bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials
Authors: Antonarakis Emmanuel S. , Subudhi Sumit K. , Pieczonka Christopher M. , Karsh Lawrence I. , Quinn David I. , Hafron Jason M. , Wilfehrt Helen M. , Harmon Matthew , Sheikh Nadeem A. , Shore Neal D. , Petrylak Daniel P.
Published: September 2024

AbstractPurpose:
We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival.
Results:
Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed.
Conclusions:
Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Data from Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials
Authors: Antonarakis Emmanuel S. , Subudhi Sumit K. , Pieczonka Christopher M. , Karsh Lawrence I. , Quinn David I. , Hafron Jason M. , Wilfehrt Helen M. , Harmon Matthew , Sheikh Nadeem A. , Shore Neal D. , Petrylak Daniel P.
Published: September 2024

Abstract
Purpose: We present long-term outcomes from two randomized studies (STAMP [with abiraterone, NCT01487863] and STRIDE [with enzalutamide, NCT01981122]) that were performed to study the impact of sequential or concurrent administration of ARTAs on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer. Experimental design: Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival. Results: Updated data reduced patient censoring in each study compared with the original analyses; the 95% CIs for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS (hazard ratio [HR], 0.727 [0.458–1.155]; P=0.177, reference = STRIDE). OS with sequential administration was similar to concurrent administration (NDI update: HR, 0.963 [0.639–1.453]; P=0.845, reference = concurrent arm). Sipuleucel-T potency, measured as antigen-presenting cell activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated vs baseline. No new safety signals were observed. Conclusions: Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Data from The impact of germline alterations in appendiceal adenocarcinoma
Authors: Foote Michael B. , Walch Henry , Kemel Yelena , Vakiani Efsevia , Johannet Paul , Sheehan Margaret , Chatila Walid , Chung Sebastian , NASH Garrett , Maio Anna , Shia Jinru , Mandelker Diana , Berger Michael , Schultz Nikolaus , Diaz Luis A. , Cercek Andrea , Stadler Zsofia K.
Published: September 2024

Abstract
Purpose: Over 10% of assessed patients with appendiceal adenocarcinoma (AC) have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch Syndrome. We defined the clinical and molecular impact of heritable alterations in AC to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants. Experimental Design: We performed an integrated germline and somatic molecular analysis for patients with confirmed AC. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer-risk genes and 505 genes for somatic mutation profiling. We defined the co-occurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated. Results: Twenty-five out of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and AC-specific survival were similar in patients with or without germline variants. Most (92%, N=23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However only one patient tumor exhibited APC-mediated WNT-signaling dysregulation; a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch Syndrome, yet their cancers were microsatellite-stable. Conclusions: Germline variants are likely incidental without a contributory driver role in AC. AC screening in patients with germline variants is not clearly merited.
Data from Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers
Authors: DiPeri Timothy P. , Evans Kurt W. , Raso Maria Gabriela , Zhao Ming , Rizvi Yasmeen Q. , Zheng Xiaofeng , Wang Bailiang , Kirby Bryce P. , Kong Kathleen , Kahle Michael , Yap Timothy A. , Dumbrava Ecaterina E. , Ajani Jaffer A. , Fu Siqing , Keyomarsi Khandan , Meric-Bernstam Funda
Published: September 2024

AbstractPurpose:
Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.
Experimental Design:
Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array.
Results:
Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody–drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd–treated colon cancer model.
Conclusions:
We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications.

See related commentary by Rolfo et al., p. 4317
Data from Phase II study of docetaxel and trametinib in patients with KRAS mutation positive recurrent non-small cell lung cancer (NSCLC) (SWOG S1507, NCT-02642042)
Authors: Gadgeel Shirish M. , Miao Jieling , Riess Jonathan W. , Moon James , Mack Philip C. , Gerstner Gregory J. , Burns Timothy F. , Taj Asma , Akerley Wallace L. , Dragnev Konstantin H. , Laudi Noel , Redman Mary W. , Gray Jhanelle E. , Gandara David R. , Kelly Karen
Published: September 2024

Abstract
Purpose: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and co-mutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC. Patients and Methods: S1507 is a single arm phase II assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients with at least 25 with G12C mutation. The design was 2-stage design to rule out a 17% RR, within the overall population at the 1-sided 3% level and within the G12C subset at the 5% level. Results: Between July 18, 2016 and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% (95%CI- 22-48) overall and 28% (95%CI- 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR:2.85, 95%CI 1.16-7.01) and RR (0% vs. 56%, p = 0.004) were worse in patients with TP53 mutated versus wild type cancers. Conclusions: RRs were significantly improved in the overall population. Contrary to pre-clinical studies, the combination showed no improvement in efficacy in G12C patients. Co-mutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation.
Data from A Phase 1/2 Multicenter Randomized Trial of Local Ablation Plus Toripalimab Versus Toripalimab Alone for Previously Treated Unresectable Hepatocellular Carcinoma
Authors: Zhou Chunhui , Li Yan , Li Jiaping , Song Botian , Li Hanfeng , Liang Bin , Gu Shanzhi , Li Haiping , Chen Changyong , Li Sai , Peng Changli , Liu Fei , Xiao Juxiong , Long Xueying , Li Ping , Xiong Zhengping , Yi Xiaoping , Liao Weihua , Shi Liangrong
Published: September 2024

Abstract
Purpose: To assess the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable hepatocellular carcinoma (HCC). Patients and Methods: In the multicenter, two-stage, and randomized phase 1/2 trial, patients were randomly assigned to receive toripalimab alone (240mg, every 3 weeks), subtotal local ablation followed by toripalimab starting on post-ablation day 3 (Schedule D3) or on post-ablation day 14 (Schedule D14). The first endpoint of stage 1 was to determine which combination schedule could continue and progression-free survival (PFS) as the primary endpoint for stage 1/2. Results: A total of 146 patients were recruited. During stage 1, Schedule D3 achieved numerically higher objective response rate than Schedule D14 for non-ablation lesions (37.5% versus 31.3%), and was chosen for stage 2 evaluation. For the entire cohort of both stages, patients with Schedule D3 had a significantly higher objective response rate than with toripalimab alone (33.8% versus 16.9%, P = 0.027). Moreover, patients with Schedule D3 had improved median PFS (7.1 months versus 3.8 months, P ﹤0.001) and median overall survival (18.4 months versus 13.2 months, P = 0.005), as compared with toripalimab alone. In addition, six (9%) patients with toripalimab, 8 (12%) with Schedule D3, and 4 (25%) with Schedule D14 developed grade 3 or 4 adverse events, and one patient (2%) with Schedule D3 manifested grade 5 treatment-related pneumonitis. Conclusions: In patients with previously treated unresectable HCC, subtotal ablation plus toripalimab improved the clinical efficacy as compared with toripalimab alone with an acceptable safety profile.
Data from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: September 2024

Abstract
Purpose: Resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting C797S mutation. Patients and Methods: Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the efficacy of BBT-176 both in vitro and in vivo. Patient cases are derived from an ongoing phase 1 clinical trial (NCT04820023). Results: The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S protein were measured at 4.36, 1.79 and 5.35 nM, respectively (vs. 304.39, 124.82, and 573.72 nM, for osimertinib). IC50 values of BBT‑176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183 and 202 nM, respectively (vs 869, 1134, 2799, and 2685 nM for osimertinib). N-Ethyl-N-nitrosourea (ENU) mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT‑176 effectively suppressed the growth of BBT-176-resistant clones. BBT‑176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients from harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiological improvements. Conclusions: BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKIs.
Data from Patient-Reported Outcomes as Inter-Radiographic Predictors of Response in Non-Small Cell Lung Cancer
Authors: Bhatt Ambika , Schabath Matthew B. , Hoogland Aasha I. , Jim Heather S.L. , Brady-Nicholls Renee
Published: September 2024

Abstract
Purpose: Minimally-invasive biomarkers have been used as important indicators of treatment response and progression in cancers such as prostate and ovarian. Unfortunately, all biomarkers are not prognostic in all cancer types and are often not routinely collected. Patient-reported outcomes (PROs) provide a non-obtrusive, personalized measure of a patient’s quality of life and symptomatology, reported directly from the patient and are increasingly collected as part of routine care. Previous literature has shown correlations between specific PROs (i.e., insomnia, fatigue) and overall survival. Though promising, these studies often only consider single time points and ignore patient-specific dynamic changes in individual PROs, which might be early predictors of treatment response or progression. Experimental Design: In this study, PRO dynamics were analyzed to determine if they could be used as inter-radiographic predictors of tumor volume changes among 85 non-small cell lung cancer patients undergoing immunotherapy. PRO questionnaires and tumor volume scans were completed biweekly and monthly, respectively. Correlation and predictive analysis were conducted to identify specific PROs that could accurately predict patient response. Results: Changes in tumor volume over time were significantly correlated with dizziness (p<0.005), insomnia (p <0.05), and fatigue (p<0.05). Additionally, cumulative changes in insomnia could predict progressive disease with a 77% accuracy, on average 45 days prior to the next imaging scan. Conclusions: This study presents the first time that patient-specific PRO dynamics have been considered to predict how individual patients will respond to treatment. This is an important first step in adapting treatment to improve response rates.
Data from Dual targeting of apoptotic and signaling pathways in T-lineage acute lymphoblastic leukemia
Authors: Saygin Caner , Giordano Giorgia , Shimamoto Kathryn , Eisfelder Bart , Thomas-Toth Anika , Venkataraman Girish , Ananthanarayanan Vijayalakshmi , Vincent Tiffaney L. , DuVall Adam , Patel Anand A. , Chen Yi , Tan Fenlai , Anthony Stephen P. , Chen Yu , Shen Yue , Odenike Olatoyosi , Teachey David T. , Kee Barbara L. , LaBelle James , Stock Wendy
Published: September 2024

Abstract
Purpose: Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL in order to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. Methods: We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways. Results: Typical T-ALL cells had increased dependence on BCL-xL, while early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling pathways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-κB pathway and the expression of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling up-regulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity. Conclusions:LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.
Data from Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study
Authors: Oaknin Ana , Pothuri Bhavana , Gilbert Lucy , Sabatier Renaud , Brown Jubilee , Ghamande Sharad , Mathews Cara , O'Malley David M. , Kristeleit Rebecca , Boni Valentina , Gravina Adriano , Banerjee Susana , Miller Rowan , Pikiel Joanna , Mirza Mansoor R. , Dewal Ninad , Antony Grace , Dong Yuping , Zografos Eleftherios , Veneris Jennifer , Tinker Anna V.
Published: September 2024

AbstractPurpose:
This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.
Patients and Methods:
A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR).
Results:
A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports.
Conclusions:
Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab.

See related commentary by Jangra and Dhani, p. 4521
Data from Results of an Open-label, Phase 1a/b Study of Pembrolizumab plus Olaratumab in Patients with Unresectable, Locally Advanced or Metastatic Soft Tissue Sarcoma
Authors: Schöffski Patrick , Bahleda Rastislav , Wagner Andrew J. , Burgess Melissa A. , Junker Niels , Chisamore Michael , Peterson Patrick , Szpurka Anna M. , Ceccarelli Matteo , Tap William D.
Published: September 2024

Abstract
Purpose: The study evaluated safety and efficacy of olaratumab+pembrolizumab in patients with unresectable locally advanced/metastatic soft-tissue sarcoma with disease progression on standard treatment. Patients and Methods: This was open-label, multicenter, nonrandomized, phase 1a/1b dose-escalation study followed by cohort expansion (olaratumab+pembrolizumab intravenous infusion). Primary objectives were safety and tolerability. Results: Majority of patients enrolled (41) were female (phase 1a: 9 of 13, phase 1b/dose-expansion cohort [DEC]: 17 of 28), aged <65 years. In phases 1a and 1b, 13 and 26 patients received prior systemic therapy, respectively. Patients received olaratumab 15mg/kg (phase 1a; cohort 1) or 20mg/kg (phase 1a; cohort 2 and phase 1b) and pembrolizumab 200mg (phase 1a/1b). The median (Q1–Q3) duration of therapy (olaratumab) was 6.0 (3.0-11.9) (cohort 1), 14.4 (12.4-20.9) (cohort 2), and 14.0 (6.0-21.8) weeks (DEC). No dose-limiting toxicities and few Grade ≥3 treatment-emergent adverse events (TEAEs, 15 mg/kg: 2 [increased lipase], 20mg/kg: 1 [increased lipase], 1 [colitis], 2 [diarrhea], 3 [anemia]) were reported. Two TEAEs (increased lipase) were related to study discontinuations. Twenty-one patients reported mild (Grade ≤2) TEAE. Phase 1a, disease control rate (DCR):14.3% (1/7, cohort 1); 66.7% (4/6, cohort 2); no responses were reported. Phase 1b, DCR: 53.6% (15/28); objective response rate: 21.4% (6/28) (RECIST and irRECIST criteria). No response in patients with programmed death ligand-1 positive tumors. Conclusions: Antitumor activity was observed in some patients in DEC, combination was well tolerated with manageable safety profile. Further studies are warranted to evaluate efficacy/mechanistic impact of platelet-derived growth factor receptors inhibitor with immune checkpoint modulator coadministration.
Data from A phase Ib, open-label study evaluating the safety and efficacy of ipatasertib plus rucaparib in patients with metastatic castration-resistant prostate cancer
Authors: Pook David , Geynisman Daniel M. , Carles Joan , de Braud Filippo , Joshua Anthony M. , Perez-Gracia Jose Luis. , Pérez Casilda Llácer. , Shin Sang Joon , Fang Bruno , Barve Minal , Maruzzo Marco , Bracarda Sergio , Kim Miso , Kerloeguen Yannick , Gallo Jorge Daniel. , Maund Sophia L. , Harris Adam , Huang Kuan-Chieh , Poon Victor , Sutaria Dhruvitkumar S. , Gurney Howard
Published: September 2024

Abstract
Purpose: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen-receptor inhibitors. Patients and Methods: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400mg daily [QD]) plus rucaparib (400 or 600mg twice daily [BID]) to assess safety and identify a recommended phase 2 dose (RP2D). A Part 1 dose-escalation phase was followed by a Part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on tumor mutational status. Results: Fifty-one patients were enrolled (Part 1=21; Part 2=30). Ipatasertib 400mg QD plus rucaparib 400mg BID was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per RECIST 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months (95% CI, 4.0-8.1), and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). Conclusion: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.
Data from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: September 2024

Abstract
Purpose: Approximately 8-10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. Experimental Design: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multi-gene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. Results: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the mitogen activated kinase (MAPK) pathway, including BRAF mutations and in-frame deletions and receptor-tyrosine kinase (RTK) fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers such as GNAS, MYC, PIK3CA and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid (PDO) models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (Median Age: 62.6 vs. 65.7 years , p = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. Conclusions: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials.
Data from Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance
Authors: Hanna Glenn J. , Roof Scott A. , Jabalee James , Rettig Eleni M. , Ferrandino Rocco , Chen Sida , Posner Marshall R. , Misiukiewicz Krzysztof J. , Genden Eric M. , Chai Raymond L. , Sims John , Thrash Elaine , Stern Scott J. , Kalman Noah S. , Yarlagadda Sreenija , Raben Adam , Clements Lydia , Mendelsohn Abie , Kaczmar John M. , Pandey Yadav , Bhayani Mihir K. , Gupta Piyush , Kuperwasser Charlotte , Del Vecchio Fitz Catherine , Berger Barry M.
Published: September 2024

Abstract
Background: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of post-treatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. Methods: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at 8 U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). Results: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pre-treatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had 3 or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% (95%CI: 87.5-97.5) and 87.3% (95%CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95%CI: 98.9-99.8) and 98.4% (95%CI: 97.3-99.5), respectively. Conclusions: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue re-imaging following first disease restaging and could inform future surveillance practice. Additional study of how pre-treatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.
Data from Baseline mutations and ctDNA dynamics as prognostic and predictive factors in ER-positive/HER2-negative metastatic breast cancer patients
Authors: Pascual Javier , Gil-Gil Miguel , Proszek Paula , Zielinski Christoph , Reay Alistair , Ruiz-Borrego Manuel , Cutts Rosalind , Ciruelos Gil Eva M. , Feber Andrew , Muñoz-Mateu Montserrat , Swift Claire , Bermejo Begoña , Herranz Jesus , Margeli Vila Mireia , Antón Antonio , Kahan Zsuzsanna , Csöszi Tibor , Liu Yuan , Fernandez Garcia Daniel , Garcia-Murillas Isaac , Hubank Michael , Turner Nicholas C. , Martín Miguel
Published: September 2024

Abstract
Purpose: Prognostic and predictive biomarkers to CDK4/6 inhibitors are lacking. Circulating tumour DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy. Experimental Design: Correlative blood samples were collected at baseline (C1D1) and prior to treatment (C1D15). Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A pre-specified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model. Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse PFS/OS. Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n=120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms. Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with HR+/HER2- MBC harbouring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.
Data from Neoantigen targetability in progressive advanced melanoma
Authors: van den Bulk Jitske , Verdegaal Els M.E. , van der Ploeg Manon , Visser Marten , Nunes Joana B. , de Ru Arnoud H. , Tjokrodirijo Rayman T.N. , Ijsselsteijn Marieke E. , Janssen Natasja I. , van der Breggen Ruud , de Bruin Linda , de Kok Pita , Janssen George M.C. , Ruano Dina , Kapiteijn Ellen H.W. , van veelen Peter A. , de Miranda Noel F.C.C. , van der Burg Sjoerd H.
Published: September 2024

Abstract
Purpose: The availability of (neo)antigens and the infiltration of tumors by (neo)antigen-specific T cells are crucial factors in cancer immunotherapy. In this study, we aimed to investigate the targetability of (neo)antigens in advanced progessive melanoma and explore the potential for continued T cell-based immunotherapy. Experimental Design: We examined a cohort of eight melanoma patients who had sequential metastases resected at early and later time points. Antigen presenting capacity was assessed using immunohistochemistry and flow cytometry. T cell infiltration was quantified through multiplex immunofluorescence. Whole-exome and RNA sequencing were conducted to identify neoantigens and assess the expression of neoantigens and tumor-associated antigens. Mass spectrometry was employed to evaluate antigen presentation. Tumor recognition by autologous T cells was assessed by coculture assays with cell lines derived from the metastatic lesions. Results: We observed similar T cell infiltration in paired early and later metastatic lesions. While elements of the antigen presenting machinery were affected in some later metastatic lesions, both the early and later metastasis-derived cell lines were recognized by autologous T cells. At the genomic level, the (neo)antigen landscape was dynamic, but the (neo)antigen load was stable between paired lesions. Conclusions: Our findings indicate that subsequently isolated tumors from late-stage melanoma patients retain sufficient antigen presenting capacity, T cell infiltration, and a stable (neo)antigen load, allowing recognition of tumor cells by T cells. This indicates a continuous availability of T cell targets in metastases occurring at different time points and supports further exploration of neoantigen-specific T cell-based therapeutic approaches for advanced melanoma.
Data from HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion
Authors: Nguyen Andrew , Brown Dominique , Krishnan Ramya , Bastin Donald , Deng Li , Chen Lan , Salem Omar , Walsh Scott R. , Bramson Jonathan L. , Wan Yonghong
Published: September 2024

Abstract
Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.
Data from Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib vs Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer
Authors: Grisham Rachel N. , Vergote Ignace , Banerjee Susana , Drill Esther , Kalbacher Elsa , Mirza Mansoor Raza. , Romero Ignacio , Vuylsteke Peter , Coleman Robert L. , Hilpert Felix , Oza Amit M. , Westermann Anneke , Oehler Martin K. , Pignata Sandro , Aghajanian Carol , Colombo Nicoletta , Cibula David , Moore Kathleen N. , del Campo Josep M. , Berger Regina , Marth Christian , Sehouli Jalid , O'Malley David M. , Churruca Cristina , Kristensen Gunnar , Clamp Andrew , Farley John , Iyer Gopakumar , Ray-Coquard Isabelle , Monk Bradley J.
Published: September 2024

Abstract
Purpose: We present the results of a post-hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Experimental Design: Mutation/copy number analysis was performed on tissue obtained pre-randomization. Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1·1. Results: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22-79, from 6/2013-4/2016. Patients were randomized 2:1 to binimetinib or physician’s choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n=11, 8·1%), BRAF V600E (n=8, 5·9%), RAF1 (n=2, 1·5%), and NF1 (n=7, 5·2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared to those without, MAPK pathway alterations treated with binimetinib (HR 0·5; 95% CI: 0·31, 0·79). There was a nonsignificant trend towards PFS improvement in PPC-treated patients with MAPK pathway alterations compared to those without (HR 0·82; 95% CI: 0·43-1·59). Conclusions: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with LGSOC treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and utilized as a future stratification factor.
Data from The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 After Progression on Rucaparib
Authors: Brown Timothy J. , Yablonovitch Arielle , Till Jacob E. , Yen Jennifer , Kiedrowski Lesli A. , Hood Ryan , O'Hara Mark H. , Teitelbaum Ursina , Karasic Thomas B. , Schneider Charles , Carpenter Erica L. , Nathanson Katherine , Domchek Susan M. , Reiss Kim A.
Published: September 2024

Abstract
Purpose: Poly-(ADP-ribose) polymerase inhibitors provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. Experimental Design: We collected paired cfDNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. Results: Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (mPFS 3.7mo vs 12.5mo, p=0.001) and poor overall survival (mOS 6.2mo vs 23.0mo, p<0.0001). All patients with reversions received re-challenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (rwTTD 2.4mo vs 5.8mo, p = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second line therapy was significantly lower in those with reversion variants than in those without (5.5mo vs 12.0 mo, p = 0.002). Finally, high levels tumor shedding were independently associated with poor outcomes in patients who received rucaparib. Conclusions: Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA or PALB2 related PDAC who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment and poor overall survival of patients. The identification of such variants in the blood may have both predictive and prognostic value.
Supplementary Table S2 from Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib Plus Osimertinib in an EGFR-Mutation Positive, MET-Amplified Non-Small Cell Lung Cancer Model
Authors: Jones Rhys D.O. , Petersson Klas , Tabatabai Areya , Bao Larry , Tomkinson Helen , Schuller Alwin G.
Published: September 2024

Supplementary Table S2
Supplementary Figure S3 from Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib Plus Osimertinib in an EGFR-Mutation Positive, MET-Amplified Non-Small Cell Lung Cancer Model
Authors: Jones Rhys D.O. , Petersson Klas , Tabatabai Areya , Bao Larry , Tomkinson Helen , Schuller Alwin G.
Published: September 2024

Supplementary Figure S3
Supplementary Figure 4 from Novel arginase inhibitor, AZD0011, demonstrates immune cell stimulation and anti-tumor efficacy with diverse combination partners
Authors: Doshi Aatman S. , Cantin Susan , Hernandez Marylens , Srinivasan Srimathi , Tentarelli Sharon , Griffin Matthew , Wang Yanjun , Pop-Damkov Petar , Prickett Laura B. , Kankkonen Cecilia , Shen Minhui , San Martin Maryann , Wu Song , Castaldi M Paola , Ghadially Hormas , Varnes Jeffrey , Gales Sonya , Henry David , Hoover Clare , Mele Deanna A. , Simpson Iain , Gangl Eric T. , Mlynarski Scott N. , Finlay M. Raymond V. , Drew Lisa , Fawell Stephen E. , Shao Wenlin , Schuller Alwin G.
Published: September 2024

Supplementary Figure 4
Supplementary Figure 3 from Novel arginase inhibitor, AZD0011, demonstrates immune cell stimulation and anti-tumor efficacy with diverse combination partners
Authors: Doshi Aatman S. , Cantin Susan , Hernandez Marylens , Srinivasan Srimathi , Tentarelli Sharon , Griffin Matthew , Wang Yanjun , Pop-Damkov Petar , Prickett Laura B. , Kankkonen Cecilia , Shen Minhui , San Martin Maryann , Wu Song , Castaldi M Paola , Ghadially Hormas , Varnes Jeffrey , Gales Sonya , Henry David , Hoover Clare , Mele Deanna A. , Simpson Iain , Gangl Eric T. , Mlynarski Scott N. , Finlay M. Raymond V. , Drew Lisa , Fawell Stephen E. , Shao Wenlin , Schuller Alwin G.
Published: September 2024

Supplementary Figure 3
Supplementary Figure 1 from Novel arginase inhibitor, AZD0011, demonstrates immune cell stimulation and anti-tumor efficacy with diverse combination partners
Authors: Doshi Aatman S. , Cantin Susan , Hernandez Marylens , Srinivasan Srimathi , Tentarelli Sharon , Griffin Matthew , Wang Yanjun , Pop-Damkov Petar , Prickett Laura B. , Kankkonen Cecilia , Shen Minhui , San Martin Maryann , Wu Song , Castaldi M Paola , Ghadially Hormas , Varnes Jeffrey , Gales Sonya , Henry David , Hoover Clare , Mele Deanna A. , Simpson Iain , Gangl Eric T. , Mlynarski Scott N. , Finlay M. Raymond V. , Drew Lisa , Fawell Stephen E. , Shao Wenlin , Schuller Alwin G.
Published: September 2024

Supplementary Figure 1
Supplementary Figure S1-S10 from Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer
Authors: Khan Imran , Gril Brunilde , Paranjape Anurag N. , Robinson Christina M. , Difilippantonio Simone , Biernat Wojciech , Bieńkowski Michał , Pęksa Rafal , Duchnowska Renata , Jassem Jacek , Brastianos Priscilla K. , Metellus Philippe , Bialecki Emilie , Woodroofe Carolyn C. , Wu Haitao , Swenson Rolf E. , Steeg Patricia S.
Published: September 2024

Supplementary Figures S1-S10
Movie S1 from 3D-informed targeting of the Trop-2 signal-activation site drives selective cancer vulnerability
Authors: Guerra Emanuela , Trerotola Marco , Relli Valeria , Lattanzio Rossano , Tripaldi Romina , Ceci Martina , Boujnah Khouloud , Pantalone Ludovica , Sacchetti Andrea , Havas Kristina M. , Simeone Pasquale , Travali Nicole , Querzoli Patrizia , Pedriali Massimo , Roversi Pietro , Iezzi Manuela , Tinari Nicola , Antolini Laura , Alberti Saverio
Published: September 2024

Supplementary Movie S1
Supplementary Figure 18 from Arginase 1/2 inhibitor OATD-02: from discovery to first-in-man setup in cancer immunotherapy
Authors: Borek Bartlomiej , Nowicka Julita , Gzik Anna , Dziegielewski Marek , Jedrzejczak Karol , Brzezinska Joanna , Grzybowski Marcin , Stanczak Paulina , Pomper Paulina , Zagozdzon Agnieszka , Rejczak Tomasz , Matyszewski Krzysztof , Golebiowski Adam , Olczak Jacek , Lisiecki Kamil , Tyszkiewicz Magdalena , Kania Magdalena , Piasecka Sylwia , Cabaj Anna , Dera Paulina , Mulewski Krzysztof , Chrzanowski Jacek , Kusmirek Damian , Sobolewska Elzbieta , Magdycz Marta , Mucha Lukasz , Masnyk Marek , Golab Jakub , Nowotny Marcin , Nowak Elzbieta , Napiorkowska-Gromadzka Agnieszka , Pikul Stanislaw , Jazwiec Radoslaw , Dzwonek Karolina , Dobrzanski Pawel , Meyring Michael , Skowronek Krzysztof , Iwanowski Piotr , Zaslona Zbigniew , Blaszczyk Roman
Published: September 2024

Individual body weight changes in animals treated with OATD-02