bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-antigen active specific immunotherapy induced long-term remission and prevent colorectal cancer relapse.
Authors: Marquez-Manriquez Juan Pablo , Lucero-Diaz Pedro Alejandro , Camacho-Hernandez Alejandro , Gallardo-Rincon Dolores , Rosas-Delgado Martin Orlando , Perez-Astorga Mario Alberto , Fernandez-Felix Daniel Adrian , Cisneros-Ruiz Jorge Alberto ALBERTO , Banuelos Maria Olga Rocha , Durazo Alberto
Published: May 2020

3138

Background: Clinical effective multi-antigen active immunotherapy for colorectal cancer (CRC) is still limited and most studies have failed. We consider this is because the targets in some of the studies are not oncogenic drivers. This is especially important for patients that progressed to standard of care treatment. Also, most of the studies with Immune checkpoint inhibitors (ICH) have failed in CRC but potentially may impact and provide better outcomes if used as combination therapies. We treated CRC patients with progressive disease in a pilot study n = 15 and found clinical responses that correlate with the CD8, delayed-type hypersensitivity (DTH) and Th1 parameters. After patients achieved remission we used the same peptides to prevent relapse with clinical and statistics significance. Methods: N = 15 CRC patients were enrolled in this pilot trial after approval for the ethic IRB committee from CICS Mexico. Patients were treated with an intradermal vaccine every week for four weeks, every two weeks four times in axillary and inguinal lymph nodes (LN) areas, and finally subcutaneously every month six times in the sites with tumor activity. Previously to the treatment we perform Granzyme B ELISPOT, ELISA, DTH and CT scan as initial controls. We delivered intradermal four peptides from sixteen peptides predicted from four proteins such as Fascin-1, Ape-1, VCP and RCAS1. Results: 86% of the patients had an objective clinical responses and 14% stable disease. All the patients had a correlation with the immunological assays as following. 58% of patients had an increased in the CD8 cells demonstrated by Granzyme B; DTH reactions were gradually increasing and by the first month of treatment the DTH were positive for Fascin-1 (78%), Ape-1 (85%), VCP (95%) and RCAS1 (83%) peptides. The more immunogenic peptides by ELISA were Fascin-1 A (P = 0.001), Fascin-1 D (P = 0.005), Ape-1 C (p = 0.001), VCP A (P = 0.003), RCAS1 A (p = 0.001) and RCAS1 B (P = 0.01). Conclusions: The treatment was effective with CR and SD responses. Once we validate this data we are planning a clinical study combining the treatment with low dose of ICH. Currently all the patients with CR are now under relapse prevention. We are still treating the patients with SD until disease progression. Importantly we believe that this data may impact the PFS and OS in CRC patients who have Karnoksky > to 80% despite progressive disease to standard of care.
Phase I/II study of avadomide (CC-122) in combination with R-CHOP for newly diagnosed DLBCL.
Authors: Mehta-Shah Neha , Chavez Julio C. , Abrisqueta Pau , Johnson Nathalie , Bergua Burgues Juan Miguel , Grande-Garcia Carlos , Stewart Douglas , Dunleavy Kieron , Rodriguez Guillermo , Sancho Juan-Manuel , Drew James , Wu Chengqing , Hagner Patrick R. , Delarue Richard , Martin Alejandro
Published: May 2020

3501

Background: In certain subsets of patients (pts) with diffuse large B-cell lymphoma (DLBCL), the failure rate of standard R-CHOP treatment is high. Pts with high-risk disease (International Prognostic score [IPI] 3-5) have a particularly poor prognosis, with 3-y survival rates of ~62% with R-CHOP alone. The cereblon E3 ligase modulator avadomide (CC-122) showed activity in pts with relapsed or refractory DLBCL. We report results of avadomide plus R-CHOP in previously untreated pts with high-risk DLBCL. Methods: CC-122-DLBCL-002 (NCT03283202) is a phase 1/2 study of avadomide plus R-CHOP-21 in pts newly diagnosed with DLBCL not otherwise specified with IPI scores 3-5 who were aged ≥18 y. Pts received standard R-CHOP and escalating doses (1-3 mg) of oral avadomide for up to six 21-d cycles (Table). All pts received pegfilgrastim support. Primary objectives were to assess safety, tolerability, and complete response (CR) rate. Secondary objectives include evaluation of additional efficacy parameters (objective response rate [ORR], progression-free survival [PFS], and overall survival) and biomarkers. Results: As of July 30, 2019, 35 pts were enrolled in the phase 1 part of the study. Median age was 66 y (range, 20-75), 23 pts (66%) were aged > 60 y, 18 (51%) had an IPI score of 3, and 17 (49%) had an IPI score of 4-5. Thirty-two pts (91%) completed 6 cycles of treatment. Median relative total dose intensity of avadomide was 99% and the average relative dose intensity of R-CHOP was 95%. Six pts had dose-limiting toxicities: 1 pt had neutropenia and bacterial hepatic infection; 1 had pneumonia; 1 had febrile neutropenia (FN); 1 had FN and hypotension; 1 had FN due to skin infections; and 1 had sepsis. The recommended phase 2 dose was 3 mg 2/3 wk. Grade 3/4 adverse events in ≥10% of pts were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and FN (11%). Among 34 efficacy-evaluable pts, the ORR was 88% (n = 30/34), including a CR rate of 79% (n = 27/34) at the end of treatment. With a median follow-up of 10 mo, the 1-y PFS rate was 80% (95% CI, 58-92). Correlative analyses will be presented at the meeting. Conclusions: Avadomide plus R-CHOP was well-tolerated with no significant additive toxicities. The promising efficacy in this high-risk pt population warrants further evaluation of immunomodulatory drugs combined with immunochemotherapy for pts with previously untreated DLBCL. Clinical trial information: NCT03283202 . [Table: see text]
Phase II study of copanlisib in patients with tumors with PIK3CA mutations (PTEN loss allowed): NCI MATCH EAY131-Z1F.
Authors: Damodaran Senthil , Zhao Fengmin , Deming Dustin A. , Mitchell Edith P. , Wright John Joseph , Doyle Laurence A , Gray Robert James , Li Shuli , McShane Lisa , Rubinstein Larry V , Patton David R , Williams Mickey , Hamilton Stanley R. , Suga Jennifer Marie , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith
Published: May 2020

3506

Background: The NCI-MATCH (EAY131) is a platform trial that enrolls patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on matching genomic alterations of interest (NCT02465060). Arm Z1F evaluated copanlisib, a highly selective, pan-Class 1 PI3K inhibitor with predominant activity against both the δ and α isoforms in pts with PIK3CA mutations. Methods: Pts received copanlisib (60 mg IV) on days 1, 8, and 15 in 28-day cycles until progression/toxicity. Tumor assessment was every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints were PFS, 6-month PFS, and predictive biomarkers. Pts with KRAS mutations, HER2+ve breast cancers, lymphomas were excluded. Results: 35 pts were enrolled (from 8/2/18 to 12/27/18), of which, 28 pts were available for analysis (7 patients, not eligible or did not start therapy). Multiple histologies were enrolled with gynecologic (n = 7), gastrointestinal (n = 6), and genitourinary (n = 5) the most common tumors. Median age 61 (range 42-78). 75% of pts had ≥ 3 lines of prior therapy. 54% of PIK3CA mutations were located in the helical domain, 32% in kinase domain and 14% in other domains. Twenty-six pts had co-occurring gene alterations (median 3; range 1-9), with 9 patients having 4 or more gene alterations. The ORR was 11% (3/28, 90% CI: 3%-25%). Partial responses were seen in uterine cancer, clear cell carcinoma of anterior abdominal wall, and liposarcoma. 6 pts had > 6 months of stable disease and clinical benefit rate was 32% (9/28). Two pts are still on treatment. The most common reason for protocol discontinuation was disease progression (n = 18, 69%). Thirty pts were included for toxicity analysis. Ten pts (33%) had grade 1 or 2 toxicities, 16 pts (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 11), hypertension (n = 10), diarrhea (n = 10), and nausea (n = 9). Total of 5 deaths were reported, none related to treatment. Conclusions: Copanlisib showed meaningful clinical activity across various tumors with PIK3CA mutation in the late-line refractory setting. Further study either alone or in combinations in select tumors is warranted. G3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Clinical trial information: NCT02465060 .
First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors.
Authors: Lakhani Nehal J. , Rasco Drew W. , Zeng Qi , Tang Yuefen , LIANG ZHIYAN , Wang Hengbang , Lu Ming , Chen Jason , Fu Lei , Wang Cunlin , Yang Dajun , Zhai Yifan
Published: May 2020

3509

Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that Cmax and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .
Phase Ib study of a novel, small-molecule MDM2 inhibitor APG-115 combined with pembrolizumab in U.S. patients with metastatic solid tumors.
Authors: Tolcher Anthony W. , Karim Raghad , Tang Yuefen , Wang Hengbang , Ji Jiao , Chen Jason , Kaiser Angela , Sheladia Piyush , Ahmad Mohammad , LIANG ZHIYAN , Yang Dajun , Zhai Yifan
Published: May 2020

3512

Background: APG-115 activates p53-mediated apoptosis in tumor cells retaining wild-type TP53. It also functions as a host immune modulator and enhances antitumor activities when combined with PD-1 blockade preclinically. MDM2 amplification is associated with hyperprogression in patients treated with checkpoint inhibitors. Methods: The Phase Ib / II study was designed to evaluate APG-115 combined with pembrolizumab in patients with metastatic solid tumors (NCT03611868). APG-115 was administered orally every other day for 2 weeks, at dose ranging from 50 mg – 200 mg, with pembrolizumab at 200 mg IV on Day 1 of a 21-day cycle. Study objectives were to assess safety including dose-limiting toxicity (DLT), serious adverse events (SAEs), treatment-related AEs (TRAEs), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed by RECIST v1.1), to determine recommended phase 2 dose (RP2D). Results: As of December 25, 2019, the enrollment of phase 1b study was completed. Total 19 patients had been treated in four APG-115 cohorts: 50 mg (n = 3), 100 mg (n = 3), 150 mg (n = 6), and 200 mg (n = 7). No DLT was observed, The TRAEs (≥15%) were nausea (47.4%), fatigue (36.8%), decreased platelet count (26.3%), and decreased appetite (21.1%), as well as diarrhea, vomiting, decreased neutrophil or white blood cell count, and hypothyroidism in 15.8% each. Grade > 3 TRAEs included decreased neutrophil and thrombocytopenia in 15.8% each. Two SAEs were treatment related: G3 febrile neutropenia and G3 adrenal insufficiency. No new safety finding from combination with Pembrolizumab. The RP2D of APG-115 was 150 mg. One patient with ovarian cancer has a CR lasting for 15 months, 2 patients had PR for 8-9 months: one NSCLC failed IO therapy, another with appendix cancer, and 7 had SD for 1.5-7 months. The objective response rate was 15.8%, and the disease control rate (DCR) was 52.6%. PK data indicated an approximately dose-proportional increase in APG-115 exposure over the range of 50-200 mg on Day 1. PD-PK analyses showed that serum macrophage inhibitory cytokine-1 (MIC-1) increase was time and dose dependent, the MIC-1 elevation correlated with APG-115 exposure, indicating p53 activation in these patients. Conclusions: APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling. Clinical trial information: NCT03611868 .
Lurbinectedin (LUR) in combination with Irinotecan (IRI) in patients (pts) with advanced solid tumors: Updated results from a phase Ib-II trial.
Authors: Ponce Aix Santiago , Cote Gregory Michael , Falcon Gonzalez Alejandro , Sepulveda Juan Manuel , Jimenez Aguilar Elizabeth , Sanchez-Simon Inmaculada , Flor Maria José , Nuñez Rafael , Gonzalez Eva Maria , Insa Monica , Siguero Mariano , Cullell-Young Martin , Kahatt Carmen Maria , Zeaiter Ali Hassan , Paz-Ares Luis G.
Published: May 2020

3514

Background: LUR is a novel agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this clinical trial. Methods: Phase Ib-II trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75 mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors (+/- G-CSF, if dose-limiting toxicities [DLTs] were neutropenia). Starting dose was LUR 1.0 m/m2 + IRI 75 mg/m2. Results: 77 pts have been treated to date at 5 dose levels, 51 of them at the recommended dose (RD). Baseline characteristics of all 77 pts were: 48% females, 68% ECOG PS=1; median age 57 years (range, 19-75 years); median of 2 prior lines (range, 0−4 lines). The maximum tolerated dose (MTD) was LUR 2.4 mg/m2 + IRI 75 mg/m2 with G-CSF, and the RD was LUR 2.0 mg/m2 + IRI 75 mg/m2 with G-CSF. DLTs in Cycle 1 occurred in 2/3 evaluable pts at the MTD and 3/13 evaluable pts at the RD, and comprised omission of IRI D8 infusion due to grade (G) 3/4 neutropenia (n=3 pts) or G2-4 thrombocytopenia (n=2). At the RD (n=51), common G1/2 non-hematological toxicities were nausea, vomiting, fatigue, diarrhea, anorexia and neuropathy. G3 non-hematological toxicities (diarrhea 10%, fatigue 10%) and G3/4 hematological abnormalities (neutropenia 49%, thrombocytopenia 10%) were transient. Conclusions: The combination of LUR and IRI had acceptable tolerance, with no unexpected toxicities. Transient myelosuppression was dose-limiting. The RD is LUR 2.0 mg/m2 on D1 + IRI 75 mg/m2 on D1 and D8 q3w with G-CSF. Antitumor activity was observed at the RD in SCLC pts, as well as in endometrial carcinoma pts. Hints of activity were also observed in STS pts. Updated results will be presented. Clinical trial information: NCT02611024 . [Table: see text]
An open-label, multicenter, phase II study of ceritinib in patients with advanced ALK+ non-lung solid tumors and hematological malignancies (ASCEND-10).
Authors: Moreno Victor , Kim Tae Min , Rha Sun Young , Longo Federico , Sathornsumetee Sith , Zhang Shirong , Hirschberg Yulia , Pramanik Barnali , Wamil Barbara D , Kiss Igor
Published: May 2020

3520

Background: Prior studies have confirmed the efficacy and safety of ceritinib in patients (pts) with advanced ALK+ non-small cell lung cancer (Soria, et al, Lancet 2017; Shaw et al, Lancet Oncol 2017; Cho et al, JTO 2019). Ceritinib also demonstrated antitumor activity in pediatric pts with ALK+ inflammatory myofibroblastic tumor (IMT) and ALCL (Georger et al, ASCO 2015 [abstract#10005]). Long-term clinical benefits of ceritinib treatment were shown in pts with anaplastic large cell lymphoma (ALCL) (Richly et al, Blood 2015). The aim of the current study was to examine ceritinib efficacy and safety in pts with advanced ALK+ non-lung solid tumors and hematological malignancies. Methods: In this open-label, multi-arm, phase 2 (NCT02465528) trial, adult pts with ALK gene abnormalities who had received ≥1 prior systemic therapy were administered oral ceritinib 750 mg/day, under fasted conditions. Primary endpoint: investigator assessed disease control rate (DCR); secondary endpoints: investigator assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), and safety. Results: Overall, 22 pts (ALCL [n = 1], IMT [n = 4], glioblastoma multiforme [GBM, n = 12] and others [n = 5]) were enrolled; median (m) age: 52.5 years; male: 50%; Stage ≥IV: 95.4%. Key efficacy results are shown in the Table. mTTR in pts with confirmed complete response (CR) or partial response (PR) [n = 4] was 7.4 (range, 6–25) weeks. mDOR was not reached. mPFS (95% CI) was 2.6 (1.6, 3.7) weeks. Most common adverse events (AEs; ≥30%) were: diarrhea and nausea (59.1% each), vomiting (50.0%) and increased alanine aminotransferase (31.8%). Most common grade ≥3 AEs (≥10%): hyperglycemia (18.2%), increased gamma-glutamyl transferase, thrombocytopenia, and anemia (13.6% each). Clinical trial information: NCT02465528 . Conclusions: Ceritinib 750 mg/day under fasted conditions showed antitumor activity in pts with ALK+ ALCL and IMT; however, data interpretation is limited due to the small sample size. Safety findings were consistent with the known ceritinib safety profile. [Table: see text]
Liquid biopsy: A community-based oncology practice experience.
Authors: Choucair Khalil , Mattar Bassam Ibrahim , Truong Quoc Van , Koeneke Travis Lee , Truong Phu Van , Dakhil Christopher , Cannon Michael W. , Page Seth Joel , Deutsch Jeremy Michael , Carlson Eric A. , Moore Dennis Frederic , Nabbout Nassim H. , Kallail K. James , Dakhil Shaker R. , Reddy Pavan S.
Published: May 2020

3527

Background: Liquid biopsy is a promising and minimally invasive genetic test examining plasma circulating tumor DNA. Coupled with the rapidly developing next-generation sequencing (NGS) technologies, it holds the potential for implementation in selecting signal-matched therapeutic options. Methods: A retrospective chart review was conducted on adult patients with advanced solid tumors whose tumors were tested with Guardant360 assay, between December 2018 and December 2019. A total of 178 patients were referred for testing by 12 oncologists within a single community cancer center. Results: Referral rates varied widely (2.25% - 22%). The majority of patients (98%) were tested upfront for molecular marker evaluation, in either newly diagnosed advanced cancer patients, or in recurrent patients without enough tissue for testing. Other patients (2%) were evaluated after failure of 1 st line therapy to assess for acquired mutations. A total of 18 histological types were tested, with lung (LCa; n = 90; 50.56%), breast (BCa; n = 31; 17.42%), and colorectal (CRCa; n = 14; 7.87%) cancers being the most common types. In 86.11% of all tests (n = 180), ≥ 1 alteration was detected, while 13.89 % of tests did not reveal any tumor-related mutation, and were considered negative. The average number of alterations per test was 3.1 (±2.14; n = 481), and varied across types: CRCa (4.36), prostate cancer (2.73), BCa (2.97), and LCa (2.59), had the highest average number of alterations per test. Similarly, LCa (48.44%), BCa (19.13%), and CRCa (12.68%), harbored most of the detected somatic alterations (n = 481). Of all the alterations of practical significance (n = 457), TP53 (32.17%), PIK3CA (8.53%), EGFR (7.66%) and KRAS (7.22%), were the most commonly altered genes. Only 1 patient had a positive MSI-H status, amenable to immune-therapy. Of those with positive test results (n = 155), 31 (20%) had ≥ 1 FDA approved, target-matched therapeutic opportunity. Similarly, 71 patients (45.81%) had ≥ 1 target-matched therapeutic opportunity, outside current indications. Lastly, when no FDA-approved target-matched therapy was available (n = 39), results from liquid biopsy testing offered signal-based clinical trial opportunity in 39/39 patients. Conclusions: Implementation of NGS-based liquid biopsy testing is feasible within a community practice. In the era of precision oncology, such assays have the potential to expedite the efforts towards target-matched therapies and signal-based clinical trial opportunities. Further studies are warranted to identify the most-cost effective testing strategies.
Genomically informed longitudinal monitoring of circulating tumor DNA (ctDNA) to predict outcomes of cancer therapy.
Authors: Gouda Mohamed Alaa , Huang Helen J , Piha-Paul Sarina Anne , Call S. Greg , Karp Daniel D. , Fu Siqing , Naing Aung , Subbiah Vivek , Pant Shubham , Tsimberidou Apostolia Maria , Hong David S. , Rodon Ahnert Jordi , Meric-Bernstam Funda , Janku Filip
Published: May 2020

3533

Background: Short fragments of ctDNA can be detected and quantified from blood samples of patients with cancer. We hypothesize that dynamic changes in quantity of ctDNA in patients with advanced solid cancers during the first few weeks of therapy can predict treatment outcomes reported by standard imaging. Methods: We enrolled patients with advanced cancers treated with experimental therapies, who had blood collection for ctDNA isolation and testing at baseline, mid-cycle and at the time of restaging imaging. Patients who were treated with multiple treatment lines were included with separate record for each therapy. Genomically informed molecular testing of ctDNA was performed using unamplified droplet digital PCR (QX200, Bio-Rad) designed based on known molecular profile of tumor tissue and ctDNA was quantified as aggregate variant allele frequency (VAF%) for detected molecular aberrations. Patients were classified based on results of their first restaging imaging as responders (complete [CR] or partial response [PR]) vs. non-responders (stable disease [SD], progressive disease [PD]) and progressors (PD) vs. non-progressors (CR, PR, SD). Results: Total of 85 patients who received 132 courses of therapies between May 2012 and June 2019 were analyzed. Breast (N = 21), melanoma (N = 14) and cholangiocarcinoma (N = 14) were most frequent tumor types. Aggregate VAF at mid-cycle was higher in non-responders (3.98%) compared to responders (0.40%, P = 0.016) and in progressors (4.40%) compared to non-progressors (2.10%, P = 0.019) as measured by 5% trimmed mean. Similarly, aggregate VAFs at first imaging restaging was higher in non-responders (5.10%) compared to responders (0.10%, P = 0.001) and in progressors (10.80%) compared to non-progressors (0.90%, P < 0.001). Progressors demonstrated increase in ctDNA VAF at the time of the first imaging restaging compared to decrease in non-progressors (0.7% vs. -4%, P = 0.015). In addition, increase in ctDNA VAF at the first imaging restaging was associated with more PD (44% vs. 8%, P = 0.019) and less PR/CR (0% vs. 31%, P < 0.001). Median time-to-treatment failure was shorter in patients with increase in ctDNA VAF at the time of the first imaging restaging (52 days vs. 89 days, P = 0.002). Conclusions: Dynamic changes in quantity of blood-derived ctDNA within the first few weeks of therapy correspond with treatment outcomes reported by the first restaging imaging and time-to-treatment failure.
Circulating tumor DNA dynamics to predict cancer recurrence/metastasis in Chinese pathologic stage I lung adenocarcinoma.
Authors: Cheng Chao , Yang Weixiong , You Na , Jia Minghan , Yeung Sai-Ching , Yu Man , Wang Yinguang , Fu Xiayu , Liu Zhenguo , Zeng Bo , Ou Qiuxiang , Wu Xue , Shao Yang , Wang Siyu
Published: May 2020

3537

Background: Pathologic(p)stage I lung adenocarcinoma (LUAD) patients exhibit high levels of genetic heterogeneity and the association between the genomic characteristics of (p)stage I LUADs and tumor recurrence remains poorly understood. Circulating tumor DNA (ctDNA) monitoring after resection represents a useful tool to predict response to therapy and tumor recurrence but its application in (p)stage I LUAD patients remains controversial. In addition, it is of great clinical interest to decipher the difference of genetic features between ground-glass opacity (GGO) and solid nodules (non-GGO) subgroups. Methods: Tumor tissues and matched post-operative plasma samples were collected from a total of 86 Chinese (p)stage I LUAD patients who were enrolled in a clinical study (NCT03172156). Comprehensive genomic profiling was performed using capture-based hybrid next generation sequencing by targeting 422 cancer relevant genes. Results: EGFR and TP53 represent commonly mutated genes in this cohort of (p)stage I lung adenocarcinoma, followed by alterations in ALK, PIK3CA, STK11and MYC. For a median follow up period of 21.54 months after surgical resection, we observed that ctDNA positivity significantly correlated with an increased probability of early tumor recurrence or metastasis ( P= 0.03, HR = 7.9), and in particular, the EGFR mutation status of ctDNA samples rather than that of primary tumor samples significantly correlated with shorter disease-free survival (DFS). Further comparison between GGO and non-GGO subgroups indicated that the frequency of TP53 mutations in non-GGO was markedly higher than that in GGO (48% vs 20%, P< 0.05). In addition, pathway analysis showed that the epigenetic regulation pathway was more frequently affected in the GGO subgroup, while impaired apoptosis/cell cycle pathway was more enriched in the non-GGO LUADs. Conclusions: Our data show that ctDNA positivity, including the EGFR mutation status, significantly correlated with early relapse or metastasis after surgery, representing a useful tool to predict treatment response and tumor relapse in (p)stage I LUAD patients. Mutated TP53 was more abundant in non-GGO comparing to GGO (p)stage I LUADs that may act as potential oncogenic driver in LUAD development and/or disease progression. Clinical trial information: NCT03172156 .
Noninvasive identification of lineage-specific circular RNA for ER-positive breast cancer.
Authors: Brown Jason , Shah Palak , Vo Josh , Xiao Lanbo , Niknafs Yashar , Cao Xuhong , Chinnaiyan Arul
Published: May 2020

3543

Background: Non-invasive testing in plasma using RNA biomarkers has been limited by exoribonuclease-mediated degradation of RNA. Circular RNA (circRNA) are covalently closed RNA structures that resist this degradation due to their circular structure. Therefore circRNA are more stable than their linear counterparts. CircRNA are formed by alternative backsplicing of the 3’ end of a downstream exon to the 5’ end of an upstream exon. Here, we propose a novel method for non-invasive identification of circRNA and demonstrate circularized forms of several lineage and cancer specific targets for estrogen receptor-positive breast cancer. Methods: Capture RNA sequencing on cancer tissue was previously performed to determine the relative expression of potential circRNA isoforms in breast cancer patients. These isoforms as well as those predicted by intron length were screened using a quantitative PCR-based assay on ER-positive breast cancer cells. RNA extracted from breast cancer cells are exposed to ribonuclease R to demonstrate stability of circRNA. CircRNA derived from targets with known universal expression are used as positive controls as well as for analysis on plasma. Results: We identify the circRNA isoforms with highest expression for five genes, including ESR1, that are differentially expressed in ER-positive breast cancer compared to other cancers and normal breast tissue. We determine that the circRNA corresponding to all five targets is specifically expressed in breast cancer cell lines with at least 1000-fold higher expression than in non-ER positive breast cancer cell lines. We demonstrate that the highest expressing circRNA isoforms are resistant to degradation by ribonuclease R, whereas corresponding linear mRNA is susceptible. We also demonstrate the presence and stability of positive control circRNA in plasma from patients without cancer. Conclusions: CircRNA are promising biomarkers for early non-invasive detection of cancer due to their stability in plasma. This assay reliably detects ER-positive breast cancer specific circRNA, and exoribonuclease resistance has been validated. Application of this diagnostic assay to plasma from breast cancer patients is underway.
Circulating microtumors: A functional hallmark for cancer detection and management.
Authors: Datta Vineet , Akolkar Dadasaheb B , Patil Darshana , Crook Timothy , Page Raymond , Limaye Sewanti , Patil Revati , Fulmali Pradip , Fulmali Pooja , Devhare Pradip , Apurwa Sachin , Patel Shoeb , Patil Sanket , Schuster Stefan , Sims Cynthe , Chougule Rohit , Srinivasan Ajay , Datar Rajan
Published: May 2020

3544

Background: There are presently no accepted non-invasive means for detection of cancers in asymptomatic individuals or suspected cases. Radiological and serological investigations, though non-invasive, are not confirmatory and necessitate an invasive biopsy to establish malignant status of suspected findings. Invasive biopsies, in turn, face challenges due to non-representative tumor tissue or in cases where biopsy is impossible or unviable. We hypothesized that Circulating Microtumors (also called as C-ETACs: Circulating Ensembles of Tumor Associated Cells) in peripheral blood are universally present in solid organ cancers and their detection can be linked to malignant status. Methods: We obtained peripheral blood from 14,138 patients with various solid organ cancers as well as 10,625 asymptomatic individuals with age associated elevated risk of cancer. Out of the 14,138 patients with cancer, 25.1 % had local (non-metastatic) disease and 56.4% had metastatic disease as confirmed by radiological evaluation. C-ETACs 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 circulating cells of tumorigenic origin and their heterotypic clusters (C-ETACs) in peripheral blood. Viable C-ETACs were identified and further characterized by immunocytochemistry (ICC) profiling. Results: C-ETACs were detected in 89.7% of samples from solid organ cancers irrespective of stage, treatment or present radiological status. C-ETACs were rarely detected (3.0%) in asymptomatic individuals. The asymptomatic individuals where C-ETACs were detected are being followed up periodically so as to enable detection of cancer based on clinical or radiological manifestation of symptoms. Conclusions: C-ETACs are ubiquitous in cancers and unexpected in asymptomatic individuals. Detection of C-ETACs in asymptomatic individuals may be indicative of risk of latent undiagnosed malignancy. The non-invasiveness of this approach makes it convenient for screening large populations for cancer.
Exploring the Cancer Genome Atlas (TCGA) for the molecular profile of young onset colorectal cancers.
Authors: Khalessi Hosseini Seyed Ali , Morrissey Christy , Nakamura Takahiro , Becker Daniel Jacob
Published: May 2020

3548

Background: Colorectal cancer (CRC) incidence and mortality has been declining, in part due to increased implementation of screening, but the incidence among patients under 50 (young onset, YO) is increasing at a rate of 2% per year. The cause of this increasing incidence remains poorly understood, but differences in mutation profiles can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Genomic and clinical data for 488 TCGA CRC patients was used to evaluate differences in genetic alterations between YO and patients over 50. Chi-squared tests were used to determine differences in somatic mutation frequency in critical pathways implicated in CRC: DNA MMR, P53, WNT, RAS-MAPK, PI3K/AKT/mTOR, and TGF-B pathways. For 85 of the patients, proteomic data via RPPA was also available and analyzed. Results: The average age of included patients was 66 (SD 12.8). 76 (12.2%) were under 50 at time of diagnosis. When comparing YO with those over 50, there were no differences in microsatellite instability, histologic type (adeno or mucinous), location (colon or rectal), tumor size, or metastasis. YO patients were more likely to have nodal involvement (p = 0.007) and higher histological grade (p = 0.022). YO patients were more likely to have mutations in the MMR pathway (43% vs 23%, p = 0.002) and the PI3K/AKT/mTOR pathway (70% vs 54%, p = 0.024). Specifically, YO were more likely to have mutations in MSH2 (7% vs 1%, p = 0.001), MSH6 (24% vs 7%, p = 0.000); ATM (46% vs 30%, p = 0.015); FZD10 (7% vs 2%, p = 0.007); ERBB2 (15% vs 7%, p = 0.027); PIK3R1 (20% vs 9%, p = 0.014), PTEN (61% vs 35%, p = 0.000), and TGFBR2 (13% vs 4%, p = 0.004). When looking at proteomic data, YO were more likely to have decreased expression of MSH2 (p = 0.003) and MSH6 (p = 0.005). Conclusions: Patients with YO CRC are more likely to have somatic mutations in genes involved in the MMR pathway and the PI3K/AKT/mTOR pathway. Specifically, in MSH2, MSH6, ATM, FZD10, ERBB2, PIK3R1, PTEN and TGFBR2. When including proteomic data, significant differences were only seen in expression of MSH2/6. Some of these genes (e.g. ERBB2/HER2) are targets for existing therapies, and others are being actively investigated as potential therapeutic targets. Establishing differences in tumor genetic profiles is a first step towards understanding the increase in YO CRC, and simultaneously identifies targets for therapy. However, because of post-transcriptional changes (e.g. RNAi, methylation), genetic profiling alone cannot always reliably establish differences in protein expression, and thus therapy targets.
Phase I expansion study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC): Preliminary efficacy, safety, and biomarker results in patients with previously treated metastatic ovarian cancer (OC) or non-small cell lung cancer (NSCLC).
Authors: Richardson Debra L. , Barve Minal A. , Strauss James Fredric , Ulahannan Susanna Varkey , Moore Kathleen N. , Hamilton Erika Paige , Johnson Melissa Lynne , Papadopoulos Kyriakos P. , Zarwan Corrine , Anderson Charles K , Buscema Joseph , Doroshow Deborah Blythe , Edenfield William Jeffery , Matulonis Ursula A. , Burns Timothy F. , Huebner Dirk , Jansen Valerie Malyvanh , Mosher Rebecca , Jarlenski Donna , Tolcher Anthony W.
Published: May 2020

3549

Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536 showed clinical activity at doses >20mg/m2 with confirmed responses and prolonged stable disease in heavily pretreated OC and NSCLC patients, without preselection for NaPi2b expression. XMT-1536 was generally well-tolerated without the severe toxicities observed with other ADC platforms such as neutropenia, peripheral neuropathy, or ocular toxicity (Tolcher et al., ASCO 2019; Richardson et al., SGO 2020). Here, we report on the expansion (EXP) cohort, which included patients with fewer prior lines of therapy, in the ongoing Phase I study. Methods: Doses administered intravenously every 4 weeks (q4w) of 36 and 43 mg/m2 were evaluated in two cohorts (1) high grade serous ovarian, fallopian tube, or primary peritoneal cancer (OC) with up to 4 prior lines of therapy and (2) NSCLC adenocarcinoma; prior treatment with a platinum-based therapy, immune checkpoint inhibitor, and TKI, if indicated. Archival tumor tissue and tissue from a new tumor biopsy were required for retrospective evaluation of NaPi2b expression. Results: As of 10 February 2020, 23 patients (19 OC and 4 NSCLC) were enrolled in the EXP cohort: 16 dosed at 36 mg/m2 and 7 dosed at 43 mg/m2. Adverse events were generally similar to those previously reported, including transient AST elevation, fatigue, nausea, and pyrexia. Clinical responses and stable diseases have been observed. Efficacy data (objective response rate) and initial correlation of NaPi2b score with clinical response will be reported. Available data from all patients with data cutoff in May 2020 will be included. Conclusions: Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Clinical trial information: NCT03319628 .
A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing, advanced solid tumors.
Authors: Mansfield Aaron Scott , Hong David S. , Hann Christine L. , Farago Anna F. , Beltran Himisha , Waqar Saiama Naheed , Hendifar Andrew Eugene , Anthony Lowell Brian , Taylor Matthew H. , Bryce Alan Haruo , Tagawa Scott T. , Lewis Karl D. , Niu Jiaxin , Chung Christine H. , Cleary James M. , Rossi Michael , Ludwig Carrianne , Valenzuela Ricardo , Luo Yan , Aggarwal Rahul Raj
Published: May 2020

3552

Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]
Validation of RecurIndex (RI) for patients with early-stage breast cancer enrolled in a Taiwanese multicenter study.
Authors: Lee Yi-Hsuan , Pennarun Nicolas , Tseng Ling-Ming , Yang Po-Sheng , Liang Ji-An , Hsieh Chia-Ming , Chang Yuan-Ching , Wang Ming-Yang , Shih Kuan-Hui , Cheng Skye Hung-Chun , Huang Chiung-Sheng
Published: May 2020

3560

Background: Numerous prospective studies, predominantly in Caucasian population, have proven the clinical utility of using multigene expression tests to prevent overtreatment in early breast cancer (EBC) patients. Since racial and ethnic disparities exist in genetic and biological factors that could influence the disease, the primary purpose of this study is to access the clinical utility of RecurIndex, a recurrence risk test, that is based on a genomic profiling derived from Asian women. Methods: A total of 298 patients with EBC, luminal subtype (85.6%), HER2 subtype (7.7%) and triple-negative subtype (6.7%), were enrolled in a retrospective study across Taiwan medical centers. Kaplan Meier and Cox Proportional Hazards model were used to, respectively, identify independent prognostic factors and calculate the survival rates. The prediction model was then tested using the area under the receiver operating characteristic curve (AUC). The primary endpoint was distant recurrence-free survival (DRFS). Results: The 10-year DRFS was significantly higher in the good-prognosis group than the poor-prognosis group (92.0% [95% CI, 86.1-98.2] versus 63.0% [95% CI, 49.9-79.5]) (Table). The overall hazard ratio for distant recurrence was 1.031 (95% CI, 1.017±1.046) per RI score increment. In addition, in a subset of 179 cases (60.1%), the model yielded an 82.3% correct classification rate for predicting DR with a sensitivity of 87.0%, a specificity of 68.6% and negative predictive values of 97.3%. Conclusions: The present study provides robust evidence of the clinical utility of RI-DR to predict clinical outcomes. RecurIndex could be used to determine the utility of chemotherapy in Asian patients, especially in hormone-receptor positive and HER2 negative disease, leading to a meaningful reduction in adjuvant chemotherapy recommendations. [Table: see text]
The utility of blood-based molecular tools-the NETest-to monitor and evaluate the efficacy of PRRT in neuroendocrine tumors.
Authors: Bodei Lisa , Kidd Mark S. , Singh Aviral , Drozdov Ignat A. , Malczewska Anna , Baum Richard P. , Krenning Eric , Modlin Irvin Mark
Published: May 2020

3568

Background: Peptide receptor radionuclide therapy (PRRT) is an effective therapy for metastatic/inoperable neuroendocrine tumors (NETs). Tools to predict and monitor the efficacy of therapy are important adjuncts in the radio-oncology armamentarium. Standard blood biomarkers are not effective by new molecular based assays such as the PRRT Predictive Quotient (PPQ) and NETest are effective as real-time predictors and monitors of therapy. We aimed to prospectively evaluate whether: 1) the NETest functioned as a surrogate biomarker for image-based per RECIST evaluation of PRRT efficacy; 2) there was a correlation between changes in NETest levels during therapy, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n= 41; Bad-Berka, Germany: n= 44; Meldola, Italy: n= 72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable<40; progressive > 40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p< 0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p< 0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels > 40 (progressive) vs stable (<40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04, 95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%); 99% accurate positive and 93% accurate negative prediction. NETest significantly ( p< 0.0001) decreased in PPQ-predicted responders (-46±3%) and remained increased in PPQ-predicted non-responders (+75±19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06, 95%CI: 0.03-0.12). In comparison, the standard biomarker, CgA, failed to predict or correlate with response to PRRT ( p= NS). Conclusions: NETest accurately (98%) monitors PRRT response and is an effective surrogate marker for radiological response (image concordance 98%). A NETest decrease identified responders (99%) and correlated ( > 97%) with the pretreatment PPQ response predictor.