HLA traits using the Med1 CDx DNA-based NGS panel targeting 601 cancer-related genes and HLA class I. TMB was calculated as the average number of coding mutations per megabase of the genome. HLA class I alleles (HLA-A, B and C) were identified and predicted using the OptiType and pVACtools software suites. TNB was defined as the number of high-affinity (IC50 ≤ 50 nM) neoantigens per megabase of the genome. Statistical analyses were performed to explore the relationship between TMB, TNB, and LOH status in critical regions of HLA. Results: This study enrolled participants across 25 cancer types. With 32.56% having non-small cell lung cancer (NSCLC), 11.79% colorectal carcinoma (CRC), and 18.34% unidentified solid tumors. The remaining 37.31% comprised cases of cholangiocarcinoma, hepatocellular carcinoma, pancreatic cancer, etc. High-affinity neoantigen-generating genes such as TP53, EGFR, KRAS, LRP1B, DMD, and FAT1 were identified. Our findings indicate substantial variation in tumor neoantigen burden (TNB) across various cancer types and even among different samples within the same type. Neuroendocrine tumors exhibited the highest TNB at 4 neoantigens/Mb, followed by esophageal cancer (3.3), melanoma and urothelial carcinoma (2.67 each), indicating higher TNB levels in these cancers compared to others. A significant positive correlation was observed between TMB and TNB (p&lt; 0.0001). Analysis revealed no significant TNB differences attributable to age (cutoff at 60 years) or gender. However, individuals aged over 70 years demonstrated a higher TNB of 4 compared to those under 70 with 3.33, highlighting potential age-related differences in TNB. Conclusions: Our analysis highlights significant variation in TNB across cancer types, with the highest TNB found in neuroendocrine tumors and the lowest in gastrointestinal stromal tumors, indicating TNB's value as a biomarker for optimizing ICI therapy. Furthermore, we found that people over 70 years old have higher TNB levels than younger individuals, suggesting a potential for improved ICI efficacy without chemotherapy. The evident strong correlation between Tumor Mutational Burden (TMB) and TNB underlines their crucial role in the success of cancer immunotherapy.
Effect of fecal transplantation on patient reported outcomes after immune checkpoint inhibitor colitis.
Authors: Malek Shatila, Krishnavathana Varatharajalu, Shu-En Shen, Mary Herrera, Xin Shelley Wang, Anusha Thomas, Herbert L. DuPont, Yinghong Wang
Journal: Journal of Clinical Oncology (2024)

2517 Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 37 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Fifty-nine patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (94.9%) and colitis grade ≥ 2 (91.5%). Ulcerous (26, 44.1%) and non-ulcerous (21, 35.6%) inflammation were the predominant endoscopic findings. Fifty-seven (96.6%) patients received corticosteroids, and 54 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 84.7% after FMT with median time to response of 4 days. The transient complication rate is 30.5% at 7 days and 18.6% at 30 days. Response rate among the 50 patients without concurrent CDI was 86.0%. Fifty (84.7%) patients demonstrated clinical remission by the end of the study period, and 11 (18.6%) were able to resume ICI treatment, and among them, 9 patients remained in remission. A total of 10 patients (16.9%) in our cohort developed recurrent colitis after FMT requiring immunosuppression; 3 of these recurrent cases were triggered by ICI resumption. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea (61% to 11%, p&lt;0.01) and abdominal bloating (36% to 7%, p&lt;0.05) during 12 weeks after FMT. There was a 49.4% reduction of moderate to severe symptoms with only 44% of patients reporting such symptoms after 12 weeks (down from 89%, p&lt;0.01). Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 .
DNA methylation variations underlie lettuce domestication and divergence
Authors: Shuai Cao, Nunchanoke Sawettalake, Ping Li, Sheng Fan, Lisha Shen
Journal: Genome biology (2024)

Abstract Background Lettuce ( Lactuca sativa L. ) is an economically important vegetable crop worldwide. Lettuce is believed to be domesticated from a single wild ancestor Lactuca serriola and subsequently diverged into two major morphologically distinct vegetable types: leafy lettuce and stem lettuce. However, the role of epigenetic variation in lettuce domestication and divergence remains largely unknown. Results To understand the genetic and epigenetic basis underlying lettuce domestication and divergence, we generate single-base resolution DNA methylomes from 52 Lactuca accessions, including major lettuce cultivars and wild relatives. We find a significant increase of DNA methylation during lettuce domestication and uncover abundant epigenetic variations associated with lettuce domestication and divergence. Interestingly, DNA methylation variations specifically associated with leafy and stem lettuce are related to regulation and metabolic processes, respectively, while those associated with both types are enriched in stress responses. Moreover, we reveal that domestication-induced DNA methylation changes could influence expression levels of nearby and distal genes possibly through affecting chromatin accessibility and chromatin loop. Conclusion Our study provides population epigenomic insights into crop domestication and divergence and valuable resources for further domestication for diversity and epigenetic breeding to boost crop improvement.
Correction: Tracking daratumumab clearance using mass spectrometry: implications on M protein monitoring and reusing daratumumab
Authors: Nadine Abdallah, David Murray, Angela Dispenzieri, Prashant Kapoor, Morie A. Gertz, Martha Q. Lacy, Suzanne R. Hayman, Francis K. Buadi, Wilson Gonsalves, Eli Muchtar, Nelson Leung, David Dingli, Taxiarchis Kourelis, Rahma Warsame, Moritz Binder, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
Journal: Leukemia (2024)
Correction: Outcomes among newly diagnosed AL amyloidosis patients with a very high NT-proBNP: implications for trial design
Authors: I. Vaxman, S. K. Kumar, F. Buadi, M. Q. Lacy, D. Dingli, Y. Hwa, A. Fonder, M. Hobbs, S. Hayman, T. Kourelis, R. Warsame, E. Muchtar, N. Leung, P. Kapoor, M. Grogan, R. Go, Y. Lin, W. Gonsalves, M. Siddiqui, R. A. Kyle, S. V. Rajkumar, M. A. Gertz, A. Dispenzieri
Journal: Leukemia (2024)
Correction: Value of bone marrow examination in determining response to therapy in patients with multiple myeloma in the context of mass spectrometry-based M-protein assessment
Authors: Jean-Sébastien Claveau, David L. Murray, Angela Dispenzieri, Prashant Kapoor, Moritz Binder, Francis Buadi, David Dingli, Amie Fonder, Morie Gertz, Wilson Gonsalves, Suzanne Hayman, Miriam Hobbs, Yi Lisa Hwa, Taxiarchis Kourelis, Martha Lacy, Nelson Leung, Yi Lin, Rahma Warsame, Robert A. Kyle, Vincent Rajkumar, Shaji K. Kumar
Journal: Leukemia (2024)
Correction: Family history of plasma cell disorders is associated with improved survival in MGUS, multiple myeloma, and systemic AL amyloidosis
Authors: Alissa Visram, Celine Vachon, Linda B. Baughn, Dirk Larson, James Smadbeck, Angela Dispenzieri, Prashant Kapoor, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
Journal: Leukemia (2024)