bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors
Authors: Wick Antje , Bähr Oliver , Schuler Martin , Rohrberg Kristoffer , Chawla Sant P. , Janku Filip , Schiff David , Heinemann Volker , Narita Yoshitaka , Lenz Heinz-Josef , Ikeda Masafumi , Ando Yuichi , Wick Wolfgang , Steinbach Joachim P. , Burger Michael C. , Wenger Katharina , Lassen Ulrik , Sankhala Kamalesh K. , Roggia Cristiana , Genvresse Isabelle , Munhoz Catya , Rentzsch Christine , Reschke Susanne , Langer Simon , Wagner Markus , Kaulfuss Stefan , Cai Charles , Lagkadinou Eleni , Jeffers Michael , Peña Carol , Tabatabai Ghazaleh
Published: April 2023

AbstractPurpose:
BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.
Patients and Methods:
The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors.
Results:
In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.
Conclusions:
BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
Data from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial
Authors: Graillon Thomas , Sanson Marc , Campello Chantal , Idbaih Ahmed , Peyre Matthieu , Peyrière Hadrien , Basset Noémie , Autran Didier , Roche Catherine , Kalamarides Michel , Roche Pierre-Hugues , Fuentes Stéphane , Tabouret Emeline , Barrie Maryline , Cohen Anita , Honoré Stéphane , Boucekine Mohamed , Baumstarck Karine , Figarella-Branger Dominique , Barlier Anne , Dufour Henry , Chinot Olivier Louis
Published: April 2023

AbstractPurpose:
Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.
Patients and Methods:
Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.
Results:
A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003).
Conclusions:
The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.
Data from Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study
Authors: Davids Matthew S. , Kuss Bryone J. , Hillmen Peter , Montillo Marco , Moreno Carol , Essell James , Lamanna Nicole , Nagy Zsolt , Tam Constantine S. , Stilgenbauer Stephan , Ghia Paolo , Delgado Julio , Lustgarten Stephanie , Weaver David T. , Youssoufian Hagop , Jäger Ulrich
Published: April 2023

AbstractPurpose:
In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.
Patients and Methods:
Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.
Results:
As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).
Conclusions:
Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.
Data from Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study
Authors: Petrylak Daniel P. , Loriot Yohann , Shaffer David R. , Braiteh Fadi , Powderly John , Harshman Lauren C. , Conkling Paul , Delord Jean-Pierre , Gordon Michael , Kim Joseph W. , Sarkar Indrani , Yuen Kobe , Kadel Edward E. , Mariathasan Sanjeev , O'Hear Carol , Narayanan Sujata , Fassò Marcella , Carroll Susheela , Powles Thomas
Published: April 2023

AbstractPurpose:
Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.
Patients and Methods:
This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.
Results:
All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.
Conclusions:
Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.
Data from Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer
Authors: Li Yingming , Yang Rendong , Henzler Christine M. , Ho Yeung , Passow Courtney , Auch Benjamin , Carreira Suzanne , Nava Rodrigues Daniel , Bertan Claudia , Hwang Tae Hyun , Quigley David A. , Dang Ha X. , Morrissey Colm , Fraser Michael , Plymate Stephen R. , Maher Christopher A. , Feng Felix Y. , de Bono Johann S. , Dehm Scott M.
Published: April 2023

AbstractPurpose:
Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.
Experimental Design:
We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V).
Results:
AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide.
Conclusions:
AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
Data from PET Imaging of TIGIT Expression on Tumor-Infiltrating Lymphocytes
Authors: Shaffer Travis , Natarajan Arutselvan , Gambhir Sanjiv S.
Published: April 2023

AbstractPurpose:
Therapeutic checkpoint inhibitors on tumor-infiltrating lymphocytes (TIL) are being increasingly utilized in the clinic. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on T and natural killer cells. The TIGIT signaling pathway is an alternative target for checkpoint blockade to current PD-1/CTLA-4 strategies. Elevated TIGIT expression in the tumor microenvironment correlates with better therapeutic responses to anti-TIGIT therapies in preclinical models. Therefore, quantifying TIGIT expression in tumors is necessary for determining whether a patient may respond to anti-TIGIT therapy. PET imaging of TIGIT expression on TILs can therefore aid diagnosis and in monitoring therapeutic responses.
Experimental Design:
Antibody-based TIGIT imaging radiotracers were developed with the PET radionuclides copper-64 (64Cu) and zirconium-89 (89Zr). In vitro characterization of the imaging probes was followed by in vivo evaluation in both xenografts and syngeneic tumor models in mouse.
Results:
Two anti-TIGIT probes were developed and exhibited immunoreactivity of >72%, serum stability of >95%, and specificity for TIGIT with both mouse TIGIT-expressing HeLa cells and ex vivo–activated primary splenocytes. In vivo, the 89Zr-labeled probe demonstrated superior contrast than the 64Cu probe due to 89Zr's longer half-life matching the TIGIT antibody's pharmacokinetics. The 89Zr probe was used to quantify TIGIT expression on TILs in B16 melanoma in immunocompetent mice and confirmed by ex vivo flow cytometry.
Conclusions:
This study develops and validates novel TIGIT-specific 64Cu and 89Zr PET probes for quantifying TIGIT expression on TILs for diagnosis of patient selection for anti-TIGIT therapies.
Data from Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance
Authors: McKay Rana R. , Kwak Lucia , Crowdis Jett P. , Sperger Jamie M. , Zhao Shuang G. , Xie Wanling , Werner Lillian , Lis Rosina T. , Zhang Zhenwei , Wei Xiao X. , Lang Joshua M. , Van Allen Eliezer M. , Bhatt Rupal S. , Yu Evan Y. , Nelson Peter S. , Bubley Glenn J. , Montgomery R. Bruce , Taplin Mary-Ellen
Published: April 2023

AbstractPurpose:
Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.
Patients and Methods:
Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.
Results:
A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression.
Conclusions:
Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.
Data from Evaluating Serum Thymidine Kinase 1 in Patients with Hormone Receptor–Positive Metastatic Breast Cancer Receiving First-line Endocrine Therapy in the SWOG S0226 Trial
Authors: Paoletti Costanza , Barlow William E. , Cobain Erin F. , Bergqvist Mattias , Mehta Rita S. , Gralow Julie R. , Hortobagyi Gabriel N. , Albain Kathy S. , Pusztai Lajos , Sharma Priyanka , Godwin Andrew K. , Thompson Alastair M. , Hayes Daniel F. , Rae James M.
Published: April 2023

AbstractPurpose:
Serum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor–positive MBC treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F).
Patients and Methods:
sTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan–Meier, log-rank tests, and Cox regression.
Results:
BL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43–2.16); P < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; 95% CI (1.91–2.98); P < 0.0001]. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; 95% CI (0.38–0.87); P = 0.0087]. Patients with low sTK1 had no difference in outcomes by therapy (P = 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, 95% CI (1.34–2.17); P < 0.0001, OS HR = 2.51, 95% CI (1.93–3.26); P < 0.0001].
Conclusions:
High sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.
Data from Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair–proficient Metastatic Colorectal Cancer
Authors: Segal Neil H. , Cercek Andrea , Ku Geoffrey , Wu Abraham J. , Rimner Andreas , Khalil Danny N. , Reidy-Lagunes Diane , Cuaron John , Yang T. Jonathan , Weiser Martin R. , Romesser Paul B. , Stadler Zsofia K. , Varghese Anna M. , Ganesh Karuna , Yaeger Rona , Connell Louise C. , Faleck David , Abou-Alfa Ghassan K. , Mcauliffe Kathleen C. , Vaiskauskas Pamela , Solter Mark L. , Ogle Martinique , Adamow Matthew J. , Holland Aliya , Vedantam Pallavi , Wong Phillip , Merghoub Taha , Vakiani Efsevia , Hollmann Travis J. , Juluru Krishna , Chou Joanne F. , Capanu Marinela , Erinjeri Joseph , Solomon Stephen , Yamada Yoshiya , Kemeny Nancy , Crane Christopher H. , Saltz Leonard B.
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.
Patients and Methods:
In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.
Results:
We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.
Conclusions:
This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.
Data from Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma
Authors: Ellingson Benjamin M. , Sampson John , Achrol Achal Singh , Aghi Manish K. , Bankiewicz Krystof , Wang Chencai , Bexon Martin , Brem Steven , Brenner Andrew , Chowdhary Sajeel , Floyd John R. , Han Seunggu , Kesari Santosh , Randazzo Dina , Vogelbaum Michael A. , Vrionis Frank , Zabek Miroslaw , Butowski Nicholas , Coello Melissa , Merchant Nina , Merchant Fahar
Published: April 2023

AbstractPurpose:
The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).
Patients and Methods:
A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.
Results:
A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007).
Conclusions:
No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
Data from Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer
Authors: Petroni Giulia , Buqué Aitziber , Yamazaki Takahiro , Bloy Norma , Liberto Maurizio Di , Chen-Kiang Selina , Formenti Silvia C. , Galluzzi Lorenzo
Published: April 2023

AbstractPurpose:
Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor–positive (ER+) breast cancer to radiotherapy. However, these findings were obtained in human ER+ breast cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule.
Experimental Design:
We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER+ and ER-negative (ER−) breast cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival in vitro, as well as tumor growth, overall survival, and metastatic dissemination in vivo.
Results:
Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects in vitro, correlating with suboptimal tumor control in vivo. However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested in vitro with enhanced cytostasis and loss of clonogenic potential, as well as in vivo with improved local and systemic tumor control.
Conclusions:
Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER+ breast cancer.
Data from The OncoMasTR Test Predicts Distant Recurrence in Estrogen Receptor–Positive, HER2-Negative Early-Stage Breast Cancer: A Validation Study in ABCSG Trial 8
Authors: Filipits Martin , Rudas Margaretha , Kainz Verena , Singer Christian F. , Fitzal Florian , Bago-Horvath Zsuzsanna , Greil Richard , Balic Marija , Regitnig Peter , Halper Stefan , Hulla Wolfgang , Egle Daniel , Barron Stephen , Loughman Tony , O'Leary Des , Gallagher William M. , Hlauschek Dominik , Gnant Michael , Dubsky Peter
Published: April 2023

AbstractPurpose:
To validate the clinical performance of the OncoMasTR Risk Score in the biomarker cohort of Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8.
Experimental Design:
We evaluated the OncoMasTR test in 1,200 formalin-fixed, paraffin-embedded (FFPE) surgical specimens from postmenopausal women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative primary breast cancer with 0 to 3 involved lymph nodes in the prospective, randomized ABCSG Trial 8. Time to distant recurrence (DR) was analyzed by Cox models.
Results:
The OncoMasTR Risk Score categorized 850 of 1,087 (78.2%) evaluable patients as “low risk”. At 10 years, the DR rate for patients in the low-risk group was 5.8% versus 21.1% for patients in the high-risk group (P < 0.0001, absolute risk reduction 15.3%). The OncoMasTR Risk Score was highly prognostic for prediction of DR in years 0 to 10 in all patients [HR 1.91, 95% confidence interval (CI) 1.62–2.26, P < 0.0001; C-index 0.73], in patients that were node negative (HR 1.79, 95% CI, 1.43–2.24, P < 0.0001; C-index 0.72), and in patients with 1 to 3 involved lymph nodes (HR 1.93, 95% CI, 1.44–2.58, P < 0.0001; C-index 0.71). The OncoMasTR Risk Score provided significant additional prognostic information beyond clinical parameters, Ki67, Nottingham Prognostic Index, and Clinical Treatment Score.
Conclusions:
OncoMasTR Risk Score is highly prognostic for DR in postmenopausal women with ER-positive, HER2-negative primary breast cancer with 0 to 3 involved lymph nodes. In combination with prior validation studies, this fully independent validation in ABCSG Trial 8 provides level 1B evidence for the prognostic capability of the OncoMasTR Risk Score.
Data from Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer
Authors: Loree Jonathan M. , Wang Yucai , Syed Muddassir A. , Sorokin Alexey V. , Coker Oluwadara , Xiu Joanne , Weinberg Benjamin A. , Vanderwalde Ari M. , Tesfaye Anteneh , Raymond Victoria M. , Miron Benjamin , Tarcic Gabi , Zelichov Ori , Broaddus Russell R. , Ng Patrick Kwok Shing , Jeong Kang Jin , Tsang Yiu Huen , Mills Gordon B. , Overman Michael J. , Grothey Axel , Marshall John L. , Kopetz Scott
Published: April 2023

AbstractPurpose:
Mutations in KRAS/NRAS (RAS) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact, and atypical mutations beyond those in standard guidelines exist.
Experimental Design:
We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations.
Results:
KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24–6.80; P = 0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts.
Conclusions:
We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant.
Data from Phase I–II Open-Label Multicenter Study of Palbociclib + Vemurafenib in BRAFV600MUT Metastatic Melanoma Patients: Uncovering CHEK2 as a Major Response Mechanism
Authors: Louveau Baptiste , Resche-Rigon Matthieu , Lesimple Thierry , Da Meda Laetitia , Pracht Marc , Baroudjian Barouyr , Delyon Julie , Amini-Adle Mona , Dutriaux Caroline , Reger de Moura Coralie , Sadoux Aurélie , Jouenne Fanélie , Ghrieb Zineb , Vilquin Paul , Bouton Didier , Tibi Annick , Huguet Samuel , Rezai Keyvan , Battistella Maxime , Mourah Samia , Lebbe Céleste
Published: April 2023

AbstractPurpose:
In BRAFV600MUT metastatic melanoma, cyclin D–CDK4/6–INK4–Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of cyclin-dependent kinase 4 (CDK4) inhibitors. In this phase I–II study, we aimed to establish the MTD of palbociclib when added to vemurafenib.
Patients and Methods:
Patients with BRAFV600E/KMUT metastatic melanoma harboring CDKN2A loss and RB1 expression were included and stratified into two groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics, and tumor molecular profiling.
Results:
Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were American Joint Committee on Cancer stage IVM1c (N = 16; 88.9%), high lactate dehydrogenase (N = 9; 50.0%), and median number of previous treatments of 2. One and 5 patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25 mg and vemurafenib 960 mg in strata 2. No significant evidence for drug–drug interactions was highlighted. The median progression-free survival was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib.
Conclusions:
Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25 mg, a significant clinical benefit was achieved in pretreated patients with melanoma. An association between the transcriptomic data and clinical response was highlighted.
Data from Preclinical Modeling of Surgery and Steroid Therapy for Glioblastoma Reveals Changes in Immunophenotype that are Associated with Tumor Growth and Outcome
Authors: Otvos Balint , Alban Tyler J. , Grabowski Matthew M. , Bayik Defne , Mulkearns-Hubert Erin E. , Radivoyevitch Tomas , Rabljenovic Anja , Johnson Sarah , Androjna Charlie , Mohammadi Alireza M. , Barnett Gene H. , Ahluwalia Manmeet S. , Vogelbaum Michael A. , Fecci Peter E. , Lathia Justin D.
Published: April 2023

AbstractPurpose:
Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment—including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment—has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined.
Experimental Design:
We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM.
Results:
Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles.
Conclusions:
These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.
Data from Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes
Authors: Chang Jason C. , Offin Michael , Falcon Christina , Brown David , Houck-Loomis Brian R. , Meng Fanli , Rudneva Vasilisa A. , Won Helen H. , Amir Sharon , Montecalvo Joseph , Desmeules Patrice , Kadota Kyuichi , Adusumilli Prasad S. , Rusch Valerie W. , Teed Sarah , Sabari Joshua K. , Benayed Ryma , Nafa Khedoudja , Borsu Laetitia , Li Bob T. , Schram Alison M. , Arcila Maria E. , Travis William D. , Ladanyi Marc , Drilon Alexander , Rekhtman Natasha
Published: April 2023

AbstractPurpose:
Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.
Experimental Design:
A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).
Results:
Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R–NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001).
Conclusions:
This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.
Data from First-Line Afatinib plus Cetuximab for EGFR-Mutant Non–Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study
Authors: Cortot Alexis B. , Madroszyk Anne , Giroux-Leprieur Etienne , Molinier Olivier , Quoix Elisabeth , Bérard Henri , Otto Josiane , Rault Isabelle , Moro-Sibilot Denis , Raimbourg Judith , Amour Elodie , Morin Franck , Hureaux José , Moreau Lionel , Debieuvre Didier , Morel Hugues , Renault Aldo , Pichon Eric , Huret Benjamin , Charpentier Sandrine , Denis Marc G. , Cadranel Jacques
Published: April 2023

AbstractPurpose:
Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non–small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC.
Patients and Methods:
In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed.
Results:
Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5–14.1) and 12.9 (9.2–14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received.
Conclusions:
These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.
Data from A Phase Ib Open-Label, Multicenter Study of Inhaled DV281, a TLR9 Agonist, in Combination with Nivolumab in Patients with Advanced or Metastatic Non–small Cell Lung Cancer
Authors: Garon Edward B. , Spira Alexander I. , Johnson Melissa , Bazhenova Lyudmila , Leach Joseph , Cummings Amy L. , Candia Albert , Coffman Robert L. , Janatpour Mary J. , Janssen Robert , Gamelin Erick , Chow Laura Q.M.
Published: April 2023

AbstractPurpose:
Although PD-(L)1 inhibitors have shown efficacy in advanced/metastatic non–small cell lung cancer (NSCLC), many patients do not respond to this treatment and more effective combinations with acceptable toxicities are needed. To assess the potential benefit of combining localized innate immune stimulation with checkpoint blockade, the TLR9 agonist DV281 was combined with nivolumab in a phase Ib study.
Patients and Methods:
Patients after one or two prior lines of systemic therapy were enrolled in a dose-escalation study with a 3+3 design. DV281 was administered via inhalation in five dose cohorts at 1 to 25 mg; nivolumab 240 mg was administered intravenously every 2 weeks. Safety, tolerability, pharmacodynamics, and response to treatment were assessed.
Results:
Twenty-six patients with advanced NSCLC enrolled. Baseline programmed death ligand 1 (PD-L1) expression was present in 16 patients (61.5%); 21 (80.7%) had received previous anti–PD-1/PD-L1. Thirteen patients (50%) had stable disease, nine (34.6%) had progressive disease, and four (15.4%) were not evaluable. Median duration of disease control was 124 days. Adverse events were seen in 16 patients (61.5%), mostly grade 1/2 chills, fatigue, flu-like symptoms, diarrhea, and rash; there was only one grade 3 adverse event (dyspnea). Pharmacodynamic assessment, measured by IFN- inducible gene expression, showed target engagement in all dose cohorts. Systemic pharmacodynamic responses plateaued in the 2 highest dose cohorts.
Conclusions:
DV281 with nivolumab was well tolerated with target engagement observed at every dose. Pharmacodynamic advantages at doses above 10 mg were unclear. The long duration of disease control in 50% of patients suggests clinically relevant activity in this population of heavily pretreated patients.
Data from Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR+/HER2− Advanced Breast Cancer after Progression on CDK4/6 Inhibitors (TRINITI-1)
Authors: Bardia Aditya , Hurvitz Sara A. , DeMichele Angela , Clark Amy S. , Zelnak Amelia , Yardley Denise A. , Karuturi Meghan , Sanft Tara , Blau Sibel , Hart Lowell , Ma Cynthia , Rugo Hope S. , Purkayastha Das , Moulder Stacy
Published: April 2023

AbstractPurpose:
Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i.
Patients and Methods:
This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis.
Results:
Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported.
Conclusions:
Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.
Data from A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors
Authors: Chida Keigo , Kawazoe Akihito , Kawazu Masahito , Suzuki Toshihiro , Nakamura Yoshiaki , Nakatsura Tetsuya , Kuwata Takeshi , Ueno Toshihide , Kuboki Yasutoshi , Kotani Daisuke , Kojima Takashi , Taniguchi Hiroya , Mano Hiroyuki , Ikeda Masafumi , Shitara Kohei , Endo Itaru , Yoshino Takayuki
Published: April 2023

AbstractPurpose:
This study performed a comprehensive molecular characterization of microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade.
Experimental Design:
Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC.
Results:
Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; P = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type PTEN (21.4 vs. 54.8%; odds, 4.45; P = 0.045). Compared with wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; P = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; P < 0.001), lower intratumoral CD8+ T-cell levels, higher intratumoral CD204+ macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas PTEN mutations in the C2 domain were not.
Conclusions:
Low TMBs and PTEN mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.
Data from Single-cell Profiles and Prognostic Impact of Tumor-Infiltrating Lymphocytes Coexpressing CD39, CD103, and PD-1 in Ovarian Cancer
Authors: Laumont Céline M. , Wouters Maartje C.A. , Smazynski Julian , Gierc Nicole S. , Chavez Elizabeth A. , Chong Lauren C. , Thornton Shelby , Milne Katy , Webb John R. , Steidl Christian , Nelson Brad H.
Published: April 2023

AbstractPurpose:
Tumor-infiltrating lymphocytes (TIL) are strongly associated with survival in most cancers; however, the tumor-reactive subset that drives this prognostic effect remains poorly defined. CD39, CD103, and PD-1 have been independently proposed as markers of tumor-reactive CD8+ TIL in various cancers. We evaluated the phenotype, clonality, and prognostic significance of TIL expressing various combinations of these markers in high-grade serous ovarian cancer (HGSC), a malignancy in need of more effective immunotherapeutic approaches.
Experimental Design:
Expression of CD39, CD103, PD-1, and other immune markers was assessed by high-dimensional flow cytometry, single-cell sequencing, and multiplex immunofluorescence of primary and matched pre/post-chemotherapy HGSC specimens.
Results:
Coexpression of CD39, CD103, and PD-1 (“triple-positive” phenotype) demarcated subsets of CD8+ TIL and CD4+ regulatory T cells (Treg) with a highly activated/exhausted phenotype. Triple-positive CD8+ TIL exhibited reduced T-cell receptor (TCR) diversity and expressed genes involved in both cytolytic and humoral immunity. Triple-positive Tregs exhibited higher TCR diversity and a tumor-resident phenotype. Triple-positive TIL showed superior prognostic impact relative to TIL expressing other combinations of these markers. TIGIT was uniquely upregulated on triple-positive CD8+ effector cells relative to their CD4+ Treg counterparts.
Conclusions:
Coexpression of CD39, CD103, and PD-1 demarcates highly activated CD8+ and CD4+ TIL with inferred roles in cytolytic, humoral, and regulatory immune functions. Triple-positive TIL demonstrate exceptional prognostic significance and express compelling targets for combination immunotherapy, including PD-1, CD39, and TIGIT.