tbuckley/cabot-search huggingface dataset:
Timing of immunotherapy in stage IV non-small cell lung cancer.
Authors: Takefumi Komiya, Junjia Zhu, Shinkichi Takamori, Max Greenberg
Journal: Journal of Clinical Oncology (2024)

8544 Background: Excluding oncogene-driven disease, a combination of cytotoxic chemotherapy and immune checkpoint inhibitor (i.e., anti-PD1/PDL1 inhibitors) became a standard management in stage IV non-small cell lung cancer (NSCLC) in 2017. Cases with a positive driver oncogene such as EGFR, however, need to be treated with rather appropriate targeted therapy. In routine practice, a lengthy turnaround time of molecular analysis to rule out oncogenes makes the chemo-immunotherapy combination a challenge. In addition, unexpected toxicities when immunotherapy and targeted therapy are combined or sequenced have been reported. Because of these restrictions many oncologists often initiate traditional chemotherapy alone for the first few cycles until molecular result becomes available so that they can modify the first-line therapy accordingly. This practice pattern to delay initiation of immunotherapy may lead to inferior cancer outcome. Keynote-189, an international phase III trial defining the role of additive pembrolizumab to first-line chemotherapy, demonstrated an overall survival advantage of chemo-immunotherapy combination over chemotherapy alone regardless of PDL1 status. In the arm of chemotherapy alone, an approximately 40% of patients received immunotherapy as second-line therapy. Despite the cross-over of the arms, this study showed a statistically significant difference in OS, suggesting the importance of early exposure to immunotherapy. Impact of delayed administration of immunotherapy in the first-line therapy is unknown. Methods: Using NCDB, a total of 99,008 patients diagnosed in 2017-2018 as stage IV NSCLC were screened. Eligible patients must have been treated with multi-agent chemotherapy as first-course of therapy. Those with neuroendocrine pathology, those who were exposed to immunotherapy prior to chemotherapy were excluded. They were assigned to a group of: (1) those who received immunotherapy within 30 days of chemotherapy, (2) 30-61 days of chemotherapy, or (3) chemotherapy alone. Those who have died within 2 months of diagnosis were excluded. Results: A total of 3291, 237, and 4309 were selected for group 1, 2, 3 for the analysis, respectively. Median OS was 14.5, 9.5, and 10.0 months for the group 1,2, 3, respectively. The significant difference in OS was observed between group 1 and 2 (HR= 0.74, 95% CI: 0.64-0.87, p=0.0003) and between group 1 and 3 (HR=0.73, 95%CI 0.70-0.78, p&lt;0.0001). There is no difference in OS between group 2 and 3. Multivariate analysis demonstrated that group 1 has a significantly prolonged OS over group 2. The significant OS difference between group 1 and 2 was confirmed by propensity-score matching analysis (N=237 each, HR=0.73, 95%CI: 0.59-0.90, p=0.004). Conclusions: This retrospective study using one of the largest cancer databases suggests that delay of immunotherapy when used in combination with chemotherapy have detrimental effect in survival outcome.
Association of immune-related adverse events, inflammatory biomarkers, and clinical outcomes in patients treated with ICIs for advanced renal cell carcinoma.
Authors: Ahmet Yildirim, Mengting Wei, Yuan Liu, Rohit Vivek Goswamy, Yujin Choi, Jacqueline T Brown, Bassel Nazha, Dylan J. Martini, Caitlin Hartman, Greta Russler McClintock, Tony Zhuang, Haydn Kissick, Wayne B. Harris, Bradley Curtis Carthon, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2024)

4556 Background: Immune Checkpoint Inhibitors (ICIs) have been the mainstay treatment for advanced renal cell carcinoma (aRCC). However, irAEs are still a challenge in clinical practice. We tested irAEs with inflammatory biomarkers and their association with clinical outcomes. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 2018 and 2023. irAEs determined by the primary oncologist and reported by CTCAE v5.0. Univariate and multivariate analyses were conducted to determine the association between race, gender, OS, PFS, clinical benefit (CB, stable disease, partial response, complete response), modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), neutrophil to eosinophil ratio (NER), and any grade irAE. MVA was built by controlling gender, race, smoking status, and prior treatment. Results: We analyzed 401 patients; 191 (47.6%) patients experienced any grade irAEs, with 41 (21.5%) of those classified as grade 3 or higher. Of 401 patients, 139 (34.6%) were treated with PD-1 inhibitor (PD-1i) monotherapy, 131 (32.6%) with PD-1i and CTLA-4 inhibitor combination, 108 (26.9%) with PD-1i and tyrosine kinase inhibitor combination. The median follow-up time was 43.0 months (36.5-51.3). On univariate analysis, the incidence of irAEs was higher in females than males (Odds ratio (OR),1.66 (1.08-2.57), p=0.021), White patients had a higher incidence of irAEs compared to African American patients (OR 2.20 (1.32-3.66), p=0.009). On multivariate analysis, low mGPS was correlated with a higher risk of irAEs (OR for mGPS of 0-1-2 was 6.03 (2.07-17.62), 3.75 (1.31-10.70), and reference respectively; p=0.004). irAEs were correlated with greater CB (OR 2.56 (1.53-4.29); p &lt;.001), longer OS (HR 0.55 (0.37-0.82); p=0.003), and longer PFS (HR 0.51 (0.37-0.71); p &lt;.001). Conclusions: Female patients, White patients, and patients with low inflammatory biomarkers may have a higher likelihood of experiencing irAEs. Patients who experienced irAEs may have better outcomes. Future prospective trials are needed for further evidence. [Table: see text]
Single agent axitinib in the management of patients with progressive pheochromocytoma and paraganglioma.
Authors: Antonio Tito Fojo, Andrea B Apolo, Maureen Edgerly, Karel Pacak, William Douglas Figg, Susan Elaine Bates, Jaydira Del Rivero
Journal: Journal of Clinical Oncology (2024)

4602 Background: Malignant pheochromocytomas and paragangliomas remain diseases that present those caring for patients with these diseases the dual challenges of hormonal excess and malignant behavior. Radiolabeled therapy with meta-iodobenzguanine (MIBG) and chemotherapy with a combination of cyclophosphamide, vincristine and dacarbazine can help in the management of patients whose disease has metastasized, but additional options are needed. The phase II FIRSTMAPPP study provided support for use of the tyrosine kinase inhibitor, sunitinib, in these malignancies with median PFS values of 8.9 vs. 3.6 months and ORRs of 31% vs. 8% for sunitinib vs placebo.Median duration of sunitinib therapy was 11 months. Concurrent with this study we launched a single arm trial to examine the activity of a similar TKI, axitinib. We report here the results of that study. Methods: Axitinib was self-administered at a dose of 5 mg every 12 hours continuously in a 28-day cycle. All patients were evaluated for dose adjustments to levels of 2, 3, 7, and 10 mg bid as options with intervals of at least 4 weeks between any dose escalations. Efficacy evaluations using conventional imaging were performed every 12 weeks. Documented evidence of disease progression was required prior to study entry. Results: Nineteen patients were enrolled; two did not receive treatment or less than one week of treatment. A partial response was achieved in 35.3% of patients, with a median reduction of tumor measurements of 34% and a median duration of response of 7.4 months. Median PFS was 7.9 months. Median duration of treatment was 9.5 months. Median OS was 29 months. Axitinib was well-tolerated with treatment-emergent adverse events with an attribution of possible, probable, and definite similar to those previously reported for the agent, including G1/2 fatigue, diarrhea, mucositis, and PPE in 42% to 63% and G1/2/3 hypertension in 79%, all managed with adjustments in antihypertensive medications No patient discontinued axitinib for an adverse event, nor had a prolonged suspension of treatment. Unfortunately, the study has been prematurely terminated by the sponsor. Conclusions: These results together with similar results reported recently with sunitinib provide strong evidence for the efficacy of sunitinib and axitinib, two VEGF tyrosine kinase inhibitors with similar characteristics, in the management of malignant pheochromocytoma and paragangliomas. Axitinib should be started at a dose of 5 mg bid and adjusted as tolerated. Despite its use in individuals with often difficult to treat hypertension, blood pressure management did not present a difficult challenge. Clinical trial information: NCT03839498 .
Survival outcomes of small cell variant bladder cancer: Analysis from nationwide study.
Authors: Mohammad Arfat Ganiyani, Atulya Aman Khosla, Shahzaib Ahmad, Karan Jatwani, Shreyas S Bellur, Nouman Aziz, Muni Rubens, Mukesh Roy, Bruno R. Bastos, Manuel Ozambela, Ahmed Eldefrawy, Murugesan Manoharan, Rohan Garje
Journal: Journal of Clinical Oncology (2024)

4606 Background: Small cell carcinoma of bladder (SCB) is a rare and aggressive histological subtype. While the survival impact of various treatment modalities for the classic urothelial bladder cancer has been well-researched, limited studies exists on the survival outcomes of these treatment modalities in patients with SCB, primarily due to the exclusion of these patients from clinical trials. This study aims to explore the impact of different treatment modalities on the survival outcome of patients with SCB using data from a large nationwide registry. Methods: This retrospective study queried the National Cancer Database from 2004 to 2020 and followed STROBE guidelines. The primary analytic cohort included patients diagnosed with locoregional SCB based on the TNM stage (T1-T4, N0-N3, M0). Treatment modalities comprised perioperative systemic therapy combined with definitive surgery (PST), concurrent chemoradiation (CR), surgery only (S), Radiation therapy only (RT) and systemic therapy only (ST). This study utilized Kaplan-Meier survival analysis and the Cox Proportional regression. Results: The study included 4,658 patients with locoregional SCB. The analysis revealed 236 (4.82%) patients with SCB received PST, 752 (15.36%) got CR, 612 (12.50%) underwent S, 3,029 (61.85%) received ST, and 268 (5.47%) had RT. The median overall survival was 64.49 months (CI: 41.4-75.1, P &lt; 0.001) with PST, 29.27 months (CI: 22.9-35.88), with CR, 14.13 months (CI: 9.92-21.65) with S alone, 21.29 months (CI: 18.53-23.69) with ST, and 7.82 months (CI: 6.24-9.53) with RT alone. In the multivariate analysis, combining perioperative systemic therapy with surgery led to a 54% reduction in hazards of death (HR: 0.46; CI: 0.37-0.58) compared to surgery alone, whereas CCR achieved a 41.16% (HR: 0.59; CI: 0.47-0.73) decrease in hazard, illustrating the effectiveness of multimodal treatment for SCB. Conclusions: Treatment approaches with either systemic therapy combined with definitive surgery or concurrent chemoradiation enhanced survival outcomes, highlighting the significance of a multimodal approach for patients with SCB. [Table: see text]
Tumor fraction and copy number burden from urinary cell-free tumor DNA (utDNA) to predict minimal residual disease prior to repeat-transurethral resection in high-risk non-muscle invasive bladder cancer (HR-NMIBC).
Authors: Joshua Linscott, Hiroko Miyagi, Billie Gould, Prithvi Murthy, Kyle M Rose, Lucia P Camperlengo, Giancarlo Bonora, Logan Zemp, Scott Michael Gilbert, Philippe E. Spiess, Wade J. Sexton, Joshua J Meeks, Pan Du, Shidong Jia, Roger Li
Journal: Journal of Clinical Oncology (2024)

4600 Background: Genomic alterations detected in urinary cell-free tumor DNA (utDNA) are concordant with those from tissue samples in patients with urothelial carcinoma. In this prospective study, we demonstrate that utDNA alterations and copy number variation can be used to detect minimal residual disease (MRD) prior to standard-of-care repeat transurethral resection of bladder tumors (rTURBT) in patients with high risk non-muscle invasive bladder cancer (HR-NMIBC). Methods: A total of 53 patients with high-risk NMIBC were enrolled prior to rTURBT. PredicineWES+ whole exome sequencing with boosted 600+ oncogene coverage was performed on the index TURBT (iTURBT) tissue. Urine samples were collected immediately prior to rTURBT (preUR). Low Pass Whole Genome Sequencing (LP-WGS) was used to detect utDNA and estimate copy number burden (CNB). Tumor fraction (tf) detected in utDNA was measured using PredicineBEACON personalized ultra-deep sequencing MRD probes designed from somatic variants detected in iTURBT tissue. MRD probes leverage up to 60 patient-specific alterations and a fixed 500 gene hotspot panel. Analysis included receiver operator curves (ROC) to establish CNB and tf efficacy in detecting residual cancer, based on the pathological findings from rTURBT. Specific thresholds for test positivity were set from ROC analysis and used to evaluate performance characteristics of CNB and tf separately and then in step-wise model. Results: In this HR-NMIBC cohort, residual disease was detected in 36/53 pts (68%) on pathologic evaluation. Using the CNB score from preUR samples, residual disease was detected with an overall AUC of 0.86. Setting the CNB threshold &gt;6.1 yielded a positive likelihood ratio of 11.7 and negative likelihood ratio of 0.37 for detecting MRD. For patients with personalized urinary tf (n=34), a receiver operator curve demonstrated an area under the curve (AUC) of 0.89. Median urinary tf was 3.5% for patients with MRD vs. &lt;0.05% (undetectable) for disease-free patients (p&lt;0.001). Best thresholds for MRD detection per Youden’s index were tf &gt;=6.8% and CNB &gt;6.1. When combined into a step-wise model, the two assays together led to improved performance with 85.7% sensitivity, 100.0% specificity and an overall accuracy of 91.4%. Conclusions: Minimal residual disease can be detected using utDNA prior to rTURBT with high accuracy, making this a promising urinary biomarker. If validated, the combined approach using CNB and tf from utDNA for the detection of MRD can be used to predict patients in need of maximal resection prior to starting intravesical therapy.
Lymph node metastasis prediction with non-small cell lung cancer histopathology imaging.
Authors: Victor Lee, Amber Loren Ong King, Durga Sritharan, Nicholas Simms Moore, Saahil Chadha, Ryan Maresca, Tommy Hager, Sanjay Aneja
Journal: Journal of Clinical Oncology (2024)

8063 Background: Lymph nodal metastasis (LNM) plays a critical role in the prognosis and treatment strategy formulation for non-small cell lung cancer (NSCLC). Initial diagnosis typically involves a CT scan, but its sensitivity for detecting mediastinal LNM is limited, sometimes as low as 51%. To improve detection, PET-CT, mediastinoscopy, and Endobronchial ultrasound-guided transbronchial needle aspiration are employed, with sensitivities of 74%, 78%, and 90%, respectively. The ability to anticipate nodal metastasis from primary tumor data could significantly influence clinical decisions, particularly for patients at risk from invasive procedures like EBUS. By leveraging the pathology data from the National Lung Screening Trial (NLST), this study aims to harness machine learning algorithms, with the goal of refining the staging process and individualizing patient care, thus enhancing the therapeutic outcome and potentially sparing patients from the morbidity associated with more invasive diagnostic techniques. Methods: This research used digital hematoxylin and eosin (H&amp;E) stained histopathology slide images of NSCLC from the NLST provided by The Cancer Imaging Archive. It excluded cases with undefined nodal or distant metastasis status (Nx or Mx), as well as those with confirmed distant metastasis (M1). Cases were categorized as node positive if they had N1, N2, or N3 disease, and node negative if they had N0 disease. The analysis of pathology slide images was performed using the CLAM analysis pipeline, which operates by creating patches, extracting features via a ResNet-50 model pre-trained on ImageNet, and training models with attention modules that assign scores to each patch. The study was performed using Python 3.7 and the CLAM library. Results: 636 whole slide images were analyzed, comprising 453 cases without lymph node metastasis (node negative) and 183 cases with lymph node metastasis (node positive). The study revealed that the CLAM model could predict LNM with an average area under the curve (AUC) of 0.78 over a series of 10 folds. The median sensitivity of the model at the threshold values of 0.3, 0.5, and 0.7 was 0.78, 0.48, and 0.24, respectively. Correspondingly, the median specificity at these same cutoffs was 0.49, 0.91, and 1.00, respectively. Conclusions: The study provided a proof of concept that nodal metastasis can be predicted from H&amp;E slide images of primary resections using solely deep learning methods. The integration of deep learning models into the diagnostic process could fundamentally transform how clinicians evaluate the risk of LNM, tailor treatment plans, and ultimately enhance survival rates and quality of life for patients with NSCLC.
Response and outcomes with immune checkpoint inhibitor (ICI) in patients (pts) with urothelial carcinoma (UC) and subtype histology (SH).
Authors: Dimitra Rafailia Bakaloudi, Dimitrios Makrakis, Rafee Talukder, Leonidas Nikolaos Diamantopoulos, Tanya Jindal, Charles B Nguyen, Charbel Hobeika, Vinay Mathew Thomas, Jeffrey Johnson, David Humberto Marmolejo Castañeda, James Korolewicz, Roubini Zakopoulou, Gavin Hui, Pedro C. Barata, Lucia Andrea Alonso Buznego, Jason R Brown, Tyler F. Stewart, Ilana B. Epstein, Ali Raza Khaki, Petros Grivas
Journal: Journal of Clinical Oncology (2024)

4580 Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1 st line [1L] upfront, maintenance avelumab [mAV], ≥2 nd line [2+L] therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival [mOS, mPFS, mDFS] using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, [95%CI 0.7-1.4]), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 [95% 0.9-2]) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 [95%CI 0.6-1.5]). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, [95%CI 0.6-1.2]), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 [95% 0.6-1.7]) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 [95%CI 0.6-2.2]); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. [Table: see text]
Efficacy and safety of MCLA-129, an anti-EGFR/c-MET bispecific antibody, in non-small-cell lung cancer (NSCLC) with c-METexon 14 skipping mutations (<i>MET</i>ex14).
Authors: Mariana da Rocha Almeida Brandao, Jon Zugazagoitia, Anne-Marie C. Dingemans, Michaël Duruisseaux, Pauline Parent, Oscar Juan-Vidal, Alexander I. Spira, Cecile Vicier, Gerard Zalcman, Ben Barasa, Chris Yan, Petra Doze, Andrew K. Joe, Gianluca Laus, Enriqueta Felip
Journal: Journal of Clinical Oncology (2024)

8583 Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET) are dysregulated in many tumors, including NSCLC. In particular, splice-site alterations resulting in the loss of transcription of exon 14 in the oncogenic driver c-MET ( METex14 skipping mutations) occur in ~3% of NSCLC and lead to oncogenic MET activation. MCLA-129 is a bispecific antibody that targets EGFR and c-MET with multiple mechanisms of action, including inhibition of EGFR and c-MET signaling, antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity. In the dose escalation part of a phase 1/2 trial (NCT04868877), the initial recommended phase 2 dose of MCLA-129 monotherapy was determined to be 1500 mg every 2 weeks (Q2W) with 28-day cycles. Significant tumor shrinkage was observed in one patient with METex14 NSCLC previously treated with multiple chemotherapy agents and the c-MET tyrosine kinase inhibitor (TKI) capmatinib. Preliminary data are presented of patients (pts) with advanced or metastatic METex14 NSCLC treated with MCLA-129 in the dose expansion phase of the trial. Methods: Pts with advanced/metastatic METex14 NSCLC Pts received MCLA-129 1500 mg IV Q2W, until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. Primary endpoint: investigator-assessed ORR (RECIST v1.1), in pts with measurable disease, ≥2 MCLA-129 cycles, and ≥1 post-baseline scan. Secondary endpoints: DCR and safety. Biomarker analyses of EGFR/c-MET expression and ctDNA mutation status are planned. Results: As of December 1, 2023, 15 pts were dosed. The median age was 72 years (range 61-83), 40% were male, and 13%/87% of pts had ECOG performance status 0/1 respectively. The trial is ongoing; further analysis of safety and efficacy is planned with a later data cutoff date and will be presented at the meeting. Conclusions: MCLA-129 is being evaluated as monotherapy for the treatment of patients with locally advanced/metastatic c-MET exon 14 skipping NSCLC. Clinical trial information: NCT04868877 .