bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors.
Authors: Liu Dan , Gong Jifang , Liu Tianshu , Li KunYan , Yin Xianli , Liu Yunpeng , Wang Yongsheng , Wang Linna , Wang Wenliang , Zhang Yanyan , Shen Lin
Published: June 2021

2503

Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a promising therapeutic strategy for multiple tumor types. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. This dose escalation and expansion phase 1 study aimed to evaluated the safety and preliminary anti-tumor acitivity of SHR-1701 in refractory solid tumors. Methods: The dose escalation period was initiated by accelerated titration (1 mg/kg Q3W) and then switched to 3+3 scheme (3, 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W). The dose expanded at doses of 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W. The primary objectives were to determine the safety profile, MTD, and RP2D of SHR-1701. Results: 17 pts (1 mg/kg Q3W [n = 1]; 3, 10, 20 and 30 mg/kg Q3W [n = 3 each]; 30 mg/kg Q2W [n = 4]) were enrolled in dose escalation part. No DLT was observed and MTD was not reached. Another 32 pts (10 mg/kg Q3W [n = 8]; 20 and 30 mg/kg Q3W [n = 9 each]; 30 mg/kg Q2W [n = 6]) were enrolled in dose expansion part. Of 49 enrolled pts, 33 pts (67.3%) had received ≥2 lines of prior systemic therapy. As of data cutoff on Oct 30, 2020, the median duration of SHR-1701 exposure was 6.0 weeks (range, 2.0-78.6). The most common reported TRAEs were increased ALT/AST, anemia, hypothyroidism, and increased bilirubin/conjugated bilirubin, with incidence > 15%. The incidence of irAEs reported by the investigator was 46.9% and 4 pts received systemic corticosteroids. Hypothyroidism and rash were the most common irAEs with incidence > 10%. The incidence of Grade ≥3 TRAEs was 18.4%. The incidence of Grade ≥3 irAEs was 10.2%. 1 pt suffered early death for liver failure more likely caused by tumor progression. PK analysis showed a linear dose-exposure relationship with SHR-1701 dosing from 1 to 30 mg/kg. The peripheral PD-L1 target occupancy rate exceeded 90%, and nearly complete TGF-β1 trapping was detected in all dose groups. Of 49 enrolled pts, 45 pts completed at least once efficacy evaluation. The ORR was 17.8% (95% CI, 8.0%-32.1%), with 8 pts achieving PR (2 lung adenocarcinoma, 1 HCC, 1 ESCC, 1 dMMR-CRC, 1 renal cancer, 1 epiglottis cancer, and 1 pancreatic acinar cell carcinoma). The DCR was 40.0% (18/45; 95% CI, 25.7%-55.7%). Majority of responses (7/8) were still ongoing, and the median DoR had not been reached yet. Based on data of saftety, PK, PD, and efficacy, we recommended 30 mg/kg Q3W as the RP2D. Conclusions: SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration. Clinical trial information: NCT03710265.
Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Coward Jermaine , Abed Afaf , Nagrial Adnan , Markman Ben
Published: June 2021

2580

Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.
Safety, pharmacokinetics, pharmacodynamics profiles and preliminary antitumor activity of phase 1b/2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab in patients with advanced solid tumors: The phase 1b data report.
Authors: Naing Aung , Fan Jean , Lee Byung Ha , Basudhar Debashree , Pant Shubham , Chaney Marya F. , Laviada Cristina , Rajan Cynthia , Le Ngocdiep T. , Barve Minal A.
Published: June 2021

2594

Background: NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 which can increase the number and functionality of T cells in the peripheral blood (PB) of patients (pts). The combination of NT-I7 and pembrolizumab (pembro), a PD-1 Checkpoint Inhibitor (CPI), may augment and broaden the efficacy of CPIs. Methods: This is an open-label, phase 1b/2a study in pts with relapsed/refractory (R/R) advanced solid tumors. In the phase 1b (Dose Escalation), which followed the 3+3 design, pts received NT-I7 intramuscularly (IM) at 3 dose levels (DLs): 480, 960, and 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously (IV) Q3W. The objectives of the phase 1b were to evaluate Dose Limiting Toxicity (DLT), determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity. Results: As of 12 January 2021, 12 pts were enrolled in the phase 1b: DL1 (n=3), DL2 (n=3) and DL3 (n=6). Median age 58.0 years [43-77], ECOG PS 0 (50%), PS 1 (50%), median number of prior therapies 4 [1-8]. MTD was not reached. One DLT (Grade [G] 3 ALT increased) was reported in DL3. Treatment-related adverse events (AEs) occurred in 11 (91.7%) pts, 11 (91.7%) G1-2 and 4 (33.3%) G3; no G4 or G5 AEs reported. Common treatment-emergent AEs were injection site reaction (n=8, 66.7%), chills (n=7, 58.3%), nausea (n=6, 50%) and pyrexia (n=6, 50%). Preliminary PK analysis showed Tmax = 24 hours and T1/2 = 123 hours for NT-I7 at DL3. NT-I7 + pembro induced dose-dependent lymphocyte proliferation in the PB, with ̃ 3-fold increase at DL3, and a corresponding decrease in neutrophil to lymphocyte ratio at 14 days after the 1st treatment. Importantly, increased number of T cells in the tumor microenvironment (TME) was also observed (Table). One pt with metastatic mucosal melanoma who had not responded to prior combination of nivolumab and ipilimumab had a rapid, confirmed partial response with 46% tumor reduction. Patient follow-up continues and updated data will be presented. The combination of NT-I7 1200 µg/kg IM Q6W + pembro 200 mg IV Q3W has been selected as the RP2D. Conclusions: The combination of NT-I7 + pembro was well tolerated in pts with R/R advanced solid tumors. NT-I7 + pembro significantly increased T cell numbers in both the TME and the PB, and there was encouraging antitumor activity with the combination in this pt population. These results support continued evaluation of NT-I7 in combination with pembro in pts with R/R advanced solid tumors. The phase 2a of the study is enrolling pts with either CPI-pretreated or CPI-naïve solid tumors (NCT04332653). Clinical trial information: NCT04332653. [Table: see text]
Real-world pan-cancer landscape of frameshift mutations (FSM) and their role in predicting responses to immune checkpoint inhibitors (ICI) in patients (pts) with tumors with low tumor mutational burden (TMB).
Authors: Florou Vaia , Floudas Charalampos S. , Maoz Asaf , Naqash Abdul Rafeh , Hildebrand Gregory , Sokol Ethan , Frampton Garrett M. , Puri Sonam , Swami Umang , Wilky Breelyn A. , Hosein Peter Joel , Trent Jonathan C. , Lopes Gilberto , Park Wungki , Garrido-Laguna Ignacio
Published: June 2021

2599

Background: Pembrolizumab was recently approved in tumors with TMB ≥10 mut/Mb. FSM can complement TMB in predicting ICI responses. We obtained a real-world dataset of genomic alterations from 250,813 samples to examine the distribution of TMB and FSM across a variety of malignancies. We then conducted a multi-institutional retrospective review of pts treated with ICI. Methods: Database samples were sequenced by Foundation Medicine using hybrid capture genomic profiling to evaluate all classes of genomic alterations in at least 315 genes. The clinical cohort included pts with metastatic solid malignancies who received ICI and had undergone commercial next-generation sequencing (NGS). Pts were classified into four distinct groups: TMB-L ( < 10mut/Mb)/ FS-A (absent FSM), TMB-H (≥10mut/Mb)/ FS-A, TMB-L /FS-P (present, ≥1 FSM) and TMB-H/FS-P. Progression-free survival (PFS), overall survival (OS), and response rate (RR) were compared between the groups. Results: 246,252 MSS and 4,561 MSI-High samples were segregated by histology and divided into four distinct groups based on the TMB and FSM. For the MSS cohort the distribution was: TMB-L/FS-A (N = 111,065, 45%), TMB-H/FS-A(N = 15,313, 6%), TMB-L /FS-P (N = 98,389, 40%) and TMB-H/FS-P (N = 21,485, 9%). In the ICI-treated clinical cohort, there were 230 pts in 12 histology groups; 212 had information on TMB and FSM. The most common primary sites were GI (N = 39), melanoma (N = 37), GU (N = 32) and H&N cancer (N = 21). 159 pts received single ICI and 53 dual ICI. 196 tumors were MSS, 11 MSI, and 5 unknown. Group distribution: TMB-L/FS-A 80 pts (38%), TMB-L/FS-P 57pts (27%), TMB-H/FS-A 36pts (17%), TMB-H/FS-P 39pts (18%). FS-P was associated with higher RR 23.81 vs. 12.8 % (p = 0.02). Regardless of TMB, the median PFS for FS-P vs. FS-A was 7.9 and 4.0 mo, respectively (p < 0.01). TMB-L/FS-P had superior PFS (5.1 mo) compared to TMB-L/FS-A (3.6 mo) group (p < 0.01). The 15-month PFS probability was 12% for TMB-L/FS-A vs. 38% for TMB-L/FS-P. No statistically significant difference was detected in OS between the groups. From the pan-cancer cohort, histologies with more than 40% of samples in the TBM-L/FS-P (MSS) group were: CRC, RCC, PDAC, biliary, breast, esophageal, and endometrial cancers. Additional genomic data will be presented. Conclusions: FSM are frequently found on commercial NGS testing in tumors that are MSS and TMB-L. The presence of FSM may complement TMB in predicting benefit from immunotherapy. If validated in additional cohorts, FSM presence could be utilized to identify pts that may benefit from ICI, particularly for tumors with low TMB.
Phase 2 study of DRD2 antagonist/ClpP agonist ONC201 in neuroendocrine tumors.
Authors: Anderson Peter Meade , Gortz Janette
Published: June 2021

3002

Background: ONC201, an imipridone with specificity for the dopamine-like DRD2 receptor and the mitochondrial protease ClpP, imparts anti-cancer effects via up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and promotion of an integrated stress response. Select neuroendocrine tumors are known to secrete dopamine and harbor elevated DRD2 expression, which is most pronounced in pheochromocytoma-paraganglioma (PC-PG). Methods: This investigator-initiated single center trial (NCT03034200) enrolled 10 patients with metastatic PC-PG to cohort A and 12 patients with other neuroendocrine tumors to cohort B. The primary endpoint was response using MRI or CT, PET-CT and/or PET-MRI imaging defined as CR + PR + SD > 3 months by RECIST criteria assessed by investigator. Secondary endpoints included progression-free survival, overall survival and safety. ONC201 was administered at 625 mg by oral capsules once each week. CT scans and tumor markers (plasma chromogranin and metanephrines) were followed at 6 weeks, 3 months and then every 3 months. Patients with clinical benefit could receive stereotactic body radiotherapy (SBRT) for non-indicator (e.g. bone) metastases. The data cutoff for this analysis is December 1, 2020. Results: In Arm A (n = 10; all paraganglioma) 5 patients exhibited a PR and 2 additional patients exhibited SD > 3 months. Median duration of therapy for patients was 9 months (range: 1.5-33) with 5 patients > 1 year. In Arm B (n = 12) there were 1 PR and 2 SD > 3 months. Median duration of therapy was 3 months (range: 1-33). The partial response occurred in a patient with desmoplastic small round cell tumor who remains on treatment for > 2 years. There was no instance of dose modification or discontinuation due to treatment-related adverse events. Conclusions: ONC201 is well tolerated at 625mg weekly in adults with advanced neuroendocrine tumors and is associated with clinical benefit that includes tumor response, particularly in paraganglioma patients. A more intense schedule of 2 daily doses each week is under evaluation, in addition to other neuroendocrine tumors. Clinical trial information: NCT03034200.
BRCA reversion mutations in a pan-cancer cohort to reveal BRCA-dependence in select noncanonical BRCA-mutant histologies.
Authors: Murciano-Goroff Yonina R. , Schram Alison M. , Rosen Ezra , Janjigian Yelena Y. , Berger Michael F. , Donoghue Mark , Bandlamudi Chaitanya , Drilon Alexander E.
Published: June 2021

3012

Background: Loss of BRCA1/2 function leads to homologous recombination deficiency (HRD) and can enhance platinum and PARP inhibitor sensitivity in breast, pancreas, prostate, and ovarian cancers. In BRCA-associated cancers, resistance can result from the development of BRCA1/2 reversion mutations, which restore BRCA1/2 function. By contrast, a BRCA mutation may be an incidental finding in other tumor histologies. Methods: To determine the distribution of reversion mutations in a pan-cancer cohort, the MSK-IMPACT clinical sequencing cohort was mined to identify patients who had both a germline BRCA1/2 mutation and a frameshift somatic reversion mutation that restored BRCA1/2 function. Whole exome resequencing was used to detect HRD signatures. Chart review enabled collection of data on treatment history in patients consented to germline testing. Results: Of the 33,277 patients with matched tumor and normal sequencing profiled in this study, 861 patients were found to have germline pathogenic BRCA1/2 alterations, including 347 (40%) in BRCA1 and 514 (60%) in BRCA2. Somatic BRCA1/2 driver alterations were also found in tumor tissue from an additional 447 patients, with 156 (35%) having BRCA1 mutations, and the remainder having alterations in BRCA2 (65%) . Among the 1,308 germline or somatic BRCA1/2 mutant tumors, we identified reversion mutations in 12 patients, all of whom were germline carriers of BRCA1/2, comprising 3 BRCA1 and 9 BRCA2 tumors. 7 patients consented to germline testing enabling review of clinical characteristics and treatment history, 5 of whom received PARP inhibitor or platinum-therapy prior to reversion detection. Ten of 12 tumors with reversion mutations were in canonical BRCA-associated cancers. Interestingly, reversion mutations were also found in patients with lung adenocarcinoma (n=1) and gastroesophageal junction adenocarcinoma (n=1). In both these non-canonical histologies, the reversion was detected following progression on platinum-based therapy. Whole exome resequencing of the lung tumor revealed the classic somatic molecular phenotypes of HRD that are characteristic of BRCA-dependent tumors, including in terms of large-scale transitions, HRD-loss of heterozygosity, signature 3, and the number of telomeric allelic imbalance score. Conclusions: Matched tumor and normal sequencing from a large cohort of patients with diverse cancer histologies reveals that reversion mutations are found across BRCA-associated cancer types. In rare cases, reversion mutations in BRCA1/2 following platinum-based therapy may be indicative of prior BRCA-dependence in select non-canonical tumor histologies.
Evaluating clinical activity of MAPK targeted therapies (TT) in cancer patients (pts) with non-V600 BRAF mutations: A systematic scoping review and meta-analysis.
Authors: Dankner Matthew , Wang Yifan , Fazelzad Rouhi , Spreafico Anna , Cescon David W. , Zogopoulos George , Rose April A. N.
Published: June 2021

3089

Background: Oncogenic nonV600 BRAF mutations (muts) can be classified according to distinct molecular characteristics. TT strategies for class 2 and 3 BRAF muts have not been established. In recent years there have been numerous reports of clinical activity for various TT in pts with nonV600 muts. We performed a systematic scoping review and meta-analysis to assess treatment outcomes with MAPK TT according to BRAF class, cancer type and TT type. Methods: An extensive literature search was conducted from 2010-20. All studies were independently reviewed and extracted by 2 reviewers and in accordance with PRISMA guidelines. Individual patient level data were collected and analyzed from studies that met the following inclusion criteria: published reports of 1) advanced cancer pts with; 2) class 2 or class 3 nonV600 BRAF muts; 3) who received MAPK TT; 4) with treatment response (TR) data available. Primary outcome was overall TR rate (TRR). To assess differences between groups, odds ratios (OR) were calculated using a multi-level mixed-effects logistic regression model. Results: 15,171 studies were screened and 168 were included for data extraction. We identified 100 studies with a total of 396 pts that met inclusion criteria. There were 17 reports (161 pts) of prospective clinical trials and 83 retrospective studies (235 pts). RECIST criteria were used for TR assessment in 183 (46%) pts. The entire study included 280 pts with class 2 and 116 pts with class 3 BRAF muts. Overall, 111 (28%) pts achieved a TR. TRR according to primary tumor type, BRAF class, and TT type is indicated in Table. TRR was lower in reports of prospective studies compared to retrospective studies (OR 0.14, P = 0.002), and in studies that employed RECIST criteria vs. those that didn’t (OR 0.29, P = 0.044). TRR was higher among pts with class 2 muts vs. those with class 3 muts (OR 2.21, P = 0.042). Conclusions: These data establish that MAPK TT have demonstrated clinical activity in cancers with oncogenic nonV600 mutations, and that BRAF mutation class may dictate responsiveness to different TT strategies. TRR may be over-estimated in the retrospective literature. This analysis will be valuable for molecular tumor boards and to guide future clinical trial design. Prospective clinical trials of TT in this pt population are warranted.[Table: see text]
Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment: Results from the randomized FOCUS4-N trial.
Authors: Adams Richard , Fisher David , Graham Janet , Seligmann Jenny F. , Seymour Matthew , Kaplan Richard S. , Yates Emma , Richman Susan D , Quirke Philip , Butler Rachel , Brown Ewan , Falk Stephen , Collinson Fiona Jane , Wilson Richard H. , Brown Louise C. , Maughan Tim ,   FOCUS4 Investigators
Published: June 2021

3504

Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]
Multi-omics characterization of left-right colorectal cancer.
Authors: Marshall John , Yoshino Takayuki , Rha Sun Young , Church David N. , Coutinho Anelisa Kruschewsky , Sampaio-Filho Carlos Alberto , Gallagher David James , García-Foncillas Jesús , von der Heyde Silvia , Juhl Hartmut , Woodsmith Jonathan , Kerr David J.
Published: June 2021

3542

Background: Right (R) vs left (L) sided colorectal cancers are clinically distinguishable based on prognosis and response to certain therapies, but as of yet, limited data have emerged to explain these differences. The science of molecular testing has evolved rapidly. Enabled by improved technologies and computing power, it is now feasible to obtain to systematic multi-omic datasets covering DNA, RNA, proteins, phospho-proteins and metabolomics on large numbers of patients. Multi-omic analysis can further define disease specific subgroups but pre-analytic quality of the tissues (ischemia time) and comparison to normal tissue controls is paramount to optimize results. Methods: Following informed consent, 450 colorectal cancer primary tumors and paired normal tissues were collected following an SOP to minimize ischemia time, and were analyzed using comprehensive genomics, transcriptomics, proteomics, phosphoproteomics, morphology and annual clinical information. Right (C18.0,2,3) and left (C18.6,7) CRC tumors, normal tissue were compared using machine learning tools to unravel the molecular mechanisms that underpin these clinically distinguishable phenotypes as well as correlating with known genomic metrics such MSI and KRAS mutation status. Results: Through leveraging the tumor and paired normal patient samples, systematic differences between left and right tumor samples were observed including specific molecular events associated with these anatomical differences. The detailed results will be presented at the meeting. Conclusions: Progress in precision medicine requires the inclusion of multi-omics which in turn requires changes to our current SOPs of tissue collection. The ability to define molecular distinctions such as between R and L colon cancer will permit the rapid discovery of clinically useful prognostic and predictive markers, dramatically adding to our fundamental understanding to colon cancer biology. Future work will focus on the discovery of novel targets and signatures, creating innovative tools that depict multi-omic results for clinicians.
PMC: A more precise classifier of POLE mutations to identify candidates for immune therapy.
Authors: Zeineddine Fadl , Garmezy Benjamin , Yap Timothy A. , Shen John Paul Y.C.
Published: June 2021

3548

Background: Specific somatic mutations in DNA polymerase epsilon ( POLE) can cause a hypermutant phenotype with tumor mutation burden (TMB) in excess of 100 mutations per megabase. It has been reported that POLE mutant tumors are enriched in response to immune therapy and this association is being tested in multiple active clinical trials. However, most POLE mutations are passenger mutations and have no pathogenic role. Current methods to classify POLE mutations are limited in both accuracy and completeness, which could lead to inappropriate use of immune agents in tumor such as MSS CRC, where response rate is 5% or less. Here we present a new classifier, POLE Mutation Classifier or PMC, based on the unique trinucleotide mutation signature caused by selective loss of the proofreading function (LOP) of POLE. Methods: cBioPortal was queried to identify all tumors with POLE mutation. TMB was calculated for each, additionally, trinucleotide mutation signatures were obtained for all POLE mutant tumors in TCGA. Using OncoKB to identify a gold standard of 12 functional POLE mutations (n = 98 tumors) a POLE mutational signature was created. A combination of mutational signature, amino acid location, and TMB was used to classify each POLE variant. Results: Among all 48035 unique tumors the overall frequency of POLE mutations was 2.5% (n = 1184), however only 9.2% (n = 110) were determined to cause the selective LOP. The incidence of LOP POLE mutation was highest in uterine carcinoma and CRC, these tumors also had the highest ratio of LOP to passenger mutations. In a pan-cancer analysis the overall survival of LOP POLE patients was significantly better than those with passenger mutations (not-yet-reached vs. 51 mo, HR = 4.4, p < 0.0001). A similar analysis performed using the polyphen-2 classifier to identify functional POLE mutations did not show a difference in overall survival (HR = 1.0, p-value = 0.57). To further validate the improved specificity of the PMC classifier TMB was used as a surrogate marker, using the PMC classifier 98% of tumors with LOP showed hypermutation (TMB > 20mut/Mb), vs. 53% called functional by polyphen-2. A retrospective analysis of MD Anderson CRC patients identified 25 patients with LOP POLE mutation, who had improved OS relative to 267 CRC patients with passenger POLE mutation (not-yet-reached vs. 70 mo, HR:4.2, p = 0.028). Four metastatic CRC patients with LOP POLE mutation were treated with immune therapy (nivolumab, or ipilimumab/nivolumab) in 2nd or 3rd line, all four achieved objective response and remain on therapy (mean time on treatment 15 mo). Conclusions: The PMC classifier specifically identifies mutations in POLE that cause loss of the proofreading function, outperforming both manually curated databases and machine learning-based methods. Clinical trials that use POLE mutation as a selection criteria for immune therapy should be restricted to just those POLE mutations that cause LOP.
Consensus molecular subtypes and RAS status as biomarker of treatment intensity with fluoropyrimidine, bevacizumab, and irinotecan in metastatic colorectal cancer (XELAVIRI, AIO KRK 0110).
Authors: Stahler Arndt , Heinemann Volker , Schuster Veronika , Alig Annabel Helga Sophie , Fischer Laura Elisabeth , Weiss Lena , Heinrich Kathrin , Kurreck Annika , Jelas Ivan , von Einem Jobst C. , Giessen-Jung Clemens , Fischer von Weikersthal Ludwig , Vehling-Kaiser Ursula , Decker Thomas , Neumann Jens , Kirchner Thomas , Jung Andreas , Kumbrink Joerg , Stintzing Sebastian , Modest Dominik Paul
Published: June 2021

3552

Background: Prognostic biomarkers beside RAS/BRAF status are necessary to identify metastatic colorectal cancer (mCRC) patients who benefit from combined (COMB) versus sequential (SEQ) treatment with fluoropyrimidine, bevacizumab and irinotecan (randomized phase III XELAVIRI trial). Methods: mRNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissue of 337 patients, gene expression was measured by the Nanostring PanCancer Progression Panel. Consensus molecular subtypes (CMS) classification was re-derived using a multinomial regression model. Data of Guinney et al. (Nat. Med. 2015. 21:1350-6) and FIRE-3 served as training and validation set. RAS/BRAF MUT were assessed by pyrosequencing. Median overall (OS) and progression free survival (PFS), hazard ratios (HR) and 95% confidence interval (CI) were estimated by Kaplan-Meier method and univariate Cox regression. Results: The multinomial regression model employed in the present analysis correctly predicted CMS labels in 98.3 % of the original Guinney- and 100.0 % of FIRE-3 population. In XELAVIRI, CMS subgroups were predicted as follows: CMS1: n = 62 (18.4 %); CMS2: n = 174 (51.6 %); CMS3: n = 9 (2.7 %); CMS4: n = 92 (27.3 %). A general prognostic impact of CMS was not observed when all patients were analysed. In RAS/BRAF WT mCRC patients, substantial benefit of COMB versus SEQ treatment was shown for OS and PFS in CMS2 and CMS4, but not in CMS1. Conversely, OS was significantly longer for COMB treatment in patients with RAS MUT and CMS1 mCRC, while SEQ treatment was not inferior in RAS MUT and CMS2 or CMS4 subgroups (see TABLE). Additional data for overall response rates, early tumor shrinkage and sidedness might be presented at the meeting. Conclusions: This retrospective analysis of XELAVIRI suggests that CMS may serve as biomarker that predicts response to initially combined versus less intensive sequential chemotherapy in patients with RAS/BRAF WT mCRC.[Table: see text]
LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.
Authors: Gomez-Roca Carlos A. , Yanez Eduardo , Im Seock-Ah , Castanon Alvarez Eduardo , Senellart Hélène , Doherty Mark , Garcia-Corbacho Javier , Lopez Juanita Suzanne , Basu Bristi , Maurice-Dror Corinne , Gill Sanjeev Singh , Ghori Razi , Kubiak Peter , Jin Fan , Norwood Kevin Glen , Chung Hyun Cheol Cheol
Published: June 2021

3564

Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (̃2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mo (range, 5.9-13.1). ORR was 22% (95% CI, 9–40; table). Grade 3–5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. Clinical trial information: NCT03797326. [Table: see text]
Treatment responses and disease dynamics in patients with untreated metastatic colorectal cancer receiving bevacizumab-based sequential versus combination chemotherapy: Analysis of a phase 3 trial (AIO KRK0110, XELAVIRI study).
Authors: Kurreck Annika , Heinemann Volker , Fischer von Weikersthal Ludwig , Decker Thomas , Kaiser Florian , Uhlig Jens , Schenk Michael , Freiberg-Richter Jens , Peuser Bettina , Denzlinger Claudio , Graeven Ullrich , Heinrich Kathrin , Held Swantje , Stahler Arndt , Alig Annabel Helga Sophie , Jelas Ivan , von Einem Jobst C. , Stintzing Sebastian , Giessen-Jung Clemens , Modest Dominik Paul
Published: June 2021

3571

Background: Early response parameters such as early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy endpoints and potential predictors of long-term outcome. We analyzed the association of these endpoints with bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within a randomized phase III trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR-image) were analyzed in the XELAVIRI-trial. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated with ETS as stratification parameter (ETS vs. no ETS) according to treatment arm, molecular subgroup, and sex. Results: 370 patients were available for analysis of early treatment response parameters. A higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination compared to the sequential therapy arm, respectively. The improvement of ETS and DpR was pronounced in the subpopulation of RAS/ BRAF wildtype patients. Male in contrast to female patients significantly benefitted from initial combination treatment in terms of median DpR (male: -40.0% vs. -22.2%; p < 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS (male: 64.8% vs. 40.2%; p < 0.001; female: 52.5% vs. 49.3%; p = 0.73). Achievement of ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Whereas the survival benefit in male patients achieving ETS was statistically significant (PFS: p < 0.001, HR 0.532 (0.409-0.692); OS: p < 0.001, HR 0.574 (0.437-0.756)), there were no significant differences in PFS (p = 0.107) and OS (p = 0.965) of female patients depending on ETS. Conclusions: In the XELAVIRI trial, initial irinotecan-based combination therapy with bevacizumab improves ETS and DpR in mCRC patients. Improvement in early response parameters appears pronounced in patients with RAS/ BRAF wildtype tumors suggesting a high sensitivity to irinotecan-based treatment. ETS was predictive of PFS and OS regardless of treatment arm. This finding was rather driven by male than female patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.
ENSURE: An international multicenter study exploring whether surveillance after esophageal cancer surgery impacts oncological and quality-of-life outcomes.
Authors: Elliott Jessie A , Markar Sheraz , Klevebro Fredrik , Johar Asif , Goense Lucas , Lowery Maeve Aine , Lagergren Pernilla , Zaninotto Giovanni , van Hillegersberg Richard , Nilsson Magnus , Hanna George , Reynolds John V. ,   ENSURE Study Group
Published: June 2021

4032

Background: Although established and emerging therapies for recurrent esophageal cancer (EC) may impact on survival and health related quality of life (HRQL), surveillance protocols after the primary curative treatment of EC are varied and inconsistent, reflecting a limited evidence-base to guide an optimum approach. Specifically, whether advantages exist for an intensive surveillance protocol is unknown and was the focus of this study. Methods: European iNvestigation of SUrveillance after Resection for Esophageal cancer (ENSURE) is an international multicenter retrospective observational study of consecutive patients undergoing surgery with curative intent for esophageal and gastroesophageal junction cancers (2009 – 2015) across 20 European and North American cancer centers (NCT03461341). Intensive surveillance (IS) was defined as routine annual CT/PET-CT along with clinical assessment during the first three postoperative years, and compared with standard surveillance (SS) with investigation as clinically indicated. The primary outcome measure was overall survival (OS), secondary outcomes included treatment administered, disease-specific survival (DSS), disease-free survival (DFS), recurrence pattern, and HRQL. Multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of surveillance on oncologic outcomes and HRQL. Results: 4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy). 45.5% underwent IS. At a median follow-up of 60 months, 47.5% developed disease recurrence. Oligometastatic recurrence occurred in 39% of cases, with 31% receiving best supportive care, 60% chemotherapy and/or radiation, and 8% surgical resection. IS was associated with reduced symptomatic recurrence (odds ratio [OR] 0.17 [0.12–0.25]), increased tumor-directed therapy (OR 2.09 [1.58–2.77]), and improved OS (HR 0.90 [0.82–0.98], 5-year OS 47.9±1.2% versus 43.2±1.1%). After adjusting for confounders, significantly improved overall survival with IS was maintained for patients who underwent surgery alone as initial therapy (HR 0.60 [0.47–0.78]) and in those with lower pathological (y)pT stages (Tis-2, HR 0.72 [0.58–0.89]). IS was associated with greater anxiety ( P= 0.016), but similar overall HRQL. Conclusions: These data suggest that IS may improve oncologic outcomes, particularly in patients with early stage disease at presentation or with a favorable pathological stage post induction therapy. This may be relevant to guideline development and provide a framework and rationale for RCTs. It may also inform shared decision-making with patients at a time where therapeutic options for recurrence are expanding.
Circulating tumor DNA (ctDNA) analysis by low-coverage whole genome sequencing (lcWGS) of resectable esophageal adenocarcinoma (rEAC) patients.
Authors: van den Ende Tom , Creemers Aafke , van der Pol Ymke , Boers Dries , Van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Geijsen E. Debby , Hulshof Maarten C.C.M. , Dijk Frederike , van Grieken Nicole C.T. , Pegtel D. Michiel , Derks Sarah , Bijlsma Maarten F. , Moulière Florent , Van Laarhoven Hanneke W.M.
Published: June 2021

4033

Background: ctDNA is becoming an established marker to assess tumor burden, relapse after surgery, and to identify responders in immunotherapy studies. In the phase II PERFECT trial rEAC patients were treated with neoadjuvant chemoradiotherapy (nCRT) and a PD-L1 inhibitor (van den Ende et al. CCR. 2021). Here we evaluated the potential of cell-free DNA (cfDNA) to predict pathological complete response (pCR) and recurrence. Methods: The cohort consisted of 40 patients and 145 plasma samples. EDTA blood samples were drawn at baseline (B, N = 40), in week 5 of nCRT (W5, N = 40), before surgery (OR, N = 33) and 3 months after surgery (FU, N = 32). cfDNA was isolated by affinity columns (CNAkit, QIAgen) quantified by spectrofluorometer (BioAnalyzer, Agilent), sequencing libraries were prepared for lcWGS ( < 5-fold coverage, Tag-seq, Takara) and sequenced on a NovaSeq (S4, PE150). Sequencing data were processed with an in-house pipeline. Copy number aberrations (CNA) and the tumor fraction were estimated using the ichorCNA tool. Insert sizes were recovered and we determined a Tumor Enriched Fragment Fraction (TEFF), calculated by doing the ratio of fragments between 90-150 bp and 250-320 bp (enriched in tumor signal) and fragments between 150-250 bp and 320-360 bp (poor in tumor signal). ichorCNA and TEFF were used to quantify the ctDNA fraction in plasma samples. pCR was defined as ypT0N0. Residual tumor, progression or death before surgery were considered non-pCR. Relapse-free survival (RFS) was defined as the time after surgery until recurrence. Results: The pCR rate was 25% (10/40). The median fold change TEFF between B and W5 was -0.15 (range -0.67 to 0.44) in the pCR group and 0.16 (range -1.40 to 0.76) in the non-pCR group (Mann–Whitney U; p = 0.047). Of the 17 patients in whom ctDNA was detected (TEFF≥0.3 and/or ichorCNA≥0.03) in the FU sample, 13 (76%) showed a recurrence. Of the 15 patients with no ctDNA detected 5 (33%) showed a recurrence. Patients with ctDNA detected at FU had worse RFS, HR = 2.72 (95%CI 0.96-7.71; p = 0.050). Recurrences were detected earlier by FU ctDNA than by imaging due to physical complaints with a median of 312 days (163-798 days). Conclusions: lcWGS appears to be a useful tool to predict pCR and recurrence in resectable esophageal cancer. These lcWGS results will be further combined with fragmentomics analysis and targeted mutational data (Ion Torrent next-generation sequencing) in order to assess response to immunotherapy. Clinical trial information: NCT03087864.
Risk factors for recurrence in each pattern after curative gastrectomy for pStage II/III gastric cancer: An exploratory analysis of a randomized controlled trial (JCOG1001).
Authors: Toriumi Tetsuro , Terashima Masanori , Mizusawa Junki , Sato Yuya , Kurokawa Yukinori , Takiguchi Shuji , Doki Yuichiro , Kawachi Yasuyuki , Shinohara Hisashi , Choda Yasuhiro , Ito Seiji , Yoshikawa Takaki , Sano Takeshi , Sasako Mitsuru
Published: June 2021

4052

Background: Peritoneal, lymph node, and hematogenous recurrence are frequently observed as patterns of recurrence after surgery for gastric cancer. However, the clinicopathological characteristics associated with each recurrence have rarely been comprehensively reported in a multicenter study. Understanding the risk factors for each pattern of recurrence would be helpful for the early detection of recurrence and the initiation of optimal treatment. This study investigated the risk factors for the first recurrence in each pattern after curative gastrectomy, using data from a multicenter randomized controlled trial (JCOG1001) that was designed to investigate the efficacy of bursectomy. Methods: Patients of 20-80 years of age, with cT3(SS)-T4a(SE) gastric carcinoma according to the 14th Japanese Classification of Gastric Carcinoma, with an ECOG PS of 0-1, and a body mass index of < 30 kg/m2, and without bulky lymph nodes, Borrmann type 4 or large type 3 carcinoma were eligible for inclusion in JCOG1001. Of the 1204 patients who were enrolled in JCOG1001, 932 pStage II/III patients with a common histological type were included in this study. Risk factors for hematogenous, lymph node, and peritoneal patterns of recurrence were estimated by a multivariable Fine and Grey model considering death or site of recurrence other than the first site of recurrence as competing risks. Results: The overall rate of recurrence was 27.1%. Hematogenous recurrence was the most frequent pattern (12.3%), followed by peritoneal (11.2%) and lymph node (7.5%) recurrence. Differentiated type (HR, 1.818; 1.237-2.674; p = 0.0024), pT4 (in comparison to pT1-3, HR, 1.511; 95% CI, 1.011-2.257; p = 0.0440), and pN3 (in comparison to pN0-2, HR, 2.431; 95% CI, 1.635-3.616; p < 0.0001) were associated with an increased incidence of hematogenous recurrence. Conversely, more than D2 lymphadenectomy reduced this pattern of recurrence (in comparison to D1+or D2 lymphadenectomy, HR, 0.575; 95% CI, 0.364-0.907; p = 0.0174). Peritoneal recurrence was significantly associated with large (≥5 cm) tumor (HR, 1.649; 95% CI, 1.034-2.629; p = 0.0356), pT4 (in comparison to pT1-3, HR, 3.222; 95% CI, 2.086-4.976; p < 0.0001), pN3 (in comparison to pN0-2, HR, 1.865; 95% CI, 1.275-2.727; p = 0.0013), and undifferentiated type (HR, 2.674; 95% CI, 1.628-4.394; p = 0.0001). Extended lymph node metastasis (pN3) was the only risk factor (in comparison to pN0-2, HR, 8.030; 95% CI, 4.605-14.002; p < 0.0001) for lymph node recurrence. Conclusions: The risk factors for recurrence differed according to the patterns of recurrence. Vigilant follow-up with an understanding of patterns of recurrence is required, especially for high-risk patients.
IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study.
Authors: Breder Valeriy Vladimirovich , Vogel Arndt , Merle Philippe , Finn Richard S. , Galle Peter R. , Zhu Andrew X. , Cheng Ann-Lii , Feng Yin-Hsun , Li Daneng , Gaillard Vincent E. , Li Lindong , Nicholas Alan , Lencioni Riccardo
Published: June 2021

4073

Background: Atezo + bev has been approved in >60 countries for pts with unresectable HCC who have not received prior systemic therapy, based on IMbrave150 (NCT03434379; Finn RS NEJM 2020). Due to their poor prognosis and the hemodynamic changes from increased portal vein pressure, pts with main portal vein tumor thrombus are often excluded from pivotal HCC trials. Here, we report exploratory efficacy and safety results of pts with Vp4 (presence of a tumor thrombus in the main trunk and/or contralateral portal vein) using updated IMbrave150 data (Finn RS ASCO GI 2021). Methods: Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. IMbrave150 enrolled 501 systemic treatment (tx)–naive unresectable HCC pts, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1, including 73 (15%) Vp4 pts. This post hoc exploratory analysis was conducted with a median follow-up of 15.6 mo in ITT pts. Results: Of the Vp4 pts, 48 received atezo + bev and 25 received sor. Median OS (mOS) was 7.6 vs 5.5 mo (HR, 0.62; 95% CI: 0.34, 1.11) and median PFS (mPFS) per independent review facility (IRF)–assessed RECIST 1.1 was 5.4 vs 2.8 mo (HR, 0.62; 95% CI: 0.35, 1.09) with atezo + bev and sor, respectively. ORR per IRF RECIST 1.1 was 23% (11/47) with atezo + bev (2 [4%] pts had CR) vs 13% (3/23) with sor (1 [4%] pt had CR). All-grade variceal bleeding was higher with atezo + bev in Vp4 (13.6%) vs rest of ITT pts (2.5%). See table for further efficacy and safety data. Conclusions: The benefits of atezo + bev over sor in Vp4 pts are consistent with those in ITT pts across all efficacy endpoints, despite the expected disease-intrinsic increase in variceal bleeding in Vp4 vs rest of ITT pts. The overall positive benefit-risk profile supports the use of atezo + bev in pts with Vp4. Clinical trial information: NCT03434379. [Table: see text]