BACKGROUND: Inclusion of diverse groups of participants in cancer clinical trials is an important methodological and clinical issue. The quality of the science and generalizability of results depends on the inclusion of study participants who represent all populations among whom these treatment and prevention approaches will be used. METHODS: We conducted a systematic review using OVID as the primary source of reports included. Based on 304 peer-reviewed publications, diversity in the inclusion and reporting of study participants during a decade of cancer treatment and prevention trials (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010) is summarized. Recommendations are made for improvements in the science and reporting of cancer clinical trials. RESULTS: Of the 277 treatment trials and 27 prevention trials included in this report, more than 80% of participants were white and 59.8% were male. In the recent decade, race and sex are rarely used as selection criteria unless the trial is focused on a sex-specific cancer. 1 Their results were not encouraging. We report an update of that study, focused on identifying changes in enrollment in cancer treatment and prevention clinical trials a decade later (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010).It is understood that cancer treatment and preventive efforts are not generalizable to the entire treatable population. Historically, however, the majority of studies assessing the effectiveness of cancer treatment and prevention has been conducted using white men.1 An improved understanding of the differences between subgroups (race/ethnicity and sex) is critical to improving the risk/benefit profile for a wide range of chemotherapeutics and prevention efforts.Though much effort had been devoted to planning and implementation of programs aimed at reducing health disparities, the 2002 paper reported that minorities were still unlikely to be enrolled in clinical trials. There were 105 treatment trials that reported including both men and women, representing 42,355 participants; 38.6% of the participants were women. Results were fairly similar (34.7% of the participants were women) for the prevention studies. Age distribution and sex were reported in more than 90% of the trials (both treatment and prevention), yet race or ethnicity were reported in only 35.1% of the included treatment trials and 53.6% of the prevention trials. Within the 57 treatment trials (with 45,815 participants) which reported race or ethnicity, 10.5% of participants were reported as African American, and fewer than 1% were reported as Hispanic, Asian, or Native American. There was even less racial and ethnic diversity within the prevention trials: only 5.5% of participants were African American, 1.7% were Hispanic, and fewer than 1% were Asian or Native American.

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PURPOSE Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples. MATERIALS AND METHODS We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)–based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial ( NCT03061305 ). Sample characteristics and PCR-CGP performance were assessed across all tested samples, including exception samples not meeting minimum input quality control (QC) requirements (< 20% tumor content [TC], < 2 mm2 tumor surface area [TSA], DNA or RNA yield < 1 ng/µL, or specimen age > 5 years). Tests reporting ≥ 1 prioritized alteration or meeting TC and sequencing QC were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting ≥ 1 actionable or informative alteration or meeting TC and sequencing QC were considered actionable. RESULTS Among 31,165 (97.2%) samples where PCR-CGP was attempted, 10.7% had < 20% TC and 59.2% were small (< 25 mm2 tumor surface area). Of 31,101 samples evaluable for input requirements, 8,089 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.5% of exception samples. Positive predictive value of PCR-CGP for ERBB2 amplification in exceptions and/or sequencing QC-failure breast cancer samples was 96.7%. Importantly, 84.0% of tested prostate carcinomas and 87.9% of lung adenocarcinomas yielded results informing treatment selection. CONCLUSION Most real-world tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for > 94% of samples, potentially expanding the proportion of CGP-testable patients and impact of biomarker-guided therapies.

Background Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. Methods Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. Results Here, by Cox modeling, we develop IRS—which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression—to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. Conclusions The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications.

There have been dramatic improvements in our ability to more accurately diagnose the underlying genetic causes of developmental delay/intellectual disability; however, there is less known about the treatment trajectory and whether or not patient management and outcomes have changed due to the information gained from genetic testing. Here we report a case study of a 20-month-old male first referred to the genetics clinic in 2008 for interhemispheric cysts, agenesis of the corpus callosum, left cortical dysplasia, and developmental delay of unknown etiology. The diagnostic work-up for this patient included chromosomal microarray which detected >20% mosaicism for monosomy 7, which raised concern for a possible myelodysplastic syndrome. The clone was not detected in stimulated peripheral blood cultures and his karyotype was reported as a normal male. Because of this microarray finding, he was referred to pediatric hematology/oncology where he was confirmed to have a pre-symptomatic diagnosis of myelodysplastic syndrome and was treated with chemotherapy and a bone-marrow transplant. This case illustrates the clinical utility of microarray testing and the importance of long-term follow-up to assess patient outcomes.

3574 Background: Tissue-based h-CGP is increasingly utilized for treatment selection in patients with advanced solid tumors but has high tumor surface area [TSA] requirements (≥25mm2 for leading commercial tests). P-CGP is recommended when tissue is insufficient for H-CGP. Here we assessed the feasibility and clinical impact on actionable biomarker identification of PCR-CGP. Methods: We performed a post-hoc, non-prespecified analysis on 21,743 consecutive subjects with advanced solid tumors who sent TTS for PCR-CGP from 5/17-12/19 as part of an ongoing observational trial at > 20 U.S. health systems (NCT03061305). PCR-CGP was performed using StrataNGS, a single-site laboratory developed test assessing all CGP biomarker classes (including microsatellite instability (MSI) status and tumor mutation burden [TMB]). We predicted actionable biomarker identification rates for PCR-CGP, H-CGP and P-CGP if applied to all U.S. patients with advanced solid tumors through incorporating population incidence, biomarker frequencies, test TSA and tumor content requirements (or cfDNA detection rates), and performance characteristics. Actionable biomarkers were the 30 in 11 tumor types from the MolDX p-CGP local coverage determination (L38043), pan-tumor NTRK fusions and MSI, and TMB in lung cancer. Results: Among TTS from 21,734 patients with advanced cancer, 20,493 (94.3%) met TSA requirements for PCR-CGP (≥2mm2) vs. 9,281 (42.7%) for H-CGP. PCR-CGP reported results for 98.0% and 95.0% of patients with large (≥25mm2 TSA) and small (2-24mm2) TS, respectively, in a median of 7 business days. Compared to 1,882 orthogonal actionable biomarker results, PCR-CGP accuracy was 96.6% and 96.5% in large and small TTS, respectively. Actionable biomarker frequency was highly correlated in PCR-CGP tested large vs. small TTS (r2= 0.99), as well as in this PCR-CGP cohort vs. a MSKCC institutional pan-cancer H-CGP cohort (r2= 0.92). If applied to all U.S. patients with advanced solid tumors, PCR-CGP has significantly greater predicted actionable biomarker identification rate (88.5%) compared to P-CGP (77.0%, N-1 chi-squared test, p < 0.0001) or H-CGP (54.3%, p < 0.0001). Conclusions: Half of TTS submitted for PCR-CGP did not meet H-CGP tissue requirements. PCR-CGP is feasible for the vast majority of patients and is predicted to expand the actionable biomarker evaluable proportion of patients with advanced solid tumors compared to H-CGP or P-CGP. Clinical trial information: NCT03061305 .

3073 Background: Widespread integration of systematized next generation sequencing (NGS)-based precision oncology is hindered by numerous barriers. Hence, we developed the Strata trial (NCT03061305), a screening protocol to determine the impact of scaled precision oncology. Methods: We implemented no-cost NGS on formalin fixed paraffin embedded (FFPE) clinical samples for all patients with advanced tumors, a common portfolio of partnered therapeutic clinical trials, and robust infrastructure development across the Strata Precision Oncology Network. Results: Across the network of 17 centers, specimens from 8673/9222 (94%) patients were successfully tested in the Strata CLIA/CAP/NCI-MATCH accredited laboratory using comprehensive amplicon-based DNA and RNA NGS. Patients were tested with one of three StrataNGS test versions; the most recent panel assesses all classes of actionable alterations (mutations, copy number alterations, gene fusions, microsatellite instability, tumor mutation burden and PD-L1 expression). Median surface area of received FFPE tumor samples was 25mm2 (interquartile range 9-95mm2), and the median turnaround time from sample receipt to report was 6 business days. 2577 (27.9%) patients had highly actionable alterations, defined as alterations associated with within-cancer type FDA approved or NCCN guideline recommended therapies (1072 patients), NCI-MATCH trial arms (1467 patients), Strata-partnered therapeutic trials (327 patients), or specific alteration-matched FDA approved therapies in patients with cancers of unknown primary (71 patients). Of the 1467 patients matched to an NCI-MATCH trial arm, 15 enrolled. Of the 327 patients matched to one of nine Strata-partnered clinical trials, 77 (24%) were screen failures, while 250 (76%) have either enrolled or are being actively followed for enrollment upon progression. Conclusions: Through streamlined consent methods, electronic medical record queries, and high throughput laboratory testing at no cost to patients, we demonstrate that scaled precision oncology is feasible across a diverse network of healthcare systems when paired with access to relevant clinical trials. Clinical trial information: NCT03061305.