bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhaled corticosteroid use and risk of pneumonitis in patients treated with immune checkpoint inhibitors.
Authors: Li Mingjia , Spakowicz Daniel , Zhao Songzhu , Patel Sandip H. , Johns Andrew , Grogan Madison , Miah Abdul , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Wei Lai , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Owen Dwight Hall
Published: May 2020

3140

Background: The identification of risk factors for immune-related adverse events (irAEs) is an important area of research. Among irAEs, pneumonitis carries one of the highest morbidities. There is a lack of strong predictors for pneumonitis in patients (pts) treated with ICI. We sought to identify predictors for the development of pneumonitis, and whether the use of inhaled corticosteroids (ICS) at time of ICI could be protective. Methods: Pts with advanced cancer treated with ICI from 2011 and 2018 were included in this retrospective study. Pneumonitis attribution to ICI was determined by treating physician at time of diagnosis. Time to pneumonitis was defined as days from the start of ICI to pneumonitis diagnosis. Pts who never had pneumonitis were censored at the time of last follow up or death. Predictors of pneumonitis were assessed by univariate Cox proportional hazard models at a significance threshold of alpha = 0.05. Results: A total of 837 pts were identified, and 30 (3.6%) pts developed any grade pneumonitis (12 grade 2, 14 grade 3, 1 grade 4, 3 grade 5) after receiving ICI (Table). Pts with age ≥65 years (y) had increased risk of developing pneumonitis over pts with age < 65y (HR 2.1, 95 CI: 1.02-4.4, p=0.041). 82 (9.7%) of the total cohort were on inhaled corticosteroid (ICS) at time of ICI, and 9 (11%) developed pneumonitis. Rather than being protective, pts on ICS had higher risk of pneumonitis (HR 4.2, 95 CI: 1.9-9.2, p=0.001). Pts with lung cancer had an increased risk for pneumonitis compared to pts with other cancers (HR 3.2, 95 CI: 1.5-6.4, p =0.003). Other risk factors included performance status, smoking history, line of therapy, or prior treatment including radiation were not statistically significant. Conclusions: Rather than a protective effect of ICS, our analysis found a higher risk of pneumonitis in pts treated with ICS. We confirmed an increased risk of pneumonitis for lung cancer pts compared to pts with other cancers, and higher risk of pneumonitis in pts age >65y. We hypothesize that the increased inflammatory status in chronic lung inflammation may predispose pts to pneumonitis that was not ameliorated by ICS. Future study is needed in prospective cohorts to further clarify the underlying inflammatory mechanism. [Table: see text]
Response criteria for intratumoral immunotherapy in solid tumors: ItRECIST.
Authors: Goldmacher Gregory V. , Khilnani Anuradha D. , Andtbacka Robert H. I. , Luke Jason J. , Hodi F. Stephen , Marabelle Aurelien , Harrington Kevin Joseph , Perrone Andrea Marie , Tse Archie N. , Madoff David C. , Schwartz Lawrence Howard
Published: May 2020

3141

Background: The approval of intratumoral (IT) immunotherapy for metastatic melanoma and the active development of numerous novel IT drugs have created a need for standardized evaluation of response to this unique treatment strategy. The Response Evaluation Criteria in Solid Tumors (RECIST) is not suitable for assessing responses separately for injected and noninjected tumors. Building on RECIST concepts, we propose an IT immunotherapy RECIST (itRECIST) to capture data and assess local and systemic responses in a standardized fashion for clinical trials involving IT immunotherapies. Methods: itRECIST will address the unique needs of IT immunotherapy trials but, where possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject but provides guidelines for collecting data and assessing response as treatment evolves. Results: itRECIST enables overall response assessment, separate response assessments in injected and noninjected lesions, and continued assessment following modifications of therapy at initial progression. At baseline, lesions are classified into 4 categories: target injected, target noninjected, nontarget injected, and nontarget noninjected. After baseline, lesions can be reclassified from noninjected to injected if the investigator decides to change the lesions to inject, but target and nontarget designations never change. Overall response at each assessment is based on target lesion response (injected and noninjected), nontarget lesion response, and absence/appearance of new lesions. Noninjected lesion response is determined by comparing tumor burden with baseline and nadir values. Injected lesion assessment is based on visit-to-visit changes in the lesions injected during treatment and on a combined assessment once the patient is off treatment. A new response category is defined to capture progression that would be “confirmed” per iRECIST even though injected lesions are responding and therapy continues. Multiple examples have been created to aid in training and adoption. Conclusions: itRECIST is an important step toward a standardized method of response assessment for this promising and evolving therapeutic modality. The proposed guidelines can be adopted into trial protocols and routine clinical practice without the need for complex additional assessments by treating physicians. Until there is evidence to support wider use, itRECIST is intended only to support standardized collection of data and to facilitate exploratory analysis. Authors G.V.G. and A.D.K. contributed equally to this work.
Tolerability and preliminary efficacy of BXQ-350 for refractory solid tumors and high-grade gliomas: First-in-human, first-in-class phase I trial.
Authors: Rixe Olivier , Morris John Charles , Wesolowski Robert , Yilmaz Emrullah , Curry Richard , Wise-Draper Trisha Michel , Puduvalli Vinay K.
Published: May 2020

3505

Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for > 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .
Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors.
Authors: Rasco Drew W. , Lakhani Nehal J. , Tang Yuefen , Wang Hengbang , Ji Jiao , Chen Jason , LIANG ZHIYAN , Amaya Alex , Yang Dajun , Zhai Yifan
Published: May 2020

3508

Background: APG-1387 is an IAP (inhibitor of apoptosis proteins) antagonist that has strong antitumor activity in multiple xenograft cancer models and acts as a host immune modulator, supporting its exploration for use in combination with checkpoint inhibitors for cancer therapy. Methods: This “3+3” dose escalation and dose expansion study evaluated APG-1387 combined with pembrolizumab in patients with refractory or intolerant advanced solid tumors (NCT03386526). APG-1387 was administered IV once weekly with pembrolizumab 200 mg on day 1 of a 21-day cycle. Study aims were to assess safety/tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of December 25, 2019, total 28 patients had been treated in 3 dose cohorts of APG-1387: 20 mg (n = 4), 30 mg (n = 3), and 45 mg (n = 21, 18 in dose expansion). The median line of prior systemic cancer therapies was 3.0 (1-12). No dose-limiting toxicity was observed. The most common treatment-related adverse events (TRAEs; ≥10%) were fatigue (28.6%), arthralgia (14.3%), headache (14.3%), and tumor pain (10.7%). One patient in the 45-mg cohort had grade 2 Bell’s Palsy. G3+ TRAEs were autoimmune colitis, hypoxia, increased lipase, mucosal inflammation, pneumonitis, and tumor pain in 1 patient each (3.6%). Treatment-related SAEs were 1 G3 autoimmune colitis, 1 G2 myocarditis, and 1 G3 pneumonitis. The maximum tolerated dose (MTD)/RP2D for APG-1387 was 45 mg. Among 25 efficacy-evaluable patients, 1 with ER+, HER2‒ breast cancer receiving APG-1387 30 mg after failing 5 lines of therapy (PD-1 treatment-naïve, microsatellite stable) achieved confirmed PR (-79.2%) for 6 cycles but discontinued due to pneumonitis; another patient with PD-L1‒ non‒small-cell lung cancer treated at 45 mg had confirmed PR (-65.0%) for 6 cycles (ongoing). Other 11 patients had SD for 2-11 cycles. The disease control rate was 52%. Preliminary PK data showed a dose-proportional increase in APG-1387 exposure from 20 mg to 45 mg. Preliminary PD data showed that APG-1387 induced rapid degradation of cellular IAP1 and X-linked IAP in peripheral blood mononuclear cell samples; Increased serum release of interleukins (IL-12, IL-10) and monocyte chemotactic protein 4 was dose and time dependent. Conclusions: APG-1387 combined with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in patients with several tumor types. The ongoing study will further evaluate the efficacy of this combination. Clinical trial information: NCT03386526 .
Safety and efficacy of pyrotinib in patients with NSCLC and other advanced solid tumors with activating HER2 alterations: A phase I basket trial.
Authors: Li Bob T. , Li Tianhong , Johnson Melissa Lynne , Waqar Saiama Naheed , Zhu Viola Weijia , Ou Sai-Hong Ignatius , Lin Jessica Jiyeong , Wang Ding , Shapiro Geoffrey , Wang Judy Sing-Zan , Liu Dazhi , Ye Yuqing , Kosar Hana , Hee Angela , Berk Greg , Zhang Sean , Wang Junsheng , Patel Manish R.
Published: May 2020

3510

Background: Pyrotinib is a potent, irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the erythroblastic leukemia viral oncogene homolog (erbB) receptors, which has previously demonstrated promising antitumor activity in patients (pts) with breast cancers. We studied the safety and efficacy of pyrotinib in pts with non-small cell lung cancer (NSCLC) and other solid tumors with activating human epidermal growth factor receptor 2 ( HER2, ERBB2) alterations. Methods: This is an open-label, multicenter phase 1 dose expansion basket trial of pyrotinib given 400mg oral daily at 28-day cycles. Expansion cohorts included pts with HER2-mutant NSCLC and advanced solid tumors with HER2 mutation or amplification. HER2 testing was conducted using next generation sequencing or fluorescence in situ hybridization. Primary endpoints included toxicities as evaluated by NCI CTCAE v5.0, and overall response rate (ORR) as evaluated by RECIST v1.1. Secondary objectives included progression-free survival (PFS). Results: A total of 62 pts were enrolled. The median age was 67 (range 40 – 86 years), 61% were female and the median lines of prior systemic therapy was 3 (range 1-11). There were no treatment related deaths. The most common adverse events were diarrhea (96.8%), nausea (82.3%) and vomiting (41.9%). The only ≥ grade 3 treatment related toxicity was diarrhea (24.2%). Prophylactic anti-diarrhea treatment was introduced to facilitate continuation of pyrotinib. At the Jan 13, 2020 cut-off, 24 pts with HER2-mutant NSCLC (20, i.e. 65% of which were the A775_G776insYVMA mutation) and 18 pts with HER2-mutant or amplified solid tumors completed end of Cycle 2 imaging scan and were evaluable for tumor responses. The ORR was 19% (8/42, 95% CI 7-31%); confirmed responses include a complete response (CR) and 3 partial responses (PRs) in HER2-mutant NSCLC, and 4 PRs in HER2-amplified cholangiocarcinoma, ovarian, endometrial and salivary gland carcinomas. There were 7 stable disease ≥ 6 months. Median progression-free survival was 5.4 months (95% CI 4.4-7.3). Conclusions: Pyrotinib demonstrated a manageable safety profile and encouraging efficacy in pts with heavily pre-treated HER2-mutant NSCLC. Furthermore, it is the first TKI to produce durable responses in pts with HER2-amplified biliary tract, ovarian, endometrial and salivary gland cancers. These results warrant further clinical development of pyrotinib. Clinical trial information: NCT02500199 .
CodeBreak 100: Phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
Authors: Hong David S. , Kuo James , Sacher Adrian G. , Barlesi Fabrice , Besse Benjamin , Kuboki Yasutoshi , Dy Grace K. , Dembla Vikas , Krauss John C. , Burns Timothy F. , Kim June , Henary Haby , Ngarmchamnanrith Gataree , Li Bob T.
Published: May 2020

3511

Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation occurs in approximately 13% of NSCLC and 1%–3% of CRC and other solid tumors. AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. Previously, AMG 510 showed preliminary antitumor activity and favorable tolerability in pts with KRAS p.G12C mutant NSCLC or CRC in the phase 1, first-in-human trial. Here, we report results in pts with other tumor types from the same trial. Methods: This study evaluates AMG 510 in pts with locally-advanced or metastatic KRAS p.G12C mutant solid tumors. Key inclusion criteria: KRAS p.G12C mutation via local testing and prior systemic anticancer treatment (tx). Oral daily doses of 180, 360, 720, and 960 mg were tested in the dose escalation, and 960 mg was selected for expansion. Primary endpoint is safety; key secondary endpoints include pharmacokinetics and objective response rate as assessed per RECIST 1.1. Response is assessed every 6 weeks (wks) for 24 wks then every 12 wks thereafter. Results: As of January 8, 2020, 25 pts (9 female, median age 60 years [range: 40–75]) with tumor types categorized by investigators as histology other than NSCLC and CRC were enrolled and dosed (10 pancreatic cancer, 4 appendiceal cancer, 2 endometrial cancer, 2 unknown primary cancer, 1 bile duct cancer, 1 sinonasal cancer, 1 ampullary cancer, 1 small bowel cancer, 1 melanoma, 1 small cell lung cancer, and 1 esophageal cancer). 23 pts received 960 mg dose. 20 pts (80.0%) had ≥2 prior lines of tx. At data cutoff, 13 pts (52.0%) remained on tx; 9 (36.0%) and 3 (12.0%) pts remained on tx for ≥3 and ≥6 months, respectively. Median follow up was 4.3 months (range: 0.1–12.6). Tx-related adverse events (TRAEs) occurred in 9 pts (36.0%). 2 pts (8.0%) had grade 3 TRAEs, including diarrhea (1/25) and pneumonia (1/25, serious AE). No dose-limiting toxicities, grade ≥4, or fatal TRAEs were reported. No TRAEs led to tx discontinuation. 3 pts had not been followed up for ≥7 wks by the data cutoff. 22 pts were followed up for ≥7 wks, and their best overall responses were: 3 confirmed partial response (1 appendiceal, 1 melanoma, and 1 endometrial), 13 stable disease (6 pancreatic, 2 appendiceal, 1 ampullary, 1 bile duct, 1 endometrial, 1 sinonasal, and 1 unknown primary), and 6 progressive disease. Conclusions: AMG 510 was well tolerated and demonstrated clinical activity in pts with advanced KRAS p.G12C mutant solid tumors other than NSCLC and CRC. Clinical trial information: NCT03600883 .
Intratumoral exposure levels of pentaglutamated pemetrexed following treatment with LEAF-1401 and pemetrexed.
Authors: Kim Gwangseong , Nyinawabera Angelique , Xu Zhenghong (Hannah) , DeFuria Jason , Sezibera Alvin , Cui Yanyan , Geng Bolin , Khalifa Khaniz , Dhindsa Navreet , Niyikiza Clet , Moyo Victor M.
Published: May 2020

3524

Background: The activity of pemetrexed is highly dependent on the intracellular enzyme folypolyglutamate synthase (FPGS) which adds glutamates to pemetrexed and yields very potent pemetrexed polyglutamates. Pemetrexed pentaglutamate (tetraglutamated pemetrexed) is 80-fold more potent than pemetrexed in inhibiting thymidylate synthase. Yet it is a poor drug candidate because it cannot readily cross the negatively charged cell membrane due to its own negative charge. We are developing LEAF-1401, a novel nanoliposomal encapsulation of gamma L-pentaglutamated pemetrexed. Because liposomes can readily be taken up by tumor cells, for its anti-tumor effect, LEAF-1401 can directly deliver pentaglutamated pemetrexed into tumor cells, bypassing the need for transmembrane folate carriers and FPGS which are both downregulated in resistant tumors. Methods: To measure drug levels in tumor, blood and various tissues (biodistribution), in vivo testing of LEAF-1401 and pemetrexed was conducted in a CT-26 murine colorectal carcinoma xenograft model. Animals were treated with a single dose of either LEAF-1401 (80mg/kg; equivalent to 32 mg/kg pemetrexed) or pemetrexed (118mg/kg). Tumor growth inhibition and clinical assessments were conducted. Animals were sacrificed: 5 mice per timepoint in each group and tumor, blood, liver, spleen and other tissues were harvested. Pentaglutamated pemetrexed levels were quantitatively analyzed by LC/MS/MS. Results: Compared to pemetrexed, LEAF-1401 treatment resulted in a 19-fold increase in exposure levels of pentaglutamated pemetrexed in the tumor and significant tumor growth inhibition. Plasma levels of pentaglutamated pemetrexed were high with LEAF-1401, but undetectable with pemetrexed. Like other liposomes, LEAF-1401 also resulted in accumulation of pentaglutamated pemetrexed in the liver and spleen (See Table below). Treatment appeared to be generally well tolerated. Conclusions: LEAF-1401, given at approximately a quarter of the equivalent pemetrexed dose, resulted in a 19-fold increase in pentaglutamate pemetrexed in tumor tissue compared to regular pemetrexed. LEAF-1401 represents a promising new class of novel nanoliposomal antifolates, that enhance the intratumoral delivery of potent polyglutamate antifolates, and improve antitumor activity while retaining an acceptable safety profile. [Table: see text]
Liquid biopsies to enable non-invasive real-time functional chemoresistance profiling in solid organ cancers.
Authors: Akolkar Dadasaheb B , Crook Timothy , Page Raymond , Patil Darshana , Limaye Sewanti , Datta Vineet , Schuster Stefan , Sims Cynthe , Patil Sanket , Apurwa Sachin , Mhase Vishakha , Pawar Sushant , Gawai Ashok , Bodke Harshal , Srinivasan Ajay , Datar Rajan
Published: May 2020

3525

Background: Despite the development of targeted therapy agents and immune checkpoint inhibitors (ICI), cytotoxic anticancer agents remain the mainstay of treatment in several solid organ cancers. However, instances of innate and acquired resistance towards these anticancer agents can lead to treatment failures, which remain undetectable until clinical or radiological manifestation of symptoms suggestive of disease progression. There are presently no viable means or markers to detect or monitor for chemoresistance in real time. Owing to this unmet need, cancer treatment strategies face risks of failure and poor outcomes. Methods: We obtained 15 mL blood from 3,662 patients with various solid organ cancers, of various states and including treatment-naïve and pretreated patients. Circulating Tumor Associated Cells (C-TACs) were enriched and harvested from PBMCs using an epigenetically activating medium that is cytotoxic towards non-malignant epithelial and hematolymphoid cells in blood, but confers survival benefit on apoptosis resistant cells of tumorigenic origin (Circulating Tumor Associated Cells, C-TACs). In a subset of patients, fresh tumor tissue was also obtained from which viable tumor derived cells (TDCs) were obtained. Viable TDCs and C-TACs were treated with a panel of anticancer agents and the surviving cell fraction estimated to determine chemoresistance. Results: Among the 1,325 therapy naïve patients, resistance towards treatment agents was observed in C-TACs from 56.3 % of samples. Among 2,201 pretreated patients’ samples, resistance towards treatment agents was observed in C-TACs from 77.8% of samples. The increased resistance in C-TACs from pretreated patients indicated that the C-TACs had been resistance-educated by prior therapies. In a subset of patients, Chemoresistance profile of C-TACs was observed to be 96.9% concordant with that of tumor derived cells (TDCs) which were concurrently obtained from tumor tissue indicating that C-TACs accurately represent chemo-antecedents of the tumor. Conclusions: Non-invasive chemoresistance profiling of C-TACs is a viable strategy to monitor treatment efficacy in real time. Adoption of this strategy in the clinic will not only guide treatment selection with reduced risk of failure, but will also enable timely therapeutic course correction upon detection of acquired chemoresistance.
Exploitation of treatment induced tumor lysis to enhance sensitivity of ctDNA analysis: A first-in-human pilot study.
Authors: Breadner Daniel Adam , Vincent Mark David , Correa Rohann Jonathan Mark , Black Morgan , Warner Andrew , Qu Melody , Logan Diane , Sanatani Michael Susmoy , Younus Jawaid , Yaremko Brian P , Rodrigues George , Blanchette Phillip S. , Laba Joanna , Bhat Vasudeva , Morris Clive D. , Green Emma , Jones Greg , Allan Alison L , Palma David A. , Raphael Jacques
Published: May 2020

3530

Background: Blood based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remains a barrier to ctDNA replacing tissue-based testing. There is a paucity of data regarding the dynamics of ctDNA levels in the hours to days following a new treatment. We hypothesize that chemotherapy or radiation will yield an increased abundance of ctDNA in plasma by inducing tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. Methods: Two prospective cohorts of 20 patients (pts) with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained pts starting the first cycle of platinum doublet chemoradiation (C1a, n=10) or the first cycle of platinum doublet cytotoxic chemotherapy ± immunotherapy without radiation (RT) (C1b, n=10). Cohort 2 (C2) contained pts receiving palliative RT alone. Two baseline samples were collected, the first ≤ 14 days prior to starting treatment and one immediately prior to treatment. In C1, subsequent samples were collected 3, 6, 24 and 48 hours post initiation of chemotherapy. Pts in C2 had samples collected immediately prior to RT fractions 2, 3, and 4. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst-Lung assay. Results: Complete results were available for the first 35 of 40 enrolled pts, C1a – 10 pts, C1b – 9 pts, C2 – 16 pts. Detectable ctDNA was present at baseline in 27 pts (77%), 4 additional pts (11%) had detectable ctDNA in post treatment samples. Four of the patients with detectable ctDNA at baseline (15%) had new genetic alterations detected in post treatment samples. A total of 8/35 pts (23%) had new genetic alterations detected in the post treatment samples. Mutant molecule numbers increased with treatment in 23 of 31 (74%) pts with detectable ctDNA, C1 - 13 of 19 pts (68%) and C2 - 10 of 16 pts (63%). ctDNA levels peaked a median of 2.2 hours (IQR: 1.5 – 2.9 hours) after the initiation of chemotherapy and a median of 1 day (IQR: 1-2 days) after radiation was commenced. The percentage increase in ctDNA levels was a median of 29% (IQR: -18 to +112%) in C1. C2 had a median increase of 16% (IQR: 0 to +131%). Conclusions: ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post treatment phase can yield results that were not evident in pretreatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.
Clinical potential of ctDNA-based TMB in small cell lung cancer recieving chemoradiotherapy.
Authors: Jin Ying , Chen Yamei , Tang Huarong , Li Qian , Li Pansong , Hu Xiao , Guan Yan-Fang , Xia Xuefeng , Yi Xin , Zhang Jianjun , Chen Ming
Published: May 2020

3536

Background: Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis. Chemotherapy and / or radiotherapy is the main choice of SCLC treatment. Circulating tumor DNA (ctDNA) has received substantial attention in recent years owing to the potential of patient stratification and monitoring. Here, we assessed the value of prediction and prognosis using ctDNA in SCLC. Methods: SCLC patients (pts) with limited-stage disease (LD) receiving chemoradiotherapy and extensive-stage disease (ED) receiving chemotherapy were enrolled. Baseline plasma samples were collected for NGS using a 1021-gene-panel. Mutational features and blood-based tumor mutation burden (bTMB) were analyzed using ctDNA. pyClone software was used to cluster the mutations. The mutations in the cluster with the highest cancer cell fraction (CCF) were defined as clonal mutations. Progression-free survival (PFS) was followed. Results: 58 SCLC pts (35 LD and 23 ED) and 58 plasma samples were enrolled. Smoking pts accounted for 84% (49/58). In all samples, recurrent genes were TP53 (86%), RB1 (57%), LRP1B (34%), CREBBP (26%), and MLL3 (22%). The median of bTMB and clone count were 7.9 [0-26] and 7 [0-25]. Significant higher bTMB and clone count were observed in ED pts compared with LD (Mann Whitney test, p = 0.019 and p = 0.041, respectively). Mutated CREBBP (10/23 ED versus 5/35 LD) was enriched in ED (Fisher exact test, p = 0.017 and OR = 0.223). Mutations in NOTCH signaling pathway were enriched in ED (l6/23 ED versus 13/35 LD, p = 0.031, OR = 0.265). In LD group, there were trend toward prolonged PFS in pts with higher bTMB(p = 0.065), and pts with higher clonal bTMB (cbTMB) exhibited significant longer PFS (p = 0.016, HR 0.37, 95% CI [0.12-1.11]). Patients with alteration in PIK3CA showed shorter PFS than wild type (p < 0.001, HR 0.11, 95% CI [0-2.86]). There were no significant difference in median PFS in LD stage pts with any detectable pathway alterations. Whereas, LD pts whose ctDNA contained RTK-RAS signaling pathway alterations exhibited shorter PFS than pts without those alterations (p = 0.135). In ED pts, NOTCH1 gene wild type displayed longer PFS than mutant type (p = 0.036, HR 0.38, 95% CI [0.1-1.53]). There were no difference in PFS between pts with higher and lower bTMB and cbTMB. Conclusions: ctDNA can characterize the mutational feature of SCLC. There are differences in the molecular characteristics between ED and LD pts. Clonal bTMB is a potential prognostic biomarker for LD SCLC chemoradiotherapy. The prognostic marker of ED chemotherapy is different from LD.
Analytical validation of digital cytometry (iSort) for leukocyte enumeration using stored blood.
Authors: Newman Aaron M. , Nakao Aki , Li Kathy , Liu Chih-Long , Mathi Kavita , Sigal Natalia , Maecker Holden , Diehn Maximilian , Alizadeh Ash A.
Published: May 2020

3542

Background: Blood leukocyte enumeration is a cornerstone for clinical diagnosis and immune monitoring of diverse cancers and immunotherapies. Existing methods rely on intact/living cells and can thus be limiting due to handling time constraints and need for predefined antibody panels. While indirect cytometry methods including digital cytometry can overcome this limitation on archival specimens, their clinical performance has not been extensively characterized. We developed iSort, a novel transcriptome deconvolution method based on CIBERSORTx. Here, we comprehensively evaluated iSort and validated it against established diagnostic standards. Methods: We recruited 36 healthy adult blood donors and characterized their blood leukocyte profiles. We used several established clinical cytometry methods requiring intact cells in a CLIA laboratory including Complete Blood Count [CBC] and 6-color TBNK [TBNK]. We also immunophenotyped leukocytes by a research flow cytometry panel (FACS) and by mass cytometry (CyTOF). We then used these techniques as standards for validating leukocyte populations enumerated by iSort. iSort was performed on whole blood through deconvolution of 22 subsets from RNA-Seq. We assessed iSort’s analytical detection performance by spiking purified lymphocyte subsets into lymphodepleted human blood and by simulating blood mixtures using defined leukocyte mixtures within latin square designs. We assessed iSort concordance with an FDA approved IVD assay (TBNK) comparing distinct RNA-Seq library preparation chemistries. Results: iSort was highly correlated with TBNK/CBC across CD4 T, CD8 T, B cells, NK cells, monocytes, and neutrophils (r≥0.95). When comparing correlations to TBNK/CBC, we found no significant differences between iSort, CyTOF, and FACS, nor between RNA-Seq library chemistries. iSort demonstrated high linearity at low abundance levels (0.1 - 1%, r = 0.99, B-cells spiked into lymphodepleted blood samples after Rituximab) and at higher abundance levels (0.5 - 90%, r > 0.99) across lymphoid and myeloid subsets. iSort also showed high reproducibility among triplicate blood tubes for each population (median CV = 11%). Conclusions: iSort digital cytometry achieves highly accurate and robust leukocyte enumeration for diverse hematopoietic subsets. Given its favorable performance against existing clinical standards that require intact/living cells, iSort is a promising approach for the development of immunotherapy biomarkers.
Identification of FGFR2/3 fusions from clinical cfDNA NGS using a de novo fusion caller.
Authors: Yablonovitch Arielle , Gnerre Sante , Kiedrowski Lesli Ann , Yen Jennifer , Liu Leo , Helman Elena , Fairclough Stephen R , Nagy Rebecca , Chudova Darya , Talasaz AmirAli
Published: May 2020

3545

Background: FGFR2/ 3 rearrangements are promising therapeutic targets, especially in advanced urothelial cancer (aUC) with FDA-approved erdafitinib. Liquid biopsy is an attractive non-invasive method to identify these fusions, but detection in cfDNA is technically challenging due to low tumor shedding levels, short molecules, and wide variation in gene partners. To address this, we developed an assembly-based fusion detection algorithm to call rearrangements in a de novo fashion without reliance on a fixed partner set and applied it to > 15,000 clinical samples. Methods: A cohort of 15,218 patients with mixed cancer types (including 698 aUC patients, as well as breast, cholangiocarcinoma, colorectal, and gastric), plus 276 healthy control samples were previously tested with Guardant360(R), a clinical 74-gene cfDNA NGS-based assay. The median unique molecule coverage was approximately 3,000 molecules sequenced to 15,000x read depth. Samples were reanalyzed in silico using the novel algorithm: in brief, reads aligned to candidate fusion breakpoints were assembled into de Bruijn graphs. Resulting contigs were aligned to the reference and filters were applied to remove technical artifacts. Results: The majority of FGFR2 (86%) and FGFR3 fusion partners (73%) in the mixed cancer cohort were observed only once, consistent with previous reports (Helsten 2016). FGFR3-TACC3 was the most common fusion, occurring in 72% of FGFR3 fusion-positive patients. In 37% of FGFR2 fusion positive patients, the de novo caller detected partners not previously described. In the aUC cohort, FGFR3 fusions were detected in 3.3% of patients, with 8/10 (80%) partner genes/intergenic regions occurring only once, which is in line with previous reports (Nassar 2018). No fusions were identified in 276 healthy control samples. In the mixed cancer cohort, common mutations co-occurring with FGFR2 fusions were FGFR2 N549K, PIK3CA H1047R, and TP53 R175H (5.6% each); KRAS Q61H was observed in 28% of patients with FGFR3 fusions. Conclusions: FGFR2/ 3 fusion partners detected by a highly specific assembly-based de novo fusion caller were heterogeneous and individually rare, highlighting the importance of a de novo approach. We observed an FGFR3 fusion prevalence in cfDNA from aUC patients that is comparable to previous reports for tissue testing, demonstrating an ability to capture targetable genomic rearrangements with plasma-based NGS in this patient population.
High intratumoral tryptophan metabolism is a poor predictor of response to pembrolizumab (pembro) in metastatic melanoma (MM): Results from a prospective trial using baseline C11-labeled alpha-methyl tryptophan (C11-AMT) PET imaging for response prediction.
Authors: Oldan Jorge D. , Ollila David W. , Giglio Ben C. , Smith Eric , Bouchard Deeanna M. , Ivanovic Marija , Lee Yueh Z. , Collichio Frances A. , Meyers Michael O. , Wallack Diana E. , Khandani Amir H. , Abernathy-Leinwand Amber , Long Patricia K. , Ezzell Jennifer Ashley , Trembath Dimitri G. , Li Zibo , Wong Terence Z. , Moschos Stergios J.
Published: May 2020

3556

Background: Molecular imaging of metabolic pathways critical for effector T cell response other than glucose could predict response to PD1 inhibitors. We have previously shown that high expression of tryptophan metabolic pathway enzymes in stage III/IV melanoma correlates with reduced abundance of tumor-infiltrating lymphocytes (TILs, ASCO 2019, e21014). Here we investigated C11-AMT, a PET tracer that images tryptophan metabolism, as a predictor of response to pembro in patients (pts) with PD1 inhibitor-naïve MM. Methods: In this trial (NCT03089606) pts must have had measurable MM by RECIST, have undergone IV contrast CT, FDG-PET, and C11-AMT PET scan (30-40 min dynamic imaging), plus a mandatory tumor biopsy prior to pembro treatment. Results: 21 pts (16 males; 15 stage IV; median age 61) had all 3 baseline scans and evaluable research biopsies. 13 pts were non-progressors (CR = 4, PR = 6, and SD = 3). At a median f/u of 13.7 mons (2.8-25.1+), 6 pts are dead from MM, 11 are alive without MM and 4 are alive with MM. 46 tumor lesions were assessed by all 3 scans. Of the pts with tumor lesion, C11-AMT PET SUVmax < 7 and skewness < +0.3 of the tumor lesion with the highest C11-AMT SUVmax was associated with non-progression by RECIST (SUVmax < 7/skewness < +0.3 in progressors vs. non-progressors; Fisher’s 2-tail test p= 0.055). The corresponding association between baseline FDG-PET (SUVmax < 14 and skewness < +0.3) with treatment response was insignificant ( p= 0.08). There was a weak (Spearman ρ= 0.33) but significant correlation ( p= 0.001) in SUVmax between FDG-PET and C11-AMT among the 46 tumors analyzed. There was no significant correlation between melanoma-specific expression of the tryptophan- (TPH1, TPH2, IDO1, TDO2, LAT1) and glucose-metabolizing enzymes (GLUT1, HK1, HK3) by immunohistochemistry. Response to pembro trends to associate with present TILs (Fisher’s p= 0.087). Conclusions: Baseline C11-AMT PET imaging using simple radiomics measures (highest metabolic activity, SUVmax, and tumor heterogeneity, skewness) may better predict clinical benefit from pembro in MM than FDG PET. Variability in C11-AMT’s SUVmax cannot be solely explained by FDG-PET’s SUVmax, suggesting that these two imaging modalities may provide complementary information about intratumoral metabolic dysregulation that may relate with pembro response. Texture analysis using LifeX v4.0 will be presented at the meeting. Clinical trial information: NCT03089606 .
Molecular profiling of metastatic breast cancer (MBC) and target-based therapeutic matching in an Asian tertiary phase I oncology unit.
Authors: Walsh Robert John , Ngoi Natalie , Ong Rebecca Jia Min , Ow Samuel Guan Wei , Wong Andrea , Eng Lim Siew , Lim Yi Wan , Heong Valerie , Sundar Raghav , Soo Ross A. , Yong Wei-Peng , Chee Cheng Ean , Goh Boon Cher , Lee Soo-Chin , Tan David Shao Peng , Lim Joline Si Jing
Published: May 2020

3561

Background: Somatic profiling of MBC has highlighted actionable mutations and driven trials of matched targeted therapy (tx). Previous phase I studies have reported improved outcomes following matched therapies with tumour molecular profiles. Here, we review next generation sequencing (NGS) and treatment outcomes of Asian MBC patients (pts) in the phase I unit of a tertiary centre. Methods: Pts with MBC referred to a phase I unit underwent NGS (n = 152). Tumour tissue was sequenced via the amplicon based Ion Ampliseq Cancer (IAC) v2 (50 genes) platform from 2014-2017 prior to institutional change to Foundation Medicine 1 (FM1) (324 genes) 2017-2019. Patients were counselled on findings and enrolled onto matched therapeutic trials where available. Results: NGS was successfully performed in 107 pts (IAC 46%, FM1 54%) of which tumour subtypes include hormone receptor positive 63%, triple negative breast cancer (TNBC) 28% and Her2 positive 19%. Median lines of prior tx for MBC was 4 (range 0-12). 89% had prior chemotherapy (CT), 57% prior endocrine therapy (ET). 72/107 (67%) sequenced patients had further treatment and 18 (25%) were matched to tx based on NGS findings (15 clinical trial, 3 off trial). Matching rates on both NGS platforms were similar (IAC 22% vs FM1 28%). Mutated pathways with potential matched tx included PIK3CA/AKT/PTEN (52%), DNA damage response (DRR) (15%), and FGFR (11%) pathways. PIK3 mutations were seen in 43% and associated with higher number of metastatic sites (p = 0.03); most prevalent aberrations were PIK3CA H1047R (41%) and PIK3CA E542K (13%). Matched cases were more heavily pretreated (mean lines of prior tx 5.3 matched vs 3.7, unmatched p = 0.05), and showed a median progression free survival (mPFS) of 24 weeks [w] and clinical benefit rate (complete/partial response or stable disease ≥ 12 weeks) of 53% on matched tx. Comparison by NGS platform showed improved mPFS for matched vs unmatched pts sequenced on FM1 vs IAC (FM1: 26 vs 19w, HR = 0.76 [95% CI: 0.3-1.9]; IAC: 8 vs 12w; HR = 1.21 [95% CI: 0.5-2.8]). Interestingly, 1 pt with SMARCB mutation, reportedly associated with the FGFR pathway, had a PFS of 70w on tx with a pan-FGFR inhibitor after progressing on 3 prior lines of tx (ET and CT). Conclusions: Molecular profiling of MBC in a phase I unit led to matched tx in 25% of cases. Matched pts showed encouraging mPFS with a suggestion of benefit in those matched after sequencing on a broader gene panel (FM1).
Machine learning radiomics signature on magnetic resonance imaging associated with phenotypes and disease-free survival in patients with breast cancer (RBC-01): A registry-based, multicenter cohort study.
Authors: Yao Herui , Yu Yunfang , Tan Yujie , Hu Qiugen , Ouyang Jie , Chen Yongjian , Gu Yang , Li Anlin , He Zifan , Yang Yaping , Chen Kai , Ma Jiafan , Li Chenchen , Ma Mudi , Li Xiaohong , Zhong Haitao , Ou Qiyun , Wu Zhuo , Su Fengxi , Song Erwei
Published: May 2020

3563

Background: The early stage breast cancer patients can vary in disease-free survival (DFS), innovative predictors evaluate the prognostic capacity are urgently needed. We aimed to develop and independently validate a radiomics signature based on MRI associated with phenotypes and DFS in patients with breast cancer and to establish a radiomics nomogram that incorporates the radiomics signature and clinicopathological findings using computational algorithms. Methods: In this multicenter, retrospective, cohort study, we analyzed preoperative contrast–enhanced MRI data from the prospective cohort study (n = 123) of patients who had been treated with neoadjuvant chemotherapy in phase 3 trials and independent cohort (n = 438) at the Sun Yat-sen Memorial Hospital as training cohort to develop the radiomic signature, and validated it in validation cohort (Foshan cohort, n = 121; Dongguan cohort, n = 89) between November 17, 2011, and September 21, 2019, and validated in TGCA cohort (n = 84). Machine-learning algorithm to identify robust imaging subtypes and evaluated their clinical and biologic relevance. A nomogram combining the radiomic signature and clinicopathological findings to predict individual survival based on Cox regression model. The primary endpoint was disease-free survival (DFS). This study is registered with ClinicalTrials.gov, number NCT04003558, and Chinese Clinical Trail Registry, number ChiCTR1900024020. Results: A total of 855 breast cancer patients were included. Radiomics signature was generated to classify patients into high-risk and low-risk groups in the Guangzhou training cohort. Patients with low-risk scores in the training cohort had higher DFS (hazard ratio [HR] 0.55, 95% CI 0.31 to 0.99; P= 0.045) than patients with high-risk scores, and validated in in validation cohort (HR 0.14, 95% CI 0.03 to 0.62; P= 0.003). The nomogram combined radiomics score with clinicopathological factors could accurately predict DFS benefits in training cohort (C-index = 0.83; AUC, 1, 2, 3-year were 0.80, 0.85, 0.82, respectively) and validated in validation cohorts. Conclusions: The radiomics signature are significantly associated with the DFS in patients with breast cancer. Combining the radiomics nomogram improved individualized DFS pretiction. Clinical trial information: NCT04003558 .
High-risk breast cancer genes at 8q22-24 and their role in over 5,000 patients evaluated with the 70-gene risk of recurrence assay.
Authors: Diab Sami , Socoteanu Matei P. , Encarnacion Carlos A. , Osborne Cynthia R. C. , Hendricks Carolyn B. , McIntyre Kristi , Thomas Vibha Taneja , Bhaskaran Rajith , Mittempergher Lorenza , Menicucci Andrea , Audeh William , O'Shaughnessy Joyce ,   FLEX Investigators' Group
Published: May 2020

3569

Background: Previous studies have shown that CCNE2 expression is higher in patients’ cancers resistant to CDK4/6 inhibitors. Increased expression of CCNE2, MTDH, or TSPYL5, genes contained within the 70-gene risk of distant recurrence signature (70GS), has also been implicated in breast oncogenesis, poor prognosis, and chemoresistance. These genes are located on chromosome region 8q22.1, one of the most recurrently amplified regions out of all 70GS genes in breast tumors (Fatima et al. 2017). MYC, located on 8q24, is overexpressed in 40% of all breast cancers (BC). Here we examined the expression of CCNE2, MTDH, and TSPYL5 in relation to 70GS risk and the 80-gene molecular subtype signature (80GS), and their correlation with MYC expression in early stage BC patients. Methods: CCNE2, MTDH, TSPYL5, and MYC mRNA expression was measured in 5022 BC samples sent to Agendia (Irvine, CA) for 70GS and 80GS testing, which included FFPE microarray full-transcriptome data. 70GS was used to stratify patients into Ultra Low Risk (UL), Low Risk (LR), High Risk (HR), and Ultra High Risk (UH). Both 70GS and 80GS were used to classify patient samples into Luminal A, Luminal B, HER2, or Basal type. Wilcoxon rank sum test was used to assess expression differences. Results: The expression of CCNE2, MTDH, and TSPYL5 significantly correlated with each other and was higher in HR patients compared to LR patients (p < 0.001) and higher in UH patients compared to HR patients (p < 0.001). Expression of these genes was highest in Basal type tumors, 83% of which were UH, followed by Luminal B type tumors, and lowest in Luminal A type tumors. CCNE2 and MYC expression was elevated in LR compared to UL patients (p < 0.001 and p = 0.0043). There was no difference in MYC expression between HR vs. LR or UH vs. HR. Lastly, there was no association between the expression of 8q22.1 genes and MYC in any 70GS subgroup. Conclusions: Within the 70GS, CCNE2, MTDH, and TSPYL5 have similar expression patterns and when overexpressed may identify an UH cohort of BC. This observation, in addition to their physical proximity at 8q22.1 suggests a possible amplicon in this region. The highest expression of CCNE2, MTDH, and TSPYL5 associated with UH patients and is concordant with previous studies that support the role of these genes in BC metastasis. Furthermore, this analysis suggests MYC may not stratify patients based on metastatic potential. These data may be clinically relevant for stratifying patients in ongoing clinical trials evaluating response and resistance to targeted therapies in early stage BC.
Comparison of recurrence patterns after surgery and radiation therapy with 68Ga-PSMA-11 PET/CT in nonmetastatic castrate-sensitive prostate cancer patients: A single-center post-hoc retrospective analysis in 787 patients.
Authors: Armstrong Wesley R , Thin Pan , Nguyen Kathleen , Alano Rejah M. , Booker Kiara M , Gartmann Jeannine , Lok Vincent , Lira Stephanie , Czernin Johannes , Kishan Amar Upadhyaya , Nickols Nicholas George , Calais Jeremie
Published: May 2020

3577

Background: 20 to 50% of prostate cancer (PCa) patients undergoing radical prostatectomy (RP) or definitive radiation therapy (dRT) will experience disease recurrence. However, anatomical recurrence patterns may differ depending on the therapeutic approaches. The aim of this post-hoc retrospective analysis was to investigate if the relapse pattern as assessed by 68Ga-PSMA-11 PET/CT was different depending on the type of local pelvic therapy (RP, dRT, salvage RT (SRT), pelvic lymph node dissection (PLND), pelvic lymph node RT (PLNRT)) in patients with non-metastatic castrate sensitive (nmCS) recurrent disease after primary definitive therapy. Methods: Patients who underwent a 68Ga-PSMA-11 PET/CT for nmCS PCa recurrent disease after primary definitive therapy were screened from a database of 4 prospective studies (NCT02940262, NCT03515577, NCT04050215, NCT03582774). Patients who underwent primary staging (n = 95), without definitive therapy (n = 68), with known metastatic disease (M1) (n = 68) or with castrate resistant (CR) disease (n = 291) were excluded. We examined the relationship between recurrence patterns as assessed by 68Ga-PSMA-11 PET/CT (PROMISE criteria) and prior local treatments: i) RP, ii) dRT, iii) RP + SRT. Results: 787 patients were included in the analysis. Positive scan rates were 60%, 94% and 75% in RP, dRT and RP + SRT populations, respectively. Median pre-scan PSA levels were 0.50 (0.02-72.5) ng/ml, 4.4 (0.1-202) ng/ml, and 1.07 (0.04-33) ng/ml for patients who underwent RP (n = 464), dRT (n = 109) and post-RP SRT (n = 214). Median time to first recurrence was 27.7 after RP and 54.6 months after dRT (p = < 0.0001). Patients who underwent RP had lower local recurrence (LR) pattern (T+) rates by PSMA PET than those with dRT (99/464; 21% vs 69/109; 63%; p = < 0.0001). Nodal metastasis (N1) positivity rate was similar between RP and dRT (179/464; 39% vs 43/109; 39%; p = 0.87). Extrapelvic metastasis (M1) positivity rate was lower for RP than dRT (93/464; 20% vs 51/109; 47%; p = < 0.0001). Median time from post-RP SRT to second recurrence was 22.3 months. In patients who had a second recurrence after RP and SRT the positivity rate of LR (T+), N1 disease and M1 disease by PSMA PET/CT was 12% (24/214), 46% (99/214) and 44% (95/214). Conclusions: In this cohort of patients with nmCS PCa recurrent disease after primary definitive therapy, the patterns of failure differ based on prior local treatments.