Non-trial Patients Research Articles

Abstract CT031: A pilot clinical trial of neoadjuvant modified FOLFIRINOX plus nivolumab in borderline resectable pancreas cancer

Abstract Background: Combinations of chemotherapy and checkpoint inhibitors have failed to show improvements in pancreas cancer (PC) but all studies reported to date have been in the metastatic setting. Perioperative strategies of PD1 inhibitor combinations have shown promise in many malignancies. The A021501 trial established modified FOLFIRINOX (mFFX) as a reference neoadjuvant regimen for patients (pts) with borderline resectable pancreas cancer (BRPC). Here, we present clinical and pathologic results from a phase 1/2 investigator-initiated study investigating the safety and efficacy of mFFX and Nivolumab in pts with BRPC. Methods: Pts with ECOG PS 0-1 and BRPC confirmed by qualified surgeons were treated with a maximum of 6 cycles of mFFX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours) on days 1 and 15 of a 28-day cycle and Nivolumab (480 mg Iv q 4 weeks). The primary endpoint was safety (including post-operative fistula formation) and pathologic response to neoadjuvant therapy. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR) and overall survival (OS). RNA sequencing was performed on 16 post-treatment resected tumors, 5 patient-matched diagnostic pre-treatment biopsies, and 9 resected tumors from non-trial patients treated with mFFX alone. Results: Overall, 28 pts (median age 68, M: 16, F, 12) were enrolled. 26 (93%) pts completed at least 3 cycles of mFFX and Nivo and 24 (86%) pts underwent surgery (23 R0/1R1). There were no grade 2 post-operative fistulas observed and the rates of grade 3 or higher adverse events was 55% with all being related to mFFX and none attributed to nivolumab. At a median follow-up of 24 months, the median PFS was 34.8 months, and the median OS was 35.1 months. Among pts who underwent pancreatectomy, the 18-month OS rate was 90%. There were 2 pathologic complete responses and 2 near complete responses. Compared to pre-treatment biopsies, RNA sequencing from resected specimens revealed higher CD8 (P=0.018) and Granzyme A (P=0.024) expression. In patients with pathologically node negative disease (n=11), elevated Granzyme A expression was associated with significantly improved PFS (P=0.046). Adenosine-related gene expression increased in 50% (n=8) of post-treatment samples (P<0.022) and correlated with expression of adenosine-generating CD73 (P=0.008). Conclusions: Neoadjuvant mFOLFIRINOX and Nivolumab was associated with favorable rates of R0 resection, PFS and OS relative to historical data in patients with BRPC in this pilot trial. The addition of Nivolumab did not increase rates of G3 AE’s and there were no unexpected safety signals. The addition of Nivolumab to neoadjuvant FOLFIRINOX may benefit some patients by enhancing cytolytic T cell function and decreasing immunosuppressive adenosine. This is the first trial reported with a PD1 inhibitor in neoadjuvant pancreas cancer and a Phase II trial is ongoing. Citation Format: Zev A. Wainberg, Jason Link, David Dawson, Lee Rosen, Stephen Kim, Mark Girgis, Jon King, Joe Hines, Saeed Sadeghi, Olga Olevsky, Deborah J. Wong, Harsimran Multani, Jenna Davis, Lisa Yonemoto, Ann Marie Siney, Christine Kivork, Chi-Hong Tseng, Timothy Donahue. A pilot clinical trial of neoadjuvant modified FOLFIRINOX plus nivolumab in borderline resectable pancreas cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT031.

A multicenter evaluation of the HeartMate 3 risk score

BackgroundThe Heartmate 3 (HM3) risk score (HM3RS) was derived and validated internally from within the MOMENTUM 3 trial population and provides 1- and 2-year mortality risk prediction for patients in those prior to HM3 left ventricular assist device (LVAD) implantation. We aimed to evaluate the HM3RS in non-trial unselected patients, including those not meeting inclusion criteria for MOMENTUM 3 trial enrollment. MethodsPatients who underwent HM3 LVAD implant at one of 7 US centers between 2017-2021, with at least 1 year follow up, were included in this analysis. Patients were retrospectively assessed for their eligibility for the MOMENTUM 3 trial based on study inclusion and exclusion criteria. HM3RS risk discrimination was evaluated using time-dependent receiver operating characteristic (ROC) curve analysis for 1-year mortality for all patients, and further stratified by MOMENTUM 3 trial eligibility. Kaplan Meier curves were constructed using the HM3RS-based risk categories. ResultsOf 521 patients included in the analysis, 266 (51.1%) would have met enrollment criteria for MOMENTUM 3. The 1- and 2-year survival for the total cohort was 85% and 81%, respectively. There was no statistically significant difference in survival between those who met and did not meet enrollment criteria at 1 (87% vs 83%; P=0.21) and 2 years post-implant (80% vs 78%; P=0.39). For the total cohort, HM3RS predicted 1-year survival with an AUC of 0.63 (95% CI: 0.57-0.69, P<0.001). HM3RS performed better in the subset of patients meeting enrollment criteria: AUC 0.69 (95% CI:0.61-0.77, P<0.001) compared to the subset that did not: AUC 0.58 (95% CI: 0.49-0.66, P= 0.078). ConclusionIn this real-world evidence, multi-center cohort, 1- and 2-year survival after commercial HM3 LVAD implant was excellent, regardless of trial eligibility. The HM3RS provided adequate risk discrimination in “trial-like” patients, but predictive value was reduced in patients who did not meet trial criteria.

Abstract A128: A novel approach to understanding disparities in cancer clinical trial enrollment

Abstract Background: Cancer patients who participate in clinical trials have access to novel therapies, increased monitoring, and potentially improved survival. However, this access is not universal. Striking disparities in clinical trial enrollment have been linked to race, sex, and geography. However, studies on this topic are limited due to a lack of patient-specific socioeconomic data. Methods: This analysis used a novel linkage of administrative patient data from University Hospitals Seidman Cancer Center (Cleveland, Ohio) linked to the LexisNexis Socioeconomic Health Attributes, a robust dataset containing 442 patient-specific attributes gathered from public records regarding income, education, housing stability, property ownership and value, social support, and many others. We included cancer patients aged 18-75 years at the time of the latest cancer diagnosis (before trial enrollment if patient was enrolled) during 2007-2022. Because of the substantial differences in the demographic and clinical characteristics between the trial and non-trial patients, we applied the propensity score matching technique to one-to-one match all trial patients to non-trial patients by age, sex, race/ethnicity, cancer type, and year of the latest cancer diagnosis. Next, we applied the classification and regression tree (CART) machine learning algorithm to identify “phenotypes”, or combinations of patient socioeconomic characteristics that predict their trial enrollment status. We additionally performed the random forest algorithm to determine whether our CART model captured the most important variables in predicting trial enrollment. Results: We identified 28,671 cancer patients with a mean and median age of 60 and 62 years. Of those, 2,479 patients were enrolled in trials, and a corresponding 2,479 non-trial patients were matched. We identified 9 phenotypes of trial enrollment from the results of CART. The percentage of patients enrolled in trials ranges from 30% to 80%. Patients belonging to the highest-enrollment phenotype were identified by their estimated annual income exceeding $50,000, higher fraud-risk level, and age under 61 years. Patients falling into the lowest-enrollment phenotype were characterized by an estimated annual income below $30,000, an estimated home value below $243,000, and no college attendance. Variables identified by CART were also among the top-ranked variables in the random forest regarding their variable. Other important variables identified by random forest include, whether the patient ever registered to vote, risk of not being motivated to manage one's own health, and business records. Conclusion: Compared to community-level data, the use of patient-specific socioeconomic data provides a more granular understanding of clinical trial disparities. The use of machine learning methods of CART and random forest offers a promising avenue for future disparities research. This novel approach will deepen our understanding of cancer disparities and improve our ability to intervene and improve care for our most vulnerable patients. Citation Format: Weichuan Dong, Jamie Shoag, Tamila Kindwall-Keller, Ali Kara, John Shanahan, Debora Bruno, Johnie Rose, Siran Koroukian, Richard Hoehn. A novel approach to understanding disparities in cancer clinical trial enrollment [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A128.

INNV-16. COMPARISON OF SURVIVAL OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS: A COMPARISON BETWEEN PATIENTS ENROLLED INTO CLINICAL TRIALS AND PATIENTS THAT DID NOT ENROLL INTO TRIALS AT FIRST PROGRESSION

Abstract BACKGROUND Clinical trials in neuro-oncology use stringent eligibility criteria to select patients. We examined potential differences of survival outcomes in recurrent glioblastoma patients participating in clinical trials compared to trial-eligible patients treated outside of a trial. METHODS We reviewed 378 adult IDH-wild-type glioblastoma patients treated for first recurrence at our institution 2014-2020. We retrospectively evaluated patients for clinical trial eligibility based upon review of performance status, laboratory values (e.g. comprehensive metabolic panel, complete blood count), and other common eligibility criteria. Overall survival was defined as time from date of first recurrence to death. Cox proportional hazards modeling were used to evaluate outcomes of trial eligible patients compared to patients who received treatment on a clinical trial. RESULTS Among 378 patients, 171 patients (47%) enrolled onto a trial at first recurrence. Amongst 207 non-trial patients, 65 patients were excluded due to ineligibility or missing data. The primary reasons for trial ineligibility was known additional malignancy, thrombocytopenia, KPS &amp;lt; 60, active autoimmune disease, and presence of diffuse leptomeningeal disease. There were 142 (69%) patients deemed trial-eligible per our retrospective screening. In trial-eligible non-trial and trial participants (N=313), trial participation was associated with improved survival (Adjusted-HR 0.58, 95%CI 0.43-0.77, p&amp;lt; 0.001) after adjustment for age (HR 1.02, 95%CI:1.01-1.03, p=0.01), MGMT promoter methylation (HR 0.64, 95%CI:0.47-0.88, p=0.008), KPS at first recurrence (HR 0.99, 95%CI:0.97-1.00, p=0.02), time to first recurrence (HR 1.00, 95%CI:0.999-1.00, p=0.07), surgery at first recurrence (HR 0.96, 95%CI:0.72-1.27, p=0.77), standard 6 weeks radiation upfront (HR 0.47, 95%CI:0.25-0.87, p=0.02), and concurrent temozolomide use upfront (HR 0.71, 95%CI:0.43-1.15, p=0.18). CONCLUSION The most common reasons for clinical trial ineligibility in our cohort was additional malignancy, thrombocytopenia and poor performance status. In a single institution recurrent glioblastoma cohort, trial participation was associated with improved survival after adjustment of clinical covariates in this cohort.

Clinical outcomes of stereotactic biopsy on children with pontine diffuse midline glioma.

Diffuse midline glioma (DMG) of the pons occurs in pediatric patients and carries a dismal prognosis. Biopsy is not necessary for diagnosis but provides information, particularly H3K27M status, with prognostic implications. Additionally, biopsy information may open therapeutic options such as clinical trials that require mutation status. Therefore, we sought to assess the safety of surgical biopsy in DMG patients as well as its potential impact on clinical course. Retrospective analysis of patients who were radiographically and clinically diagnosed with pontine DMG in the last 5years was performed. We assessed demographic, clinical, radiographic, surgical, and follow-up data. 25 patients were included; 18 (72%) underwent biopsy while 7 (28%) declined. 12 biopsies (67%) were performed with robotic arm and 5 (27%) with frameless stereotaxy. Three biopsied patients (17%) experienced new post-operative neurologic deficits (1 facial palsy, 1 VI nerve palsy and 1 ataxia) that all resolved at 2-week follow-up. All biopsies yielded diagnostic tissue. Fourteen patients (78%) had H3K27M mutation. Median OS for H3K27M patients was 10months compared to 11months in the wild-type patients (p = 0.30, log-rank test). Median OS for patients enrolled in clinical trials was 12months compared to 8months for non-trial patients (p = 0.076). In our series, stereotactic pontine DMG biopsies did not carry any permanent deficit or complication and yielded diagnostic tissue in all patients. Similar post-operative course was observed in both robot-assisted and frameless stereotactic approaches. There was no significant difference in survival based on mutation status or clinical trial enrollment.

Adverse outcomes in nontrial like patients on commercial HeartMate 3 LVAD support

Adverse outcomes in nontrial like patients on commercial HeartMate 3 LVAD support

Immune Checkpoint Inhibitors in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience from a Canadian Comprehensive Cancer Centre.

Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. Of the 36 patients identified, the best overall response (BOR) to ICI was a partial response (PR) in 41.7%, a complete response (CR) in 27.8%, and stable disease in (SD) 13.9%. The progression-free survival (PFS) rate for 1 year was 58.1%; the median PFS was 21.3 months (95% CI 6.4-NE). The 1-year overall survival (OS) was 76.7%, and the median OS was 38.6 months (95% CI 25.4-NE). Immune-compromised patients, ECOG performance 2-3, and age ≥ 75 years were not significantly associated with PFS or OS. IrAE grades 3-4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefits with ICI regardless of age, immune status or ECOG performance status. We acknowledge the small sample size and retrospective methodology as the main limitations of our study.

Comparison of patients with renal cell carcinoma in adjuvant therapy trials to a real-world population.

To compare characteristics and outcomes of patients included versus those not in adjuvant therapy trials post complete resection of renal cell carcinoma (RCC). Adult patients following complete resection for clear cell RCC between January 1, 2011, and March 31, 2021, were included. Patients had intermediate high, high risk nonmetastatic disease (modified UCLA Integrated Staging System) or fully resected metastatic (M1) disease as per the inclusion criteria of adjuvant studies. Demographic, clinical, and outcomes between trial and nontrial patients were compared. Of 1,459 eligible patients, 63 (4.3%) participated in an adjuvant trial. Disease characteristics were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6 years; P < 0.0001) and had lower Charlson Comorbidity Index scores (mean 4.2 vs. 4.9; P = 0.009). Unadjusted disease-free survival (DFS) at 5 years for trial patients was 48.6% and 39.2% for nontrial patients (HR 0.71, 0.48-1.05, P = 0.08). Median DFS was higher for trial patients in comparison to nontrial patients (4.4 years, IQR 1.7- not reached; vs. 3.0 years, IQR 0.8-8.6; P = 0.08). Cancer specific survival (CSS) at 5 years for trial patients was 85.2% in comparison to 78.6% for nontrial patients (HR 0.45, 0.22-0.92, P = 0.03). Unadjusted estimated overall survival (OS) at 5 years was 80.8% for trial patients and 74.8% (HR 0.42, 0.18-0.94; P = 0.04) for nontrial patients. Patients in adjuvant trials were younger and healthier with longer CSS and OS in comparison to those not included in adjuvant trials. These findings may have implications when we generalize trial results to real world patients.

Immune checkpoint inhibitors in advanced cutaneous squamous cell carcinoma: Real-world evidence.

e21519 Background: Immune checkpoint inhibitors (ICI) Cemiplimab and Pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate efficacy and safety of ICI in a real-world cSCC population, including patients with conditions which would exclude trial participation. Methods: In this single-center retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We aimed to assess efficacy outcomes according to age, comorbidities, and immune-related adverse events (irAE). Best overall response (BOR) was investigator-assessed. X2, Fisher’s exact, and Mann-Whitney U tests were used to compare subgroups of interest, and Cox proportional hazards models were fitted. The log-rank test was used to assess progression free survival (PFS) and overall survival (OS). Results: We identified 35 patients. Characteristics are displayed in the table. Median follow-up was 21.8 months (95% CI 19.3-24.4). BOR to ICI was partial response (PR) in 42.9%, complete response (CR) in 28.6%, and stable disease in (SD) 14.3% of patients. Main reasons for discontinuation of treatment were progression of disease (PD) in 20%, achievement of maximum benefit in 17.1%, and toxicities in 14.3%. Treatment beyond progression was given to 22.9% patients. The PFS rate at 1 year was 62%; median PFS was not reached (NR). PFS and OS were similar between patients with or without comorbidities, ECOG performance status 0-1 versus 2-3, or between age groups ≥75 years versus &lt;75. IrAE grade 1-2 and 3-4 were seen in 80% and 14.3% of patients, respectively. Patients with grade 1-2 irAE had greater PFS than those without toxicities (HR 0.16; 95%CI 0.045-0.567, p=0.005). The OS rate at 1 year was 76%, with a median OS of 38.57 months (95% CI 19.4-57.7). Responders (CR+PR) had a prolonged median OS compared to non-responders (SD+PD): 38.57 months versus 9 months (HR 0.083; 95%CI 0.17-0.406, p=0.002). Conclusions: ICI were effective and safe among real-world cSCC patients, independent of age, comorbidities or ECOG. Our BOR was higher than in the published clinical trials, which might reflect the subjective nature of investigator-assessed response or the small sample size assessed. [Table: see text]

(180) Multicenter Analysis of Outcomes in Non-Trial versus Trial-Like Patients with Commercial Heartmate 3 LVAD

(180) Multicenter Analysis of Outcomes in Non-Trial versus Trial-Like Patients with Commercial Heartmate 3 LVAD

Validation of a risk-based algorithm to reduce poor operative outcomes after complex surgery for ovarian cancer

ObjectiveWe developed an algorithm that identifies patients at high risk of morbidity/mortality after cytoreductive surgery for advanced ovarian cancer. We have previously shown that the Mayo triage algorithm reduces operative...

Single-Cell RNA-Sequencing Identifies Immune Biomarkers of Progression in Patients with High-Risk Smoldering Multiple Myeloma Treated with Immunotherapy

Introduction Patients with Smoldering Multiple Myeloma (SMM) have altered immune cell composition in the bone marrow (BM) and show inferior responses to SARS-CoV-2 vaccination, which indicates defective immune cell function. Data from two randomized Phase III trials suggest that therapeutic intervention prior to progression can prolong progression-free survival (PFS) in patients with high-risk SMM (Mateos et al., 2013; Lonial et al., 2020). However, little is known about the role of BM-based immune profiling in risk stratification and patient selection or the utility of peripheral blood (PB) for the detection of immune alterations related to disease. Methods Here, we performed single-cell RNA- and T-cell receptor (TCR) sequencing on 149 samples, drawn from 34 patients with high-risk SMM who were enrolled on a Phase II clinical trial of Elotuzumab, Lenalidomide, and Dexamethasone (E-PRISM), and 21 healthy donors. Specifically, we profiled 60 CD138- BM mononuclear cell samples drawn at baseline (n=28), cycle 9, day 1 (C9D1, n=16) and end of treatment (EOT, n=16), 68 PB mononuclear cell (PBMC) samples drawn at baseline (n=33), C9D1 (n=14), and EOT (n=21), and 11 BM and 10 PBMC samples from age-matched healthy donors. For 24 patients and 40 samples, data was generated from matched BM and PB immune cells to enable head-to-head comparisons. We also integrated non-trial patients with our E-PRISM cohort, including MGUS (n=6), low-risk SMM (LRSMM, n=3), high-risk SMM (HRSMM, n=12), newly diagnosed MM (NDMM, n=9) and healthy donors (n=11), reaching a total of 190 samples and 231,608 cells. Libraries were prepared using Chromium Single-Cell 5' and 3' kits by 10X Genomics and sequenced on NovaSeq at the Genomics Platform of the Broad Institute of MIT and Harvard (Cambridge, MA). Results First, we hypothesized that the similarity of a patient's BM immune cell composition to that of healthy donors may have prognostic value. We trained a Naïve Bayes classifier on BM samples (n=41) from patients and healthy donors to identify the presence of SMM, which achieved 94% accuracy in the testing set (n=16). We computed normalization scores for each sample by summing the product of each cell type's proportion and its corresponding signed importance to the classification, and classified patients based on the median as least (reactive) or most normal-like (non-reactive) at baseline. Patients classified as reactive (n=12) had significantly prolonged PFS in response to therapy (p=0.011). Furthermore, reactive patients showed significantly lower abundance of pro-inflammatory monocytes and pDCs, while their granzyme K (GZMK)-expressing CD8+ T-cells showed lower levels of exhaustion markers (including PDCD1, TNFRSF9, and TOX) and higher levels of genes associated with long-lived memory T-cells (CD27, IL7R), and functionality (IFNG, TNF). On average, patients showed significantly higher normalization scores at EOT (p=0.018). Based on the change in normalization scores from baseline to EOT, we defined a state of post-therapy immune normalization (PIN) and classified four patients who showed no or minimal increase in their normalization score at EOT as PIN-negative. Patients who achieved PIN at EOT (n=8) had significantly longer PFS (p=0.032). Next, we tested whether PB can be used reliably for immune profiling of patients with HRSMM, as BM biopsies are invasive and carry risk, which prohibits regular sampling. Indeed, by comparing PB samples between patients and healthy donors, we recovered compositional changes discovered in our BM-based analysis and showed that the TCR repertoire of patients with SMM is significantly less diverse than that of HD in both the BM and PB. Strikingly, our BM-trained classifier was able to correctly infer the presence or absence of SMM in nearly all PB samples from patients and healthy donors with an accuracy of 97%. Discussion Collectively, our results indicate that the similarity of a patient's BM immune cell composition to that of healthy donors can be harnessed for prognostication both at diagnosis and post-therapy, which could have implications in risk stratification at diagnosis, trial design and monitoring of response to therapy. Moreover, PB-based immune profiling may have diagnostic and prognostic utility, potentially enabling regular assessments of immune dysregulation in patients.

Enhancing Radiation Therapy Plan Quality in a Multi-Site Randomized Clinical Trial with a Benchmark Credentialing Exercise: The VA STARPORT Experience

<h3>Purpose/Objective(s)</h3> VA STARPORT is a phase 2/3 trial comparing systemic therapy +/- PET-directed, metastasis directed radiation therapy (RT) for oligo recurrent prostate cancer enrolling at 16 sites. RT options include SBRT to metastases only or elective nodal RT with a simultaneous integrated boost (ENRT+SIB). We hypothesized that benchmark credentialing exercise results that were shared across study sites would enhance protocol understanding, increase compliance, and identify opportunities to improve the study protocol. <h3>Materials/Methods</h3> A hypothetical benchmark patient scenario was created including prior definitive prostate RT with recurrences in a right obturator node, right external iliac node, and right iliac bone. OARs, target structures, and prior RT dosimetry were created on an open-source CT dataset. The benchmark exercise included: Phase 1: Each site described their preferred protocol treatment approach (SBRT or ENRT+SIB) and RT details (dose, fractions, PTV margins, and method to address prior RT). Phase 2: Each site performed 2 standardized treatment planning exercises on the dataset (SBRT vs. ENRT+SIB). Compliance worksheets summarized and assessed dose metrics, target coverage, and conformality. Plan DICOM files, worksheets, and IMRT QA were submitted for central RT quality assurance (RTQA). Phase 3: SBRT and ENRT + SIB plans were scored by the study RTQA team using a numerical plan scoring system. Scorecards and lessons learned were discussed with local investigators and further communicated to all study sites. <h3>Results</h3> Site survey results (n=16) revealed 8 preferred ENRT+SIB. Only 4 ENRT+SIB prescriptions were per-protocol, and there was PTV margin non-compliance in an intended SBRT plan. Benchmark lessons learned are summarized in the Table. <h3>Conclusion</h3> A practical and useful benchmark exercise successfully assessed protocol compliance, revealed key lessons, and identified ways to improve the protocol's RT section and RTQA process. Teaching points and learned planning strategies were shared across study sites and have a potential to improve metastasis-directed RT planning for both trial and non-trial patients at each facility.

Comparison of survival outcomes of patients with newly diagnosed glioblastoma treated with standard chemoradiation in and outside of clinical trials.

2051 Background: Randomized clinical trials use stringent eligibility criteria to select patients which can raise concerns about generalizability of study results. Recent interest in external controls and new trial designs has increasingly focused on the possible use of real-world data sources. We examined potential differences of survival outcomes in clinical trial and real-world datasets in newly diagnosed glioblastoma. Methods: Patient-level data from 4 independent datasets were analyzed. Non-trial data were derived from an institutional dataset of 453 patients with newly diagnosed glioblastoma treated outside of a clinical trial with standard radiation therapy with concurrent and adjuvant temozolomide at a large academic center. Trial patients included patients on the control arm of several multi-institutional trials (NCT00689221, n = 273; NCT00813943, n = 89; NCT00943826; n = 459) and patients treated on trial at our institution (n = 210). Non-trial patients were compared with each of the 4 clinical trial datasets in pairwise comparisons with Cox regression with adjustments for age, sex, extent of resection, KPS and MGMT status. Results: Patient-level data from 1,484 patients were analyzed. Non-trial patients were older compared to patients in the multi-institutional trials (mean 58.6 vs. 56.1 years (NCT00943826), 53.9 years (NCT00813943), 55.7 years (NCT00689221); p &lt; = 0.001). The non-trial cohort had fewer women (43.5% vs. 35.9%, p = 0.02), greater proportion of lower KPS patients (47% KPS &lt;90 vs. 31% KPS &lt;90, p &lt; 0.001) and greater proportion of MGMT methylated patients (49% vs. 33%, p &lt; 0.001) compared to NCT00943826 patients. There were no other significant differences between patient characteristics of non-trial patients and the 4 trial datasets. Trial participation was not associated with improved survival in multivariable analysis after adjustments for clinical covariates (non-trial patients vs. each trial dataset; Table, P &gt; 0.05). Conclusions: Glioblastoma patients treated on multi-institutional clinical trials that were included in our analysis did not have statistically significant differences in survival compared to patients treated outside of a clinical trial at a large academic center after adjustment for relevant variables. Our findings support the possible use of real-world data in the development of external control arms for future trials in newly diagnosed glioblastoma. [Table: see text]

Translation of Prognostic and Pharmacodynamic Biomarkers from Trial to Non-trial Patients with Metastatic Castration-resistant Prostate Cancer Treated with Docetaxel

AimsWe conducted a pooled analysis of four randomised controlled trials and a non-trial retrospective dataset to study the changes in serum prostate-specific antigen (PSA) concentrations during treatment and its impact on survival in men treated with docetaxel for metastatic castration-resistant prostate cancer. We also compared the outcomes and pre-treatment prognostic factors between trial and non-trial patients. Materials and methodsData were obtained from four randomised controlled trials and a non-trial cohort from a tertiary cancer centre. The PSA kinetics covariates chosen were absolute value (PSAT), best percentage change (BPCH) and tumour growth rate (K). The association between the covariates collected and overall survival was assessed within a Cox proportional hazards model. How well a covariate captured the difference between trial and non-trial patients was assessed by reporting on models with or without trial status as a covariate. ResultsWe reviewed individual datasets of 2282 patients. The median overall survival for trial patients was 20.4 (95% confidence interval 19.6–22.2) months and for the non-trial cohort was 12.4 (10.7–14.7) months (P < 0.001). Of the pre-treatment factors, we found that only lactate dehydrogenase fully captured the difference in prognosis between the trial and non-trial cohorts. All PSA kinetic metrics appeared to be prognostic in both the trial and non-trial patients. However, the effect size was reduced in non-trial versus trial patients (interaction P < 0.001). Of the time-dependent covariates, we found that BPCH best captured the difference between trial and non-trial patient prognosis. ConclusionsThe analysis presented here highlights how data from open-source trial databases can be combined with emerging clinical practice databases to assess differences between trial versus non-trial patients for particular treatments. These results highlight the importance of developing prognostic models using both pre-treatment and time-dependent biomarkers of new treatments.

Comparison of patients with high-risk nonmetastatic clear cell renal carcinoma in adjuvant therapy trials versus nonclinical trial patients.

361 Background: Characteristics of patients with high risk for recurrence non-metastatic renal cell carcinoma (nmRCC) participating in adjuvant therapy clinical trials post-nephrectomy have not been well described. We evaluated high risk nmRCC patients in the CKCis database to explore differences between trial and non-trial patients. Methods: Adult patients undergoing partial or radical nephrectomy for clear cell nmRCC between January 1, 2011 and March 31, 2021 were included. CKCis is a prospective cohort of patients from 14 Canadian academic institutions. Patients with high risk nmRCC (using modified UCLA Integrated Staging System) were included. Demographic, clinical, and survival statistics were analyzed for all patients and comparatively for the trial and non-trial groups. Results: 1459 patients, including 63 in adjuvant trials, were evaluated. 71% were male, 91% had pT3N0M0 disease. Disease characteristics including tumor size, stage, grade, location, necrosis, and margin status were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6; p &lt; 0.0001) and had lower Charlson Comorbidity Index scores (median 4 [3,6) vs. 5 [4,6] p &lt; 0.001). Estimated overall survival (OS) at 5 years was 80.8% (95% CI, 65,90) for trial patients and 74.8% (95% CI, 71,78.2) for non-trial patients. Recurrence-free survival at 5 years for trial patients was 48.6% (95% CI, 34,61.7) and 39.2% (95% CI, 35.2,43.1) for non-trial patients. Conclusions: Patients in adjuvant trials were younger and healthier at baseline than the average high risk nmRCC CKCis patient. Trial patients appear to have had longer time to recurrence and longer survival compared to non-trial patients, although not reaching statistical significance. Selection bias is common in clinical trials and evaluation of real-world population-based evidence of patients receiving adjuvant therapy will be important to ensure phase 3 trial results have external validity.

Pomalidomide in Patients With Relapsed and/or Refractory Multiple Myeloma: A Prospective Study Within the Nationwide Netherlands Cancer Registry.

Patients with relapsed and/or refractory multiple myeloma (RRMM) generally have limited treatment options and a poor prognosis. Previous trials demonstrated that pomalidomide combined with low-dose dexamethasone (Pd) is effective in these patients with significant responses and improved progression-free survival (PFS). Pd has been approved in RRMM patients who received ≥2 prior lines of therapy. Here, we present the results of a population-based study of patients with RRMM treated with Pd in The Netherlands from time of pomalidomide approval. Using the nationwide Netherlands Cancer Registry, data from all nontrial patients with RRMM treated with Pd were collected. Data were analyzed of response, PFS, and overall survival (OS). A total of 237 patients were included in this analysis. Previous treatment consisted of a proteasome inhibitor in 227 patients (96%) and/or an immune-modulating agent in 235 patients (99%). One hundred forty patients (59%) were refractory to an immune-modulating agent in their last line of therapy. Median time from diagnosis to treatment with Pd was 4.9 years (interquartile range, 2.7–7.9), and the median number of prior treatments was 4 (interquartile range, 3–5). Median PFS and OS for all patients were 3.6 months (95% confidence interval [CI], 3.1–3.8) and 7.7 months (95% CI, 5.7–9.7), respectively. For patients achieving ≥PR, median PFS and OS were 10.6 months (95% CI, 8.3–12.9) and 16.3 months (95% CI, 13.6–23.2), respectively. This nationwide, population-based registry study confirms data shown in pivotal clinical trials on Pd. PFS in this analysis is comparable to PFS observed in those clinical trials.

Cardiovascular Event Reporting in Modern Cancer Radiation Therapy Trials

PurposeCardiovascular disease (CVD) is the leading cause of morbidity and mortality in cancer survivors, particularly after chest radiation therapy (RT). However, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown. Methods and MaterialsFrom 10 high-impact RT, oncology, and medicine journals, we identified all latter phase trials from 2000 to 2019 enrolling patients with breast, lung, lymphoma, mesothelioma, or esophageal cancer wherein chest-RT was delivered. The primary outcome was the report of major adverse cardiac events (MACEs), defined as incident myocardial infarction, heart failure, coronary revascularization, arrhythmia, stroke, or CVD death across treatment arms. The secondary outcome was the report of any CVD event. Multivariable regression was used to identify factors associated with CVD reporting. Pooled annualized incidence rates of MACEs across RT trials were compared with contemporary population rates using relative risks (RRs). ResultsThe 108 trials that met criteria enrolled 59,070 patients (mean age, 58.0 ± 10.2 years; 46.0% female), with 273,587 person-years of available follow-up. During a median follow-up of 48 months, 468 MACEs were reported (including 96 heart failures, 75 acute coronary syndrome, 1 revascularization, 94 arrhythmias, 28 strokes, and 20 CVD deaths; 307 occurred in the intervention arms vs 144 in the control arms; RR, 1.96; P < .001). Altogether, 50.0% of trials did not report MACEs, and 37.0% did not report any CVD. The overall weighted-trial incidence was 376 events per 100,000 person-years compared with 1408 events per 100,000 person-years in similar nontrial patients (RR, 0.27; P < .001). There were no RT factors associated with CVD reporting. ConclusionIn contemporary chest RT–based clinical trials, reported CVD rates were lower than expected population rates.

A nationwide analysis of pancreatic cancer trial enrollment reveals disparities and participation problems

BackgroundOur research group recently surveyed the clinical trial landscape in pancreatic adenocarcinoma and identified 430 active trials. These represent an opportunity to expand treatment options for patients with pancreatic adenocarcinoma. Our primary objective was to detail clinical trial participation among patients with pancreatic adenocarcinoma. Our secondary objective was to evaluate survival. MethodsWe queried the National Cancer Database (2004–2016) for patients with pancreatic adenocarcinoma. Patients were stratified by trial participation: clinical trial or non-trial. Multivariable logistic regression was used to identify variables associated with trial participation. The Kaplan-Meier method and multivariable Cox hazards regression were used to analyze survival. ResultsIn total, 261,483 patients were included: 1,110 (0.4%) were enrolled in a clinical trial. A total of 57 Black patients participated in a clinical trial (0.19% of Black patients). This was lower compared to White patients (n = 955, 0.49% of White patients, P < .001). After adjusting for demographic and clinical factors, Black patients were less likely to be enrolled in a clinical trial (odds ratio = 0.387, P < .001). Patients treated at nonacademic medical centers were less likely to be in a clinical trial.Trial participation was associated with an increased median survival relative to non-trial patients (stage IV: 9.0 vs 3.8 months, P < .001), and this association remained on multivariable regression (hazard ratio = 0.779, P < .001). ConclusionFewer than 1% of patients with pancreatic adenocarcinoma participated in a clinical trial. There are racial and sociodemographic disparities in clinical trial enrollment. An association was observed between clinical trial participants and prolonged survival.

Umbilical Cord Blood or HLA-Haploidentical Transplantation: Real-World Outcomes versus Randomized Trial Outcomes

Randomized clinical trials offer the highest-quality data for modifying clinical practice. Results of a phase III randomized trial of nonmyeloablative transplantation for adults with high-risk hematologic malignancies with 2 umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM; n=154) revealed a 2-year progression-free survival (PFS) of 41% after Haplo-BM transplantation and 35% after 2-unit UCB transplantation (P=.41), with overall survival (OS) of 57% and 46%, respectively (P=.04). We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's prespecified 2-year outcomes. All transplantations were performed between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial would be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM with those after haploidentical peripheral blood (Haplo-PB). The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select nontrial subjects. Extended follow-up of trial subjects was obtained from this data source. Three separate analyses were performed: (1) trial subjects beyond the trial's 2-year endpoint; (2) comparison of trial subjects with a contemporaneous cohort of nontrial subjects (195 2-unit UCB, 358 Haplo-BM, and 403 Haplo-PB); and (3) comparison of nontrial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. With longer follow-up of the trial cohorts, 5-year PFS (37% versus 29%; P=.08) and OS (42% versus 36%; P=.06) were not significantly different between the treatment groups. We then compared the trial results with outcomes of comparable real-world transplantations. Five-year OS did not differ between trial and nontrial 2-unit UCB transplantations (36% versus 41%; P=.48) or between trial and nontrial Haplo-BM transplantations (42% versus 47%; P=.80), confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in PFS. With substantially larger numbers of nontrial Haplo-BM transplantations, 5-year survival was higher after nontrial Haplo-BM compared with trial 2-unit UCB (47% versus 36%; P=.012). Nontrial patients who underwent Haplo-PB transplantation had higher 5-year survival (54%) compared with trial Haplo-BM (hazard ratio [HR], 0.76; P=.044) and nontrial Haplo-BM (HR, 0.78; P=.026). Similarly, survival was better after Haplo-PB compared with trial UCB (HR, 0.57; P < .0001) and nontrial UCB (HR, 0.63; P=.0002). When considering alternative donor low-intensity conditioning regimen transplantation, a haploidentical relative is preferred, and PB is the preferred graft source.