tbuckley/cabot-search huggingface dataset:
Effect of antibiotic, proton pump inhibitor, H2 blocker, metformin and statin use on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Charbel Hobeika, Scott Dawsey, Ubenthira Patgunarajah, David Lynn, Nikhil Pramod, Wei Wei, Monica Nair, Kimberly Maroli, Allison Martin, Moshe Chaim Ornstein, Christopher Eing Wee, Timothy D. Gilligan, Amanda Nizam, Amanda Bonham, Omar Y. Mian, None Paul G. Jr., C. Marcela Diaz-Montero, Shilpa Gupta
Journal: Journal of Clinical Oncology (2024)

4589 Background: Some reports suggest that concomitant medications like metformin (M) and statins (S) may enhance efficacy of ICIs in various solid tumors via immune remodeling. Meanwhile other drugs like antibiotics (Abx), proton-pump inhibitors (PPI), H2 blockers (H2b)—may negatively impact outcomes with ICI by affecting the gut microbiome. We report the effect (Abx), (PPI), (H2b), (M)and (S) in our larger cohort of mUC pts treated with ICI; atezolizumab (A), pembrolizumab (P), and maintenance Avelumab (Av). Methods: In our cohort of 474 pts with mUC treated with &gt;/=2 cycles of ICI with A, P or Av between 2015 and 2023, we retrospectively reviewed the use of (Abx), (PPI), (H2b), (M) and (S) and their timing in relation to ICI start (within 60 or 30 days (d) prior to and after ICI start). Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression analysis. Results: Of 474 pts, 18.99% received A, 56.75% received P and 24.26% received Av. Median follow-up was 15.6 months. Survival data was available for 455 pts. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with significantly worse OS while Abx use within 60 (d) post ICI start was associated with significantly worse PFS. PPI use was associated with significantly worse OS and PFS when used 60 (d) prior to ICI use. Metformin was associated with significantly worse PFS when used 60 days prior to ICI start and H2b and Sta did not have any effect on survival outcomes in our cohort. (Table) Conclusions: In our large cohort of pts with mUC treated with either A, P or Av, (Abx), (PPI) and (M) use 60 (d) prior to ICI start were associated with worse OS and PFS. These findings have the potential to influence clinical practice, considering a higher threshold for prescribing antibiotics or PPIs in mUC pts planned to start ICI. These findings warrant further validation in prospective trials. [Table: see text]
Applying genomic analysis to refine unclassified renal cell carcinoma.
Authors: Emre Yekeduz, David A. Braun, Razane El Hajj Chehade, Marc Eid, Chris Labaki, Marc Machaalani, Amin Nassar, Rashad Nawfal, Eddy Saad, Renee Maria Saliby, Karl Semaan, Maxine Sun, Michelle S. Hirsch, Yüksel Ürün, Talal El Zarif, Toni K. CHOUEIRI
Journal: Journal of Clinical Oncology (2024)

4551 Background: Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate. Results: Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P&gt;0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q&lt;0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2(15.8%), TP53 (13.9%), TERT(13.4%), and VHL(11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q&lt;0.001), chRCC (0.7%, Q&lt;0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2(n=29) than in those with unaltered NF2(n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q&lt;0.001), followed by VHL and BAP1 (Q&lt;0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%). Conclusions: uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2alterations were frequent and correlated with a poorer prognosis. [Table: see text]
Landscape analysis and oncologic outcomes in advanced urothelial carcinoma (UC) by NECTIN4 RNA expression.
Authors: Tyler F. Stewart, Sarah Elizabeth Fenton, Shayan Nazari, Andrew Elliott, Rohan Garje, Amirali Salmasi, Aditya Bagrodia, Chadi Nabhan, David James VanderWeele, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

4585 Background: Advanced UC is a devastating disease, however recent advances with antibody drug conjugates (ADCs), including enfortumab vedotin (EV), have improved outcomes significantly. Currently no biomarkers are clinically available to predict response to therapy. We hypothesized that benefit from EV may correlate with mRNA expression of NECTIN4, the gene encoding the relevant cell surface antigen for EV. Therefore, we performed a landscape analysis of NECTIN4 in advanced UC and correlated expression with oncologic outcomes. Methods: Bladder and upper tract UC samples were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and NovaSeq on RNA (whole transcriptome). UC samples were stratified by NECTIN4 mRNA levels into four quartiles. Tumor mutational burden (TMB) totaled somatic nonsynonymous mutations per tumor (high &gt;10 mut/Mb). Insurance claims data were used to calculate survival outcomes using Kaplan-Meier estimates. Overall survival (OS) was calculated from the date of sample collection and date of treatment initiation to date of last follow up. Time on treatment (TOT) was calculated from date of treatment initiation to date of last treatment.Survival analysis was performed between top and bottom quartiles of NECTIN4 expression. Results: A total of 6,395 patient samples were analyzed [n=4335 from primary tumor (3496 bladder/urethra, 839 upper tract), n= 2060 from metastases]. Expression of NECTIN4 was associated with higher rates of mutations in FGFR3 (18.9% vs 6.9%), ERBB2 (11.8% vs 5.9%), pTERT (77.3% vs 62.6%), CCNE1 (5.6% vs 1.7%), SDHC (8.3% vs 0.6%) and with TMB-H status (46.2% vs 35.8%) but lower rates of TP53 mutations (54.6% vs 67.7%). NECTIN4 expression positively correlated with expression of TACSTD2 (TROP2), ERBB2 (HER2) and SLITRK6. Interestingly, NECTIN4 expression inversely correlated with PDL1 expression by IHC (22c3, 26.9% vs 59.2%). Similar findings were found when analysis was performed by primary bladder versus primary upper tract, as well as primary versus metastatic site. NECTIN4 expression was associated with longer OS in the overall population, and improvement in TOT (HR 0.53) and OS (HR 0.67) for patients treated with EV (Table). NECTIN4 expression was not associated with benefit with anti-PD1/L1 therapy. Conclusions: In the largest study investigating NECTIN4 expression in UC, we demonstrate co-expression of TACSTD2 (TROP2), ERBB2 (HER2) and SLITRK6 with NECTIN4. Expression of NECTIN4 correlated with favorable prognosis and predicted benefit from EV. NECTIN4 RNA expression could be a potential biomarker for selecting patients for treatment with EV. Further validation is required. [Table: see text]
Clinical outcomes of maintenance durvalumab after definitive concurrent chemoradiotherapy in unresectable locally advanced stage III non-small cell lung cancer according to epidermal growth factor receptor and anaplastic lymphoma kinase status: Korean Cancer Study Group LU-22-18.
Authors: Dae-Ho Choi, Myung-Ju Ahn, Miso Kim, Young Saing Kim, Keon Uk Park, Jang Ho Cho, Hongsik Kim, Ki Hyeong Lee, Heejoon Ahn, Il-Hwan Kim, Kyung-Hee Lee, Gyeong-Won Lee, Seong Yoon YI, Beung Chul AHN, Min-Young Lee, Hyun Ae Jung, Sehhoon Park, Jong-Mu Sun, Jin Seok Ahn, Se-Hoon Lee
Journal: Journal of Clinical Oncology (2024)

8061 Background: The role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR) mutation or anaplastic lymphoma kinase ( ALK) translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR/ALK wild-type versus those with EGFRor ALK mutations. Methods: In this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results ( EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR/ ALK wild-type and EGFRor ALKmutant NSCLC. Secondary objectives include overall survival according to EGFRor ALK mutation and programmed cell death-ligand 1 (PD-L1) expression. Results: Among 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 males (81.4%) and 63 females (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histological types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. The majority of patients (n=288, 85%) achieved partial response to CCRT, 2 (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding 4 patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1-49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% CI 17.3–25.3) for the EGFR/ ALK wild-type group and 21.0 months (95% CI 15.7–NA) for the EGFR or ALK mutant group with no significant difference (p=0.74). Significant differences occurred in PFS based on PD-L1 expression with values of 13.6 (95% CI 10.5–NA), 18.7 (95% CI 15.1–26.9), and 24.7 (95% CI 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p=0.02). Conclusions: Durvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFRor ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.
Efficacy and safety of vebreltinib in patients with advanced NSCLC harboring MET exon 14-skipping: Results of 2.5-year follow-up in KUNPENG.
Authors: Jin-Ji Yang, Yan Zhang, Lin Wu, Jie Hu, Zhe-Hai Wang, Jing-Hua Chen, Yun Fan, Gen Lin, Qiming Wang, Yu Yao, Jun Zhao, Yuan Chen, Jian Fang, Yong Song, Wei Zhang, Ying Cheng, Ren-Hua Guo, XingYa Li, Yi-Long Wu
Journal: Journal of Clinical Oncology (2024)

8557 Background: Vebreltinib (PLB1001), a potent and highly selective c-MET inhibitor, demonstrated superior objective response rate (ORR) benefits in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients (pts) with MET exon 14 (METex14) skipping mutations in the previous analysis of the phase II KUPENG study. Here we present results from 2.5 years of follow-up of pts in KUNPENG. Methods: In this Phase Ⅱ, open-label, multicenter, and multi-cohort study, tumor tissue was assessed for METex14 skipping mutation using next-generation sequencing (NGS) from CAP or CLIA certificated local or central laboratories. Pts in Cohort 1 received 200 mg of vebreltinib twice daily (28 days per cycle) until discontinuation criteria were met. The primary endpoint was ORR assessed by blinded independent review committee (BIRC). Results: Between Jan 17, 2020 and Feb 09,2021, 52 pts were enrolled in Cohort 1. As of the data cutoff date (Aug 09, 2023), the median duration of follow-up was 19.1 months (range, 1.0-42.7) and the median duration of treatment was 9.9 months (range, 0.6-42.7). Per BIRC assessment, the ORR was 75% (95% CI: 61.1-86.0), the disease control rate (DCR) was 96.2% (95% CI 86.8-99.5), the median duration of response (DoR) was 16.5 months (95% CI 9.2-19.4), the median time to response (TTR) was 1.0 month (95% CI 1.0-2.8), the median progression-free survival (PFS) was 14.3 months (95% CI 6.4-18.2), and the median overall survival (OS) was 20.3 months (95% CI 16.2-29.7). The 3-year OS rate was 35.1%. Subgroup analyses showed the ORR was 100.0%, 66.7%, 85.7% and 100.0% among pts with any baseline brain metastases (N=5), pts with any baseline liver metastases (N=6), pts aged 75 years and older (N=21) and pts with co-occurring of MET amplification (N=12), respectively. The most common (≥20%) treatment-related adverse events (TRAEs) in all the 135 pts enrolled in this study were peripheral edema (56.3%), hypoalbuminemia (27.4%), hypoproteinemia (25.9%) and anemia (20.7%). TRAEs were mainly grade 1 or 2. No new safety signals were reported with long-term vebreltinib treatment. Conclusions: Vebreltinib consistently showed promising efficacy and favorable safety in NSCLC pts with METex14 mutations. Clinical trial information: NCT04258033 . [Table: see text]
Tumor-specific MHC class II upregulation associated with response to anti-PD-L1 therapy in patients with urothelial cancer.
Authors: İlayda Hasakioğulları, Mark Kockx, Bernadett Szabados, Matthew Young, Thomas Powles
Journal: Journal of Clinical Oncology (2024)

4584 Background: The mechanism of response and resistance to immune checkpoint inhibition (ICI) remains to be defined in urothelial cancer. Methods: The abacus study explored neo-adjuvant atezolizumab prior to cystectomy in muscle-invasive bladder cancer (MIBC, NCT02662309). In this post hoc exploratory analysis, we utilized samples from the Abacus. Nanostring GeoMx Digital Spatial Profiler (DSP), a spatial transcriptomics platform enabling comprehensive characterization of the entire human transcriptome while preserving spatial information, was performed on Formalin Fixed Paraffin Embedded (FFPE) tissue from 12 paired biopsies (3 pCR, 3 MPR, and 6 relapse tumors). To guide region selection and tissue segmentation on the GeoMx DSP, we utilized SYTO 13, PanCK, CD45, and CD3 markers. Subsequently, we quantified the entire transcriptome in selected regions and conducted differential gene expression analysis using the DSP data analysis suite and BioTuring Lens platforms. Results: Tumor cells of the MPR samples showed upregulation of MHC class II genes (log2FC &gt;1.52, q &lt; 5.5E-04, p&lt; 9.7E-07). pCR samples showed numerous tertiary lymphoid structures (TLS) in the remaining tumor bed. We then performed MHC class II (HLA-DR) immunohistochemistry staining to confirm this transcriptome-level finding on available FFPE samples from Abacus. The MPR response group (n=4) had significantly higher levels of MHC class II expression on tumor cells after the treatment than relapse (n=12) and stable disease (n=15) patients ( p &lt; 0.001). Conclusions: Upregulation of MHC class II on tumor cells in anti-PD-L1 responding patients is a novel finding. Together with the TLS presence, they offer insights into potential mechanisms underlying treatment response, thus aiding in identifying predictive biomarkers for ICI therapy in MIBC.
Intracranial outcomes of 1L selpercatinib in advanced <i>RET</i> fusion-positive NSCLC: LIBRETTO-431 study.
Authors: Maurice Perol, Koichi Goto, Benjamin J. Solomon, Keunchil Park, Ernest Nadal, Emilio Bria, Claudio Martin, Jair Bar, Justin Williams, Tarun Puri, Jian Li, Minji Uh, Boris K. Lin, Caicun Zhou
Journal: Journal of Clinical Oncology (2024)

8547 Background: Selpercatinib is a highly selective and potent CNS active RET inhibitor approved for treatment of advanced RET fusion-positive ( RET+) NSCLC. Treatment or prevention of CNS disease is critical in RET+ NSCLC patients (pts), who have nearly a 50% lifetime prevalence of brain metastases (mets) (Drilon et al. JTO 2018). LIBRETTO-431 is the first study to compare intracranial (IC) efficacy of a targeted therapy to chemo/IO in pts with oncogene driven NSCLC. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. As previously reported, the study met its primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in all pts who had a baseline and one or more post-baseline CNS scans (CNS-evaluable) and were designated to receive pembrolizumab if randomized to the control arm (CNS-pembro population). Adverse events were evaluated in the CNS safety population. Results: A total of 192 of 261 pts enrolled were CNS-evaluable (selpercatinib: 120, control: 72). Baseline characteristics were generally balanced with the selpercatinib arm having a slightly lower proportion of pts with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT; 6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12 mo cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in pts with and without brain mets (Table). In pts with measurable brain mets at baseline (n=29), median time to IC response per RECIST 1.1 was similar between selpercatinib and control (1.4 mo [range: 1.2-2.9] vs 1.6 mo [range: 1.2-2.9]); however, as previously reported the IC response rates were higher (82% vs 58%) and more durable (12 mo DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in pts without prior CNS RT (14/15, 93%) than with prior CNS RT (3/6, 50%). Conclusions: Selpercatinib delayed IC progression in advanced RET+ NSCLC pts with or without baseline brain mets and achieved higher IC response rates compared to chemotherapy + pembrolizumab. LIBRETTO-431 is the first study to demonstrate IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in pts with advanced RET+ NSCLC. Clinical trial information: NCT04194944 . [Table: see text]
Trastuzumab deruxtecan (T-DXd) in patients with <i>HER2</i>-mutant metastatic non–small cell lung cancer (mNSCLC): Final analysis results of DESTINY-Lung02.
Authors: Pasi A. Janne, Yasushi Goto, Toshio Kubo, Kiichiro Ninomiya, Sang-We Kim, David Planchard, Myung-Ju Ahn, Egbert F. Smit, Adrianus Johannes De Langen, Maurice Perol, Elvire Pons-Tostivint, Silvia Novello, Hidetoshi Hayashi, Junichi Shimizu, Dong-Wan Kim, Kaline Pereira, Fu-Chih Cheng, Ayumi Taguchi, Yingkai Cheng, Koichi Goto
Journal: Journal of Clinical Oncology (2024)

8543 Background: In the DESTINY-Lung02 primary analysis (data cutoff, Dec 23, 2022), T-DXd 5.4 mg/kg and 6.4 mg/kg demonstrated strong and durable responses and an acceptable and generally manageable safety profile in patients with previously treated HER2 ( ERBB2)-mutant ( HER2m) mNSCLC (Goto et al. 2023). We report updated efficacy and safety results from the final analysis of DESTINY-Lung02. Additional analyses, including data on clinically relevant subgroups and patient-reported outcomes, are planned for presentation. Methods: In this randomized, blinded, multicenter, phase 2 trial, patients with previously treated HER2m mNSCLC were randomly assigned 2:1 to receive T-DXd 5.4 mg/kg or 6.4 mg/kg once every 3 weeks. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR), and key secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The study was not powered to statistically compare the 2 doses. Results: Patients were randomly assigned to T-DXd 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50). At the final analysis data cutoff (Aug 25, 2023), the median duration of follow-up (range) was 15.8 months (mo) (1.1-28.6) and 16.5 mo (0.6-28.7) with T-DXd 5.4 and 6.4 mg/kg, respectively (additional 8 mo follow-up since last DCO). Updated efficacy results are presented in the table. After a median treatment duration (range) of 7.7 mo (0.7-27.6) and 8.3 mo (0.7-24.0) with T-DXd 5.4 and 6.4 mg/kg, respectively, drug-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 39.6% (40/101) and 60.0% (30/50) of patients in each arm. Lower rates of drug-related TEAEs associated with drug discontinuation (14.9% [15/101]), dose reduction (16.8% [17/101]), and drug interruption (30.7% [31/101]) were observed with T-DXd 5.4 mg/kg than 6.4 mg/kg (26.0% [13/50], 34.0% [17/50], and 54.0% [27/50], respectively). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis was reported in 14.9% (15/101) and 32.0% (16/50) of patients in the T-DXd 5.4 and 6.4 mg/kg arms, respectively; most events were grade 1 or 2 (1 grade 5 event in each arm). Conclusions: In this final analysis, T-DXd 5.4 and 6.4 mg/kg continued to show strong and durable responses, which was consistent with the primary analysis, and no significant changes in toxicity were observed with longer follow-up. The approved T-DXd 5.4 mg/kg dose was associated with a more favorable benefit-risk profile and a reduced incidence of adjudicated drug-related ILD/pneumonitis. Clinical trial information: NCT04644237 . [Table: see text]