FGFR3 Alterations Research Articles

CtDNA-based genomic landscape analysis to evaluate molecular brake and gatekeeper mutations in FGFR2 alterations.

3049 Background: FGFR2 and FGFR3 (FGFR2/3) gene alterations are oncogenic drivers found across various cancer types and have been successful targets of drug development. Several FGFR inhibitors (FGFRi) are approved for clinical use, and most are ATP-competitive, reversible inhibitors (1st-gen). Efficacy of the 1st-gen FGFRi can be limited by acquired resistance mutations in the FGFR kinase domain, typically molecular brake or gatekeeper mutations, which disrupt compounds binding through conformational changes or through direct steric hindrance, respectively. Irreversible (covalent) FGFRi, such as futibatinib, are in development to overcome kinase domain resistance mutations. However, preclinical evidence indicates that some of the known resistance mutations (eg. V564L) remain insensitive to futibatinib. Methods: To assess the landscape of FGFR-driven cancers and to better understand the prevalence of molecular brake and gatekeeper mutations, we analyzed the distribution of FGFR2/3 alterations in a large clinical genomic research database. This ctDNA-based genomic database was selected for the analysis given that liquid biopsy is a fit-for-purpose method to detect acquired resistance mutations. Results: We identified over 2,100 patients with FGFR2/3 alterations. Non-small cell lung cancer (NSCLC), breast, bladder, and cholangiocarcinoma (CCA) had the highest number of patients with FGFR2/3 alterations. 36% of all FGFR2 alterations across all cancer indications consisted of molecular brake or gatekeeper mutations. This finding was most enriched in CCA and breast cancer where 51% and 57%, respectively, of FGFR2 alterations were molecular brake or gatekeeper mutations. In breast cancer patients, molecular brake mutations were common and represent activating mutations in FGFRi-naïve patients. A small number of FGFR3 gene fusions were detected in CCA patients who had significantly shorter time on 1st-line treatment and trended toward shorter overall survival when compared to patients with FGFR2 fusions. We also identified CCA patients with FGFR2 fusions and one or more concurrent FGFR2 SNVs; primarily those in the kinase domain and associated with FGFRi resistance. Most of these putative cases of acquired resistance were polyclonal, with 2 or more (up to 8) FGFR2 SNVs coexisting with the fusion. Bladder cancer and NSCLC had the highest numbers of FGFR3 alterations. FGFR2/3 alterations were typically found without other driver mutations in CCA, bladder, and NSCLC patients. However, in breast there was a large overlap between FGFR2/3 alterations and other drivers. Conclusions: Herein, we identify a cohort of patients with FGFR2/3 molecular brake and gatekeeper mutations that may benefit from next-generation FGFR2/3-targeted therapies designed to inhibit a broad spectrum of both primary and secondary resistance mutations.

Genomic characterization of FGFR-altered solid tumors using a clinically annotated pan-cancer repository.

3074 Background: Somatic mutations, gene fusions, and amplifications in FGFR1/2/3 are found across solid tumors. FGFR2/3 fusions and select mutations have matched FDA-approved therapies in intrahepatic cholangiocarcinoma (iCCA) and urothelial carcinoma (UC). Identification of FGFR-altered tumors may inform patient selection for future drug development. Methods: All solid tumors that underwent MSK-IMPACT, a DNA-based NGS panel with coverage of FGFR1-4, were queried for FGFR1-4 alterations. FGFR structural variants (SV) were manually reviewed and compared to RNA sequencing data (RNAseq, Archer FusionPlex) when available. Alteration (alt) frequencies of iCCA and UC tumors with target FGFR alt (level 1 OncoKB evidence), non-target FGFR alt (lacking level 1 evidence) and no FGFR alt were compared using chi-squared tests and odds ratios. Euclidean distance was calculated between cohorts based on prevalence of frequently altered genes (>5%). Consensus clustering was used to identify optimal number of clusters and compare genomic profiles between clusters. Results: At data lock of June 1, 2022, 5695 tumors among 48,416 patients harbored an FGFR alteration (11.8%). FGFR SV were identified in 347 tumors on MSK-IMPACT. Of these 111/140 (79.2%) with RNAseq were positive. 98% (203/207) of SV without RNAseq were considered likely activating (canonical SV, n=125; in-frame inclusive of kinase domain, n=78). The most frequent fusion was FGFR3-TACC3 (n=124), followed by fusions unique to a single patient (n=100). Fusions were discovered in >15 tumor types, most frequently in iCCA (n=93), UC (n=50) and high-grade glioma (n=44). Among 1176 iCCA tumors, 9.9% (n = 117) had a target FGFR2 fusion. Target FGFR tumors were enriched for concurrent BAP1 alt (18%) compared to tumors without FGFR alt (58/969, 5.9%) and with non-target FGFR alt (7/90, 7.8%). Both groups without target alt were enriched in TP53, ARID1A and IDH1 alts compared to target group. Four optimal genomic clusters were identified, with FGFR2 fusions enriching in cluster 4 (29% vs 3%, 7% and ≤1%); 21 non-target FGFR alt were also in cluster 4. Among 2720 UC tumors, 24.7% (n=672) had target FGFR alt (select FGFR3 mutations and FGFR2/3 fusions). Three genomic clusters were identified, with target FGFR enriched in cluster 3 (42% target FGFR vs cluster 1: 11%, cluster 2: 18%) and non-target FGFR alterations enriched in cluster 1 (13% vs. cluster 2: 9.4 %, cluster 3: 7.0%); 68 non-target FGFR alt were in cluster 3. Tumors with non-target FGFR alterations and no FGFR alterations had close genomic association (Euclidean distance: 0.18). Conclusions: Activating FGFR fusions, which occur across tumor types with marked diversity in fusion partners, present opportunities for future drug development. Non-target FGFR alterations in iCCA and UC, particularly those that cluster with target FGFR alterations, may be candidates for future FGFR-targeted strategies.

Fibroblast growth factor receptor 3 (FGFR3) alterations in PROOF 302: A phase III trial of infigratinib (BGJ398) as adjuvant therapy in patients (pts) with invasive urothelial carcinoma (UC).

4511 Background: Radical surgery with or without (neo)adjuvant cisplatin-based chemotherapy [(N)AC] is standard in fit pts with muscle invasive UC of bladder (UBC) or upper tract (UTUC). However, recurrence rates are high, underscoring the need for novel therapies. Since up to 70% of UTUC and 20% of UBC tumors were reported to harbor FGFR3 alterations, targeting this pathway is a rational approach. Infigratinib is a selective FGFR1–3 inhibitor with efficacy in advanced UC with FGFR3 alterations [Pal et al. 2018]. PROOF 302 investigated the efficacy and safety of adjuvant infigratinib vs placebo in pts with high-risk invasive UC. Methods: PROOF 302 was a global, randomized, double-blind, placebo-controlled, phase III trial for pts with high-risk invasive UTUC or UBC (≤15%) with FGFR3 alteration (i.e. mutation, gene fusion / translocation) with residual (≥ypT2 and/or ypN+) tumor after NAC, or pts ineligible for, or refusing, cisplatin-based AC, ≤120 days post-surgery. Pts were randomized 1:1 to infigratinib 125 mg or placebo daily on days 1–21 every 28 days for up to 52 weeks or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: investigator-assessed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: QOL, pharmacokinetics, genomic analysis of tumor and cfDNA. Assessment of genomic alterations was pursued using descriptive statistics. Results: We present the results of the genomic analysis of radical surgery tissues from pts screened for the trial using the FoundationOne platform. Out of 617 pts screened, 188 (30.5%) had alterations in FGFR 1-4 genes: 102/237 (43%) in UTUC, 85/369 (23%) in MIBC and 1/11 (9%) with unknown tumor origin. Of these 188 pts, median age 74 (32-90 years), 76% were male, 55% had UTUC, 44% had UBC. Genomic alterations are shown. In UTUC, FGFR3 had 56% single-nucleotide variations (SNV) and insertions/deletions (INDELS), 40% amplifications and 70% structural variants (SV). In UBC, FGFR3 had 44% SNV and INDELS, 60% amplifications and 30% SV. Conclusions: FGFR3 alterations were seen in only 19% of all pts screened for PROOF-302, a trial that was enriched for UTUC: 71/237 (30%) of UTUC and 48/369 (13%) of UBC. The trial was stopped early by the sponsor, but the genomic analysis provides insights into the prevalence of FGFR3 alterations; assessment of correlations with the primary/secondary endpoints is ongoing. The nature and frequency of co-occurring alterations in tissue samples is being investigated to help inform combination therapy strategies and putative resistance mechanisms. Clinical trial information: NCT04197986 . [Table: see text]

Erdafitinb in patients with FGFR-altered tumors: Results from the NCI-COG Pediatric MATCH trial arm B (APEC1621B).

10007 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1-21 years with relapsed or refractory solid tumors, CNS tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations in their tumor. Arm B (APEC1621B) evaluated the orally bioavailable FGFR inhibitor erdafitinib in patients whose tumors harbored activating alterations in FGFR 1/2/3/4. Methods: Patients received oral erdafitinib 4.7 mg/m2/dose (Max dose: 8 mg) daily for 28-day cycles until disease progression or drug related dose limiting toxicity (Max 26 cycles). Disease assessments were performed every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included progression free survival (PFS). Results: A total of 20 evaluable patients (median age: 15 yrs) were enrolled from June 2018 to July 2022 in this first study of erdafitinib in pediatric patients. The most common diagnosis (n = 17) was glioma or glioneuronal tumor (11 low grade and 6 high grade). Three patients had non-CNS solid tumors (1 each with neuroblastoma, osteosarcoma, and rhabdomyosarcoma). FGFR alterations detected consisted of activating hotspot mutations in FGFR1 (n = 16), FGFR2 (n = 1), FGFR4 (n = 1), and FGFR1 fusions (n = 2; FGFR1: TACC1, FGFR1: TACC3). Partial responses were confirmed by central review in 2/20 patients (10%, 90%CI: 3.4%, 26.2%), both with low grade gliomas or glioneuronal tumors (LGG, LGGNT) and FGFR1 hotspot mutations (K687E and N577K). A best response of stable disease (SD) was observed in 6 additional patients with gliomas with a median duration of SD of 6.5 cycles. Six-month PFS was 45% (95% CI: 23.1%, 64.7%) and six-month OS was 89.7% (95%CI: 64.8%, 97.3%). Treatment related adverse events included those previously reported with FGFR inhibitors including hyperphosphatemia and nail changes or infections. Grade 1 vision changes were also reported. There was one Grade 3 spinal cord compression and one Grade 4 intracranial hemorrhage. Conclusions: Erdafitinib was generally well tolerated in this heavily pre-treated cohort of children with relapsed tumors harboring FGFR alterations. Partial responses or stable disease were observed in the majority (6/11, 54%) of patients with FGFR1-mutant low grade gliomas or glioneuronal tumors, suggesting the possible benefit of FGFR inhibitor therapy for these patients. Further studies would be necessary to more thoroughly evaluate the activity of erdafitinib for patients with other histologies and FGFR alteration types or combination approaches that include other targeted and/or cytotoxic agents. Clinical trial information: NCT03210714 .

Real world genomics in metastatic urothelial carcinoma (mUC).

e16583 Background: Next generation sequencing (NGS) has therapeutic value in mUC. Beyond FGFR3 alteration and tumor mutational burden, genetic testing can identify novel predictive and prognostic biomarkers. In clinical practice, variability is introduced between assays due to genomic coverage, sequencing depth, timing, and tissue used. Methods: A single-institution retrospective database of patients (pts) diagnosed with mUC between 2013 and 2022 was generated. Clinicopathologic features and NGS results, including mutations, fusions, and copy number alterations, were abstracted from pt records. Progression free survival was calculated from start of first-line (1L) treatment (PFSFLT) and of 1L/maintenance/2L immunotherapy (PFSIO) to date of disease progression or death, censored at last follow up for pts alive without progression. Overall survival (OS) was calculated from diagnosis date of mUC to the date of death or censored at last follow up. Association between two categorical factors was estimated by chi-square test. Time-to-event data were analyzed by Kaplan-Meier method with log-rank test and Cox model. Results: 251 records were reviewed, of which 79 unique mUC pts with somatic NGS testing were identified. Pts were predominantly male (70.9%), white (86.1%), past/present smokers (65.8%), with bladder primary site (78.5%) and urothelial histology (72.2%). NGS was performed on 37 (46.8%) primary and 42 (53.2%) metastatic specimens, including 57 solid tumor (72.2%), 12 liquid biopsy (15.2%), and 10 (12.7%) with both. NGS was performed prior to or during 1L treatment for 61 pts (77.2%) and later for 18 pts (22.8%). Median TMB, where measured (n = 43), was 9 mut/Mb (2-40). The most prevalent genes with pathogenic variants identified were TP53 (37, 46.8%), TERT (32, 40.5%), PIK3CA (22, 27.8%), FGFR3 (18, 22.8%), ARID1A (16, 20.3%), CDKN2A/B (13, 16.5%) and ERBB2 (13, 16.5%). Several TP53 (45) and ARID1A variants (19) were observed, and fewer TERT (3) and FGFR3 (6) variants were seen. Among prevalent mutant genes, TP53 and TERT were most commonly concordant (68.4%, p = 0.0068). TERT was significantly co-mutated with ARID1A (64.6% concordant, p = 0.00479) and exclusive with mutant PIK3CA (41.8% concordant, p = 0.012). ERBB2 and FGFR3 alterations were mutually exclusive. ERBB2 alterations significantly correlated with lack of metastasis to lung, liver, or bone (p = 0.00355), though no genes predicted metastasis to those sites. ERBB2 alterations also correlated with improved PFSIO (HR 0.3, 95% CI 0.09-0.99, p = 0.049), but not with PFSFLT. FGFR3 mutation is associated with inferior OS (HR 1.88., 95% CI: 1.03 – 3.43, p = 0.04), especially for male pts (HR 2.85, 95% CI: 1.26-6.51, p = 0.013). Conclusions: A diverse array of NGS testing was performed on mUC pts, collected at varying timepoints. Despite inherent heterogeneity, these results yielded prognostic and predictive information for ERBB2 and FGFR3 alterations to be further studied in larger cohorts.

Updated dose escalation results for ReFocus, a first-in-human study of highly selective FGFR2 inhibitor RLY-4008 in cholangiocarcinoma and other solid tumors.

4009 Background: Oncogenic FGFR2 alterations (fusions/rearrangements (f/r), amplifications, mutations) represent a broad therapeutic opportunity as they drive multiple solid tumors, particularly cholangiocarcinoma (CCA). However, off-isoform toxicity and on-target resistance limit the benefit of approved pan-FGFR inhibitors (FGFRi). RLY-4008 is the first potent, highly selective, oral FGFR2 inhibitor designed to overcome these limitations by targeting FGFR2 driver alterations and resistance mutations. Here, we present updated dose escalation results from ReFocus (NCT04526106), a seamless Phase I/II, open label study evaluating the safety and preliminary efficacy of RLY-4008 in patients (pts) with advanced, FGFR2-altered solid tumors. Methods: Adult pts received RLY-4008 BID, QD, QD discontinuous on a 4-week (wk) cycle following a Bayesian Optimal Interval design. Treatment-related adverse events (TRAEs), PK, ctDNA and anti-tumor activity (RECIST v1.1) were assessed. Results: As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA. 50% had prior FGFRi, and median lines of prior therapies was 3 (1-15). 28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46). RLY-4008 had favorable PK with doses ≥40 mg QD providing FGFR2 occupancy ≥90%. 70 mg QD was the RP2D based on PK, safety, anti-tumor activity and exposure-dependent tumor regressions in FGFRi-naïve CCA f/r pts. Anti-tumor activity was observed in CCA and solid tumors across doses and FGFR2 alterations with radiographic tumor reductions in 74 (64%), SD/PR in 83 (72%), including 4/4 (100%) FGFRi-naïve CCA f/r pts at RP2D achieving confirmed PR. Clinically meaningful disease control and durable responses were observed in pts with FGFR2 f/r CCA. Overall, median treatment duration was 24 wks (range <1-108 wks). 105 pts discontinued (PD (81%), AE (3%), other (7%)). Across doses, most common TRAEs were low-grade PPE (57%), stomatitis (56%), dry mouth (38%), alopecia (28%), and dry eye (22%). No grade 4/5 TRAEs were observed. Conclusions: These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106 . [Table: see text]

Generalizable FGFR prediction across tumor types using self supervised learning.

e15057 Background: Deep Learning models have demonstrated the ability to detect tumors, classify disease state, or infer genetic biomarkers from digital whole slide images (WSI) of Hematoxylin and Eosin (H&E)-stained tissue. Such models can be deployed to improve clinical practice or efficiently recruit for clinical trials. However, the data to train these models is often very limited and image capture protocols vary between labs. We propose to use Self Supervised Learning (SSL) on large unlabeled histopathology data sets to improve generalizability and predictive performance of deep learning models on unseen data. Methods: We pre-trained a Convolutional Neural Network (CNN) using SSL on 25,120 unlabeled, digital WSIs from various sources (multiple scanners, hospital systems, labs, diseases, tissue sites). We then fine-tuned the pre-trained CNN to infer the presence or absence of select FGFR alterations in Muscle Invasive Bladder Cancer (MIBC) from the digital WSI. We applied this model (FGFRSSL) to WSIs of biopsies from other data sources and tumor types and compared with a model (FGFRTRAD) that was trained exclusively on MIBC samples without self-supervised learning. Results: The FGFRSSL model achieved an Area Under ROC Curve (AUC = 0.80) on MIBC WSIs and maintained performance on images from an independent lab (AUC=0.82). We further show that the model generalizes to Non-Muscle Invasive Bladder Cancer (NMIBC) samples with (AUC = 0.76) and Pan-Tumor WSIs (AUC: 0.83). The FGFRTRAD model trained without SSL-based pre-training achieved an Area Under ROC Curve (AUC: 0.76) on MIBC WSIs was less generalizable, showing lower performance for independent data (AUC = 0.72), NMIBC samples (AUC = 0.72), and Pan-Tumor samples (AUC = 0.64). Conclusions: We leveraged SSL pretraining to improve the reliability and generalizability of AI-based models across multiple data sources. We also demonstrate our model’s ability to infer FGFR status across multiple solid tumor types after training on only MIBC samples, suggesting the cell morphology conferred by FGFR alteration in cancer may be shared across diverse tumor types. These models represent a means for efficiently screening patients for actionable clinical biomarkers in a robust manner to guide clinical decisions and inform drug development efforts. [Table: see text]

A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.

TPS4608 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224 .

Landscape of FGFR2/3 alterations in genitourinary cancer.

e15047 Background: FGFR2/3 is frequently activated by mutation or overexpression, and it is a validated therapeutic target in several cancers. However, the molecular profile of FGFR2/3 in genitourinary cancer is still lacking. In this study, we assessed FGFR2/3 alterations for better understanding therapeutic implications in genitourinary cancer. Methods: Patients diagnosed with genitourinary cancer were enrolled in the study. Tumors and plasma samples of participants were sequencing for next-generation sequencing from Chinese cohort and TCGA database. Results: A total of 3858 patients were enrolled with 1640 renal cell cancer (RCC), 1300 prostate cancer (PC), and 918 urothelial cancer (UC), containing 2482 tumor tissues and 1376 baseline plasma samples were collected. A total of 14.6% patients (563/3858) harbored at least one FGFR2/3 alterations . 24.1% (221/918) UC carried the most FGFR2/3 alterations , including somatic mutation (18.2%), CNV (5.7%), and fusion (2.1%). Furthermore, the altered FGFRs targets are mainly S249C (6.5%), Y373C (2.5%), FGFR3-TACC3 fusion (1.6%). R248C (1.2%), and G370C (0.5%) in UC. FGFR2/3 alterations were found in 14.0% (182/1300) PC, including somatic mutation (8.2%), CNV (5.8%), and fusion (0.4%). However, only 2 patients were found to have altered FGFRs targets including R248C mutation and FGFR3-TACC3 fusion (n = 1 each). Regarding of RCC, only 9.8% (160/1640) patients had FGFR3 alterations , including somatic mutation (5.8%), CNV (5.0%), and fusion (0.5%). Furthermore, the altered FGFRs targets are mainly R248C, S249C, Y373C (n = 4 each). Moreover, patients with FGFR2/3 alterations harbored a significantly higher TMB than those in patients without FGFR2/3 alterations (Mean: 13.3 vs 9.4; p < 0.001). There was a significant difference in TMB among different cancers with FGFR2/3 alterations , with UC being the highest and PC the lowest (Mean: 17.0 vs 13.0 vs 10.2; p < 0.001). Conclusions: FGFR2/3 alterations are frequently altered in genitourinary cancer, especially UC. Comprehensive genomic profiling of FGFR2/3 alterations highlights the clinical and therapeutic implication.

Clinical utility of plasma ctDNA sequencing in metastatic urothelial carcinoma.

4576 Background: Genomic stratification may help to improve the management of patients with metastatic urothelial cancer (mUC) given the recent identification of targetable molecular alterations in this disease. However, collecting tissue samples in mUC remains challenging. We assessed the clinical utility of plasma circulating tumor DNA (ctDNA) sequencing in mUC. Methods: mUC patients were prospectively enrolled in the STING trial (NCT04932525) whereby ctDNA was profiled using the FoundationOne Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESCAT tier leading to molecular-based treatment suggestions whenever it was possible. Results: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. Median time to assay results was 20 days. ctDNA abundance was correlated with number of prior lines and number of metastatic sites. ctDNA analysis reproduces the somatic genomic landscape reported by previous tissue-based cohorts. Concordance for serial tumor tissue was moderate (r=0.545 CI95: [0.121-0.801], p= 0.016). At least one actionable target was detected in 63 patients (45 %) with a total of 35 actionable alterations including TMB high (≥12 mutations/Mb) (N= 39, 21.1%), FGFR3 (N= 20, 10.8%) and HRD alterations (N= 14, 7.6%). The MTB recommended a matched therapy for 63 patients (45.0%). In total, 8 patients (5.7 %) were treated with an overall response rate of 50% (95%: 15.70-84.30) and a median PFS of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with lower progression-free survival in patients treated with immunotherapy. Conclusions: Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in mUC is a reliable and feasible approach to timely initiate genotype-matched therapies. Clinical trial information: NCT04932525 .

P-137 Phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced cholangiocarcinoma (CCA) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations

P-137 Phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced cholangiocarcinoma (CCA) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations

Are FGFR and IDH1-2 alterations a positive prognostic factor in intrahepatic cholangiocarcinoma? An unresolved issue.

Despite representing some of the most common and investigated molecular changes in intrahepatic cholangiocarcinoma (iCCA), the prognostic role of FGFR and IDH1/2 alterations still remains an open question. In this review we provide a critical analysis of available literature data regarding this topic, underlining the strengths and pitfalls of each study reported. Despite the overall poor quality of current available studies, a general trend toward a better overall survival for FGFR2 rearrangements and, possibly, for FGFR2-3 alterations can be inferred. On the other hand, the positive prognostic role of IDH1/2 mutation seems much more uncertain. In this scenario, better designed clinical trials in these subsets of iCCA patients are needed in order to get definitive conclusions on this issue.

Correlation between fibroblast growth factor receptor mutation, programmed death ligand-1 expression and survival in urinary bladder cancer based on real-world data.

Background: Programmed cell death (PD)-1/PD-ligand 1 (PD-L1) inhibitors have made a breakthrough in the therapy of advanced urothelial bladder cancer (UBC). The impact of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the effectiveness of PD-L1 treatment remains still unclear. Objective: Our study aimed to investigate the frequency of FGFR mutations at different tumor stages, and their relation to PD-L1 status and survival. Methods: 310 patients with urothelial bladder cancer and subsequent radical cystectomy were included in a retrospective study over a 10-year study period at the University of Szeged, Hungary. FGFR3 mutations from the most infiltrative areas of the tumor were analyzed by targeted next-generation sequencing and PD-L1 (28-8 DAKO) tests (tumor positive score -TPS and combined positives score-CPS). In T0 cases FGFR3 mutations were analyzed from the earlier resection samples. Survival and oncological treatment data were collected from the National Health Insurance Fund (NHIF). Neoadjuvant, adjuvant and palliative conventional chemotherapies were allowed; immunotherapies were not. The relationship between the covariates was tested using chi-square tests, and survival analysis was performed using the Kaplan-Meier model and Cox proportional hazards regression. Results: PD-L1 and FGFR could be tested successfully in 215 of the 310 UBC samples [pT0cyst 19 (8.8%); St.0-I 43 (20%); St.II 41 (19%); St.III-IV 112 (52%)]. Significant pairwise dependency was found between tumor stage, FGFR3 mutation status and PD-L1 expression (p < 0.01). Samples with FGFR mutation were more common in less advanced stages and were also less likely to demonstrate PD-L1 expression. The effect of all investigated factors on survival was found to correlate with tumor stage. Conclusion: FGFR alteration frequency varied between the different stages of cancer. Higher positivity rates were observed at early stages, but lower levels of PD-L1 expression were detected in patients with FGFR mutations across at all stages of the disease.

Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a "non-inflamed" tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (p = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the "inflamed" group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (p = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the "non-inflamed" tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA.

Abstract 4867: Effect of FGFR3 activity on Nectin-4 expression in urothelial carcinoma

Abstract Bladder cancer is a common malignancy in the U.S. and cause of significant morbidity and mortality. Combination platinum-based chemotherapy has long been the mainstay in the treatment of metastatic urothelial carcinoma (mUC); however, over the last decade there have been significant advances in systemic therapy, which includes the FDA approval of the pan-FGFR inhibitor erdafitinib (approved for tumors with FGFR2/3 alterations) and the antibody drug conjugate (ADC) enfortumab vedotin (which targets the cell surface protein Nectin-4). Despite these advances, most patients with mUC will progress and succumb from their disease, highlighting the need for further therapeutic development. In parallel to therapeutic advances, there have been significant advances in the molecular characterization of UC, including identification of luminal and basal subsets. NECTIN4 and FGFR3 alterations are known to be enriched in luminal subtypes and we have found, via query of the TCGA data, that NECTIN4 expression was significantly higher in FGFR3 altered tumors. Given this association we sought to investigate the effect of FGFR3 activity on Nectin-4 expression. Using erdafitinib, in select luminal UC cell lines (RT112, RT4, SW780) with FGFR3 fusion proteins, we found, much to our surprise, that FGFR inhibition increased Nectin-4 expression. Western blots, probing for Nectin-4, following 24H, 48H, and 72H of treatment with erdafitinib (50 nM) showed a significant increase in protein expression in all three cell lines. Importantly, we consistently saw increased expression of what we believe corresponds to the membrane bound form of Nectin-4 and have now confirm such by flow cytometry and immunofluorescence probing for Nectin-4 in the RT112 cell line. We have also seen statistically significant increases in NECTIN4 on RT-PCR following treatment with erdafitinib; however, we believe that Nectin-4 regulation by FGFR inhibition is not merely transcriptional because the induction of Nectin-4 protein appears significantly greater than the fold increase in mRNA. Notably, in two additional UC cell lines (HT1376 - a luminal cell line with high Nectin-4 expression &amp; UMUC3 - a basal cell line with low Nectin-4 expression), with no alterations in FGFR3, we did not see a significant change in Nectin-4 expression following treatment with erdafitinib. Based on our above results, we hypothesize that FGFR3 inhibition, in tumors harboring FGFR3 alterations, may act as a sensitize agent to Nectin-4 ADC targeted therapy; however, our results are preliminary and further investigation, particularly with in vivo models, is warranted. Citation Format: Sean Clark-Garvey, Mi Zhou, Andrew Truong, Wolfgang Beckabir, Michael Sturdivant, William Kim. Effect of FGFR3 activity on Nectin-4 expression in urothelial carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4867.

Abstract 3395: Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer

Abstract Objectives: Here we describe the durable clinical outcomes of four FGFR2 fusion positive pancreatic cancer patients treated with FGFR inhibitors as well as a pancreatic specific analysis of FGFR alterations through our collaboration with Foundation Medicine, Inc. (FMI). Methods: We identified four patients with FGFR2 fusion positive metastatic pancreatic cancer through tumor RNAseq (OSU-SpARKFuse) which identifies gene fusions from cell free DNA (cfDNA). We assessed two tumor markers (Ca19-9 and FGFRDx, an FGFR-focused cell free DNA liquid biopsy assay) and various clinical outcomes (Best overall response, duration, and side effects to their treatments). Additionally, 10,146 tumor-tissue clinical cases of pancreatic cancers were assayed by hybrid-capture based comprehensive genomic profiling (Foundation Medicine, Inc.) to identify genomic alterations in &amp;gt;300 cancer-associated genes, MSI, and tumor mutation burden (TMB). Results: All four patients demonstrated durable clinical responses to various FGFR inhibitors. Patient 1 harbored an FGFR2-USP33 fusion and exhibited a partial response to pemigatinib for 25 months following progression on gemcitabine/abraxane and FOLFIRI chemotherapy. Patient 2 harbored an FGFR2-INA fusion with 12 months of stable disease to pazopanib after experiencing progression from chemotherapy. Patient 3 harbored an FGFR2-INA fusion and exhibited a 12+ month on-going, partial response to pemigatinib. Patient 4 harbored an FGFR2-CEP55 fusion and demonstrated stable disease on ponatinib for 15 months, a 24-month response to gemcitabine/platinum chemotherapy, and a 7+ month on-going partial response to infigratinib. Through the genomic profiling of 10,146 tumor-tissue clinical cases of pancreatic cancer, we identified 108 FGFR fusions resulting in a prevalence of 1%. We are currently investigating co-occurring and mutually-exclusive genomic alterations, including TMB and MSI-H status, for pancreatic cancer patients harboring FGFR alterations. Conclusions: This retrospective analysis provides clinical evidence that there is a subpopulation of KRAS wild-type FGFR2 fusion positive pancreatic patients who can have beneficial and lasting responses to FGFR inhibitors further suggesting a need to investigate and expand the availability of FGFR inhibitors to more cancer types. Citation Format: Leah Stein, Julie W. Reeser, Michele R. Wing, Karthikeyan Murugesan, Anoosha Paruchuri, Zachary Risch, Eric Samorodnitsky, Emily L. Hoskins, Amy Smith, Thuy Dao, Melissa Babcook, Muhammad Imam, Aharon Freud, Sameek Roychowdhury. Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3395.

Abstract 1439: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations

Abstract Fibroblast growth factor receptor (FGFR) mutations, fusions, and rearrangements have been linked to the pathogenesis of multiple tumor types. FGFR2 alterations have emerged as oncogenic drivers across a variety of tumor types, including cholangiocarcinoma, lung, endometrial, and uterine cancer. Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations. In addition, pan-FGFR inhibitors are associated with dose-limiting hyperphosphatemia linked to the inhibition of FGFR1. To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 and the broader kinome could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors. Additionally, maintaining potency against molecular brake and gatekeeper mutations may result in significantly improved clinical response. In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and pharmacodynamics (PD) in tumor bearing mice. Most importantly, efficacy in a mouse tumor xenograft model at a dose that does not show elevated plasma phosphorus levels in the rat hyperphosphatemia model will be presented. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described. Citation Format: John Fischer, Karyn Bouhana, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, YeYun Zhou. In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1439.

Abstract 4528: Evaluation of plasma circulating tumor DNA (ctDNA)-based whole genome sequencing (pWGS) and whole exome sequencing (pWES) and concordance with tumor tissue whole exome sequencing (tWES): a pilot study in patients with recurrent or metastatic head and neck squamous cell carcinoma or metastatic urothelial carcinoma

Abstract Background: The genetic heterogeneity and clonal evolution of tumors is hypothesized to influence disease response and acquisition of resistance during treatment. However, comprehensive analysis of the changing tumor molecular landscape to support evaluation of such a hypothesis is often difficult to quantify due to the lack of accessibility to longitudinal biopsy samples in a large number of patients (pts). Longitudinal analyses using pWGS or pWES may allow the delineation of the genetic evolution of tumors and its impact on treatment outcomes. We conducted a pilot study to evaluate the feasibility of obtaining pWGS and pWES data from ctDNA in pretreatment samples from pts enrolled in 2 phase 3 trials that evaluated second-line pembrolizumab versus chemotherapy/standard-of-care therapy: KEYNOTE-040 (recurrent or metastatic head and neck squamous cell carcinoma; NCT02252042) and KEYNOTE-045 (metastatic urothelial carcinoma, NCT02256436). Concordance between pWES and tWES was also evaluated. Methods: Cell-free DNA was isolated from 1-3 mL of plasma; pWGS (via low-pass WGS) and pWES were performed on samples from pts with available tWES data generated as part of planned tissue biomarker analyses for the respective studies. Tumor burden in ctDNA was estimated from pWES data using single nucleotide variant (SNV)-based maximum somatic allele frequency (MSAF) and from pWGS data using a copy number variation-based measure of mutational burden in the tumor fraction. Concordance between the pWES and tWES mutational spectrum was determined using the Jaccard index. Concordance of key driver somatic events (FGFR3, TP53, and HPV status) was evaluated. Results: Plasma samples from 47 pts (KEYNOTE-040, n = 24; KEYNOTE-045, n = 23) were analyzed. Tumor burden estimates from pWGS (median coverage, 5.84; range, 4.28-8.18) and pWES (median coverage, 1806; range, 1038-2413) data were highly correlated (Spearman ρ = 0.94). A range of 0 to 956 nonsynonymous SNVs (median, 50) per pt was identified in ctDNA. When the ctDNA tumor burden was high (MSAF ≥5%, observed in two-thirds of pts), a relatively high concordance was observed for individual alterations in TP53, FGFR3, and HPV status (overall agreement: 0.87, 0.97, and 0.96, respectively); between tissue- and plasma-based tumor mutational burden (R = 0.49); and in overall mutational landscape overlap (Jaccard index: median, 0.30; range, 0.002-0.53). Conclusions: These data show that pWES exhibits reasonably high concordance with tWES when the tumor burden in ctDNA is relatively high and may be informative regarding tumor genomic characteristics. Extensive longitudinal studies are still needed to understand tumor genetic evolution using plasma ctDNA. Citation Format: Razvan Cristescu, Andrew Albright, Steven Townson, Cai Chen, Blanca Homet Moreno, Nati Lerman, Z. Alexander Cao, Carol Peña. Evaluation of plasma circulating tumor DNA (ctDNA)-based whole genome sequencing (pWGS) and whole exome sequencing (pWES) and concordance with tumor tissue whole exome sequencing (tWES): a pilot study in patients with recurrent or metastatic head and neck squamous cell carcinoma or metastatic urothelial carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4528.

Abstract 2127: TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation

Abstract Introduction: Bacillus Calmette-Guérin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) following transurethral resection. However, patients often have heterogeneous responses. Even among those who initially respond well to BCG, 10-20% relapse. Identification of reliable biomarkers predicting the efficacy of BCG remains an unmet need. En bloc resection is a novel technique representing a substantial advancement in the surgical management of NMIBC. We sought to investigate genomic and tumor microenvironmental (TME) profiles in NMIBC and explore potential predictive markers for BCG treatment following en-block resection. Methods: A total of 40 patients with high-risk NMIBC (cTis-T1N0M0) were retrospectively enrolled who underwent en bloc resection followed by BCG instillation. Surgical samples were subjected to NGS sequencing using a 520-gene panel (Burning Rock Biotech, Guangzhou) and multiplex immunofluorescence (mIF) assay. Results: The cohort had a median age of 63 years, and 80% were male. After a median follow-up of 21.8 months, 19/40 patients relapsed with a one-year relapse-free survival (RFS) rate of 57.5%. All tumors were microsatellite stable and showed a median TMB of 7.98muts/Mb. Genomic profiling revealed a high prevalence of alterations in TERT (55%), KDM6A (32.5%), KMT2D (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%), KMT2C (25%), and ARID1A (20%). TME analysis showed higher proportions of M1 macrophages and CD56 dim NK cells in the tumoral compartment and more intense infiltration of CD8+ T cells, exhausted CD8+T, CD56 bright NK cells, and M2 macrophages in the stromal compartment. Multivariate analysis identified TERT C228T mutation (HR=3.28 [95%CI:1.225-8.79], p=0.0181) and alteration in KDM6A (HR=2.94 [95%CI:1.040-8.29], p=0.042) as two independent factors associated with inferior RFS. Patients with concomitant TERT C228T and KDM6A alteration had the shortest RFS (median RFS:5.83months) compared with those who were free of (median RFS: NR) or harbored either one of the two alterations (median RFS:9.13months) (p=0.0022). We also found that tumoral infiltration of CD8+T cells was positively associated with RFS (HR=0.29 [95%CI:0.097-0.885], p=0.0208). Conclusion: The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. Our findings may facilitate the stratification of patients and better guide the clinical decision-making on the management of NMIBC. Citation Format: Qi-Dong Xia, Yao-Bing Chen, Jian-Xuan Sun, Chen-Qian Liu, Jin-Zhou Xu, Zhi-Peng Yao, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Lin Shao, Si-Qi Li, Zheng Liu, Shao-Gang Wang. TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2127.

Abstract 2634: AMB302/GR1017, an antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor shows therapeutic potency in orthotopic glioblastoma PDX and bladder cancer models with FGFR3-TACC3 fusion

Abstract Background: FGFR3-TACC3 (F3-T3) fusion leads to FGFR3 kinase activation constitutively and acts as a driver mutation in several solid tumors. AMB302/GR1017 is a novel FGFR3 targeting ADC that was developed using the intelligent Ligase-Dependent Conjugation (iLDC) technologies from GeneQuantum (GQ) that provide high homogeneity, excellent druggability and high linker stability, and contains a topoisomerase 1 inhibitor as a payload. Based on the preclinical characterization, AMB302/GR1017 shows impressive anti-tumor activities against glioblastoma (GBM) and bladder cancer (BC) models with either FGFR3 amplification or F3-T3 fusion, and demonstrates the potential as a first-in-class FGFR3 ADC against FGFR3 active solid tumor indications. Methods: in vitro anti-tumor effects and mechanism of action for AMB302/GR1017 were assessed on patients-derived cells with F3-T3 using a 3D-spheroid high throughput assay. in vivo anti-tumor effect of AMB302/GR1017 were assessed on F3-T3 fusion GBM orthotopic PDX model and several FGFR3+ or F3-T3 fusion BC models Results: AMB302/GR1017 was generated by linking FGFR3 targeting antibody (AimedBio) with TopoIx (GQ), a next generation Topoisomerase 1 inhibitor via a cleavable linker using the iLDC technologies. In a 3D-spheroid high throughput assay system, AMB302/GR1017 showed significant anti-tumor activity against glioblastoma patients-derived cells (PDCs) in F3-T3 dependent manner, which is superior to chemical conjugate applying the same antibody and Dxd payload. Also, AMB302/GR1017 prolonged the survival of GBM orthotopic PDX models with F3-T3 fusion by 200 % and achieved complete tumor regression in RT112 BC model with F3-T3 fusion. AMB302/GR1017 treatments were well-tolerated up to 200 mg/kg in a mouse safety study. Conclusion: AMB302/GR1017 showed robust anti-tumor efficacies in F3-T3 fusion and FGFR3 overexpression models derived from GBM and BC in vitro and in vivo. In addition, AMB302/GR1017 was well tolerated with no adverse effects in rodent model. Our data suggest AMB302/GR1017 has a potential therapeutic option as a first-in-class FGFR3 targeting ADC for GBM, BC, and other solid tumors with FGFR3 overexpression or alterations. Citation Format: Byeongkwi Min, Lily Shi, Hye Jin Kim, Sangwoo Kim, Beibei Fan, Cao Lv, Yajun Sun, Nam-Gu Her, Paul Song, Gang Qin, Do-Hyun Nam. AMB302/GR1017, an antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor shows therapeutic potency in orthotopic glioblastoma PDX and bladder cancer models with FGFR3-TACC3 fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2634.