tbuckley/cabot-search huggingface dataset:
Economic impact of compassionate use of medicines.
Authors: Claudio Jommi, Federico Pantellini, Lisa Stagi, Marianna Cavazza
Journal: Journal of Clinical Oncology (2021)

e18840 Background: The economic impact of clinical trials in the perspective of trial sites has been already investigated. Instead, there is no evidence on the economic net benefit of compassionate use programs for medicines (CUP). This research aims to fill the information gap, investigating the economic consequences of 8 CUP in Italy carried out from May 2015 to December 2020 in the hospitals’ perspective. These programs concern five cancer medicines (alectinib, atezolizumab, cobimetinib, polatuzumab vedotin, trastuzumab emtansine TDM-1), for a total of 8 programs. Methods: Economic net benefit includes avoided costs for standard of care (SoC) the patient would have received if he/she has not joined the CUP and costs not covered by the pharmaceutical industry and sustained by the hospital hosting CUP. The latter include costs of adverse event (only severe sides effects generating hospitalisation and ascribed to medicines used in CUP), combination therapies and diagnostic procedures not covered by the sponsor. SoC costing relied on publicly available estimation. Adverse events and diagnostic procedures were retrieved from the CUP and monetized using the relevant fee for episode. Results: 1635 cancer patients were treated in eight CUPs. The SoC mean cost per patient ranges from €13355 to €28098 for all cancer drugs. The total cost of the SoC ranges from €21.8 - €45.9 million. The mean cost per patient covered by hospitals hosting CUP was equal to €2732 for cancer drugs, with a total cost of €4.5 million. The net economic benefit ranges from €17.4 million to €41.5 million for cancer treatments. Conclusions: Despite its limitations this paper illustrates for the first time the net economic impact of CUP in oncology patients in the perspective of payers. Additional evaluations are ongoing to better understand the overall effects of CUP implementation, i.e. the economic value of the comparative benefit profile of medicines used in CUP versus the SoC, including potential effects on indirect costs.
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: Sophia Frentzas, Tarek Meniawy, Steven Chuan-Hao Kao, Ruihua Wang, Yunxia Zuo, Hao Zheng, Wei Tan
Journal: Journal of Clinical Oncology (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.
Parkinson’s disease–associated VPS35 mutant reduces mitochondrial membrane potential and impairs PINK1/Parkin-mediated mitophagy
Authors: Kai Yu Ma, Michiel R. Fokkens, Fulvio Reggiori, Muriel Mari, Dineke S. Verbeek
Journal: Translational Neurodegeneration (2021)

Abstract Background Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease (PD), and several genes linked to familial PD, including PINK1 (encoding PTEN-induced putative kinase 1 [PINK1]) and PARK2 (encoding the E3 ubiquitin ligase Parkin), are directly involved in processes such as mitophagy that maintain mitochondrial health. The dominant p.D620N variant of vacuolar protein sorting 35 ortholog (VPS35) gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2 . Methods To better mimic and study the patient situation, we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35 . These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce the PINK1/Parkin-mediated mitophagy, which was assessed using biochemical and microscopy approaches. Results Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state. As a result, the mitochondria of these cells were desensitized to the CCCP-induced collapse in mitochondrial potential, as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult. Consequently, Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired. Conclusion Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35, PINK1 and Parkin in PD.
Heterogeneous Histories of Recombination Suppression on Stickleback Sex Chromosomes
Authors: Jason M Sardell, Matthew P Josephson, Anne C Dalziel, Catherine L Peichel, Mark Kirkpatrick
Journal: Molecular Biology and Evolution (2021)

Abstract How consistent are the evolutionary trajectories of sex chromosomes shortly after they form? Insights into the evolution of recombination, differentiation, and degeneration can be provided by comparing closely related species with homologous sex chromosomes. The sex chromosomes of the threespine stickleback (Gasterosteus aculeatus) and its sister species, the Japan Sea stickleback (G. nipponicus), have been well characterized. Little is known, however, about the sex chromosomes of their congener, the blackspotted stickleback (G. wheatlandi). We used pedigrees to obtain experimentally phased whole genome sequences from blackspotted stickleback X and Y chromosomes. Using multispecies gene trees and analysis of shared duplications, we demonstrate that Chromosome 19 is the ancestral sex chromosome and that its oldest stratum evolved in the common ancestor of the genus. After the blackspotted lineage diverged, its sex chromosomes experienced independent and more extensive recombination suppression, greater X–Y differentiation, and a much higher rate of Y degeneration than the other two species. These patterns may result from a smaller effective population size in the blackspotted stickleback. A recent fusion between the ancestral blackspotted stickleback Y chromosome and Chromosome 12, which produced a neo-X and neo-Y, may have been favored by the very small size of the recombining region on the ancestral sex chromosome. We identify six strata on the ancestral and neo-sex chromosomes where recombination between the X and Y ceased at different times. These results confirm that sex chromosomes can evolve large differences within and between species over short evolutionary timescales.
AKT1 in Asia: A landscape analysis of 11,813 Chinese tumor samples.
Authors: PingPing Gan, Yi Lu, Xiaomin Li, Wanglong Deng, Tiantian Han, Wenjing Xi, Fanfeng Bu
Journal: Journal of Clinical Oncology (2021)

e15076 Background: AKT1 is a key gene of the PI3K/AKT/mTOR signalling pathway. The recent development of ATK1 targeting drug has shown great promise. It is thus important to understand the genomic landscape of AKT1 in a specific population. Methods: Sequencing data of 11,813 tumor samples collected in China were analyzed for AKT1 mutation status. Concomitant genomic aberrations were further analyzed in tumors with AKT1 mutations. Results: AKT1 mutations were observed in 173 of 11,813 tumor samples (1.46%). The most common cancer types in our study included cervical (5.17%), breast (5.15%), osteosarcoma (3.51%), brain (3.14%), head and neck (2.22%) and colorectal (2.02%). We included only the cancer types with more than 50 cases for analysis. Higher frequencies of AKT1 mutation were observed in several common cancers, including brain glioma (1.38% vs 0.67%), breast (5.15% vs 2.92%), cervical (5.17% vs 2.93%), head and neck (2.22% vs 0.95%) cancer in our study than reported in TCGA, but showed no statistically significant difference. The main common type of variation was SNV/Indel (67.63%), amplification (20.81%), deletion (11.56%), fusion (1.16%). Among SNV/Indel, E17K accounted for 32.9% of AKT1 mutations, Q79K only accounted for 0.79%. AKT1 E17K was more commonly found in breast (3.09%), brain (1.96%) and cervical (1.72%) cancer. There is no significant difference between wild type and AKT1 mutated groups in age and gender. III/IV patients were identified in 85.71% of AKT1 mutated group, which were significantly higher than that of wild type group (73.76%; p&lt;0.05).MSI-H patients were identified in 12.16% of AKT1 mutated group, which were significantly higher than that of wild type group (1.8%; p&lt;0.001). Frequencies of specific concomitant aberrations varied between AKT1 mutated and wild type groups. In AKT1 mutated groups, 57 genes are more frequently altered, and mainly enriched in PI3K-Akt signaling pathway (26, q= 2.97E-20, MAPK signaling pathway (count:20, q= 9.74E-15), Central carbon metabolism in cancer (19, q= 5.01E-25), EGFR tyrosine kinase inhibitor resistance (19, q= 3.36E-24). Conclusions: Higher frequencies of AKT1 mutation were observed in several common cancers, including cervical, breast, osteosarcoma, brain, head and neck and colorectal in our study. AKT1 E17K was more commonly found in breast, brain and cervical cancer. Given the fact that III/IV patients are more common in AKT1 mutated group, it coincides with AKT inhibitors therapeutic prospects in a variety of advanced malignant tumors. MSI-H patients are more common in AKT1 mutated group, and it provides possibility for immune checkpoint inhibitors combined with targeted signaling pathway therapy. The enrichment results of the common co-occurring genes with AKT1 in this study, further investigations are still needed.
Trial in progress: Open-label, randomized, comparative phase 2/3 study of combination immunotherapy plus standard-of-care chemotherapy and SBRT versus standard-of-care chemotherapy for the treatment of locally advanced or metastatic pancreatic cancer.
Authors: Tara Elisabeth Seery, Chaitali Singh Nangia, Leonard S. Sender, Sandeep K. Reddy, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2021)

TPS4174 Background: Pancreatic cancer will claim an estimated 47,050 lives in the USA in 2020, with an expected 5 year survival of 10%. Thus there is an urgent need for novel treatment options in this disease. We hypothesize that effective response against pancreatic cancer requires a coordinated approach that orchestrates both the innate and adaptive immune system. We further hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with durable responses in this disease. We describe a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine fusion protein), and off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: The ongoing QUILT 88 phase II/III, multi-center, three-cohort, open-label, US study (NCT04390399) to evaluate the comparative efficacy and overall safety of standard-of-care chemotherapy versus standard-of-care chemotherapy in combination with aldoxorubicin HCl, N-803, and PD-L1 t-haNK in subjects with locally advanced or metastatic pancreatic cancer. Each treatment setting (ie, first line maintenance, second line, or third line or greater) will be evaluated independently as a separate cohort. Subjects with locally advanced or metastatic pancreatic cancer who have received at least 16 weeks of treatment with gemcitabine plus nab-paclitaxel, and have had either a partial response (PR), CR, or stable disease (SD), will be enrolled into Cohort A to receive first-line maintenance therapy. Subjects who have disease progression on or after receiving first-line treatment with gemcitabine plus nab-paclitaxel or another first-line chemotherapy regimen (eg, FOLFIRINOX), or who have discontinued first-line treatment (eg, due to toxicity or intolerance) will be enrolled into Cohort B to receive second-line therapy randomized to irinotecan-liposome/5FU/LV versus experimental arm. Subjects who have disease progression after receiving at least 2 lines of therapy for pancreatic cancer, will be enrolled into Cohort C to receive third-line or greater treatment. Primary endpoints by cohort are: A) PFS per RECIST V1., B &amp; C) OS. The secondary endpoints include overall response rate, DoR, DCR, OS(cohort A) and QoL by patient-reported outcomes. Clinical trial information: NCT04390399.
Complementary detection of genomic alterations in metastatic castration-resistant prostate cancer (mCRPC) from CheckMate 9KD through analyses of tumor tissue and plasma DNA.
Authors: Mark Sausen, Jonathan F. Baden, Natallia Kalinava, Xuya Wang, Jun Li, Esperanza Anguiano, Keziban Unsal-Kacmaz, Megan Wind-Rotolo, Katie Quinn, George Green
Journal: Journal of Clinical Oncology (2021)

5038 Background: Accurate analysis of the genomic alteration landscape within tissue- and plasma-derived tumor DNA using next-generation sequencing (NGS) may provide insights into specific patient populations that benefit from different therapies. The interchangeable use of tissue- and plasma-based assessments may benefit patients when tissue availability is limited, a common occurrence in individuals with mCRPC. To understand the potential sources of technical and biological variability in this setting, we performed comprehensive comparative analyses across 3 NGS platforms, using samples from patients enrolled in CheckMate 9KD, a phase 2 study of nivolumab combined with docetaxel, rucaparib, or enzalutamide for patients with confirmed mCRPC (NCT03338790). Methods: We performed retrospective integrated analyses of sequence and structural alterations identified through comprehensive genomic profiling (CGP) of DNA obtained from formalin-fixed, paraffin-embedded tissue specimens and cell-free DNA obtained from plasma. Tissue-based analysis was performed using the FoundationOne assay (F1, 395 genes), while the FoundationACT (FACT, 70 genes) and GuardantOMNI (OMNI, 500 genes) assays were used for plasma-based analysis. Analysis was performed on samples from 103 patients for which datasets from all 3 assays were available. Inter-platform analysis considered variants with ≥ 0.50% variant allele fraction and common to the shared pairwise targeted regions, while excluding synonymous variants. Results: Through broad profiling of DNA obtained from tissue and plasma, we uncovered previously identified recurrent alteration of AR, TP53, PTEN, and TMPRSS2 fusion with ETS genes. Additionally, we found that 42% (F1), 45% (FACT), and 34% (OMNI) of patients harbored a combination of germline and somatic mutations in homologous recombination repair pathway genes. Across all samples, median tumor mutational burden was 3.5 mutations per megabase (mut/Mb) by F1 and 8.6 mut/Mb by OMNI. Inter-platform variant analyses demonstrated concordance of 52% for F1 vs FACT, 40% for F1 vs OMNI, and 75% for FACT vs OMNI. Conclusions: Overall, these data demonstrate the value of integrated tissue and liquid biopsy profiling in mCRPC. Both technical and biological sources of variation, including panel size, mutation detection algorithms, variant annotation and reporting, analytical performance, circulating tumor DNA levels, and tumor heterogeneity, may be captured differently by tissue- and plasma-based techniques, accounting for the discordance in reported results. Clinical trial information: NCT03338790.
RARE-09. POORLY DIFFERENTIATED CLIVAL CHORDOMA IN EXTREME YOUNG AGE; CASE ILLUSTRATION AND REVIEW OF LITERATURE
Authors: Malak Altewerki, Abdullah AlRamadan, Hindi AlHindi, Essam AlShail
Journal: Neuro-Oncology (2021)

Abstract Chordomas are rare tumors believed to be originated from notochordal remnants. Of all intracranial neoplasms, the incidence of cranial chordomas is less than 1%1. The youngest patient with an intracranial chordoma reported in the literature was a newborn in the first few days after birth9. Intracranial chondroma are more predominant in males compared to females1. The clinical features of intracranial chondroma in the pediatric age group commonly include increased Intracranial pressure, lower cranial nerves palsy, and torticollis2. There is no optimum treatment, however, surgical resection of the tumor followed by radiation therapy reported successful outcome3. This is a case of a poorly differentiated clival chordoma of a 23-month old boy. The clinical features, pathological, radiological findings, and surgical technique are discussed with an elaboration of the current review of the literature of clival chordoma in the extreme young age group. To the best of our knowledge, this is the youngest age of clivus chordoma reported in Saudi Arabia.
Randomized phase III Trial of MEDI4736 (durvalumab) as concurrent and consolidative therapy or consolidative therapy alone for unresectable stage 3 NSCLC: A trial of the ECOG-ACRIN Cancer Research Group (EA5181).
Authors: John M. Varlotto, Zhuoxin Sun, Suresh S. Ramalingam, Heather A. Wakelee, Christine M. Lovly, Kurt R. Oettel, Gregory A. Masters, Nate Pennell
Journal: Journal of Clinical Oncology (2021)

TPS8584 Background: Platinum-based concurrent chemoradiation(CRT) followed by one year of the human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, durvalumab, which blocks the interaction of PD-L1 with its receptors PD-1 and CD80, is the standard of care for locally advanced, unresectable non-small cell lung cancer (NSCLC). Early studies have noted the feasibility of concomitant administration of radiotherapy and immune checkpoint inhibition in NSCLC. EA5181 will evaluate the use of concomitant durvalumab with chemo-radiotherapy for locally advanced NSCLC. Methods: EA5181 is a randomized, multi-center, phase III study for patients with unresectable Stage III NSCLC comparing the efficacy of CRT with concomitant durvalumab to CRT, followed by one year of durvalumab. Eligibility criteria include: an ECOG PS of 0-1, adequate pulmonary function (FEV1 and DLCO both &gt; 40%), no history of auto-immune disease and no past chemotherapy or RT for this lung cancer. Stratification factors include age, sex, stage, and planned concurrent chemotherapy type. Eligible patients with be randomized 1:1 to receive 60Gy RT (2Gy fractions) CRT and durvalumab (Arm A) or 60Gy CRT (Arm B). Investigators will be allowed to choose from three different chemotherapy options: cisplatin/etoposide q 28 days, Pemetrexed/cisplatin q 21 days, and weekly paclitaxel/Carboplatin. Arm A will use 750mg fixed of durvalumab (considered equivalent to 10mg/kg) on days 1, 11, and 21 of RT. Assuming no disease progression, patients in both arms will be followed by monthly (q28 days) fixed dose of 1500mg durvalumab for one year which will be given optimally within 14 days of radiation or when (non)hematologic toxicity is &lt; Grade 2. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, incidence of local/distant progression and toxicity. The target sample size is 660 patients, anticipated to recruit over 55 months, with follow up for an additional 42 months. This provides approximately 82% power if the true hazard ratio for overall survival was 0.75 or less, with 2-sided alpha of 0.05, and assuming a median survival of 42.5 months in the control arm. The study was activated on 04/09/20 and has currently accrued 90 patients on 02/03/21. Clinical trial information: NCT04092283.