bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
Authors: Ryan Meagan B. , Fece de la Cruz Ferran , Phat Sarah , Myers David T. , Wong Edmond , Shahzade Heather A. , Hong Catriona B. , Corcoran Ryan B.
Published: April 2023

AbstractPurpose:
Although KRAS represents the most commonly mutated oncogene, it has long been considered an “undruggable” target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance.
Experimental Design:
A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRASG12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy.
Results:
We observed rapid adaptive RAS pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRASG12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo.
Conclusions:
These data identify feedback reactivation of wild-type RAS as a key mechanism of adaptive resistance to KRASG12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRASG12C inhibitors.

See related commentary by Yaeger and Solit, p. 1538
Data from Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma
Authors: Tannir Nizar M. , Signoretti Sabina , Choueiri Toni K. , McDermott David F. , Motzer Robert J. , Flaifel Abdallah , Pignon Jean-Christophe , Ficial Miriam , Frontera Osvaldo Arén , George Saby , Powles Thomas , Donskov Frede , Harrison Michael R. , Barthélémy Philippe , Tykodi Scott S. , Kocsis Judit , Ravaud Alain , Rodriguez-Cid Jeronimo R. , Pal Sumanta K. , Murad Andre M. , Ishii Yuko , Saggi Shruti Shally , McHenry M. Brent , Rini Brian I.
Published: April 2023

AbstractPurpose:
Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC.
Patients and Methods:
Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.
Results:
Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.
Conclusions:
NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.

See related commentary by Hwang et al., p. 5
Data from Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study
Authors: Rivas-Delgado Alfredo , Nadeu Ferran , Enjuanes Anna , Casanueva-Eliceiry Sebastián , Mozas Pablo , Magnano Laura , Castrejón de Anta Natalia , Rovira Jordina , Dlouhy Ivan , Martín Silvia , Osuna Miguel , Rodríguez Sonia , Simó Marc , Pinyol Magda , Baumann Tycho , Beà Silvia , Balagué Olga , Delgado Julio , Villamor Neus , Setoain Xavier , Campo Elías , Giné Eva , López-Guillermo Armando
Published: April 2023

AbstractPurpose:
We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL).
Experimental Design:
A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available.
Results:
Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2–78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and β2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; P < 0.004), shorter progression-free survival (65% vs. 85%; P = 0.038), and overall survival (73% vs. 100%; P = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses.
Conclusions:
In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.
Data from Development of a Histopathology Informatics Pipeline for Classification and Prediction of Clinical Outcomes in Subtypes of Renal Cell Carcinoma
Authors: Marostica Eliana , Barber Rebecca , Denize Thomas , Kohane Isaac S. , Signoretti Sabina , Golden Jeffrey A. , Yu Kun-Hsing
Published: April 2023

AbstractPurpose:
Histopathology evaluation is the gold standard for diagnosing clear cell (ccRCC), papillary, and chromophobe renal cell carcinoma (RCC). However, interrater variability has been reported, and the whole-slide histopathology images likely contain underutilized biological signals predictive of genomic profiles.
Experimental Design:
To address this knowledge gap, we obtained whole-slide histopathology images and demographic, genomic, and clinical data from The Cancer Genome Atlas, the Clinical Proteomic Tumor Analysis Consortium, and Brigham and Women's Hospital (Boston, MA) to develop computational methods for integrating data analyses. Leveraging these large and diverse datasets, we developed fully automated convolutional neural networks to diagnose renal cancers and connect quantitative pathology patterns with patients' genomic profiles and prognoses.
Results:
Our deep convolutional neural networks successfully detected malignancy (AUC in the independent validation cohort: 0.964–0.985), diagnosed RCC histologic subtypes (independent validation AUCs of the best models: 0.953–0.993), and predicted stage I ccRCC patients' survival outcomes (log-rank test P = 0.02). Our machine learning approaches further identified histopathology image features indicative of copy-number alterations (AUC > 0.7 in multiple genes in patients with ccRCC) and tumor mutation burden.
Conclusions:
Our results suggest that convolutional neural networks can extract histologic signals predictive of patients' diagnoses, prognoses, and genomic variations of clinical importance. Our approaches can systematically identify previously unknown relations among diverse data modalities.
Data from Computationally Derived Image Signature of Stromal Morphology Is Prognostic of Prostate Cancer Recurrence Following Prostatectomy in African American Patients
Authors: Bhargava Hersh K. , Leo Patrick , Elliott Robin , Janowczyk Andrew , Whitney Jon , Gupta Sanjay , Fu Pingfu , Yamoah Kosj , Khani Francesca , Robinson Brian D. , Rebbeck Timothy R. , Feldman Michael , Lal Priti , Madabhushi Anant
Published: April 2023

AbstractPurpose:
Between 30%–40% of patients with prostate cancer experience disease recurrence following radical prostatectomy. Existing clinical models for recurrence risk prediction do not account for population-based variation in the tumor phenotype, despite recent evidence suggesting the presence of a unique, more aggressive prostate cancer phenotype in African American (AA) patients. We investigated the capacity of digitally measured, population-specific phenotypes of the intratumoral stroma to create improved models for prediction of recurrence following radical prostatectomy.
Experimental Design:
This study included 334 radical prostatectomy patients subdivided into training (VT, n = 127), validation 1 (V1, n = 62), and validation 2 (V2, n = 145). Hematoxylin and eosin–stained slides from resected prostates were digitized, and 242 quantitative descriptors of the intratumoral stroma were calculated using a computational algorithm. Machine learning and elastic net Cox regression models were constructed using VT to predict biochemical recurrence-free survival based on these features. Performance of these models was assessed using V1 and V2, both overall and in population-specific cohorts.
Results:
An AA-specific, automated stromal signature, AAstro, was prognostic of recurrence risk in both independent validation datasets [V1,AA: AUC = 0.87, HR = 4.71 (95% confidence interval (CI), 1.65–13.4), P = 0.003; V2,AA: AUC = 0.77, HR = 5.7 (95% CI, 1.48–21.90), P = 0.01]. AAstro outperformed clinical standard Kattan and CAPRA-S nomograms, and the underlying stromal descriptors were strongly associated with IHC measurements of specific tumor biomarker expression levels.
Conclusions:
Our results suggest that considering population-specific information and stromal morphology has the potential to substantially improve accuracy of prognosis and risk stratification in AA patients with prostate cancer.
Data from Altered Gemcitabine and Nab-paclitaxel Scheduling Improves Therapeutic Efficacy Compared with Standard Concurrent Treatment in Preclinical Models of Pancreatic Cancer
Authors: Wolfe Adam R. , Robb Ryan , Hegazi Ahmad , Abushahin Laith , Yang Linlin , Shyu Duan-Liang , Trevino Jose G. , Cruz-Monserrate Zobeida , Jacob John R. , Palanichamy Kamalakannan , Chakravarti Arnab , Williams Terence M.
Published: April 2023

AbstractPurpose:
Concurrent gemcitabine and nab-paclitaxel treatment is one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). Previous studies demonstrate that caveolin-1 (Cav-1) expression is critical for nab-paclitaxel uptake into tumors and correlates with response. Gemcitabine increases nab-paclitaxel uptake by increasing Cav-1 expression. Thus, we hypothesized that pretreatment with gemcitabine would further enhance the sensitivity of PDAC to nab-paclitaxel by increasing Cav-1 expression and nab-paclitaxel uptake.
Experimental Design:
We investigated the sensitivity of different gemcitabine and nab-paclitaxel treatment regimens in a panel of PDAC cell lines and orthotopic xenograft models. The sensitivity of different treatment regimens was compared with the standard concurrent treatment.
Results:
Pretreatment with gemcitabine before nab-paclitaxel increased Cav-1 and albumin uptake and significantly decreased proliferation and clonogenicity compared with concurrent treatment, which correlated with increased levels of apoptosis. Cav-1 silencing reduced the uptake of albumin, and therapeutic advantage was observed when cells were pretreated with gemcitabine prior to nab-paclitaxel. In addition, we observed that pretreatment with gemcitabine resulted in partial synchronization of cells in the G2–M-phase at the time of nab-paclitaxel treatment, providing another mechanism for the benefit of altered scheduling. In heterotopic and orthotopic xenograft models, the altered schedule of gemcitabine prior to nab-paclitaxel significantly delayed tumor growth compared with concurrent delivery without added toxicity.
Conclusions:
Pretreatment with gemcitabine significantly increased nab-paclitaxel uptake and correlated with an increased treatment efficacy and survival benefit in preclinical models, compared with standard concurrent treatment. These results justify preclinical and clinical testing of this altered scheduling combination.
Data from Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86)
Authors: Dhani Neesha C. , Hirte Hal W. , Wang Lisa , Burnier Julia V. , Jain Angela , Butler Marcus O. , Welch Stephen , Fleming Gini F. , Hurteau Jean , Matsuo Koji , Matei Daniela , Jimenez Waldo , Johnston Carolyn , Cristea Mihaela , Tonkin Katia , Ghatage Prafull , Lheureux Stephanie , Mehta Anjali , Quintos Judy , Tan Qian , Kamel-Reid Suzanne , Ludkovski Olga , Tsao Ming-Sound , Wright John J. , Oza Amit M.
Published: April 2023

AbstractPurpose:
The relevance of the MET/hepatocyte growth factor pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease.
Patients and Methods:
PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib (60 mg once daily) in women with endometrial cancer with progression after chemotherapy. Coprimary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg, carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort.
Results:
A total of 102 patients were accrued. Among 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67%, and median PFS was 4.8 months. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56%, and median PFS was 4.0 months. In a separate cohort of 32 patients with uncommon histology endometrial cancer (including carcinosarcoma), response rate was 6% and 12-week PFS was 47%. Six patients were on treatment for >12 months, including two for >30 months. Common cabozantinib-related toxicities (>30% patients) included hypertension, fatigue, diarrhea, nausea, and hand–foot syndrome. Gastrointestinal fistula/perforation occurred in four of 70 (6%) patients with serous/endometrioid cancer and five of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic CTNNB1 mutation [four partial responses (PRs) in 10 patients, median PFS 7.6 months] and concurrent KRAS and PTEN/PIK3CA mutations (three PRs in 12 patients, median PFS 5.9 months).
Conclusions:
Cabozantinib has activity in serous and endometrioid histology endometrial cancer. These results support further evaluation in genomically characterized patient cohorts.
Data from The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer
Authors: Schoenfeld Adam J. , Bandlamudi Chai , Lavery Jessica A. , Montecalvo Joseph , Namakydoust Azadeh , Rizvi Hira , Egger Jacklynn , Concepcion Carla P. , Paul Sonal , Arcila Maria E. , Daneshbod Yahya , Chang Jason , Sauter Jennifer L. , Beras Amanda , Ladanyi Marc , Jacks Tyler , Rudin Charles M. , Taylor Barry S. , Donoghue Mark T.A. , Heller Glenn , Hellmann Matthew D. , Rekhtman Natasha , Riely Gregory J.
Published: April 2023

AbstractPurpose:
SMARCA4 mutations are among the most common recurrent alterations in non–small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established.
Experimental Design:
To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering.
Results:
In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with class 1 mutations having the best response to ICIs (P = 0.027).
Conclusions:
SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.
Data from CamGFR v2: A New Model for Estimating the Glomerular Filtration Rate from Standardized or Non-standardized Creatinine in Patients with Cancer
Authors: Williams Edward H. , Flint Thomas R. , Connell Claire M. , Giglio Daniel , Lee Hassal , Ha Taehoon , Gablenz Eva , Bird Nicholas J. , Weaver James M.J. , Potts Harry , Whitley Cameron T. , Bookman Michael A. , Lynch Andy G. , Meyer Hannah V. , Tavaré Simon , Janowitz Tobias
Published: April 2023

AbstractPurpose:
Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS–standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods.
Experimental Design:
GFR measurements, biometrics, and IDMS- or non-IDMS–standardized creatinine values were collected for adult patients from three cancer centers. Using statistical modeling, an IDMS and non-IDMS creatinine-compatible eGFR model (CamGFR v2) was developed. Its performance was compared with that of the existing models Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund–Malmö revised, and CamGFR v1, using statistics for bias, precision, accuracy, and clinical robustness.
Results:
A total of 3,083 IDMS- and 4,612 non-IDMS–standardized creatinine measurements were obtained from 7,240 patients. IDMS-standardized creatinine values were lower than non-IDMS–standardized values in within-center comparisons (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in Manchester; P < 0.0001), and more consistent between centers. CamGFR v2 was the most accurate [root-mean-squared error for IDMS, 14.97 mL/minute (95% confidence interval, 13.84–16.13) and non-IDMS, 15.74 mL/minute (14.86–16.63)], most clinically robust [proportion with >20% error of calculated carboplatin dose for IDMS, 0.12 (0.09–0.14) and non-IDMS, 0.17 (0.15–0.2)], and least biased [median residual for IDMS, 0.73 mL/minute (−0.68 to 2.2) and non-IDMS, −0.43 mL/minute (−1.48 to 0.91)] eGFR model, particularly when eGFR was larger than 60 ml/minute.
Conclusions:
CamGFR v2 can utilize IDMS- and non-IDMS–standardized creatinine measurements and outperforms previous models. CamGFR v2 should be examined prospectively as a practice-changing standard of care for eGFR-based carboplatin dosing.
Data from Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction
Authors: Kobatake Kohei , Ikeda Ken-ichiro , Nakata Yuichiro , Yamasaki Norimasa , Ueda Takeshi , Kanai Akinori , Sentani Kazuhiro , Sera Yasuyuki , Hayashi Tetsutaro , Koizumi Miho , Miyakawa Yoshihiko , Inaba Toshiya , Sotomaru Yusuke , Kaminuma Osamu , Ichinohe Tatsuo , Honda Zen-ichiro , Yasui Wataru , Horie Shigeo , Black Peter C. , Matsubara Akio , Honda Hiroaki
Published: April 2023

AbstractPurpose:
Epigenetic deregulation is deeply implicated in the pathogenesis of bladder cancer. KDM6A (Lysine (K)-specific demethylase 6A) is a histone modifier frequently mutated in bladder cancer. However, the molecular mechanisms of how KDM6A deficiency contributes to bladder cancer development remains largely unknown. We hypothesized that clarification of the pathogenic mechanisms underlying KDM6A-mutated bladder cancer can help in designing new anticancer therapies.
Experimental Design:
We generated mice lacking Kdm6a in the urothelium and crossed them with mice heterozygous for p53, whose mutation/deletion significantly overlaps with the KDM6A mutation in muscle-invasive bladder cancer (MIBC). In addition, BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine), a cigarette smoke-like mutagen, was used as a tumor-promoting agent. Isolated urothelia were subjected to phenotypic, pathologic, molecular, and cellular analyses. The clinical relevance of our findings was further analyzed using genomic and clinical data of patients with MIBC.
Results:
We found that Kdm6a deficiency activated cytokine and chemokine pathways, promoted M2 macrophage polarization, increased cancer stem cells and caused bladder cancer in cooperation with p53 haploinsufficiency. We also found that BBN treatment significantly enhanced the expression of proinflammatory molecules and accelerated disease development. Human bladder cancer samples with decreased KDM6A expression also showed activated proinflammatory pathways. Notably, dual inhibition of IL6 and chemokine (C-C motif) ligand 2, upregulated in response to Kdm6a deficiency, efficiently suppressed Kdm6a-deficient bladder cancer cell growth.
Conclusions:
Our findings provide insights into multistep carcinogenic processes of bladder cancer and suggest molecular targeted therapeutic approaches for patients with bladder cancer with KDM6A dysfunction.
Data from Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial
Authors: Montfort Anne , Filleron Thomas , Virazels Mathieu , Dufau Carine , Milhès Jean , Pagès Cécile , Olivier Pascale , Ayyoub Maha , Mounier Muriel , Lusque Amélie , Brayer Stéphanie , Delord Jean-Pierre , Andrieu-Abadie Nathalie , Levade Thierry , Colacios Céline , Ségui Bruno , Meyer Nicolas
Published: April 2023

AbstractPurpose:
TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors.
Patients and Methods:
TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1.
Results:
Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts.
Conclusions:
Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.
Data from ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non–Small Cell Lung Cancer
Authors: Okura Naoko , Nishioka Naoya , Yamada Tadaaki , Taniguchi Hirokazu , Tanimura Keiko , Katayama Yuki , Yoshimura Akihiro , Watanabe Satoshi , Kikuchi Toshiaki , Shiotsu Shinsuke , Kitazaki Takeshi , Nishiyama Akihiro , Iwasaku Masahiro , Kaneko Yoshiko , Uchino Junji , Uehara Hisanori , Horinaka Mano , Sakai Toshiyuki , Tanaka Kohei , Kozaki Ryohei , Yano Seiji , Takayama Koichi
Published: April 2023

AbstractPurpose:
Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non–small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475.
Experimental Design:
We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs.
Results:
ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI–tolerant cells. In the cell line–derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib.
Conclusions:
These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.
Data from An Fc-free EGFR-specific 4-1BB-agonistic Trimerbody Displays Broad Antitumor Activity in Humanized Murine Cancer Models without Toxicity
Authors: Compte Marta , Harwood Seandean L. , Erce-Llamazares Ainhoa , Tapia-Galisteo Antonio , Romero Eduardo , Ferrer Irene , Garrido-Martin Eva M. , Enguita Ana B. , Ochoa Maria C. , Blanco Belén , Oteo Marta , Merino Nekane , Nehme-Álvarez Daniel , Hangiu Oana , Domínguez-Alonso Carmen , Zonca Manuela , Ramírez-Fernández Angel , Blanco Francisco J. , Morcillo Miguel A. , Muñoz Ines G. , Melero Ignacio , Rodriguez-Peralto José L. , Paz-Ares Luis , Sanz Laura , Alvarez-Vallina Luis
Published: April 2023

AbstractPurpose:
The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell–mediated antitumor response. Systemic administration of anti-4-1BB–agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.
Experimental Design:
Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo.
Results:
In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non–small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer.
Conclusions:
These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.
Data from Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer
Authors: Collins Denis M. , Madden Stephen F. , Gaynor Nicola , AlSultan Dalal , Le Gal Marion , Eustace Alex J. , Gately Kathy A. , Hughes Clare , Davies Anthony M. , Mahgoub Thamir , Ballot Jo , Toomey Sinead , O'Connor Darran P. , Gallagher William M. , Holmes Frankie A. , Espina Virginia , Liotta Lance , Hennessy Bryan T. , O'Byrne Kenneth J. , Hasmann Max , Bossenmaier Birgit , O'Donovan Norma , Crown John
Published: April 2023

AbstractPurpose:
Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC.
Experimental Design:
Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array–determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry–based protocols.
Results:
Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell–mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone.
Conclusions:
TKIs differentially alter tumor cell phenotype which can impact NK cell–mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.
Data from A Phase II Trial of 5-Day Neoadjuvant Radiotherapy for Patients with High-Risk Primary Soft Tissue Sarcoma
Authors: Kalbasi Anusha , Kamrava Mitchell , Chu Fang-I , Telesca Donatello , Van Dams Ritchell , Yang Yingli , Ruan Dan , Nelson Scott D. , Dry Sarah M. , Hernandez Jackie , Chmielowski Bartosz , Singh Arun S. , Bukata Susan V. , Bernthal Nicholas M. , Steinberg Michael L. , Weidhaas Joanne B. , Eilber Fritz C.
Published: April 2023

AbstractPurpose:
In a single-institution phase II study, we evaluated the safety of a 5-day dose-equivalent neoadjuvant radiotherapy (RT) regimen for high-risk primary soft tissue sarcoma.
Patients and Methods:
Patients received neoadjuvant RT alone (30 Gy in five fractions) to the primary tumor with standard margins. The primary endpoint was grade ≥2 late-radiation toxicity. Major wound complications, local recurrences, and distant metastases were also examined. In exploratory analysis, we evaluated germline biomarkers for wound toxicity and the effects of the study on treatment utilization.
Results:
Over 2 years, 52 patients were enrolled with median follow-up of 29 months. Seven of 44 evaluable patients (16%) developed grade ≥2 late toxicity. Major wound complications occurred in 16 of 50 patients (32%); a signature defined by 19 germline SNPs in miRNA-binding sites of immune and DNA damage response genes, in addition to lower extremity tumor location, demonstrated strong predictive performance for major wound complications. Compared with the preceding 2-year period, the number of patients treated with neoadjuvant RT alone at our institution increased 3-fold, with a concomitant increase in the catchment area.
Conclusions:
A shorter 5-day neoadjuvant RT regimen results in favorable rates of wound complications and grade ≥2 toxicity after 2-year follow-up. Five-day RT significantly increased utilization of neoadjuvant RT at our high-volume sarcoma center. With further validation, a putative germline biomarker for wound complications may guide safer RT utilization.
Data from Response to Standard Therapies and Comprehensive Genomic Analysis for Patients with Lung Adenocarcinoma with EGFR Exon 20 Insertions
Authors: Choudhury Noura J. , Schoenfeld Adam J. , Flynn Jessica , Falcon Christina J. , Rizvi Hira , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Heller Glenn , Yu Helena A. , Ladanyi Marc , Riely Gregory J.
Published: April 2023

AbstractPurpose:
EGFR exon 20 insertions (ex20ins) are an uncommon genotype in non–small cell lung cancer (NSCLC) for which targeted therapies are under development. We sought to describe treatment outcomes and genomic and immunophenotypic characteristics of these tumors.
Experimental Design:
We identified sequential patients with NSCLC with EGFR ex20ins and compared their clinical outcomes and pathologic features with other patients with NSCLC.
Results:
Among 6,290 patients with NSCLC, 106 (2%) had EGFR ex20ins. Patients with EGFR ex20ins were more likely to be Black (14% vs. 6%; P < 0.001) or Asian (22% vs. 10%; P < 0.001) compared with all other patients with NSCLC. Median tumor mutational burden (TMB; 3.5 vs. 5.9; P < 0.001) and proportion of tumors with PD-L1 expression ≥1% (22% vs. 60%; P < 0.001) were lower in EGFR ex20ins compared with other NSCLCs (TMB, n = 5,851 and PD-L1 expression, n = 282) and EGFR del 19/L858R (median TMB, 3.5; P = 0.001 and 39% PD-L1 ≥ 1%; P = 0.02). Compared with a 2:1 cohort of patients with metastatic NSCLC without targetable alterations (n = 192), EGFR ex20ins patients had longer overall survival (median 20 vs. 12 months; HR, 0.56; P = 0.007) and longer time to treatment discontinuation (TTD) for platinum chemotherapy (median, 7 vs. 4 months; HR, 0.6; P = 0.02) and no improvement in TTD for immune checkpoint inhibitors (ICI; HR, 1.75; P = 0.05).
Conclusions:
With better outcomes on platinum chemotherapy, patients with EGFR ex20ins NSCLC have improved prognosis, lower PD-L1 expression and TMB, and derive less benefit from ICIs compared with patients with NSCLC without targetable oncogenes. Improving molecularly targeted therapies could provide greater benefit for patients with EGFR ex20ins.
Data from Neoadjuvant Chemoradiotherapy Combined with Atezolizumab for Resectable Esophageal Adenocarcinoma: A Single-arm Phase II Feasibility Trial (PERFECT)
Authors: van den Ende Tom , de Clercq Nicolien C. , van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Geijsen E.D. , Verhoeven R.H.A. , Meijer Sybren L. , Schokker Sandor , Dings M.P.G. , Bergman Jacques J.G.H.M. , Haj Mohammad Nadia , Ruurda Jelle P. , van Hillegersberg Richard , Mook Stella , Nieuwdorp Max , de Gruijl Tanja D. , Soeratram Tanya T.D. , Ylstra Bauke , van Grieken Nicole C.T. , Bijlsma Maarten F. , Hulshof Maarten C.C.M. , van Laarhoven H.W.M.
Published: April 2023

AbstractPurpose:
The CROSS trial established neoadjuvant chemoradiotherapy (nCRT) for patients with resectable esophageal adenocarcinoma (rEAC). In the PERFECT trial, we investigated the feasibility and efficacy of nCRT combined with programmed-death ligand-1 (PD-L1) inhibition for rEAC.
Patients and Methods:
Patients with rEAC received nCRT according to the CROSS regimen combined with five cycles of atezolizumab (1,200 mg). The primary endpoint was the feasibility of administering five cycles of atezolizumab in ≥75% patients. A propensity score–matched nCRT cohort was used to compare pathologic response, overall survival, and progression-free survival. Exploratory biomarker analysis was performed on repeated tumor biopsies.
Results:
We enrolled 40 patients of whom 85% received all cycles of atezolizumab. Immune-related adverse events of any grade were observed in 6 patients. In total, 83% proceeded to surgery. Reasons for not undergoing surgery were progression (n = 4), patient choice (n = 2), and death (n = 1). The pathologic complete response rate was 25% (10/40). No statistically significant difference in response or survival was found between the PERFECT and the nCRT cohort. Baseline expression of an established IFNγ signature was higher in responders compared with nonresponders (P = 0.043). On-treatment nonresponders showed either a high number of cytotoxic lymphocytes (CTL) with a transcriptional signature consistent with expression of immune checkpoints, or a low number of CTLs.
Conclusions:
Combining nCRT with atezolizumab is feasible in patients with rEAC. On the basis of our exploratory biomarker study, future studies are necessary to elucidate the potential of neoadjuvant immunotherapy in patient subgroups.

See related commentary by Catenacci, p. 3269
Data from Designing Evolutionary-based Interception Strategies to Block the Transition from Precursor Phases to Multiple Myeloma
Authors: Maura Francesco , Landgren Ola , Morgan Gareth J.
Published: April 2023

Abstract
The development of next-generation sequencing technology has dramatically improved our understanding of the genetic landscape of multiple myeloma. Several new drivers and recurrent events have been reported and linked to a potential driver role. This complex landscape is enhanced by intraclonal mutational heterogeneity and variability introduced through the dimensions of time and space. The evolutionary history of multiple myeloma is driven by both the accumulation of different genomic drivers and by the activity of different mutational processes active overtime. In this review, we describe how these new findings and sequencing technologies have been progressively allowed to understand and reshape our knowledge of the complexity of multiple myeloma at each of its developmental stages: premalignant, at diagnosis, and in relapsed/refractory states. We discuss how these evolutionary concepts can be utilized in the clinic to alter evolutionary trajectories providing a framework for therapeutic intervention at early-disease stages.
Data from A Performance Comparison of Commonly Used Assays to Detect RET Fusions
Authors: Yang Soo-Ryum , Aypar Umut , Rosen Ezra Y. , Mata Douglas A. , Benayed Ryma , Mullaney Kerry , Jayakumaran Gowtham , Zhang Yanming , Frosina Denise , Drilon Alexander , Ladanyi Marc , Jungbluth Achim A. , Rekhtman Natasha , Hechtman Jaclyn F.
Published: April 2023

AbstractPurpose:
Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced RET fusion–positive lung and thyroid cancer. RET fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.
Experimental Design:
Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a RET structural variant of unknown significance (SVUS) were present. Canonical DNA-level RET fusions and RNA-confirmed RET fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.
Results:
A total of 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic RET fusions. The most common RET fusion–positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were KIF5B (45%), CCDC6 (29.1%), and NCOA4 (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for NCOA4-RET (66.7%, 8/12). A total of 87.5% (7/8) of RET SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: KIF5B sensitivity was highest (100%, 31/31), followed by CCDC6 (88.9%, 16/18) and NCOA4 (50%, 6/12). Specificity of RET IHC was 82% (73/89).
Conclusions:
Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4-RET fusions.
Data from Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers
Authors: Parikh Aparna R. , Mojtahed Amikasra , Schneider Jaime L. , Kanter Katie , Van Seventer Emily E. , Fetter Isobel J. , Thabet Ashraf , Fish Madeleine G. , Teshome Bezaye , Fosbenner Kathryn , Nadres Brandon , Shahzade Heather A. , Allen Jill N. , Blaszkowsky Lawrence S. , Ryan David P. , Giantonio Bruce , Goyal Lipika , Nipp Ryan D. , Roeland Eric , Weekes Colin D. , Wo Jennifer Y. , Zhu Andrew X. , Dias-Santagata Dora , Iafrate A. John , Lennerz Jochen K. , Hong Theodore S. , Siravegna Giulia , Horick Nora , Clark Jeffrey W. , Corcoran Ryan B.
Published: April 2023

AbstractPurpose:
ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer.
Experimental Design:
A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response.
Results:
A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55–7.00; P < 0.0001).
Conclusions:
Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.
Data from ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma
Authors: Myojin Yuta , Kodama Takahiro , Maesaka Kazuki , Motooka Daisuke , Sato Yu , Tanaka Satoshi , Abe Yuichi , Ohkawa Kazuyoshi , Mita Eiji , Hayashi Yoshito , Hikita Hayato , Sakamori Ryotaro , Tatsumi Tomohide , Taguchi Ayumu , Eguchi Hidetoshi , Takehara Tetsuo
Published: April 2023

AbstractPurpose:
Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because of a lack of efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC.
Experimental Design:
We performed genetic screening of HCC driver genes involved in TKI susceptibility using a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated. A biomarker candidate was evaluated in human HCC cell lines. Secreted proteins from HCC cells were then screened using mass spectrometry. Serum and tumor levels of the biomarker candidates were analyzed for their association and prediction of overall survival in patients with HCC.
Results:
We found that lenvatinib selectively eliminated FGF19-expressing tumors, whereas sorafenib eliminated MET- and NRAS-expressing tumors. FGF19 levels and lenvatinib susceptibility were correlated in HCC cell lines, and FGF19 inhibition eliminated lenvatinib susceptibility. Lenvatinib-resistant HCC cell lines, generated by long-term exposure to lenvatinib, showed FGF19 downregulation but were resensitized to lenvatinib by FGF19 reexpression. Thus, FGF19 is a tumor biomarker of lenvatinib-susceptible HCC. Proteome and secretome analyses identified ST6GAL1 as a tumor-derived secreted protein positively regulated by FGF19 in HCC cells. Serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC. Among patients with serum ST6GAL1-high HCC who underwent TKI therapy, lenvatinib therapy showed significantly better survival than sorafenib.
Conclusions:
Serum ST6GAL may be a novel biomarker that identifies lenvatinib-susceptible FGF19-driven HCC.