bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM).
Authors: Tatineni Vineeth , O'Shea Patrick Joseph , Rauf Yasmeen , Jia Xuefei , Murphy Erin Sennett , Chao Samuel T. , Suh John H. , Peereboom David M. , Ahluwalia Manmeet Singh
Published: June 2021

2034

Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Methods: NSCLCBM patients between 2010 and 2019 were evaluated. We analyzed data regarding molecular marker status, systemic therapies, and date of progression. OS was defined as the start date of systemic therapy to the date of last follow-up or death. The Cox proportional model was used to estimate OS and PFS. Results: A total of 90 patients had ALK gene rearrangement. 16 ALK positive patients received first-generation ALK inhibitor (crizotinib), with a median age of 59.2 years, 50% of the cohort being female and 83.3% being white. Another 17 patients received second-generation (alectinib, ceritinib, brigatinib) and third-generation ALK inhibitors (lorlatinib), with a combined median age of 52.2 years and a cohort of 52.6% females and 72.2% white patients. The 5-year OS rate was 49% (95% confidence interval (CI) = 24%, 71%) for first-generation ALK inhibitors and 76% (95% CI = 40%, 92%) for second and third-generation ALK inhibitors (p-value (p) = 0.019). The median PFS (mPFS) for patients who received first-generation ALK inhibitors was 45.3 months and for those who received second or third-generation ALK inhibitors was 180.1 months. The respective 5-year PFS rate was 43% (95% CI = 19%, 65%) and 72% (95% CI = 42%, 89%). Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective trend towards significant PFS benefit in newer-generation ALK inhibitors when compared to first-generation. These results are encouraging, but the effect on intracranial lesion size and response rates should be examined in the future.[Table: see text]
A phase I/IIa study to evaluate the safety and efficacy of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin.
Authors: Idbaih Ahmed , Ducray Francois , Stupp Roger , Baize Nathalie , Chinot Olivier L. , De Groot John Frederick , Guyotat Jacques , Sonabend Adam M. , Menei Philippe , Dufour Henry , Weinberg Jeffrey , Desseaux Carole , Canney Michael , Schmitt Charlotte , Carpentier Alexandre
Published: June 2021

2049

Background: Low intensity pulsed ultrasound (LIPU) in conjunction with intravenous microbubbles can transiently and reversibly disrupt the blood-brain barrier (BBB), allowing for an increase in the tissue concentration of chemotherapy agents in the brain. Mass spectrometry data from preclinical models (mouse, swine) showed a > 5x enhancement in carboplatin brain concentrations, which correlated well with the spatial distribution of a Gadolinium (Gd) contrast agent used for magnetic resonance imaging (MRI). Methods: The primary objective of this phase I/IIa study (NCT03744026) was to demonstrate the safety of BBB disruption using LIPU in patients with recurrent glioblastoma. This study was a 3+3 design using escalating numbers (3, 6, 9) of activated 1 MHz ultrasound emitters. Nine patients were treated in the escalation phase and another 12 patients were treated with 9 emitters in the expansion phase. Eligibility included recurrent GBM (any recurrence) with a maximum tumor size of < 70 mm. The SonoCloud-9 device (CarThera, Paris, France) was implanted during tumor debulking/resection surgery and replaced the bone flap, with the device targeting the tumor and surrounding peritumoral brain. The device was activated every four weeks for a duration of 270 seconds, concomitantly with IV DEFINITY microbubbles (10 ml/kg), to disrupt the BBB prior to administration of carboplatin (AUC 4-6). MRI was performed to verify safety and evaluate efficacy of BBB disruption with Gd enhancement. Results: No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with two transient, manageable grade 3 wound infections and one grade 1 acquired meningocele event considered as probably related to the overall procedure. The most frequent neurologic adverse events were grade 1 blurred vision (5%) and dizziness (5%). Conclusions: Significant Gd enhancement was observed after more than 90% of sonication sessions, suggesting effective BBB disruption and carboplatin enhancement. Clinical trial information: NCT03744026.
The clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in newly diagnosed and recurrent IDH-wildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study.
Authors: Lombardi Giuseppe , Giunco Silvia , Cavallin Francesco , Angelini Chiara , Caccese Mario , Cerretti Giulia , De Bonis Pasquale , De Rossi Anita , Zagonel Vittorina
Published: June 2021

2053

Background: the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large mono-institutional study to better investigate their impact and their interaction on clinical outcomes Methods: TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio Results: characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0-1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07-0.40). No gene interaction was significant. Conclusions: for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status.
Phase 1 trial of drug resistant immunotherapy: A first-in-class combination of MGMT-modified γδ t cells and temozolomide chemotherapy in newly diagnosed glioblastoma.
Authors: Nabors Louis B. , Lamb Lawrence S. , Beelen Melissa Jo , Pillay Thriumaine , ter Haak Mariska , Youngblood Samantha , Vaickus Louis , Lobbous Mina
Published: June 2021

2057

Background: Temozolomide (TMZ) transiently upregulates NKG2D ligands targeted by innate immune effector cells. Lymphodepletion impairs this immune response, however, genetic modification of ex vivo expanded γδ T cells with an MGMT-expressing lentivector confers resistance to TMZ, allowing concurrent chemotherapy and γδ T cell infusion, thereby targeting the tumor when NKG2DL are maximally expressed. This Drug Resistant Immunotherapy (DRI) is currently being evaluated in a Phase 1 first in human study (NCT04165941) and interim safety and biologic correlative analysis are detailed here for the first dosing cohort. Methods: Adults with newly diagnosed, untreated glioblastoma (GBM), adequate organ function, and a KPS≥70% will be enrolled. Subjects undergo subtotal resection and placement of a Rickham reservoir followed 3-4 weeks by apheresis from which γδ T cells are expanded, transduced with an MGMT-expressing lentivector, harvested, and cryopreserved. Standard of care induction TMZ/radiation therapy is initiated followed by 6 cycles of maintenance TMZ. Intravenous TMZ (150mg/m2) and intracranial dosing of 1 x 107 γδ T cells occur on day 1 of each maintenance cycle. Daily oral TMZ 150mg/m2 follows for Days 2-5. Dose level 1 (DL1) subjects receive 1 fixed dose of γδ T cells and DL2 receive 3 doses administered on Day 1 of each of first 3 cycles of TMZ dependent on absence of dose limiting toxicity. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted at specific time points from peripheral blood and cerebral spinal fluid collected from the Rickham. Results: Six subjects (4 females, 2 males) have been enrolled in DL1. All subjects were IDH1-WT with 5 subjects MGMT unmethylated and 1 methylated. Of these, 1 generated inadequate gd T cells and 2 withdrew consent prior to DRI treatment. For the 3 that received DRI, treatment-related adverse events with maximum CTCAE Grade 3 occurred in 1 subject; UTI, dehydration, and thrombocytopenia. The most common Grade 1/2 events included: fever, leukopenia, nausea, and vomiting which were attributable to TMZ or radiotherapy. Circulating T cells remained below normal range throughout maintenance phase in 2/3 subjects. NK and gd T cell numbers remained within low normal range for 3/3 and 2/3 subjects, respectively. Serum Th1 (IFNg, IL-2, TNFa) and Th2 (IL4, IL5, IL-10) cytokines were within clinical range although TNFa remained elevated from the gdT cell infusion through day +30 in 2 subjects. Conclusions: Administration of MGMT-gene modified gdT cells and TMZ as DRI is feasible in lymphodepleted subjects during TMZ maintenance phase and sufficiently safe to warrant further investigation at additional doses. Clinical trial information: NCT04165941.
Comprehensive molecular pharmacodynamic assessment identifies response markers of intermediary metabolism associated with BPM 31510-IV treatment in advanced glioblastoma multiforme patients.
Authors: Nagpal Seema , Sarangarajan Rangaprasad , Bruce Can , Miller Greg M , Rodrigues Leonardo O , Shah Punit , Searfoss Richard , Ofori-Mensa Kennedy , Tolstikov Vladimir , Greenwood Bennett , Bussberg Valerie , Kiebish Michael A. , Granger Elder , Narain Niven R. , Recht Lawrence David
Published: June 2021

2059

Background: BPM 31510-IV is a drug-lipid conjugate nanodispersion containing oxidized Coenzyme Q10 (CoQ10) in clinical development for glioblastoma multiforme (GBM). In a recently concluded Phase 1 study of BPM 31510-IV (NCT03020602), in addition to safety and tolerability, longitudinal pharmacodynamic samples (20 samples/cycle of 28 days) were collected at various times in patient’s refractory to radiation, temozolomide, and bevacizumab. Methods: Comprehensive multi-omic (proteomic, lipidomic, metabolomic) profiles were generated from buffy coat (proteomics only), plasma, and urine matrices. These data were further analyzed using bAIcis, a Bayesian statistics based artificial intelligence (AI) software, creating causal networks linking clinical information and endpoints to molecular composition of diverse biomatrices of patients prior to, as well as during, treatment with BPM 31510-IV. Twelve subjects comprised the intent to treat population (ITT) which were stratified across days of treatment (DR1; ≤28 days; DLT period; n=6) and (DR2, OS; >28 days; n=6). Bayesian networks and regression analysis were performed on the outputs of the analysis. Molecular analyte panels (combination of proteins, lipids, and metabolites) descriptive of progression free survival (PFS), adverse events (possibly/probably related to BPM 31510-IV), and of overall survival (OS) were generated. Results: Significant alteration (p<0.05) of metabolically associated protein and critical metabolite drivers of intermediary metabolism were identified as causally related to PFS. Significant quantitative changes in levels of several proteins (buffy coat) and metabolites (urine) were identified with probable or possible associations to adverse events in BPM 31510-IV treated subjects. Conclusions: Overall, alterations in proteins and metabolites influencing mitochondrial function and intermediary metabolism that differentiated responders versus non-responders and identified potential markers of adverse events associated with BPM 31510-IV exposure were identified and will be further explored for complementary diagnostic utility.
Autologous stem cell transplantation (ASCT) versus whole brain radiation (WBRT) as a consolidation therapy in primary CNS lymphoma (PCNSL): A nationwide analysis.
Authors: Samhouri Yazan , Ali Moaath M , Jayakrishnan Thejus Thayyil , Bakalov Veli , Fazal Salman , Khan Cyrus , Wegner Rodney E. , Lee Seung Tae , Lister John
Published: June 2021

2062

Background: High dose methotrexate-based regimens remain the most effective treatment against PCNSL but optimal consolidative strategy has yet to be determined. There is lack of high scale clinical trials comparing WBRT versus ASCT as consolidation therapy. Only two phase II randomized clinical trials (PRECIS and IELSG 32) have addressed this question. In this comprehensive national cancer database (NCDB) analysis, we examine the effect of WBRT versus ASCT on survival in PCNSL, we also sought to investigate clinical and socioeconomic predictors of treatment selection Methods: We conducted a retrospective cohort analysis using de-identified data accessed from the NCDB. The NCDB provided records of 16579 patients diagnosed with PCNSL between 2004 and 2016. We excluded patients who tested positive for HIV, and those who started chemotherapy > 120 days or started radiation > 365 days since diagnosis, to account for immortal time bias. Patients were divided into two treatment groups based on consolidation therapy: ASCT and WBRT. Multivariable regression models were used to analyze predictors of treatment selection. To account for variable baseline characteristics, we used propensity score weighting methodology. Survival estimates were calculated using the Kaplan-Meier and Cox proportional hazard regression methods Results: We identified 1620 patients with PCNSL who fulfilled the inclusion criteria. ASCT and WBRT were received by 197 patients and 1423 patients, respectively (Table). On multivariable analysis, increased age decreased the odds of receiving ASCT (OR 0.997, CI: 0.996-0.999, P <.001). Patients live in rural areas (OR 1.174, CI: 1.051-1.312, P=.005), those with higher education (OR 1.089, CI: 1.020-1.163, P=.01), and those who live further from the treating facility (OR 1.001, CI: 1.001-1.001, P<.001) received more ASCT. With a median follow up duration of 27.8 months, adjusted-median OS was 91.4 months and not reached for WBRT and ASCT groups, respectively (log-rank P<.001). Adjusted 3-year OS was 82% and 67% in ASCT and WBRT, respectively (HR: 0.43, CI: 0.29-0.64, P<.001) Conclusions: Consolidation with ASCT had improved OS compared with WBRT. There is a trend toward increased ASCT use and decreased WBRT use over the study period. We found clinical and socioeconomic factors that affected treatment selection.[Table: see text]
Concordance of blood and tissue TMB from NGS testing in real-world settings and their ability to predict response to immunotherapy.
Authors: Sturgill Emma , Misch Amanda , Jones Carissa , Luckett Daniel , Fu Xiaotong , Jones Suzanne Fields , Burris III Howard A. , Spigel David R. , McKenzie Andrew Jacob
Published: June 2021

2540

Background: Tumor mutational burden (TMB) detected by tissue-based Next Generation Sequencing (NGS) is a biomarker for immunotherapy (IO) response. Plasma-based NGS vendors have developed methods for quantifying TMB from circulating tumor DNA; however, the concordance of blood-TMB (bTMB) and tissue-TMB (tTMB) in real-world settings has not been examined. In this study, we analyzed paired bTMB-tTMB values from cancer patients in community oncology clinics who underwent both plasma- and tissue-based NGS testing to determine whether bTMB predicts response to IO equal to tTMB. Methods: We analyzed 112 patient-matched bTMB-tTMB pairs from 102 unique patients in community oncology settings who received both plasma- and tissue-based NGS profiling at any point in care. NGS results were reported by Foundation Medicine (n = 28 plasma, n = 66 tissue), Guardant Health (n = 78 plasma), and Caris Life Sciences (n = 42 tissue). NGS results were linked with electronic medical records in Genospace, Sarah Cannon’s precision medicine platform. Pearson’s correlation (r) and Lin’s concordance (ρ) coefficients were used for statistical analysis. Results: bTMB exceeded the patient-matched tTMB by an average 2.4-fold; therefore, while the two values showed a positive linear correlation (r2= 0.62, p = 0.01e-27) their concordance was only moderate (ρ = 0.58, n = 112). Gastrointestinal cancers exhibited the lowest correlation (r2= 0.01, p = 0.5) and concordance (ρ = 0.03, n = 35). The discordance between bTMB and tTMB was not an outcome of the specimens being collected on different dates, as the bTMB/tTMB ratio did not correlate with the time between plasma and tissue specimen collection (r2= 0.003, p = 0.84, n = 112). While a majority of bTMB-tTMB pairs had agreement in high vs. low status (High ≥ 10 mut/Mb; Low < 10 mut/Mb), a considerable portion were bTMB-High/tTMB-Low (see table). Strikingly, the bTMB-High/tTMB-Low patients who received IO had an average time to treatment failure (TTF) that surpassed that of the bTMB-High/tTMB-High cohort (see table). Considering bTMB alone, patients with a high status outperformed those with a low status on IO (bTMB-High: TTF = 200 days, n = 21; bTMB-Low: TTF = 125 days, n = 12). Conclusions: In real-world settings where tissue- and plasma-based NGS panels are ordered as standard of care, bTMB values are consistently higher than tTMB values. This discrepancy leads to plasma-based tests resulting a TMB-High designation more frequently than tissue-based NGS tests. Patients who are TMB-High by plasma perform relatively well on IO, indicating that bTMB may be a particularly effective biomarker of IO sensitivity.[Table: see text]
Efficacy of HX008 in high microsatellite instability/mismatch repair–defificient (MSI-H/dMMR) solid tumors: Results from a multicenter phase II open-label study.
Authors: Huang Jing , Song Yan , Luo Suxia , Yin Xianli , LI Enxiao , Wang Hui , He Yifu , Liu Zhihui , Fan Qingxia , Liang Xinjun , Shu Yongqian , Liu Yunpeng , Xu Nong , Zhang Shu , Zhuang Zhixiang , Zhang Jingdong , Kou Xiaoge , Wang Fen , Zhu Xiaodong , Li Shengmian
Published: June 2021

2572

Background: The subsequent treatment choices are limited for the patients with advanced solid tumors who had failed the standard therapies. PD-1 blockade monotherapy demonstrated robust antitumor activity in patients with MSI-H/dMMR. The aim of this study is to identify the efficacy and safety of HX008, an anti-PD-1 monoclonal antibody, in patients with advanced MSI-H/dMMR solid tumors. Methods: Eligible patients were age ≥18 years with histologically/cytologically confirmed advanced MSI-H/dMMR solid tumors, who have failed at least one line of standard systemic therapy. MSI-H/dMMR status was assessed centrally. Patients received HX008 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed 9 weeks after the first treatment, then every 6 weeks for the first year of therapy, and every 12 weeks thereafter. The primary end point was objective response rate (ORR) per RECIST1.1. Results: One hundred patients were enrolled from October 2018 to December 2020, with a median age of 53 (range 20-74) years. All of the patients were ≥ second-line patients. The most common cancer types were colorectal cancer (N=74) and gastric cancer (N=10). Median follow-up is 8.97 (range 0.03-25.53) months at the time of data cutoff. Among 86 patients who had reached the initial response evaluation, there were 8 CR, 33 PR, 24 SD, 17 PD and 4 NE. ORR was 47.67% (95%CI 36.79%-58.73%), and DCR was 75.58% (95%CI 65.13%-84.20%). ORR and DCR for the 66 colorectal cancer patients were 50% (95%CI 37.43-62.57%) and 75.76% (95%CI 63.64-85.46%). Median PFS was not reached (95%CI 6.18-NR) for all enrolled patients, while the 6-month and 12-month PFS rates were 62.66% (95%CI 50.98%-72.31%) and 52.70% (95%CI 39.96%-63.94%), respectively. Median OS was not reached. Treatment-related adverse events occurred in 77 patients (77%). Twelve patients (12%) had grade 3 or 4 treatment-related adverse events and there were no grade 5 treatment-related adverse events. The grade 3 or 4 treatment-related adverse events with incidence >1% included anemia (2%) and leukopenia (2%). Immune-related adverse events were observed in 15 patients (15%), including hypothyroidism in 9 patients (all were grade 1-2), and hepatitis, hyperglycemia, myocarditis, creatin kinase/creatin kinase MB increased, hypopigmentation of the vulva, rash, each in 1 patient. Conclusions: HX008 as a ≥second-line therapy showed promising efficacy and a manageable safety profile in patients with MSI-H/dMMR advanced solid tumors. Clinical trial information: NCT03704246.
AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors.
Authors: Frentzas Sophia , Meniawy Tarek , Kao Steven Chuan-Hao , Wang Ruihua , Zuo Yunxia , Zheng Hao , Tan Wei
Published: June 2021

2583

Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.
The predictive values of loss-of-function variants in histone methyltransferases for response to immune checkpoint inhibitors in solid tumors.
Authors: Liang Naixin , Niu Yanling , Zhang Xin , Ma Tonghui
Published: June 2021

2586

Background: Dysregulation of histone methyltransferases (HMTs) has been reported to play critical roles in cancer development. Previous studies showed that many HMTs were recruited to DNA damage sites where they posttranslationally modified chromatin to regulate chromatin-based DNA damage repair (DDR) activities. We hypothesized that loss-of-function (LOF) variants of HMTs may associate with genome instability and tumor mutational burden (TMB). Thus, we explored the associations of LOF variants in some HMTs with TMB and benefit from immune checkpoint inhibitors (ICIs) in solid tumors. Methods: An ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was analyzed. The following solid tumor types were enrolled: NSCLC (n = 350), colorectal cancer (n = 110), bladder cancer (n = 215), breast cancer (n = 44), esophagogastric cancer (n = 126), head and neck cancer (n = 139), glioma (n = 117), melanoma (n = 320), and renal cell carcinoma (n = 151). We evaluated 15 HMTs (KMT2A, KMT2B, KMT2C, KMT2D, SETD2, SETD8, EZH1, EZH2, PRDM1, PRDM14, SMYD3, NSD1, WHSC1, WHSC1L1, and DOT1L). Results: The data revealed that LOF variants of KMT2D, SETD2, and KMT2C were more frequent in pan-cancer dataset. Furthermore, we found that LOF variants of 7 HMTs, including KMT2A, KMT2B, KMT2C, KMT2D, NSD1, SETD2, and EZH2, were associated with higher TMB (P < 0.0001). Then we analyzed the associations between LOF variants and overall survival (OS) after ICIs therapy. The results indicated that LOF variants of KMT2A (P = 0.0295), KMT2B (P = 0.0329), KMT2C (P = 0.0122), and SETD2 (P = 0.0004) were significantly associated with prolonged median OS for all the enrolled patients. In this cohort, LOF variants of KMT2A, KMT2B, KMT2C, and SETD2 were most common in bladder cancer, colorectal cancer, colorectal cancer, and renal cell carcinoma, respectively. Then we assessed the predictive values of these four genes for each type of cancer. It was noteworthy that KMT2C LOF variants were significantly correlated with longer median OS in colorectal cancer (P = 0.0171), but not in other cancer types. Surprisingly, we did not observe the predictive roles of LOF variants in KMT2A, KMT2B, and SETD2 genes for response to ICIs therapy in any types of cancer. Conclusions: In pan-cancer dataset, we found that LOF variants of 4 HMTs, such as KMT2A, KMT2B, KMT2C, and SETD2, were correlated with better outcomes of ICIs treatment. However, for different types of cancer, only KMT2C LOF variants were associated with longer median OS in colorectal cancer, suggesting that it may be used as a predictive biomarker for ICIs efficacy in colorectal cancer. Because the sample sizes of patients with KMT2A, KMT2B, or SETD2 LOF variants were small, we did not find the predictive values of LOF variants in these three genes for different types of cancer. Next, we will enroll more patients to address this question.
Association of KMT2C mutations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.
Authors: Liu Chunling , Duan Qianqian , Zhang Qin
Published: June 2021

2600

Background: The KMT2 (lysine methyltransferase) family of histone modifying proteins play important roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many solid tumor cancers. Recently, there is emerging evidence that KMT2 family genes are involved in sensitivity to immune checkpoint inhibitors (ICIs) by modulating the immune environment. Here we explored the relationship between KMT2C mutation and its efficacy of immunotherapy. Methods: 1661 patients with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC clinical cohort were used to explore the association with KMT2C mutation and TMB and efficacy of ICIs. TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. NGS data of 6624 pan-cancer patients who also detected MSI and PD-L1 expression from the Chinese clinical dataset were also analyzed relevance of mutation and these immune-related indicators. Results: In total, 9.81% (163/1661) patients in MSKCC cohort harbored KMT2C mutation. In the Chinese cohort, the KMT2C mutation ratio (11.19%, 741/6624) was similar to MSKCC. The TMB level of KMT2C mutation group in both MSKCC cohort and Chinese pan-cancer patient cohort was significantly higher than wild-type group (P < 0.001). A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was significantly associated with better OS (hazard ratio, 0.69; 95%CI, 0.52-0.90; P = 0.006), and association remained significant with bladder (P = 0.039), colorectal (P = 0.024), melanoma (P < 0.001) and renal (P < 0.001), adjusting for cancer age, sex, metastases or primary. In addition, in Chinese cohort, KMT2C mutation was associated with higher PD-L1 positive expression (≥1%) (P = 0.01203) and MSI-H (P < 0.001). Conclusions: KMT2C mutation shows impressive association with efficacy of ICIs. Meanwhile, KMT2C-mutant group has a higher TMB, PD-L1 expression and MSI-H. These results indicated that KMT2C mutation may serve as a good potential biomarker of ICI benefit in patients with multiple cancer types.
A phase 1 study of an off-the shelf, multi-neoantigen vector (ADXS-503) in subjects with metastatic non-small cell lung cancer (NSCLC) progressing on pembrolizumab as last therapy.
Authors: Haigentz Missak , Ramalingam Suresh S. , Gerstner Gregory James , Halmos Balazs , Morganstein Neil , Vangala Surya , Parsi Megan , Kabala Victor , Simkhada Dinesh , Metran Cristiane , GUTIERREZ ANDRES A. , Goldman Jonathan Wade
Published: June 2021

2616

Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programmed death receptor-1 (PD-1)- blocking antibody approved for the treatment of advanced lung cancer. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: A phase 1 study of A503 ± Pembro has been conducted in patients (pts) with metastatic squamous or non-squamous NSCLC. In dose-escalation part B, A503 was added-on to Pembro within 12 weeks of the first scan showing disease progression per RECIST criteria v1.1. Both, A503 (1 x108 CFU) and Pembro (200 mg) were infused by IV every 3 weeks until disease progression or limiting toxicity. The dose-escalation cohort has established safety, tolerability and immunogenicity of the combination therapy and it has been further expanded to evaluate efficacy (Goldman JW et.al., SITC 2020). Results: Nine pts have been treated and evaluated in Part B. Pembro + A503 combo has been well tolerated and without immune related AEs. Of the nine evaluable pts, one has achieved partial response (PR) and 3 stable disease (SD), yielding an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Two patients have had clinical benefit for over 12 months (i.e., one PR and one SD) and both of them had been on Pembro therapy for 2 years before enrollment. The two other pts with SD have sustained it for almost 6 months thus far. Seven pts have been evaluated for immunogenicity. In all pts there was a transient release of pro-inflammatory cytokines and proliferation of cytotoxic- and memory-CD8+ T cells. Seven evaluable pts had antigen-specific T cells within 1-2 weeks after starting therapy and 4/7 showed antigen spreading. Conclusions: ADXS-503 as an add-on therapy to Pembro at disease progression has been well tolerated and it has induced antigen specific-T cell responses and durable disease control in 44% of pts. Part B cohort is currently enrolling additional pts to further explore the potential reversal of Pembro resistance with ADXS-503. Clinical trial information: NCT03847519.
Final report and long-term outcomes: Phase I trial of a HER2 intracellular plasmid-based vaccine in HER2+ advanced stage breast cancer.
Authors: Disis Mary L. , Dang Yushe , Coveler Andrew L. , Higgins Doreen , Childs Jennifer , Salazar Lupe G
Published: June 2021

2619

Background: Vaccination with the intracellular domain (ICD) of HER2 in pre-clinical models is both immunogenic and protective against the development of mammary tumors. This study (NCT00436254) was designed to examine the safety and optimal immunogenic dose of a DNA-based vaccine encoding the HER2 ICD in subjects with HER2+ breast cancer. Methods: Sixty-six patients with stage III or IV HER2 + breast cancer in remission or with stable bone only disease were enrolled into three vaccine arms: 1 (10mcg dose of plasmid), 2 (100mcg) and 3 (500mcg). Vaccines were administered i.d. monthly for three immunizations. Endpoints included safety and optimal dose. HER2 specific IFN-gamma immune responses were evaluated and DNA persistence at the vaccine site was assessed. Toxicity and clinical outcomes were followed for 10 years. Results: The majority of vaccine-related toxicity was grade 1 (89%) and grade 2 (11%) and was not significantly different between the three dose arms. All Arms developed HER2 ICD immunity after vaccination, however, patients in Arm 2 and Arm 3 had significantly better immune responses (of higher magnitude and at most time points) than patients in Arm 1 (p=0.003 and p<0.001, respectively) after adjusting for baseline factors. At 60 weeks, the number of patients who maintained the greatest fold-difference in HER2 ICD immune responses from their baseline was highest in Arm 2 (73%) when compared to Arm 1 (47%) and Arm 3 (45%). Associations between ICD responses and plasmid DNA persistence at the vaccine site were estimated via linear regression models. HER ICD immunity after the end of immunizations, relative to baseline, was significantly lower in patients with DNA persistence at week 16 compared to those without persistence (p=0.02). Patients at the highest dose demonstrated the greatest incidence of plasmid persistence (92%) as compared to 33% in Arm 1 and 10% in Arm 2. The median time of follow-up was 118.6 months (Arm 1), 99.7 months (Arm 2), and 73.5 months (Arm 3). The median OS and PFS has not been reached in any Arm and did not differ with respect to treatment arm (Log-rank p-value 0.36 for OS, and 0.63 for PFS). However, we observed a separation of Kaplan-Meier curves for OS from about 40 months and curves for PFS from about 30 months, and the separation maintained until the end of the study for Arm 2 versus Arm 1 and Arm 3. One patient in Arm 2 developed lymphocytic colitis 2.2 years from enrollment deemed possibly related to vaccination. Conclusions: An intermediate dose (100mcg) of vaccine was immunogenic and associated with persistence of immunity at 60 weeks. A randomized phase II trial of the HER2 ICD plasmid-based vaccine in the neoadjuvant setting is in development. Clinical trial information: NCT00436254.
Real world experience with standalone immunotherapy regimens: Immune-related adverse events, healthcare utilization and cost among patients with commercial or Medicare Advantage insurance.
Authors: Gunturu Krishna Soujanya , Pham Timothy , Shambhu Sonali , Fisch Michael Jordan , Barron John , Debono David Joseph
Published: June 2021

2625

Background: Immunotherapy is a fast growing class of cancer therapy. We evaluated the rates of immune-related adverse events (irAEs), healthcare utilization, and costs up to 1 year post-index among patients using monotherapy (PD-1/PD-L1 inhibitor) and combination therapy (PD-1/PD-L1 with CTLA-4 inhibitors). Methods: We reviewed claims from the HealthCore Integrated Research Database (HIRD), which contains commercially insured/Medicare Advantage members and captures clinical, utilization, and cost measures. We analyzed both the monotherapy (M) and combination therapy (C) cohorts focusing on members with ≥ 6 months of baseline continuous medical and pharmacy coverage. Descriptive and multi-variate analyses were performed. Results: The C cohort had 904 and M had 9,084 patients, with mean ages of 58 and 64 years, respectively. Prominent cancer types were melanoma for C and lung for M. The most common incident irAEs (%) for C vs. M were: endocrinopathies (27.7, 14.7), hepatitis (17.1, 7.7), nephritis (21.0, 14.0), neuropathy (6.6, 7.0), followed by colitis, dermatitis, and myocarditis. After adjustment, C therapy showed greater risk of all-cause inpatient admissions (OR 2.27, 95% CI 1.93, 2.66), all-cause emergency department (ED) visits (OR 1.55, 95% CI 1.33, 1.81) and irAE-related visits (See table). Mean adjusted all-cause cost difference for C vs M was +$43,747 (95% CI $38,440, $49,427). In age ≥65 subset, 222 received C and 4,208 received M. C therapy patients had more irAE-related hospitalizations (45.3% vs. 57.7%, p=0.0004). Costs were similar to the main cohort. Conclusions: C therapy showed greater incident irAE rates, increased utilization and medical costs compared to M therapy. Limitations include less precise ascertainment of irAEs in claims data and generalizability only to those with commercial or Medicare Advantage insurance. Our study highlights the increased toxicity and cost tradeoffs involved in choosing combination immunotherapy over monotherapy.[Table: see text]
BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results.
Authors: Schoffski Patrick , Cho Byoung Chul , Italiano Antoine , Loong Herbert H. F. , Massard Christophe , Medina Rodriguez Laura , Shih Jin-Yuan , Subbiah Vivek , Verlingue Loic , Andreas Karen , Basson Craig T. , Clawson Alicia , Ho Peter T.C. , Knight Shelley , Scheuber Anita , Keegan Mitchell
Published: June 2021

3008

Background: RET (REarranged during Transfection) gene alterations (mutations and fusions) leading to constitutive kinase activity are identified as drivers of disease progression in multiple tumor types, including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). BOS172738 is an investigational, potent, selective oral RET kinase inhibitor. This next-generation inhibitor was designed with nanomolar potency against RET and >300-fold selectivity against vascular endothelial growth factor receptor 2, to maximize the potential therapeutic window. Methods: NCT03780517 is a phase 1 study consisting of a dose-escalation and dose-expansion phase. During the escalation, 67 patients with RET-altered advanced solid tumors received once-daily oral doses of BOS172738 (10-150 mg). Intra-patient dose escalation was allowed as was over-accrual to dose levels deemed to be safe. Study endpoints were safety (CTCAE v. 4.03), tolerability and confirmed overall response rate (ORR; RECIST 1.1). The data cutoff was Dec. 11, 2020. Results: BOS172738 exhibited a favorable safety profile (n=67) for long-term administration with most treatment-emergent adverse events (TEAEs) classified as grade ≤2 and deemed unrelated to drug. The most common TEAEs were creatinine phosphokinase (CPK) increase (54%), dyspnea (34%), facial edema, aspartate aminotransferase elevation, anemia (25% each), neutropenia, diarrhea (22% each), fatigue (21%), and constipation (20%). BOS172738 was not associated with hypertension or significant hepatoxicity. BOS172738 demonstrated broad anti-tumor activity with an investigator-assessed ORR of 33% (n=18/54), a NSCLC ORR of 33% (n=10/30), MTC ORR of 44% (n=7/16, including 1 complete response) and one patient with RET fusion+ pancreatic cancer reported a partial response. Responders included patients with brain metastases with one patient whose brain lesion decreased by 43%. The median duration of response has not been reached. Many patients remain on study, including the longest of 659 days, at data cutoff. BOS172738 exhibited dose-dependent exposure (AUC, Cmax), rapid absorption (median Tmax 1 to 4.5 h), and an extended half-life (approximately 65 hours) maximizing target coverage. Conclusions: BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases. BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors. Clinical trial information: NCT03780517.
Racial and ethnic disparities among participants in precision oncology clinical studies.
Authors: Aldrighetti Christopher M. , Niemierko Andrzej , Van Allen Eliezer Mendel , Willers Henning , Kamran Sophia C.
Published: June 2021

3014

Background: Precision medicine has revolutionized oncologic care in the United States (US) in the past two decades. While the US cancer population is rapidly diversifying, enrollment of a diverse patient population into clinical trials lags behind. In particular, it is unclear whether minority patients are adequately represented in precision oncology trials. Herein, we report racial/ethnic representation in precision oncology studies spanning four common cancer types (breast, lung, prostate, colorectal cancers). Methods: Completed US clinical studies incorporating precision medicine objectives based on a set of 12 precision oncology search terms (including tumor biomarker, whole exome sequencing, tumor mutation testing, gene expression signatures, tumor microarray, tumor genomics, et cetera) were identified from Clinicaltrials.gov. Studies were reviewed for reporting race/ethnicity for inclusion in the analysis. The Surveillance, Epidemiology, and End Results (SEER) database was used to determine incidence of race/ethnicity in the US cancer population, correlated with disease site and median year of enrollment for each trial. The difference in incidence (D-I) was defined as the median absolute difference in study racial enrollment and SEER incidence, with a negative value corresponding to underrepresentation. Wilcoxon signed-rank test was used to compare median D-I to a value of 0 by racial/ethnic subgroups. Results: Overall, 156 studies were identified; 40.3 and 27.5% studies enrolling from 2000 through 2020 met the inclusion criteria for racial and ethnic subgroups reporting, respectively. Of 4,418 total enrollees, 82.5% were White, 10.5% Black, 3.8% Asian, and 0.4% American Indian/Alaskan Native (AIAN). Ethnically, 6.4% were Hispanic. The D-I was +2.2% for Whites (interquartile range (IQR) = -43.7% to 25.4%; P < 0.013), -0.74% AIAN (IQR = -0.8% to +5.9%; P < 0.001), -2.5% Asians (IQR = -4.1% to 30.4%; P < 0.152), -4.6% Blacks (IQR = -20.1% to +45.0%; P < 0.001), and -8.1% Hispanics (IQR = -14.8% to + 29.6%; P < 0.001). By disease site, Blacks were significantly underrepresented proportional to their cancer incidence among prostate (D-I of -11.8%, p = 0.009) and lung studies (D-I of -5.9%, p = 0.013), while prostate studies significantly overrepresented Whites (D-I +14.0%, p = 0.005). Lung studies overrepresented Asians (D-I +0.49%) consistent with the prominent role of targetable oncogene drivers in this population. Conclusions: Results demonstrate an underrepresentation of minority racial groups and an overrepresentation of Whites in precision oncology studies. Increased emphasis on equitable enrollment onto these studies is critical, as resulting precision Omic conclusions are used to stratify populations and personalize treatments. A continued lack of diversity among enrollees may further leave behind vulnerable minority populations in the era of precision oncology.