bluuebunny/crossref_metadata_2025 huggingface dataset:
ERBB2 amplifications and mutations in 109 advanced breast cancer patients by next-generation sequencing.
Authors: Shah Ami N. , Finkelman Brian , Gerratana Lorenzo , Davis Andrew A. , Katam Neelima , Lin Chenyu , Carroll Kristen , Jacob Saya , Wehbe Firas , Gurley Michael , Lin Fang , Blanco Luis , Vagia Elena , Platanias Leonidas C. , Gradishar William John , Behdad Amir , Cristofanilli Massimo
Published: May 2020

3565

Background: In advanced breast cancer (ABC) HER2 status is based on ASCO/CAP immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) criteria. Next generation sequencing (NGS) of tissue and blood can detect aberrations in ERBB2 such as copy number gain/amplifications (cng/amp) and mutations. Methods: We retrospectively identified patients (pts) seen at Northwestern University between 2015 and 2019 with ABC and an alteration in ERBB2 identified by tissue and/or circulating tumor DNA (ctDNA) NGS. We included pts with testing by Guardant360, TempusX, and/or FoundationOne platforms. NGS reports were evaluated for non-synonymous mutations and cng/amp. HR and HER2 status were determined based on the most recent pathologic assessment. Mutations were categorized as pathologic if they were consider oncogenic (level 1-2 evidence with direct functional data), likely oncogenic, or predicted oncogenic, based on OncoKB (Chakravarty et al., JCO PO 2017). Results: 109 cases of ABC (6 locally advanced, 103 metastatic) with ERBB2 alterations were identified. Tissue NGS was available from 43%, ctDNA from 72%, and both from 19%. The positive predictive value (PPV) of ERBB2 amp/cng by tissue NGS to predict HER2+ using the gold standard as IHC/FISH was 94% (33/35). The PPV of ERBB2 amp by ctDNA was 93% (40/43). ERBB2 mutations were detected in 52 pts. Of these, 23 pts were considered to harbor pathologic ERBB2 mutations, (19 oncogenic, 2 likely oncogenic, 1 predicted oncogenic) detected by ctDNA and tissue in 4, ctDNA in 16, and tissue in 3 pts. The most frequently detected mutations were V777L and S310. Four pts had co-mutations of ERBB2 V777L and S310F. Disease subtype among those with ERBB2 pathologic mutations was HR+ HER2- in 57%, HER2+ in 26%, and triple negative in 17%. In all patients with serial ctDNA analysis and pathologic ERBB2 mutations, the mutation was detected on the first analysis. Pathologic ERBB2 mutation represented the mutant with the highest mutant allele frequency (MAF) in 30% and top 3 highest MAF in an additional 35%. PIK3CA was co-mutated in 48%. Conclusions: The PPV of ERBB2 amp/cng by tissue and ctDNA NGS was high, and has potential utility for cancers where HER2 IHC/FISH is not standardly assessed or cases where biopsy is challenging. ERBB2 pathologic mutations were found in all breast cancer subtypes. When present, they were identified on the initial ctDNA analysis and often represented a significant clone, supporting its role as a ‘driver mutation’.
Diagnosis of leptomeningeal metastasis (LM) through identification of circulating tumor cells (CTCs) in cerebrospinal fluid (CSF).
Authors: Fenn Kathleen , Singh Veena M. , Lee Shing Mirn , Cieremans David , Lassman Andrew B. , Hershman Dawn L. , Crew Katherine D. , Accordino Melissa Kate , Trivedi Meghna S. , Iwamoto Fabio Massaiti , Schultz Robbie , Huynh Lan , Sales Edgar V. , Fisher Deanna M , Mayer Julie A , Kreisl Teri Nguyen , Kalinsky Kevin
Published: May 2020

3567

Background: Diagnosis of LM from solid tumors can be challenging. The TargetSelector (TS) CTC detection assay has demonstrated highly specific and sensitive CTC capture both for epithelial (CK+) and non-epithelial (CK-) subsets. The assay utilizes a ten-antibody (ab) capture cocktail followed by biotinylated secondary abs that bind to CTCs, enriched in a microfluidic device. TS targeted next-generation sequencing (NGS) assay detects somatic mutations in 12 breast cancer-related genes. The aim was to determine whether TS can improve sensitivity in the diagnosis of LM compared to CSF cytology by lumbar puncture (LP). Methods: CSF was collected prospectively from patients (pts) with a prior solid tumor diagnosis and suspicion of LM. CTCs were isolated from CSF using the TS platform. Cells were stained with cytokeratin (CK), CD45, streptavidin and DAPI. CTCs captured in a microchannel were classified as CK + or -. Peripheral blood samples obtained at time of LP underwent similar CTC analysis. Cell-free total nucleic acids (cfTNA) were extracted from plasma and CSF followed by NGS. Data analysis used the Ion Torrent Suite with annotation and report curation by Ion Reporter and Oncomine Knowledgebase Reporter software respectively. Results: There were 14 pts (13 women and 1 man), median age 56 years (range 32-75) with cancers of the breast (10), lung (1), colon (1), CNS lymphoma (1) or glioma (1). Pts had received a median of 2.5 lines of systemic metastatic therapy (range 0-8). CSF cytology was not sent for 1 pt and TS was not performed for 1 pt. TS and standard cytology had 89% agreement in pts with metastatic breast cancer (MBC, 8/9). Of the 6 pts for whom CTCs were detected in CSF by TS, 3 pts had + cytology (all MBC), 2 pts had - cytology and 1 pt with MBC was not tested by cytology. Of the 3 pts with + CSF by cytology (all MBC), all were detected by TS (Table). Among 5 MBC pts with CTCs present in CSF, ER status was concordant in 2 of 5 (40%). HER2 status was concordant in 3 of 4 (75%) evaluable pts and not determined in 1 pt. Analysis of cfDNA from CSF identified somatic mutations in 3 pts (TP53, PIK3CA, CCND1, respectively). In 1 of 3 pts, the mutation identified in the CSF (PIK3CA) in HR+/HER2- MBC was also identified in the blood. Conclusions: TargetSelector is a viable platform for the detection of breast cancer CTCs in the CSF. NGS performed on CSF samples can identify potentially actionable mutations. [Table: see text]
PCR-based comprehensive genomic profiling (PCR-CGP): Feasibility from >20,000 tumor tissue specimens (TTS) and predicted impact on actionable biomarker identification versus hybrid capture (H)-CGP and plasma (P)-CGP.
Authors: Rhodes Dan , Hovelson Daniel H , Suga Jennifer Marie , Anderson Daniel M. , Dees Elizabeth Claire , Koh Han A. , Burkard Mark E. , Khatri Jamil , Safa Malek M. , Matrana Marc Ryan , Yang Eddy Shih-Hsin , Menter Alex R. , Parsons Benjamin Marshall , Slim Jennifer Nadine , Falkner Jayson , Reeder Travis , Vakil Hana , Kwiatkowski Kat , Johnson Bryan , Tomlins Scott A. ,   Strata Network Investigators
Published: May 2020

3574

Background: Tissue-based h-CGP is increasingly utilized for treatment selection in patients with advanced solid tumors but has high tumor surface area [TSA] requirements (≥25mm2 for leading commercial tests). P-CGP is recommended when tissue is insufficient for H-CGP. Here we assessed the feasibility and clinical impact on actionable biomarker identification of PCR-CGP. Methods: We performed a post-hoc, non-prespecified analysis on 21,743 consecutive subjects with advanced solid tumors who sent TTS for PCR-CGP from 5/17-12/19 as part of an ongoing observational trial at > 20 U.S. health systems (NCT03061305). PCR-CGP was performed using StrataNGS, a single-site laboratory developed test assessing all CGP biomarker classes (including microsatellite instability (MSI) status and tumor mutation burden [TMB]). We predicted actionable biomarker identification rates for PCR-CGP, H-CGP and P-CGP if applied to all U.S. patients with advanced solid tumors through incorporating population incidence, biomarker frequencies, test TSA and tumor content requirements (or cfDNA detection rates), and performance characteristics. Actionable biomarkers were the 30 in 11 tumor types from the MolDX p-CGP local coverage determination (L38043), pan-tumor NTRK fusions and MSI, and TMB in lung cancer. Results: Among TTS from 21,734 patients with advanced cancer, 20,493 (94.3%) met TSA requirements for PCR-CGP (≥2mm2) vs. 9,281 (42.7%) for H-CGP. PCR-CGP reported results for 98.0% and 95.0% of patients with large (≥25mm2 TSA) and small (2-24mm2) TS, respectively, in a median of 7 business days. Compared to 1,882 orthogonal actionable biomarker results, PCR-CGP accuracy was 96.6% and 96.5% in large and small TTS, respectively. Actionable biomarker frequency was highly correlated in PCR-CGP tested large vs. small TTS (r2= 0.99), as well as in this PCR-CGP cohort vs. a MSKCC institutional pan-cancer H-CGP cohort (r2= 0.92). If applied to all U.S. patients with advanced solid tumors, PCR-CGP has significantly greater predicted actionable biomarker identification rate (88.5%) compared to P-CGP (77.0%, N-1 chi-squared test, p < 0.0001) or H-CGP (54.3%, p < 0.0001). Conclusions: Half of TTS submitted for PCR-CGP did not meet H-CGP tissue requirements. PCR-CGP is feasible for the vast majority of patients and is predicted to expand the actionable biomarker evaluable proportion of patients with advanced solid tumors compared to H-CGP or P-CGP. Clinical trial information: NCT03061305 .
Highly accurate automated tissue classification using deep learning on digital pathology images: A novel tool for resolving conflicts in diagnosis.
Authors: Benz Stephen Charles , Beziaeva Liudmila , Jaber Mustafa , Rabizadeh Shahrooz , Szeto Christopher
Published: May 2020

3578

Background: Pathologist inspection of biopsy slides is the gold-standard for diagnosis and is crucial for effective therapy decisions. However, expert shortage is resulting in turnaround times exceeding College of American Pathologists’ (CAP) standards (Alshieban, 2015). Further, discrepancy between diagnoses can exceed 4% (Mukhopadhyay, 2018), and 2% of cases are designated as ‘carcinoma of unknown primary’ (CUP) negatively affect outcomes due to difficulty selecting therapies (Rassy, 2020). Here we sought to aid in diagnosing patients from whole-slide images (WSIs) using deep neural networks. Methods: > 6.3K high-resolution H&E-stained diagnostic WSI of formalin-fixed paraffin-embedded (FFPE) tumor block slices were selected from TCGA sources. Slide images were obtained from 30 different cancer subtypes including 368 Breast (5.6%), 324 Colon (5.12%), 287 Lung Adenocarcinoma (LUAD) (4.5%), Lung Squamous-Cell carcinoma (LUSC) (4.5%), and Stomach Adenocarcinoma (4.3%). Local regions containing tumor tissue were automatically identified by training an Inception V3 deep-learning network as previously presented. A separate Inception V3 network was trained to classify the primary tissue of 200mm2 tumor regions in 60% of the images, which was validated in the remaining 40% testing cohort. Results: The proposed deep-learning model was 92.7% accurate in identifying the primary tissue within the test set of WSIs. As expected, most misclassification occurred in highly-related tissue-types: Rectal cancers misclassified as colon (25%) and vice versa (4.8%), uveal melanomas misclassified as cutaneous melanomas (18.6%), cholangiocarcinomas as hepatocellular carcinomas (8.6%), and LUSC misclassified as LUAD (6.0%) and vice versa (3.4%). Combining related tissues, the classifier achieves 94.6% accuracy across 24 primary types. Unexpectedly, cutaneous melanomas samples were misclassified as breast (9.1%) and LUSC (5.6%), suggestive of related molecular phenotypes. Conclusions: By focusing machine-vision attention on tumor regions, the automated system approaches pathologist accuracy. Used in conjunction with molecular profiling, rates of CUP or misdiagnosis can feasibly be minimized to improve patient care. This system is currently being validated in an external set of > 4K unselected clinical cases from the NantHealth database.
Selpercatinib (LOXO-292) in patients with RET-fusion+ non-small cell lung cancer.
Authors: Goto Koichi , Oxnard Geoffrey R. , Tan Daniel Shao-Weng , Loong Herbert H. F. , Bauer Todd Michael , Gainor Justin F. , McCoach Caroline Elizabeth , Gautschi Oliver , Besse Benjamin , Cho Byoung Chul , Peled Nir , Weiss Jared , Kim YuJung , Ohe Yuichiro , Horiike Atsushi , Park Keunchil , Huang Xin , Olek Elizabeth , Subbiah Vivek , Drilon Alexander E.
Published: May 2020

3584

Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-fusion+ non-small-cell lung cancer (NSCLC). Methods: Patients with RET-fusion+ NSCLC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 105 consecutively enrolled patients previously treated with platinum-based chemotherapy. Treatment-naïve patients were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of platinum-treated patients (median of 3 prior systemic regimens; range 1-15), the ORR by investigator assessment was 70% (95% CI 59.8–78.1, n = 73/105). Responses did not differ by fusion partner or number or type of prior therapies, including anti-PD-1/PD-L1 agents and off-label multikinase inhibitor use. The median DoR was 20.3 months (95% CI 15.6–24.0) with 45 of 73 (62%) responders censored at a median follow-up of 14.8 months. Among 39 treatment-naïve patients, the ORR by investigator assessment was 90% (95% CI 75.8–97.1, n = 35/39, including 2 responses pending confirmation). Median DoR was not reached with 27 of 33 (82%) confirmed responses ongoing at a median follow-up of 7.4 months. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib achieved marked and durable antitumor activity in patients with RET-fusion+ NSCLC. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .
A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.
Authors: Garrido-Laguna Ignacio , Dillon Patrick Michael , Anthony Stephen Patrick , Janat-Amsbury Margit , Ashenbramer Nissa , Warner Steven L , Mouritsen Lars , Wade Mark L. , Whatcott Clifford , Bearss David , Fu Siqing
Published: May 2020

3586

Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.
Correlation between overall response rate and progression-free survival/overall survival in comparative trials involving targeted therapies in molecularly enriched populations.
Authors: Solomon Benjamin J. , Loong Herbert H. F. , Summers Yvonne J. , Thomas Zachary M , French Pearl Plernjit , Lin Boris K. , Sashegyi Andreas , Wolf Juergen , Yang James Chih-Hsin , Drilon Alexander E.
Published: May 2020

3588

Background: Randomized trials involving agents targeting oncogene addicted tumors have greatly increased over the past decade. Whether clinical response rates can predict or correlate with efficacy measures such as progression-free survival (PFS) or overall survival (OS) has not been established in molecularly enriched patient populations. In this meta-analysis, we investigated whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in PFS or OS in populations with oncogene addicted cancer. Methods: CT.gov and MEDLINE databases were queried (using commercial text mining software I2E) for randomized, phase 3 clinical trials based on the following prospectively defined criteria: (1) use of agents targeting EGFR activating mutations (erlotinib, gefitinib, afatinib, dacomitinib, osimertinib), ALK and ROS1 rearrangements (crizotinib, ceritinib, alectinib), BRAF V600E or V600K mutations (dabrafenib), and BCR-ABL fusion protein (imatinib, dasatinib, nilotinib, ponatinib); (2) must include molecularly enriched trial populations (biomarker subgroup data included if available); (3) control arms should not include targeted agents directed towards those molecularly enriched populations. ORR, OS, and PFS data were manually extracted from the relevant studies and correlative analyses (weighted Pearson correlation) were performed. Results: 61 trials were identified with 15 ultimately meeting the prespecified criteria. ORR effect size (both the ORR difference and log odds ratio) and the log PFS hazard ratio were strongly correlated (-0.78, p-value = 0.0007). No significant correlation was found between ORR and OS. Conclusions: In our analyses, a strong correlation between ORR and PFS was found in randomized clinical trials investigating agents targeting oncogene-driven cancers. Establishing a correlation between ORR and OS was limited, most probably due to confounding factors such as treatment cross-over following progression, number of subsequent therapies and long post-progression survival in this setting. These findings further warrant the use of ORR as a surrogate for PFS in biomarker-driven studies.
RICTOR amplification as a novel therapeutic target for lung cancer brain metastases.
Authors: Cheng Haiying , Fan Ni , Sokol Ethan , Wang Feng , Zou Yiyu , Feng Monica , Frampton Garrett M. , Bhagat Tushar , Verma Amit , Halmos Balazs , Perez-Soler Roman
Published: May 2020

3597

Background: Approximately 20% to 50% of patients with advanced lung cancer develop brain metastases, which are associated with debilitating neurologic impairment and a dismal prognosis. There have been very limited studies investigating the genomics of brain metastases in lung cancer. Methods: We comprehensively investigated the frequency of PI3K/AKT/RICTOR/mTOR pathway aberrations in primary and metastatic sites using an extensive database of 11845 cases of lung adenocarcinoma by NGS (FoundationOne). The potential roles of RICTOR amplification in the development of brain metastases were studied both in vitro and in vivo in orthotopic mouse models. Results: Compared to the primary tumor, PI3K/AKT/mTOR gene alterations were more frequent in metastatic sites, with particular enrichment noted in brain metastases. RICTOR amplification alone accounted for the observed higher frequency both in brain metastases (brain vs. primary: 9.73% vs 3.50%, P = 2.6E-14; brain vs. other mets: 9.73% vs. 7.3%, P = 0.03) and other metastatic sites (other mets vs. primary: 7.3% vs.3.5%, P = 10E-15), whereas the frequency of PTEN, AKT1, PK3CA or mTOR genetic alterations was not different in the primary tumor, brain and other metastatic sites. In vitro, inducible RICTOR knockdown in H23 lung cancer cells (parental line with RICTOR amplification) was associated with reduced cell migration and invasion, whereas upregulation of RICTOR in HCC827 lung cancer cells (parental line with normal RICTOR copy numbers) was associated with an increase of both processes. These results were confirmed with pharmacological inhibition using mTOR1/2 inhibitors with known CNS penetration. In vivo, both inducible ablation of RICTOR and the mTOR1/2 inhibitor TAK228 (Sapanisertinib) significantly inhibited lung cancer H23-R4-Luc tumor growth in the brain, including a number of near complete responses. Mechanistic studies suggest that RICTOR may regulate the brain metastasis process through AKT and CXCL12 chemokine-CXCR4 axis. Conclusions: RICTOR amplification is the first identified actionable target that is markedly enriched in brain metastases. Our study provides a strong rationale for the development of RICTOR-targeted therapeutic strategies for the treatment and/or prevention of these major causes of lung cancer morbidity and mortality.
Therapeutic drug monitoring of pazopanib: Using cost-neutral PK-guided interventions to optimize exposure.
Authors: Groenland Stefanie L. , van Eerden Ruben A.G. , Koolen Stijn L.W. , Moes Dirk Jan A.R. , Imholz Alex , Wilgenhof Sofie , Van Der Graaf Winette T.A. , Gelderblom Hans , Beijnen Jos H. , Mathijssen Ron H.J. , Huitema Alwin , Steeghs Neeltje ,   Dutch Pharmacology Oncology Group (DPOG)
Published: May 2020

3598

Background: Pazopanib is an approved treatment for renal cell carcinoma (RCC) and soft tissue sarcoma (STS). At the currently registered fixed dose of 800 mg QD, 20% of patients (pts) do not attain the efficacy threshold of Cmin ≥ 20.5 mg/L (Suttle et al, 2014), providing a strong rationale for therapeutic drug monitoring (i.e. individualizing the dose based on measured plasma drug concentrations). Previous studies provided cost-neutral alternatives to absolute dose increments to optimize exposure (i.e. splitting intake moments or concomitant intake with food (Groenland et al, 2020; Lubberman et al, 2019)). This study aimed to investigate the feasibility, tolerability and efficacy of TDM of pazopanib, using cost-neutral interventions. Methods: Patients starting treatment with pazopanib at the standard dose of 800 mg QD in modified fasting state were included in the prospective DPOG TDM study (www.trialregister.nl, NL6695). PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Pazopanib concentrations were measured with LC-MS/MS and Cmin was calculated. In case of Cmin < 20.5 mg/L and acceptable toxicity, a dose intervention was recommended. As a first step, intake moments were split (i.e. 400 mg BID). Secondly, concomitant intake with food was recommended. Results: In total, 34 pts were included (19 STS, 15 RCC), of whom 158 PK samples were collected. Eleven pts (32%) were underdosed and had at least 1 PK sample below the target. In 24% of the pts a PK-guided intervention could be performed, which was successful in 6 pts (75%). Median Cmin increased from 15 mg/L to 32 mg/L (p = 0.027). Eventually, 3 pts went back to 800 mg QD due to toxicity, after which Cmin remained ≥ 20.5 mg/L in 2 pts. In pts with adequate exposure throughout the study, median Cmin was 32 mg/L (range 23 – 65 mg/L). In 3 pts, a PK-guided intervention could not be performed, due to progression (n = 1) or logistical issues (n = 2). Twelve pts (35%) received a dose reduction due to toxicity (lowest dose was 200 mg QAD), exposure remained adequate at this reduced dose in all pts. For STS pts, median PFS was 19.8 months in pts with Cmin < 20.5 mg/L who did need an intervention vs. 6.4 months in pts with all Cmin ≥ 20.5 mg/L (not significant). For RCC pts, this was 15.5 months vs. 7.4 months, respectively (not significant). Conclusions: This prospective study shows that PK-guided dose optimization of pazopanib using cost-neutral interventions is feasible in daily practice. A PK-guided intervention was performed in 24% of the patients, which was successful in 75% of these patients. Clinical trial information: NL6695 .
Preliminary population pharmacokinetics supports phase II dose selection for masked anti-PD-L1 antibody CX-072.
Authors: Stroh Mark , Green Michelle , Millard Bjorn L. , Garner William , Lu Hong , Richardson Jennifer Hope , Hannah Alison L.
Published: May 2020

3602

Background: PROBODY therapeutics (Pb-Tx) are antibody prodrugs designed to reduce off-tumor, on-target toxicities. The mask inhibits Pb-Tx binding in the periphery yet can be removed by tumor-associated proteases, restricting target engagement to the tumor. This is the first report of preliminary clinical pharmacokinetic (PK) analysis supporting selection of the phase II dose for CX-072, an anti–PD-L1 Pb-Tx, from the ongoing phase I/II PROCLAIM-CX-072 study (NCT03013491). Methods: A quantitative systems pharmacology (QSP) model1 was used to project the CX-072 plasma trough level (Cmin) corresponding to 95% intratumoral receptor occupancy (RO). Human PK and anti-drug antibody (ADA) data were obtained at selected times postdose following IV administration of 0.03–30 mpk CX-072 in PROCLAIM-CX-072. Population PK (POPPK) modeling was performed with NONMEM v7.3.0. Exploratory analysis and simulations were done with R v3.3.1 or later. Covariates were selected for POPPK using forward addition ( P<0.05) followed by backward deletion ( P<0.01). Results: The preliminary POPPK analyses were informed using available PK data as of August, 2019 from 135 subjects receiving CX-072 Q2W as monotherapy in the dose-escalation and expansion cohorts of PROCLAIM-CX-072. A mixture model was used to capture time- and dose-dependent apparent ADA effect on clearance (CL). The preliminary POPPK model estimates for CX-072 CL and volume of distribution (Vd) were 0.306 L/day and 4.84 L, respectively. Statistically significant covariate effects included body weight on the central Vd and CL, and albumin on CL. The QSP model predicted a CX-072 Cmin of 13–99 nM would be required for 95% intratumoral RO. POPPK simulations suggested that >95% of patients receiving CX-072 10 mg/kg Q2W would meet or exceed this targeted Cmin regardless of ADA. Additional observed data indicated that the majority of patients receiving 10 mpk CX-072 Q3W × 4 with 3 mpk ipilimumab (IPI) Q3W × 4 in the CX-072-IPI combination part of PROCLAIM-CX-072 maintained the targeted Cmin. Simulations did not suggest there would be a clinically meaningful change in exposure following a fixed dose of CX-072 800 mg relative to the 10 mpk weight-based dose. Conclusions: Preliminary PK analysis supports selection of 800 mg CX-072 Q2W as the recommended monotherapy dose and 800 mg Q3W when combined with IPI. The combination of 800 mg CX-072 + 3 mpk IPI Q3W × 4 doses, followed by monotherapy administration of 800 mg CX-072 Q2W is being further explored in phase II. Reference: 1) Stroh M et al. CPT. 2019(9):676-84. Clinical trial information: NCT03013491 .
Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion.
Authors: Cleary James M. , Iyer Gopa , Oh Do-Youn , Mellinghoff Ingo K. , Goyal Lipika , Ng Matthew C.H. , Meric-Bernstam Funda , Matos Ignacio , Chao Tsu-Yi , Ait Sarkouh Rafik , Cretegny Kira , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Anne , Zanna Claudio , Zubel Angela , Tabernero Josep , Flaherty Keith , Hyman David Michael
Published: May 2020

3603

Background: Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Here we report the results of the expansion portion of a Phase 1 study of advanced solid tumors patients (pts) harboring an FGFR1-3 gene fusion. Methods: Pts with advanced refractory solid tumors harboring an FGFR1-3 gene fusion were enrolled. Based on results from the dose escalation portion, pts received Debio1347 80 mg once daily (qd) in 28-day cycles. Pharmacokinetics (PK) and pharmacodynamics were evaluated. The data cut-off was October 8, 2019. Results: Among 18 pts enrolled, 5 had primary brain tumors (PBT), 5 had cholangiocarcinoma, 2 had urothelial cancer, 2 had colon cancer, 1 patient each lung neoplasm, gastric cancer, endometrial cancer and squamous cell carcinoma of the chest wall. Tumors harbored fusions with FGFR1 (n = 1), FGFR2 (n = 8), and FGFR3 (n = 9). All had prior systemic therapy (median 3 lines; range 1-4). The most common treatment emergent adverse events were fatigue (50%), hyperphosphatemia (44.4%), anemia (38.9%), alopecia (33.3%), nausea (33.3%), vomiting (33.3%), constipation (33.3%), and palmar-plantar erythrodysesthesia syndrome (22.2%). Blurred vision was reported in 1 pt. There were no findings on ocular exams compatible with retinal detachment. No grade 3 AE related to study drug were reported. One patient needed dose reduction due to grade 2 nails toxicity. In PK analysis, plasma steady-state was rapidly achieved and serum phosphate increase correlated with Debio 1347 plasma exposure, confirming target engagement at 80 mg qd. Median follow-up was 18 weeks. Partial responses were observed in 3 pts harboring an FGFR2 fusion: 1 out of 2 colon cancer and 2 out 5 cholangiocarcinoma. Median duration of response was 16.1 weeks (range: 8.4-22.8+). Overall disease control was observed in 11 out of 14 pts without PBT (79%). Median PFS was 18.3 weeks. No signs of activity were observed in the 5 patients with PBT, all with an FGFR3-TACC3 fusion. Conclusions: Debio 1347 at the recommended dose of 80 mg qd was generally well tolerated and showed signs of activity in solid tumors harboring an FGFR fusion. The FUZE phase 2 clinical trial of Debio 1347 is recruiting FGFR fusion-positive advanced solid tumors irrespectively of tumor histology, excluding PBT. Clinical trial information: NCT01948297 .
Activity and safety of larotrectinib in adult patients with TRK fusion cancer: An expanded data set.
Authors: Drilon Alexander E. , Farago Anna F. , Tan Daniel Shao-Weng , Kummar Shivaani , McDermott Raymond S. , Berlin Jordan , Patel Jyoti D. , Brose Marcia S. , Leyvraz Serge , Tahara Makoto , Solomon Benjamin Maurice , Reeves John A. , Fellous Marc Mardoche , Brega Nicoletta , Childs Barrett H. , Lassen Ulrik Niels , Hong David S.
Published: May 2020

3610

Background: The highly selective TRK inhibitor larotrectinib is approved for the treatment of adult and pediatric cancers that harbor NTRK gene fusions; it achieves a 79% overall response rate (ORR) in this population (Hong et al., Lancet Oncol, 2020). The activity of larotrectinib in adults alone was further characterized in this update with a larger series of patients and more mature durability data. Methods: Adults (aged ≥18 y) with TRK fusion cancer treated in three larotrectinib clinical trials (NCT02122913, NCT02576431, and NCT02637687) were analyzed. Larotrectinib was administered 100 mg BID until disease progression, withdrawal, or unacceptable toxicity. ORR was investigator-assessed (RECIST v1.1). Compared to previously presented data on 74 patients, this expanded data set includes an additional 42 patients (data cutoff: July 15, 2019). Results: 116 adults (median age: 56 y, range 19–84 y; 53% female) with TRK fusion cancer were treated. Tumor types included thyroid cancer (22%), salivary gland cancer (19%), soft tissue sarcoma (16%), lung cancer (12%), colon cancer (7%), melanoma (5%), breast cancer (5%), GIST (3%), and 9 other types (≤2% each). NTRK fusions involved NTRK1 (43%), NTRK2 (3%), and NTRK3 (54%). 78% of patients had received prior systemic therapy (with 68% of those receiving ≥2 prior therapies). The ORR was 71% (95% CI 62–79): 10% complete response, 60% partial response (2% pending confirmation), 16% stable disease, 9% progressive disease, 3% not determined. In patients with brain metastases, the ORR was 71% (95% CI 42–92; 10 of 14 patients, all partial responses). Median duration of response for the overall data set (n = 116) was 35.2 mo (95% CI 21.6–not estimable [NE]). Median progression-free survival was 25.8 mo (95% CI 15.2–NE). Median overall survival was not reached (range 0.5+ to 51.6+ mo) at a median follow-up of 15.8 mo. Duration of treatment ranged from 0.10 to 51.6+ mo. 12% of patients had dose reductions. One patient (1%) discontinued due to a larotrectinib-related adverse event (AE). AEs were mostly grade 1–2; no new unexpected AEs were reported. Conclusions: In an expanded data set of adults with TRK fusion cancer, larotrectinib demonstrated robust and durable tumor-agnostic efficacy and favorable safety, supporting NTRK gene fusion testing in patients with solid tumors of any type. Clinical trial information: NTC02122913, NCT02576431, NCT02637687 .
Comprehensive molecular analysis of microsatellite-stable (MSS) tumors with high mutational burden in gastrointestinal (GI) cancers.
Authors: Wang Jingyuan , Xiu Joanne , Shields Anthony Frank , Grothey Axel , Weinberg Benjamin Adam , Marshall John , Lou Emil , Khushman Moh'd M. , Sohal Davendra , Hall Michael J. , Battaglin Francesca , Arai Hiroyuki , Soni Shivani , Zhang Wu , Korn Wolfgang Michael , Lenz Heinz-Josef
Published: May 2020

3631

Background: Mutational signatures contributing to high tumor mutation burden (TMB-H) independent from microsatellite instability-high (MSI-H) status are not well-studied. We aimed to characterize specific molecular features of a large cohort of GI tumors with TMB-H & MSS. Methods: We sequenced23392 GI tumors, including 2707 gastroesophageal (GE), 11616 colorectal (CRC), and 9069 others. Samples were analyzed using Next-generation sequencing (NGS) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Tumors with TMB ≥ 17 mutations/Mb were defined as TMB-H. PD-L1 was tested by IHC [22C3 (CPS score, positivity: CPS ≥ 1%) in GE tumors and SP142 (Positivity: TPS ≥ 5%) in other cancers]. Findings were compared in four groups (TMB-H/L & MSI-H/MSS) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, TMB-H & MSS was observed in 1% of patients (pts) (n = 237, including 45 GE, 124 CRC, 68 others), while TMB-H & MSI-H, TMB-L & MSS, TMB-L & MSI-H were observed in 4% (n = 936), 94.4% (n = 22089) and 0.6% (n = 130) respectively. Compared to other groups, TMB-H & MSS showed the most prevalent amplifications (AMPs), including CCND1 (5.6%), FGF3/4/19 (4.9%, 4.3%, 4.4%) , MYC (4.3%) (Top 5, adj p < .05), and the highest mutation rates in POLE (21.6%), RB1 (13.1%), CDC73 (10.3%), RUNX1 (6.5%), and genes involved in PI3K & MAPK ( PIK3R1 17%, mTOR 3.4%, MAP2K1 3.8% , MAP2K4 5.6%) and Wnt ( APC 48.5% , SMAD2 6.5% , TCF7L2 3.8%) pathways (adj p < .05). The rates of HER2 AMP and high-expression (IHC) were the highest in TMB-H & MSS, followed by TMB-L & MSS, TMB-H & MSI-H, TMB-L & MSI-H (adj p< .0001); PD-L1 positive rate was similar between TMB-H & MSS and TMB-L & MSI-H, while the highest and lowest in TMB-H & MSI-H and TMB-L & MSS respectively in GE and other GI cancers (adj p < .01) (Table). Conclusions: This is the largest study to investigate the special molecular landscape of pts with TMB-H & MSS in GI cancers. Our data may provide novel insights for pt selection and more effective targeted combination immunotherapies (e.g. HER2, PI3K inhibitors) in GI cancers. [Table: see text]
A randomized, controlled trial of structured palliative care versus standard supportive care for patients enrolled on phase I clinical trials.
Authors: Treasure Michelle Elizabeth , Daly Barbara J. , Fu PingFu , Cao Shufen , Meropol Neal J. , Dowlati Afshin
Published: May 2020

3634

Background: Phase 1 clinical trials are the first step in developing new cancer therapeutics. Patients enrolled in these studies have typically exhausted standard therapies and are at a point in their disease trajectory where they often are choosing between a phase 1 clinical trial and hospice care. These patients may have significant symptom burden, which can result in early trial discontinuation and confound phase 1 trial outcomes, including toxicity profiles, which may influence further drug development. This study aimed to determine the palliative care needs of patients enrolled on phase 1 clinical trials and their caregivers (CGs), along with differences in study duration, adverse event (AE) and symptom profiles, and quality of life (QOL) between those receiving structured palliative care vs usual supportive care. Methods: 68 patients enrolled on phase 1 clinical trials were randomly assigned to receive structured palliative care or usual supportive care. 39 of their CGs were enrolled and assigned to the same arm as the patient. Quality of life metrics were obtained monthly: the Functional Assessment of Cancer Therapy-General and Memorial Symptom Assessment Scale -Short Form for patients, and The Quality of Life in Life Threatening Illness - Family Carer Version and Caregiver Reaction Assessment for CGs. Palliative care resources utilized were assessed for those in the palliative care arm, and referrals to supportive care services assessed in those in the usual care arm. AEs recorded on the Phase 1 trials were evaluated & compared between arms. Results: Mean duration on phase 1 study was 132 days in the palliative care arm vs 114 days in the usual care arm (p = 0.55). Total weighted AE rate (# of AE [x] AE grade per month) was 26.9 in the palliative care arm vs 34.0 in the usual care arm (p = 0.53). Patients in the palliative care arm experienced better QOL and lower symptom burden, as did their CGs, compared to those in the usual care arm. While the differences in outcomes were not statistically significant, all results favored structured palliative care. Conclusions: Phase 1 patients and their CGs have physical and psychosocial needs which warrant palliative care services. Preliminary results suggest structured palliative care is associated with increased duration on study (by nearly 3 weeks), improved patient and CG QOL, and reduced patient symptom and CG burden. A larger study is warranted to confirm these results and further develop the ideal palliative care intervention in these populations. Clinical trial information: NCT02543541 .
Safety, tolerability, and preliminary pharmacokinetic/pharmacodynamic profile of JMT103 in patients with bone metastases from solid tumors: A multicenter, open-label, dose-escalation, phase I clinical study.
Authors: Li Jin , Li Huiping , Qin Shukui , Guo Ye , Liang Xu , Xue Junli , Peng Wei , Ge Xiaoxiao , Xie Changxing , Yang Xiugao , Li Tao , Xu Jinglin , Feng Li , Wu Zhufeng , Xiao Guanxi , Zhang Peng , Zhang Tianyi , Wang Chenchen , Zhang Baoxia , Hu Zijian
Published: May 2020

3638

Background: Bone is one of the most common metastatic sites of malignancies. The metastatic tumor cells activate osteoclast activity and promote bone resorption via RANKL/RANK signaling pathway, and lead to osteolytic destruction. JMT103 is an innovative fully human IgG4 monoclonal antibody targeting RANKL. It can block RANKL/RANK signaling pathway, inhibit bone resorption, and protect bones from tumor metastasis. This study aimed to evaluate the safety and tolerability of JMT103 in patients with bone metastasis. Methods: This is a multi-center, open label, dose escalation, phase I clinical trial. The patients (ECOG score: 0-1) with bone metastasis from solid tumor who had not received bisphosphonates within 6 weeks before enrollment and were naïve to denosumab were enrolled. The initial dose was 0.5 mg/kg, sequentially escalated to 1.0, 2.0, and 3.0 mg/kg. JMT103 was injected subcutaneously by accelerated titration in 0.5 and 1.0 mg/kg dose groups, but via traditional "3+3" dose-escalation design in 2.0 and 3.0 mg/kg dose groups. Expansion study was conducted for subjects in 1.0, 2.0, and 3.0 mg/kg dose groups. Specifically, 3 additional doses (q4w) were injected after the end of 12-week single-dose study. The primary endpoints were maximum tolerated dose and safety. The secondary outcome measures included PK profile, preliminary efficacy biomarkers, immunogenicity, and bone mineral density (BMD). Results: From May 2018 to January 2020, 56 patients (13 males, 43 females, mean (SD) age: 55.57 (11.42) years) were enrolled, including bone metastasis from breast cancer (n = 36), gastric cancer (n = 5), lung cancer (n = 4), rectal cancer (n = 3), colorectal cancer (n = 2), or other solid tumors (n = 6). Nineteen patients participated in the dose-escalating study and 37 patients participated in the expansion study. JMT103 showed overall good safety. There were 74 drug-related AEs in all, including grade 3 (DLT hypocalcemia, n = 1; hypophosphatemia, n = 3), grade 2 (n = 15), and grade 1 (n = 55) AEs. The most common drug-related AEs were hypophosphatemia (n = 15), hypocalcemia (n = 12), and hypermagnesemia (n = 6). Median uNTx/Cr decrease from baseline was 76.6% (n = 20). Conclusions: JMT103 shows good safety and tolerability in patients with bone metastasis. Clinical trial information: NCT03550508 .
BXQ-350 to target to the lysosome and kill glioblastoma (GBM) cells via activation of apoptotic caspases in vitro.
Authors: Felix Laura , Stephens Timothy J , Wilkins Nikhil J
Published: May 2020

3639

Background: Apoptosis is a programmed cell death mechanism where cells respond to internal or external stimuli by initiating a cascade of events and enzymes leading to cell death. One of the hallmarks of cancer is the ability of tumor cells to resist these apoptotic stimuli. This allows tumor cells to have aberrant metabolisms, such as sphingolipid metabolism in tumor cell lysosomes, or mutations which would normally commit cells to death. Saposin C, the protein component of BXQ-350, Bexion Pharmaceuticals’ proprietary biotherapeutic, is involved in normal lysosomal sphingolipid metabolism. Removing resistance, shortcutting steps leading to apoptosis, or correcting sphingolipid metabolism can result in the death of these tumor cells. Methods: The GBM cell line Gli36ΔEGFR was plated in 96 well plates at a density of 1x104 cells per well in Dulbecco’s Modified Eagle Media with 10% FBS overnight at 37oC for caspase and cytotoxicity assays. Cells were treated with 9uM to 30uM BXQ-350 in triplicate and incubated for 24 hours at 37oC. Promega’s Caspase-Glo 9 or Caspase-Glo 3/7 reagent was added to appropriate wells and the plates were incubated at room temperature in the dark for 3 hours then luminescence was read. The parallel cytotoxic assay was run under the same conditions except Roche’s MTT labeling reagent was added to the appropriate wells after 24 hours and incubated at 370C for 4 hours. Solubilization solution was added to each well and the plate was incubated at 37oC overnight then absorbance was read. The GBM cell line U87 MG was used to determine lysosomal targeting. U87 MG cells were treated with 10uM BXQ-350 and incubated at 37oC overnight. They were stained with anti-SapC (RFP) and anti-LAMP1 (GFP) antibodies and images were taken. Results: BXQ-350 mediated cell death is correlated with a rise in Caspase 3, Caspase 7 and Caspase 9 activity. The caspase activity levels did not rise until after BXQ-350 passed its IC50 and stayed elevated. Caspases 3/7 levels showed higher activity compared to untreated than Caspase 9. In addition to this, BXQ-350 was seen to colocalize to LAMP1, a lysosomal membrane protein. Conclusions: BXQ-350 tracks to the lysosomal membrane where it initiates the cascade of enzymes necessary to cause apoptosis. Caspases 3/7 are the effector caspases and are necessary for the completion of the apoptotic pathway. The higher activity levels of these caspases show the cells are committed to cell death not allowing these cells to subvert apoptosis. This removes one of the major barriers to fighting cancer.
The incidence of myelodysplastic syndrome in patients receiving poly-ADP ribose polymerase inhibitors for treatment of solid tumors: A meta-analysis.
Authors: Nitecki Roni , Gockley Allison Ann , Floyd Jessica Lauren , Coleman Robert L. , Melamed Alexander , Rauh-Hain Jose Alejandro
Published: May 2020

3641

Background: Clinical trials have reported improved outcomes with PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy in ovarian, breast, pancreatic and lung cancers. There is concern that PARPi therapy may cause myelodysplastic syndrome (MDS). In this meta-analysis we seek to quantify the risk of MDS among patients treated with PARPi for solid tumor malignancies. Methods: We searched Medline, Embase, and Cochrane databases (up to January 6, 2020) to abstract randomized controlled trials that include a PARPi in the experimental arm in solid tumors. Combinations included PARPi versus (vs.) placebo, PARPi vs. cytotoxic treatment, and PARPi with cytotoxic treatment vs. cytotoxic treatment. We used to time-to-event curves to estimate person-time and calculated the incidence of MDS among all studies. We used random-effects Poisson regression models to estimate pooled incidence risk ratio (RR) for developing MDS. Results: We identified 14 studies, 10 in ovarian, 3 in breast, and 1 in pancreatic cancer patients. Of 5,646 patients, 62.3% received a PARPi alone or in combination with chemotherapy or bevacizumab, and 37.8% received treatment consisting of placebo alone or with chemotherapy or bevacizumab. PARPi were investigated as an upfront treatment in 2,827 patients, and as treatment for recurrence in 2,819 patients. The incidence of MDS was 6.73 cases vs. 3.85 per 1000 person-years in patients receiving PARPi as compared to control corresponding to a 3-year cumulative incidence of 2.0% and 1.1%. Accounting for intra-study clustering, PARPi use was associated with a 60% increase in risk (incidence RR 1.60, 95% Confidence Interval [CI] 0.89-2.87) of MDS compared to control. In the upfront setting, patients randomized to PARPi were twice as likely to develop MDS (RR 2.08, 95%, CI 1.39-3.64). Among patients treated for recurrence, the risk of MDS appeared to be similar among patient randomized to PARPi or control treatment (RR 1.13, 95% CI 0.35-3.64). In studies that compared PARPi in combination with other cytotoxic treatment vs. cytotoxic treatment alone, PARPi was associated with a large risk of MDS (RR 5.08, 95% CI 1.36-19.03). Conclusions: In pooled estimates from randomized controlled trials in solid tumors PARPi treatment appears to be associated with an increased incidence of MDS particularly in the upfront setting and when combined with cytotoxic treatment. Despite pooling 14 randomized trials our estimates remain imprecise due to the rarity of MDS.