scholarly journals Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach—A Real World Data Analysis

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4453
Author(s):  
Louisa Hempel ◽  
Julia Veloso de Oliveira ◽  
Andreas Gaumann ◽  
Valeria Milani ◽  
Katrin Schweneker ◽  
...  
Keyword(s):  
Real World ◽  
Gastroesophageal Junction ◽  
Molecular Targets ◽  
Scoring Systems ◽  
Subsequent Treatment ◽  
Phase Iii ◽  
Precision Oncology ◽  
Sequencing Data ◽  
Companion Diagnostics ◽  
Real World Data

After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.

Avenues to Precision Oncology

2020 ◽  
pp. 36-45
Author(s):  
Alexander Meisel
Keyword(s):  
Precision Medicine ◽  
Trial Design ◽  
Ad Hoc ◽  
Molecular Targets ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Precision Oncology ◽  
Companion Diagnostics ◽  
Bona Fide ◽  
The One

Until recently, the clinical management of cancer heavily relied on anatomical and histopathological criteria, with ad hoc guidelines directing the therapeutic choices in specific indications. In the last years, the development and therapeutic implementation of novel anticancer therapies significantly improved the clinical outcome of cancer patients. Nonetheless, such cutting-edge approaches revealed the limitation of the one-size-fits-all paradigm. The newly discovered molecular targets can be exploited either as bona fide targets for subsequent drug development, or as tools to precision medicine, in the form of prognostic and/or predictive biomarkers. This article provides an overview of some of the most recent advances in precision medicine in oncology, with a focus on novel tissue-agnostic anticancer therapies. The definition and implementation of biomarkers and companion diagnostics in clinical trials and clinical practice are also discussed, as well as the changing landscape in clinical trial design.

Retrospective comparison of neoadjuvant chemoradiation (nCRT) +/- surgery using the CROSS trial regimen and definitive chemoradiation (dCRT) with carboplatin (C) and paclitaxel (P) in esophageal (EC), and gastroesophageal junction cancer (GEJC) in Canada.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 313-313
Author(s):  
Sidra Khalid ◽  
Wilma M. Hopman ◽  
Kiran Virik
Keyword(s):  
Real World ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Outcome Data ◽  
World Population ◽  
Trial Protocol ◽  
Real World Data ◽  
Eligibility Criteria ◽  
Trimodality Therapy ◽  
The Cross

313 Background: Trimodality therapy using the CROSS trial protocol is an accepted standard of care for locally advanced EC and GEJC. For medically inoperable patients (pts), CRT has been a standard. CRT with C and P is an option in the definitive setting. This single institution review aims to assess the application and outcomes of the CROSS trial protocol in our real world population. Methods: From June 2012 until June 2018, a retrospective review was undertaken of 83 pts who underwent CRT with C and P with trimodaility or upfront definitive intent. 65 pts underwent nCRT; 40 proceeded to surgery. 18 had upfront dCRT. Pt demographics, clinical, pathological, treatment and surgical characteristics were assessed. These factors and outcomes were analyzed in exploratory analyses. Results: Of the 83 pts: median (m) age was 69 yrs (range 48-82), 34% were ≥ 75 yrs, 80% were male, 21% had CAD, 43% GERD, 23% Barrett’s, 77% adenocarcinoma, m tumor length was 5 cm, 36% had BMI > 30 and 80% were Siewert I tumors. The m RT dose was 50.4 Gy, m chemo doses were 5, m time to CRT was 69 days and m time from CRT to surgery was 66 days. 23% nCRT pts and 72% dCRT pts were ≥ 75 yrs and 49% and 33% of these respectively had no interruptions to CRT. Pts who underwent surgery were younger (p = 0.04) and weighed more (p = 0.05). Pts ≥75 yrs were likely to have dCRT (p = 0.001). For nCRT and surgery, nCRT only and dCRT respectively, median overall survival (mOS) was 35.5, 12.1 and 17.1 months (M) (log rank p = 0.08), PFS was 32.2, 10 and 9.6M (log rank p = 0.01). Compared to the other 2 groups, pts who underwent surgery had: no COPD (p = 0.004), less CAD (p = 0.003), less renal impairment (p = 0.023) and had lower esophageal tumors (p = 0.027). mOS for pts who had nCRT was 28.9M and 17.1M for dCRT (log rank p = 0.70). Further correlative outcome data will be presented. Conclusions: Despite the broadening of CROSS trial eligibility criteria in our real world data, there appears to be a survival benefit with trimodality therapy. The use of C and P in dCRT may be of value especially in the elderly, and requires further study.

scholarly journals Application of Real-World Data to External Control Groups in Oncology Clinical Trial Drug Development

2022 ◽  
Vol 11 ◽  
Author(s):  
Timothy A. Yap ◽  
Ira Jacobs ◽  
Elodie Baumfeld Andre ◽  
Lauren J. Lee ◽  
Darrin Beaupre ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Real World ◽  
External Control ◽  
Control Group ◽  
Precision Oncology ◽  
Efficacy And Safety ◽  
Control Groups ◽  
Real World Data ◽  
World Data

Randomized controlled trials (RCTs) that assess overall survival are considered the “gold standard” when evaluating the efficacy and safety of a new oncology intervention. However, single-arm trials that use surrogate endpoints (e.g., objective response rate or duration of response) to evaluate clinical benefit have become the basis for accelerated or breakthrough regulatory approval of precision oncology drugs for cases where the target and research populations are relatively small. Interpretation of efficacy in single-arm trials can be challenging because such studies lack a standard-of-care comparator arm. Although an external control group can be based on data from other clinical trials, using an external control group based on data collected outside of a trial may not only offer an alternative to both RCTs and uncontrolled single-arm trials, but it may also help improve decision-making by study sponsors or regulatory authorities. Hence, leveraging real-world data (RWD) to construct external control arms in clinical trials that investigate the efficacy and safety of drug interventions in oncology has become a topic of interest. Herein, we review the benefits and challenges associated with the use of RWD to construct external control groups, and the relevance of RWD to early oncology drug development.

Prospective, multicenter, noninterventional and registry clinical study of apatinib in patients with advanced gastric cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 137-137 ◽  
Author(s):  
Chunmei Bai ◽  
Diansheng Zhong ◽  
Ruixing Zhang ◽  
Xiubao Ren ◽  
Likun Liu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Real World ◽  
Objective Response ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Efficacy Evaluation ◽  
Real World Data ◽  
Skin Reactions

137 Background: The aim of this study was to observe the safety of apatinib in the real world with wider inclusion criteria. The efficacy of apatinib was evaluated including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Methods: This trial enrolled patients from 32 centers in china with advanced gastric adenocarcinoma who had progressed after undergoing at least two lines of systemic chemotherapy, or patients who were considered to benefit from the treatment. We recommended starting from oral administration of 500mg qd, 28 days for a cycle. Dose could be appropriately adjusted according to the patients’ physical condition. Results: Between March 2015 and September 2017, 326 patients were enrolled. The average age was 62 years old, and the ratio of male to female was about 2:1. Patients received perioperative, first-line, second-line, and third-line or more treatment were 1,39,69 and 217 people respectively. There were 192 patients received efficacy evaluation, 9 patients achieved partial response(PR), 125 had disease stability(SD). The ORR and DCR were 4.6% and 69.8% respectively. The median PFS and median OS were 3.7 months and 7.3 months respectively. In the 326 patients, there were 153 patients with initial dose of 500 mg, 3 and 55 patients achieved PR and SD, respectively. The ORR and DCR were 3.3% and 63.7%, respectively. The median PFS and median OS were 3.5 months and 8.4 months, respectively. There were 237 patients in all 326 patients received safety analysis. Common adverse events were hypertension (57%), hand-foot skin reactions (26.6%), fatigue (29.5%), proteinuria (19.0%), bleeding (10.1%) and diarrhea (8.0%). The grade 3 to 4 adverse events were hypertension (6.3%), hand-foot skin reactions (3.8%), proteinuria(3.0%) and bleeding (2.1%). Conclusions: This real-world data in which more patients were given apatinib 500mg or less qd showed similar efficacy to Phase III clinical trial (850mg qd).The incidence of adverse events was consistent with that of Phase III clinical data,there was no new adverse events had been seen. Clinical trial information: NCT02668380.

Neoadjuvant chemoradiation (NCRT) for esophageal (EC) or gastroesophageal junction cancer (GEJC): A Canadian single institution real-world experience using the CROSS trial regimen.

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 25-25
Author(s):  
Sidra Khalid ◽  
Wilma M. Hopman ◽  
Beatrice Preti ◽  
Anna T. Tomiak ◽  
Kiran Virik
Keyword(s):  
Clinical Trial ◽  
Real World ◽  
Gastroesophageal Junction ◽  
Trial Protocol ◽  
Single Institution ◽  
Real World Data ◽  
Trimodality Therapy ◽  
World Data ◽  
The Real ◽  
The Cross

25 Background: NCRT followed by surgery per the CROSS trial regimen is an accepted standard of care in the treatment of EC and GEJC. When treatments are used in the real-world setting, there are often patient, treatment and potential outcome differences compared to the original clinical trial. The study aim was to assess the real-world application and outcomes of the CROSS trial protocol. Methods: A retrospective chart review was undertaken of 83 patients (pts) with EC or GEJC who were treated from June 2012 to June 2018 with CRT. 65 pts were with NCRT intent to proceed to surgery. Pts’ demographics, clinical, pathological, treatment and surgical characteristics were assessed and exploratory analyses were conducted to review these factors and outcomes. Analyses included Chi-square, t-tests and Kaplan-Meier. Results: For pts who underwent NCRT (n = 65): median age was 68 yrs (range 52-80), male 79%, adenocarcinoma 82%, median (m) tumor length 5 cm, GERD 43%, clinical stage II/III 95%, and BMI > 30 in 37%. 80% completed CRT with RT ≥ 41.4 Gy; of these 88% had ≥ 50.4 Gy. Delay/interruption in chemotherapy occurred in 46% and in RT 37%. Pts who underwent surgery were younger (p = 0.04) and weighed more (p = 0.05). mOS was 37 months (M) v 14 M in those who started CRT ≤ 8 weeks (w) from diagnosis v > 8 w (p = 0.10). The median time from CRT to surgery was 8.9 w. 40 pts had surgery with a complete response in 38% and a R0 resection in 98%. Postoperative major and minor complications occurred in 67%. Those < 75 yrs v ≥ 75 yrs had a mOS of 32 M v 15 M respectively (log rank p = 0.46). 25 pts did not get surgery; 28% was due to death/progression. Pts who proceeded to surgery had a mOS of 35 M v 12 M in pts who did not go to surgery (log rank p = 0.002). Further correlative outcome data will be presented. Conclusions: Real-world data in our center showed patient, tumor and treatment differences compared to the CROSS trial protocol. Despite the broadening of eligibility and treatment criteria, survival in a single institution setting is maintained with trimodality therapy compared to NCRT alone. Real-world data is of value in the assessment of therapeutic validity of clinical trial data.

Use of a real-world data approach to rapidly generate outcomes data following a case study of a novel treatment combination in pancreatic adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16735-e16735
Author(s):  
Lola Rahib ◽  
Karen Chen ◽  
Allyson J. Ocean ◽  
Changqing Xie ◽  
Austin Duffy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Partial Response ◽  
Median Time ◽  
Real World ◽  
Clinical Benefit ◽  
Progressive Disease ◽  
Metastatic Pancreatic Cancer ◽  
Precision Oncology ◽  
Real World Data ◽  
World Data

e16735 Background: We use a real-world data approach to report on safety and benefits on metastatic pancreatic cancer pts who were treated with a MEK inhibitor plus hydroxychloroquine (HCQ) after exhausting all other treatment options. MEK inhibition acts on the KRAS pathway, which in turn increases autophagy as a resistance mechanism, furthermore, HCQ inhibits autophagy causing a cytotoxic effect. This combination was shown to diminish tumor volume in xenograft mouse models and a partial response in one heavily pre-treated patients was reported. Methods: XCELSIOR is an IRB approved, patient-centric, real-world data and outcomes registry for developing operational and analytic methods in precision oncology. Searching the XCELSIOR database, we identified 14 pts for whom this regimen had been considered. As part of their participation in XCELSIOR, these patients shared access to their full medical records, which were collected, processed, and abstracted into a 21 CFR 11 compliant database for analysis. We additionally collected de-identified data on 12 pts treated with this combination from five academic centers. Three more patients are expected to start treatment soon. Results: Between March 2018 and January 2020, 15 patients treated with the trametinib/HCQ combination and 3 patients treated with cobimetinib/HCQ were identified in XCELSIOR and five academic institutions. The median age at diagnosis was 64 (range 43-74) and 56% were male. For patients treated with trametinib/HCQ, the median time on treatment was 67 days (range 5-172 days), 11 patients were treated for more than 30 days (median time 97 days). The median PFS for this group was 2.9 months and the median OS was 7.4 months. The clinical benefit rate was 60% for the 10 evaluable patients treated with trametinib/HCQ, 1 patient had a partial response (previously published), 5 had stable disease (for at least 8 weeks) and 4 had progressive disease (physician reported). 2/3 patients treated with cobimetinib/HCQ were on treatment for more than 30 days and all three had progressive disease within 7 weeks. The most common side effects were Grade 1 fatigue and Grade 1/2 rash for both combinations. An additional 3 patients will start treatment soon and will be included in the analysis. Conclusions: Combinatorial MEK and autophagy inhibition was well tolerated in heavily treated metastatic pancreatic cancer patients. Trametinib/HCQ demonstrates some clinical benefit for this group. We demonstrate the feasibility of utilizing real-world data in precision oncology. Clinical trial information: NCT03793088 .

Observational retrospective evaluation of treatment with liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic cancer patients: An Italian large real-world analysis.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 660-660 ◽  
Author(s):  
Antonio Pellino ◽  
Chiara Manai ◽  
Valeria Merz ◽  
Mario Scartozzi ◽  
Michele Milella ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Real World ◽  
Cox Regression ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
Rank Test ◽  
Efficacy And Safety ◽  
Real World Data ◽  
Liposomal Irinotecan ◽  
Ecog Ps

660 Background: In the NAPOLI I phase III trial, Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) showed better outcome compared to 5FU/LV in patients with metastatic Pancreatic Cancer (MPC) progressed to 1st- line gemcitabine-based therapy. Aim of this study is to explore the real-world efficacy and safety of 5FU/LV-nal-IRI by a compassionate use programme and to identify potential prognostic factors that could affect survival in this setting. Methods: This is a retrospective multi-center analysis including patients with MPC who received 5FU/LV-nal-IRI after failure of a gemcitabine-based therapy. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariate analyses were performed by using the log-rank test and the Cox regression. Results: A total of 296 pts (median age, 69 years, range 30-82; 50% male; ECOG PS 0, 44%) were treated at 11 Italian institutions from June 2016 and November 2018. 34% of the pts have been previously resected on their primary tumor, and 76% received gemcitabine-nabpaclitaxel as 1st - line treatment. 5FU/LV-nal-IRI has been administered as 2nd - line in 72% of the pts, while in 23% of the cases as 3rd - line or more. The median OS was 7.1 months [95% confidence interval (CI) 6.1 - 8.1] and the median PFS was 3.3 months (95% CI 2.9 - 3.6). At six months, OS and PFS rate were 53.4% and 31.4% respectively. ORR was 12% and DCR was 40%. 52% of pts received more than 4 cycle with dose reduction in 148 pts (50%). Most common grade 3 toxicities were neutropenia (14%), diarrhea (11%), anemia (3%), nausea (3%), fatigue (3%), mucositis (2%) and vomiting (1%). Baseline characteristics associated with better OS were ECOG PS 0, normal CEA, neutrophil-to-lymphocyte ratio ≤5 and haemoglobin ≥11 g/dL. Conclusions: These real-world data confirm the efficacy and safety of 5FU/LV-nal-IRI in patients with MPC progressed to a gemcitabine-based therapy, with outcome comparable to NAPOLI-1 even in a less selected population and with more active 1st - line combination therapy. In this cohort, well known prognostic markers has been confirmed, as expected.

scholarly journals A real-world comparative analysis of carfilzomib and other systemic multiple myeloma chemotherapies in a US community oncology setting

2019 ◽  
Vol 10 ◽  
pp. 204062071881669 ◽  
Author(s):  
Robert M. Rifkin ◽  
Rohan Medhekar ◽  
E. Susan Amirian ◽  
Kathleen M. Aguilar ◽  
Thomas Wilson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Real World Data ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Community Oncology ◽  
First Relapse ◽  
Line Of Therapy

Background: Most multiple myeloma (MM) patients ultimately progress, with remission duration decreasing after first relapse. Recently, novel agents have been approved for the treatment of relapsed MM. There is a paucity of real-world data on these treatments. We sought to compare time to next treatment (TTNT) in MM patients in their second line of therapy (LOT2), treated with common proteasome inhibitor (PI)-based triplets. Methods: Adult MM patients who received carfilzomib (K) between 1 November 2013 and 29 February 2016 at US Oncology Network (USON) clinics utilizing iKnowMed™ electronic health records (EHRs) were identified. Patients were included if they were ⩾18 years of age, not enrolled in clinical trials, had ⩾2 visits at a USON clinic and received LOT2 regimens consisting of: K+lenalidomide with steroid (KRd), bortezomib+lenalidomide with steroid (VRd), or bortezomib+cyclophosphamide with steroid (VCyd). TTNT was estimated from LOT2 initiation to LOT3 initiation using the Kaplan–Meier method, and hazard ratios (HRs) were estimated using Cox modeling. Results: A total of 718 patients received a K-containing regimen sometime during their MM treatment (LOT1 to LOT5). Of these, 156 patients received: KRd ( n = 112; 71.8%), VRd ( n =27; 17.3%), or VCyd ( n = 17; 10.9%). Baseline characteristics were similar between groups (mean age: 64.8 years; 58% male). Median TTNT was longest for KRd [25.3 months; 95% confidence interval (CI): 19.71–NR], versus VRd or VCyd (VRd median TTNT: 10.2 months, 95% CI: 4.24–12.71; VCyd: 6.5 months, 95% CI: 3.02–12.78; log-rank p < 0.0001). The adjusted HR for KRd was 0.19 (95% CI: 0.11–0.37), compared with VRd. Conclusions: Considering the real-world nature of these data, the median TTNT observed with KRd was relatively consistent, with progression-free survival (PFS) for KRd observed in the phase III ASPIRE trial (median PFS: ITT population = 26.3 months; LOT2 = 29.6 months). Patients who received KRd at first relapse had significantly longer TTNT, compared with those on VRd or VCyd, confirming the value of KRd as an important treatment option for relapsed MM.

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