Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.

533 Background: Major barriers to enrollment in therapeutic clinical trials (<5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.

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Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.26_suppl.145 ◽

2013 ◽

Vol 31 (26_suppl) ◽

pp. 145-145

Author(s):

Aditya Bardia ◽

Dejan Juric ◽

Steven J. Isakoff ◽

Darrell R. Borger ◽

Dora Dias-Santagata ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Driver Mutations ◽

Oncogenic Driver ◽

Her 2 ◽

Clinical Trial Enrollment ◽

Tumor Genotyping

145 Background: Major barriers to enrollment in therapeutic clinical trials (<5% in United States) include low response rate in phase I/II trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with metastatic breast cancer (MBC). Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). The common oncogenic mutations were seen in all breast cancer subtypes. PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with approximately one-third of patients undergoing tumor genotype testing enrolling in clinical trials, particularly phase-I genotype-directed targeted therapy, such as PI3K inhibitor, Akt inhibitor, and PI3K/MEK inhibitor combination. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.

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Clinical utility of targeted next generation sequencing assay in IDH-wildtype glioblastoma for therapy decision-making

Neuro-Oncology ◽

10.1093/neuonc/noab282 ◽

2021 ◽

Author(s):

Mary Jane Lim-Fat ◽

Gilbert C Youssef ◽

Mehdi Touat ◽

J Bryan Iorgulescu ◽

Sydney Whorral ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Targeted Therapy ◽

Clinical Utility ◽

Clinical Care ◽

Clinical Trial Design ◽

Off Label ◽

Survival Difference ◽

Clinical Trial Enrollment ◽

Clinical Records

Abstract BACKGROUND Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013-2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results. RESULTS Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a post hoc analysis. CONCLUSIONS While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.

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Utility of tumor genomic profiling in guiding targeted therapy and referral for clinical trials in the community practice.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18381 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18381-e18381

Author(s):

Yiqing Xu ◽

Jiang Yio ◽

Amber Yang ◽

Ashrei Bayewitz ◽

Daniel Benasher ◽

...

Keyword(s):

Clinical Trial ◽

Colon Cancer ◽

Clinical Trials ◽

Targeted Therapy ◽

Driver Mutations ◽

Cancer Type ◽

Tumor Type ◽

Genomic Profiling ◽

Community Practice ◽

Match Trial

e18381 Background: Next-generation sequencing (NGS), which enables tumor genomic profiling with limited tumor specimen for the guidance of targeted therapy, has been widely used in oncology practice. It also reports mutations of which no approved therapy is available, but potential therapies approved in a different tumor type may be reasonable to try, based on molecular mechanisms or limited data, either in clinical trials or off trial treatment. The utility of this information in the community practice is unclear. Methods: We performed a retrospective analysis on the usage of NGS result on patients with lung or colorectal cancers treated between November 2011 and February 2018. Patients were identified from Foundation Medicine Company database and were linked to records at Maimonides. We evaluated if NGS was used to guide FDA-approved targeted therapy, potentially-useful targeted therapy not approved for the cancer type, or referral to a clinical trial. Results: 177 patients (lung ca = 119, colon ca = 58) were included. NGS identified 34 (28.6%) lung ca patients with driver mutations, (21 EGFR, 6 RET, 3 ALK, 2 MET amplification, 1 ROS1 and 1NTRK mutation), who were all given FDA-approved therapy. 70 (58.8%) patients had at least 1 target with an FDA-approved therapy for a different cancer; 89 (74.9%) had a mutation being studied in a clinical trial, and 48 patients were eligible for the NCI-MATCH trial. None received non-FDA-approved drugs and none was referred to clinical trials. In the colon cancer cohort, NGS identified alterations in KRAS (27), BRAF (5), ERBB2 mutation (2), ERBB2 amplification (1), MLH1 (1), MSH2 (1) and BRCA 2(1). Among them, one patient received BRAF inhibitors. 45 and 24 patients were eligible for phase I/II trials and NCI-MATCH trial respectively, and none was referred. Conclusions: NGS has a high efficiency of detecting driver mutations in lung cancer; but only reveals low frequencies of alterations otherwise not tested in colon cancer. The approach of prescribing un-approved targeted treatment based on theoretical mechanism of action was very uncommon, and the referral to clinical trials was rare in this community practice, both of which decreasing the utility value of NGS.

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Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition

Cancers ◽

10.3390/cancers13071740 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1740

Author(s):

John J. Park ◽

Russell J. Diefenbach ◽

Natalie Byrne ◽

Georgina V. Long ◽

Richard A. Scolyer ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Benefit ◽

Trial Design ◽

Phase 1 ◽

Clinical Trial Design ◽

Roc Curves ◽

Circulating Tumor Dna ◽

Resistance Mechanisms ◽

Driver Mutations ◽

Targeted Next Generation Sequencing

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) (p < 0.001) and baseline disease burden (p = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65–1.0, p = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.

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Disparities in clinical trials participation in a vertically integrated care delivery system.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.128 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 128-128

Author(s):

Ahmed Megahed ◽

Gary L Buchschacher ◽

Ngoc J. Ho ◽

Reina Haque ◽

Robert Michael Cooper

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Healthcare System ◽

Care Delivery ◽

Trial Participation ◽

Cancer Type ◽

Clinical Trial Participation ◽

Integrated Healthcare ◽

Clinical Trial Enrollment ◽

Asian Pacific

128 Background: Sparse data exists on the diversity clinical trial enrollment in community settings. This information is important to ensure equity of care and generalizability of results. Methods: We conducted a retrospective cohort study of members of an integrated healthcare system diagnosed with invasive malignancies (excluding non-melanoma skin cancers) between 2013-2017 to examine demographics of the oncology population compared to those who enrolled in a clinical trial. Logistic regression was used to assess correlates of clinical trial participation, comparing general and screened samples to enrolled sample. Odds ratios were adjusted for gender, geocoded median household income, cancer type, and stage. Results: Of the 84,977 patients with a cancer diagnosis, N = 2606 were screened for clinical trial participation and consented, and of those N = 1372 enrolled. The percent of Latinx (25.8% vs 24.0%; OR 0.9? CI 0.72-1.05) and African American/Black (10.9% vs 11.1%; OR 0.92 CI 0.75-1.11) clinical trial participation mirrored that of the general oncology population, respectively using Non-Hispanic Whites as reference. Asian/Pacific Islander had equal odds of clinical trial enrollment (OR 1.08 CI 0.92-1.27). The enrolled population was younger than the general oncology population. Conclusions: This study suggests that in an integrated healthcare system with equal access to care, the clinical trials population is well representative of its general oncology population.[Table: see text]

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Hemophilia gene therapy: ushering in a new treatment paradigm?

Hematology ◽

10.1182/hematology.2021000254 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 226-233

Author(s):

Lindsey A. George

Keyword(s):

Clinical Trial ◽

Gene Therapy ◽

Clinical Trials ◽

Hemophilia A ◽

Full Potential ◽

Proof Of Concept ◽

Aav Vector ◽

Treatment Paradigm ◽

Clinical Trial Enrollment ◽

New Treatment

Abstract After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. With multiple ongoing trials, including licensing studies in hemophilia A and B, many are cautiously optimistic that the first AAV vectors will obtain regulatory approval within approximately 1 year. While supported optimism suggests that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized, a number of outstanding questions have emerged from clinical trial that are in need of answers to harness the full potential of gene therapy for hemophilia patients. This article reviews the use of AAV vector gene addition approaches for hemophilia A and B, focusing specifically on information to review in the process of obtaining informed consent for hemophilia patients prior to clinical trial enrollment or administering a licensed AAV vector.

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Abstract 16910: High-Frequency In-Person Visits During Clinical Trial Enrollment is Associated With Relative Reduction in Event Rates in Heart Failure Patients Followed Longitudinally

Circulation ◽

10.1161/circ.142.suppl_3.16910 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Liana C Brooks ◽

Rohan R Bhat ◽

Robyn F Farrell ◽

Mark W Schoenike ◽

John A Sbarbaro ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

High Frequency ◽

Trial Participation ◽

Trial Period ◽

Single Center ◽

Hospitalization Rates ◽

Visit Frequency ◽

Clinical Trial Enrollment ◽

Event Rates

Introduction: The COVID-19 Pandemic has mandated limiting routine visit frequency for patients with chronic cardiovascular (CV) diseases. In patients with heart failure (HF) followed longitudinally, the period of clinical trial participation provides an opportunity to evaluate the influence of high-frequency per-protocol in-person visits compared to less frequent routine visits during longitudinal clinical care. Hypothesis: Patients enrolled in clinical trials will have a lower CV and HF event rates during periods of trial enrollment than during non-trial periods. Methods: We examined clinical characteristics, CV and HF hospitalization rates, and outcomes in patients with HF receiving longitudinal HF care at a single center. We evaluated hospitalization rates during the 1-year preceding trial enrollment and hospitalization and death rates during enrollment in clinical trials and for up to 1 year following trial completion. Results: Among the 121 patients enrolled in HF clinical trials, 72% were HFrEF (age 62±11, 19% females, BMI 30.4±6.0, LVEF 25±7, NYHA 2.7±0.6, NT-proBNP 2336±2671) and 28% were HFpEF (age 69±9, BMI 32.1±5.5, 29% females, LVEF 60±10, NYHA 2.4±0.5, NT-proBNP 957±997). Average clinical trial exposure was 8±6.6 months. Per-protocol visit frequency was 16±7 per year during clinical trial enrollment. In the one-year pre-trial period, compared to the within-trial period, CV hospitalizations were 0.88/patient-year vs. 0.32/patient-year (p<0.001) and HF hospitalizations were 0.63/patient-year and 0.24/patient-year (p<0.001), with a mortality rate of 0.04/patient-year during trial participation. In the period of up-to 1 year following the end of trial enrollment CV and HF hospitalizations were intermediate at 0.51/patient-year and 0.27/patient-year with an annualized incremental mortality rate of 0.03/patient-year. Conclusion: In HF patients followed longitudinally at a single center, periods of clinical trial enrollment were associated with high visit frequency and lower CV and HF hospitalization rates. These findings highlight the potential benefits of trial enrollment and high-frequency visits for HF patients at a time when routine visit frequency is being carefully considered during the COVID-19 Pandemic.

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Increasing underrepresented minority cancer patient enrollment into cancer clinical trials: A systematic review.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18574 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18574-e18574

Author(s):

Rosa Nouvini ◽

Patricia A. Parker ◽

Charlotte Malling ◽

Kendra Godwin ◽

Rosario Costas-Muñiz

Keyword(s):

Systematic Review ◽

Clinical Trial ◽

Clinical Trials ◽

Minority Groups ◽

Relationship Building ◽

Institutional Research ◽

Underrepresented Minority ◽

Randomized Controlled ◽

Clinical Trial Enrollment ◽

Recruitment Model

e18574 Background: Minorities continue to be underrepresented in clinical trials despite the National Institute of Health’s Revitalization Act, passed in 1993, mandating the representation of women and underrepresented minority groups in clinical trials. Studies have shown that although Blacks represent 15% and Hispanics 13% of the cancer population, their clinical trial enrollment rates in are disproportionately low at 4-6% and 3-6% respectively. We conducted a systematic review exploring interventions aimed at improving clinical trial enrollment for racial and ethnic minorities. Methods: A systematic search of PubMed, Cochrane CENTRAL, and Ovid PsycINFO was conducted for English-language studies of humans since 1993. Inclusion criteria included peer-reviewed, U.S.-based studies with interventions aimed to recruit underrepresented minority adult cancer patients into cancer clinical trials. We defined underrepresented minority groups as Black, Hispanic/Latino, Asian, American Indian/Alaska Native and Native Hawaiian/other Pacific Islander. Results: A total of 2471 titles and abstracts were identified and 2324 were excluded based on the eligibility criteria. A full text review was conducted of the remaining 147 articles, of which only 9 met criteria for our review. The interventions included patient navigation/coaching (n = 4), a clinical trial educational video (n = 2), institutional research infrastructure changes (n = 1), a relationship building and social marketing recruitment model (n = 1) and cultural competency training for providers (n = 1). Studies were conducted in a variety of practice settings including national cancer institutes and community practices. The quality of evidence was limited by the heterogeneity of study methods, patient representation and bias. Several studies had a homogeneous population of Black patients. Most studies (n = 7) were single arm trials that compared results to either historical controls or those cited in the existing literature; two studies were randomized controlled trials. A statistically significant improvement in accrual was shown in three of the patient navigation interventions, one of the clinical trial educational videos, the institutional research infrastructure change and the relationship building and social marketing recruitment model. The common threads to many of these successful interventions were support through the cancer care continuum, cultural congruency of research staff and culturally catered clinical trial educational materials. Conclusions: This systematic review illustrates several mechanisms by which to increase cancer clinical trial recruitment for cancer patients of underrepresented minority backgrounds in a variety of clinical settings. Randomized controlled trials with representation of multiple races/ethnicities are needed to further explore the benefits of these interventions.

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Beyond KRAS: Practical Molecular Targets in Pancreatic Adenocarcinoma

Case Reports in Oncology ◽

10.1159/000496018 ◽

2019 ◽

Vol 12 (1) ◽

pp. 7-13 ◽

Cited By ~ 2

Author(s):

Albert Grinshpun ◽

Yonaton Zarbiv ◽

Jason Roszik ◽

Vivek Subbiah ◽

Ayala Hubert

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Pancreatic Adenocarcinoma ◽

Targeted Therapies ◽

Kras Mutation ◽

Molecular Targets ◽

Driver Mutations ◽

Proof Of Concept ◽

Genomic Analyses ◽

Variable Success

Pancreatic adenocarcinoma (PDAC) has a grim prognosis. Molecular and genomic analyses revealed that the striking majority of these tumors are driven by KRAS mutation, currently not amenable to targeted therapy. However, other driver mutations were found in a small fraction of patients. Herein we report of 3 cases of patients with metastatic PDAC and wildtype KRAS, found to harbor BRAF or RET pathogenic alterations. The patients were treated with targeted therapies with variable success. In our opinion, those proof-of-concept cases argue in favor of additional research and clinical trials’ effort in this small but significant PDAC population with uncommon driver mutations.

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Clinical outcomes of patients enrolled in clinical trial compared with patients outside clinical trial in advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.21 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 21-21

Author(s):

Jaejoon Han ◽

Jin Won Kim ◽

Se Hyun Kim ◽

Jeong-Ok Lee ◽

Yu Jung Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Clinical Trial ◽

Overall Survival ◽

Clinical Trials ◽

Metastatic Disease ◽

Median Overall Survival ◽

Phase 1 ◽

Second Line ◽

First Line ◽

Better Than

21 Background: Participation in clinical trials gives patients with cancer a chance to receive potential benefits, such as experimental treatment, meticulous follow-up and toxicity managements. We aimed to assess the evidence that such an effect exists in patients with gastric cancer. Methods: Clinical characteristics and overall survival of patients with metastatic or recurrent gastric cancer who received fluoropyrimidine and platinum combination palliative chemotherapy within or outside clinical trials at tertiary referral hospital from January 2010 to December 2012 were retrospectively analyzed. Results: Of the 244 patients, 84 patients (34%) were enrolled in clinical trials. During the study period, 20 patients in four phase 3 trials, 54 patients in eight phase 2 trials and ten patients in two phase 1 trials were participated in clinical trials. Twenty patients (8%) at first-line and 64 patients (38%) at second-line or later were enrolled in clinical trials. Younger age (P = 0.014), metastatic disease (P = 0.015) and HER2 IHC status (P = 0.005) were correlated with participation in clinical trials. The median overall survival of patients who participated in clinical trials at first-line was better than those who did not participated in clinical trials, although it was not statistically significant (16 months and 11 months, respectively, P = 0.407). Number of participation in clinical trials was not associated with survival outcome (1 versus ≥ 2 trials: 15 months and 18 months, respectively, P = 0.545). Second-line chemotherapy was administered in 167 patients. The median overall survival of patients who participated in clinical trials at second-line or later was also better than those who did not participated in clinical trials, however, it was not statistically significant (9 months and 6 months, respectively, P = 0.101). Conclusions: Younger patients, metastatic disease, positive HER2 IHC status, and clinical setting of second-line or later were associated with more participation in clinical trials. The median overall survival was numerically longer in patients who were enrolled in the clinical trials although it was not statistically significant.

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