bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck
Authors: Leddon Jennifer L. , Gulati Shuchi , Haque Sulsal , Allen Casey , Palackdharry Sarah , Mathews Maria , Kurtzweil Nicky , Riaz Muhammed Kashif , Takiar Vinita , Nagasaka Misako , Patil Yash , Zender Chad , Tang Alice , Cervenka Brian , McGrath Julie , Korn W. Michael , Hinrichs Benjamin H. , Jandarov Roman , Harun Nusrat , Sukari Ammar , Wise-Draper Trisha M.
Published: April 2023

AbstractPurpose:
Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection.
Patients and Methods:
This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery.
Results:
Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8–88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58–91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)–positive and PD-L1–negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083).
Conclusions:
Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.
Data from Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local–Regionally Advanced Head and Neck Squamous Cell Carcinoma
Authors: Wise-Draper Trisha M. , Gulati Shuchi , Palackdharry Sarah , Hinrichs Benjamin H. , Worden Francis P. , Old Matthew O. , Dunlap Neal E. , Kaczmar John M. , Patil Yash , Riaz Muhammed Kashif , Tang Alice , Mark Jonathan , Zender Chad , Gillenwater Ann M. , Bell Diana , Kurtzweil Nicky , Mathews Maria , Allen Casey L. , Mierzwa Michelle L. , Casper Keith , Jandarov Roman , Medvedovic Mario , Lee J. Jack , Harun Nusrat , Takiar Vinita , Gillison Maura
Published: April 2023

AbstractPurpose:
Patients with resected, local–regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%–69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear.
Patients and Methods:
Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1–3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60–66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0.
Results:
From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27–80), 30% were female, 86% had stage T3–T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%–90%) in the intermediate-risk group and 66% (95% CI, 55%–84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%–77%). No new safety signals were identified.
Conclusions:
Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.
Data from Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma
Authors: Schuler Martin , Zimmer Lisa , Kim Kevin B. , Sosman Jeffrey A. , Ascierto Paolo A. , Postow Michael A. , De Vos Filip Y.F.L. , van Herpen Carla M.L. , Carlino Matteo S. , Johnson Douglas B. , Berking Carola , Reddy Micaela B. , Harney Allison S. , Berlin Jordan D. , Amaria Rodabe N.
Published: April 2023

AbstractPurpose:
Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination.
Patients and Methods:
This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated.
Results:
Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8–34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1–48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5–5.6) and median overall survival was 11.3 months (95% CI, 9.3–14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug–drug interaction.
Conclusions:
Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit.

See related commentary by Moschos, p. 2977
Data from Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102
Authors: Brashears Caitlyn B. , Prudner Bethany C. , Rathore Richa , Caldwell Katharine E. , Dehner Carina A. , Buchanan Jane L. , Lange Sara E.S. , Poulin Neal , Sehn Jennifer K. , Roszik Jason , Spitzer Dirk , Jones Kevin B. , O'Keefe Regis , Nielsen Torsten O. , Taylor Eric B. , Held Jason M. , Hawkins William , Van Tine Brian A.
Published: April 2023

AbstractPurpose:
To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis.
Experimental Design:
ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo.
Results:
ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls.
Conclusions:
These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients.

See related commentary by Subbiah and Gan, p. 3408
Data from Clinical Significance of PIK3CA and ESR1 Mutations in Circulating Tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib plus Fulvestrant
Authors: Tolaney Sara M. , Toi Masakazu , Neven Patrick , Sohn Joohyuk , Grischke Eva-Maria , Llombart-Cussac Antonio , Soliman Hatem , Wang Hong , Wijayawardana Sameera , Jansen Valerie M. , Litchfield Lacey M. , Sledge George W.
Published: April 2023

AbstractPurpose:
PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2− advanced breast cancer (ABC). Inhibition of CDK4 and 6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2.
Patients and Methods:
MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant in 669 women with HR+, HER2− ABC, which had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA.
Results:
From the MONARCH 2 population, 219 and 248 patient samples were successfully analyzed for either PIK3CA or ESR1 mutations, respectively. Abemaciclib plus fulvestrant improved PFS compared with placebo plus fulvestrant in both PIK3CA-wild-type (median 16.9 months vs. 12.3 months; HR, 0.51; 95% CI, 0.33–0.78) and PIK3CA-mutant subgroups (median 17.1 months vs. 5.7 months; HR, 0.53; 95% CI, 0.33–0.84), as well as both ESR1-wild-type (median 15.3 months vs. 11.2 months; HR, 0.44; 95% CI, 0.27–0.71) and ESR1-mutant subgroups (median 20.7 months vs. 13.1 months; HR, 0.54; 95% CI, 5.7–16.9). Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status.
Conclusions:
Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA- or ESR1-mutant tumors compared with the respective wild-type subgroups, in women with HR+, HER2− ABC that had progressed on ET.
Data from FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GvHD after Two or More Prior Lines of Systemic Therapy
Authors: Przepiorka Donna , Le Robert Q. , Ionan Alexei , Li Ruo-Jing , Wang Ying-Hong , Gudi Ramadevi , Mitra Soumya , Vallejo Jonathon , Okusanya Olanrewaju O. , Ma Lian , Yang Yuching , Patel Paresma , Mezaache Djelila , Shah Rakhi , Banerjee Anamitro , McLamore Sherita , Maung Adam N. , Goldberg Kirsten B. , Pazdur Richard , Theoret Marc R. , De Claro R. Angelo
Published: April 2023

Abstract
On July 16, 2021, the FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic GvHD (cGvHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025–213, which included 65 patients with cGvHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% [95% confidence interval (CI), 63–85]; 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI, 1.2–2.9), and 62% (95% CI, 46–74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma-glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.
Data from Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs
Authors: Rohrer Bley Carla , Wolf Friederike , Gonçalves Jorge Patrik , Grilj Veljko , Petridis Ioannis , Petit Benoit , Böhlen Till T. , Moeckli Raphael , Limoli Charles , Bourhis Jean , Meier Valeria , Vozenin Marie-Catherine
Published: April 2023

AbstractPurpose:
The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation.
Experimental Design:
Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH.
Results:
In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7–9 months), which later resolved.
Conclusions:
The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations.

See related commentary by Maity and Koumenis, p. 3636
Data from Artificial Intelligence-Assisted Serial Analysis of Clinical Cancer Genomics Data Identifies Changing Treatment Recommendations and Therapeutic Targets
Authors: Fischer Catherine G. , Pallavajjala Aparna , Jiang LiQun , Anagnostou Valsamo , Tao Jessica , Adams Emily , Eshleman James R. , Gocke Christopher D. , Lin Ming-Tseh , Platz Elizabeth A. , Xian Rena R.
Published: April 2023

AbstractPurpose:
Given the pace of predictive biomarker and targeted therapy development, it is unknown whether repeat annotation of the same next-generation sequencing data can identify additional clinically actionable targets that could be therapeutically leveraged. In this study, we sought to determine the predictive yield of serial reanalysis of clinical tumor sequencing data.
Experimental Design:
Using artificial intelligence (AI)-assisted variant annotation, we retrospectively reanalyzed sequencing data from 2,219 patients with cancer from a single academic medical center at 3-month intervals totaling 9 months in 2020. The yield of serial reanalysis was assessed by the proportion of patients with improved strength of therapeutic recommendations.
Results:
A total of 1,775 patients (80%) had ≥1 potentially clinically actionable mutation at baseline, including 243 (11%) patients who had an alteration targeted by an FDA-approved drug for their cancer type. By month 9, the latter increased to 458 (21%) patients mainly due to a single pan-cancer agent directed against tumors with high tumor mutation burden. Within this timeframe, 67 new therapies became available and 45 were no longer available. Variant pathogenicity classifications also changed leading to changes in treatment recommendations for 124 patients (6%).
Conclusions:
Serial reannotation of tumor sequencing data improved the strength of treatment recommendations (based on level of evidence) in a mixed cancer cohort and showed substantial changes in available therapies and variant classifications. These results suggest a role for repeat analysis of tumor sequencing data in clinical practice, which can be streamlined with AI support.
Data from Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial
Authors: Meric-Bernstam Funda , Tannir Nizar M. , Iliopoulos Othon , Lee Richard J. , Telli Melinda L. , Fan Alice C. , DeMichele Angela , Haas Naomi B. , Patel Manish R. , Harding James J. , Voss Martin H. , Owonikoko Taofeek K. , Carthon Bradley , Srinivasan Ramaprasad , Bendell Johanna C. , Jenkins Yonchu , Whiting Sam H. , Orford Keith , Bennett Mark K. , Bauer Todd M.
Published: April 2023

AbstractPurpose:
Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).
Patients and Methods:
mRCC patients received escalating doses of telaglenastat [400–800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.
Results:
Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell].
Conclusions:
TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.
Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Authors: Kim Tae Won , Burris Howard A. , de Miguel Luken Maria J. , Pishvaian Michael J. , Bang Yung-Jue , Gordon Michael , Awada Ahmad , Camidge D. Ross , Hodi F. Stephen , McArthur Grant A. , Miller Wilson H. , Cervantes Andres , Chow Laura Q. , Lesokhin Alexander M. , Rutten Annemie , Sznol Mario , Rishipathak Deepali , Chen Shang-Chiung , Stefanich Eric , Pourmohamad Tony , Anderson Maria , Kim Jeong , Huseni Mahrukh , Rhee Ina , Siu Lillian L.
Published: April 2023

AbstractPurpose:
OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody.
Patients and Methods:
Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2–1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer.
Results:
MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1–2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease.
Conclusions:
Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.
Data from Phenotypic Composition of Commercial Anti-CD19 CAR T Cells Affects In Vivo Expansion and Disease Response in Patients with Large B-cell Lymphoma
Authors: Monfrini Chiara , Stella Federico , Aragona Vanessa , Magni Martina , Ljevar Silva , Vella Cristina , Fardella Eugenio , Chiappella Annalisa , Nanetti Francesca , Pennisi Martina , Dodero Anna , Guidetti Anna , Corradini Paolo , Carniti Cristiana
Published: April 2023

AbstractPurpose:
In clinical trials, the expansion and persistence of chimeric antigen receptor (CAR) T cells correlate with therapeutic efficacy. However, properties of CAR T cells that enable their in vivo proliferation have still to be consistently defined and the role of CAR T bag content has never been investigated in a real-life setting.
Experimental Design:
Residual cells obtained after washing 61 anti-CD19 CAR T product bags were analyzed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with postinfusion CAR T-cell in vivo expansion and with response and survival.
Results:
While Tisa-cel was characterized by a significant enrichment in CAR+CD4+ T cells with central memory (P < 0.005) and effector (P < 0.005) phenotypes and lower rates of CAR+CD8+ with effector memory (P < 0.005) and naïve-like (P < 0.05) phenotypes as compared with Axi-cel, the two products displayed similar expansion kinetics. In vivo CAR T-cell expansion was influenced by the presence of CAR T with a CD8+ T central memory signature (P < 0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (P < 0.05).
Conclusions:
Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR T-cell in vivo proliferation that is necessary for antitumor response.
Data from Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials
Authors: Llovet Josep M. , Singal Amit G. , Villanueva Augusto , Finn Richard S. , Kudo Masatoshi , Galle Peter R. , Ikeda Masafumi , Callies Sophie , McGrath Louise M. , Wang Chunxiao , Abada Paolo , Widau Ryan C. , Gonzalez-Gugel Elena , Zhu Andrew X.
Published: April 2023

AbstractPurpose:
Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials.
Patients and Methods:
Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated.
Results:
Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49–0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40–0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit.
Conclusions:
Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.
Data from Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma
Authors: Nayak Lakshmi , Standifer Nathan , Dietrich Jorg , Clarke Jennifer L. , Dunn Gavin P. , Lim Michael , Cloughesy Timothy , Gan Hui K. , Flagg Elizabeth , George Elizabeth , Gaffey Sarah , Hayden Julia , Holcroft Christina , Wen Patrick Y. , Macri Mary , Park Andrew J. , Ricciardi Toni , Ryan Aileen , Schwarzenberger Paul , Venhaus Ralph , Reyes Melissa de los , Durham Nicholas M. , Creasy Todd , Huang Raymond Y. , Kaley Thomas , Reardon David A.
Published: April 2023

AbstractPurpose:
PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.
Patients and Methods:
MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS).
Results:
No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome.
Conclusions:
Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.
Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Chi Ping , Qin Li-Xuan , Camacho Niedzica , Kelly Ciara M. , D'Angelo Sandra P. , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary L. , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Thornton Katherine A. , Crago Aimee M. , Francis Jasmine H. , Martindale Moriah , Phelan Haley T. , Biniakewitz Matthew D. , Lee Cindy J. , Singer Samuel , Hwang Sinchun , Berger Michael F. , Chen Yu , Antonescu Cristina R. , Tap William D.
Published: April 2023

AbstractPurpose:
This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs).
Patients and Methods:
This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy.
Results:
The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8–not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months–NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit.
Conclusions:
The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.
Data from BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma
Authors: Mehnert Janice M. , Mitchell Tara C. , Huang Alexander C. , Aleman Tomas S. , Kim Benjamin J. , Schuchter Lynn M. , Linette Gerald P. , Karakousis Giorgos C. , Mitnick Sheryl , Giles Lydia , Carberry Mary , Frey Noelle , Kossenkov Andrew , Groisberg Roman , Hernandez-Aya Leonel F. , Ansstas George , Silk Ann W. , Chandra Sunandana , Sosman Jeffrey A. , Gimotty Phyllis A. , Mick Rosemarie , Amaravadi Ravi K.
Published: April 2023

AbstractPurpose:
Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T).
Patients and Methods:
We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%.
Results:
Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%–65.5%], median PFS was 11.2 months (95% CI, 5.4–16.9 months), and response rate (RR) was 85% (95% CI, 64%–95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively.
Conclusions:
HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.
Data from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors
Authors: Demetri George D. , De Braud Filippo , Drilon Alexander , Siena Salvatore , Patel Manish R. , Cho Byoung Chul , Liu Stephen V. , Ahn Myung-Ju , Chiu Chao-Hua , Lin Jessica J. , Goto Koichi , Lee Jeeyun , Bazhenova Lyudmila , John Thomas , Fakih Marwan , Chawla Sant P. , Dziadziuszko Rafal , Seto Takashi , Heinzmann Sebastian , Pitcher Bethany , Chen David , Wilson Timothy R. , Rolfo Christian
Published: April 2023

AbstractPurpose:
Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up.
Patients and Methods:
Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose.
Results:
At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2]; median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients.
Conclusions:
With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.
Data from The Role of the TP53 Pathway in Predicting Response to Neoadjuvant Therapy in Esophageal Adenocarcinoma
Authors: Sihag Smita , Nussenzweig Samuel C. , Walch Henry S. , Hsu Meier , Tan Kay See , De La Torre Sergio , Janjigian Yelena Y. , Maron Steven B. , Ku Geoffrey Y. , Tang Laura H. , Shah Pari M. , Wu Abraham , Jones David R. , Solit David B. , Schultz Nikolaus , Ganesh Karuna , Berger Michael F. , Molena Daniela
Published: April 2023

AbstractPurpose:
In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients.
Experimental Design:
We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response.
Results:
In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR, 0.10 (95% confidence interval, 0.01–0.55); P = 0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes.
Conclusions:
MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.
Data from Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial
Authors: Shuen Timothy Wai Ho , Alunni-Fabbroni Marianna , Öcal Elif , Malfertheiner Peter , Wildgruber Moritz , Schinner Regina , Pech Maciej , Benckert Julia , Sangro Bruno , Kuhl Christiane , Gasbarrini Antonio , Chow Pierce Kah Hoe , Toh Han Chong , Ricke Jens
Published: April 2023

AbstractPurpose:
SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib ± selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction.
Experimental Design:
The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib alone. Patients were classified as responders or nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by IHC staining of liver and tumor tissues and transcriptomics of blood cells.
Results:
Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and nonresponders receiving SIRT+sorafenib and sorafenib alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP1 were identified as candidate biomarkers at baseline from the 13 responders to SIRT+sorafenib with statistically significant AUC = 1 for all and bootstrap P values 2.23 × 10−5, 2.22 × 10−5, and 2.23 × 10−5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 9 weeks after combined treatment with significant AUC and bootstrap P values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC = 0.9697 and 0.9192 as well as bootstrap P values 8.34 × 10−5 and 7.98 × 10−4, respectively. HCC tumor was the likely origin of circulating EVs.
Conclusions:
In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib-only treatment in patients with advanced HCC of metabolic origin.
Data from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment
Authors: Hoes Louisa R. , van Berge Henegouwen Jade M. , van der Wijngaart Hanneke , Zeverijn Laurien J. , van der Velden Daphne L. , van de Haar Joris , Roepman Paul , de Leng Wendy J. , Jansen Anne M.L. , van Werkhoven Erik , van der Noort Vincent , Huitema Alwin D.R. , Gort Eelke H. , de Groot Jan Willem B. , Kerver Emile D. , de Groot Derk Jan , Erdkamp Frans , Beerepoot Laurens V. , Hendriks Mathijs P. , Smit Egbert F. , van der Graaf Winette T.A. , van Herpen Carla M.L. , Labots Mariette , Hoeben Ann , Morreau Hans , Lolkema Martijn P. , Cuppen Edwin , Gelderblom Hans , Verheul Henk M.W. , Voest Emile E.
Published: April 2023

AbstractPurpose:
Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.
Experimental Design:
In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).
Results:
Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.
Conclusions:
Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.
Data from Targeting Podoplanin for the Treatment of Osteosarcoma
Authors: Takemoto Ai , Takagi Satoshi , Ukaji Takao , Gyobu Nobuhiko , Kakino Mamoru , Takami Miho , Kobayashi Asami , Lebel Marie , Kawaguchi Tokuichi , Sugawara Minoru , Tsuji-Takayama Kazue , Ichihara Kenji , Funauchi Yuki , Ae Keisuke , Matsumoto Seiichi , Sugiura Yoshiya , Takeuchi Kengo , Noda Tetsuo , Katayama Ryohei , Fujita Naoya
Published: April 2023

AbstractPurpose:
Osteosarcoma, the most common bone malignancy in children, has a poor prognosis, especially when the tumor metastasizes to the lungs. Therefore, novel therapeutic strategies targeting both proliferation and metastasis of osteosarcoma are required. Podoplanin (PDPN) is expressed by various tumors and is associated with tumor-induced platelet activation via its interaction with C-type lectin-like receptor 2 (CLEC-2) on platelets. We previously found that PDPN contributed to osteosarcoma growth and metastasis through platelet activation; thus, in this study, we developed an anti-PDPN humanized antibody and evaluated its effect on osteosarcoma growth and metastasis.
Experimental Design:
Nine osteosarcoma cell lines and two osteosarcoma patient-derived cells were collected, and we evaluated the efficacy of the anti-DPN-neutralizing antibody PG4D2 and the humanized anti-PDPN antibody AP201, which had IgG4 framework region. The antitumor and antimetastasis effect of PG4D2 and AP201 were examined in vitro and in vivo. In addition, growth signaling by the interaction between PDPN and CLEC-2 was analyzed using phospho-RTK (receptor tyrosine kinase) array, growth assay, or immunoblot analysis under the supression of RTKs by knockout and inhibitor treatment.
Results:
We observed that PG4D2 treatment significantly suppressed tumor growth and pulmonary metastasis in osteosarcoma xenograft models highly expressing PDPN. The contribution of PDGFR activation by activated platelet releasates to osteosarcoma cell proliferation was confirmed, and the humanized antibody, AP201, suppressed in vivo osteosarcoma growth and metastasis without significant adverse events.
Conclusions:
Targeting PDPN with a neutralizing antibody against PDPN–CLEC-2 without antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity is a novel therapeutic strategy for PDPN-positive osteosarcoma.