Mandrekar, Sumithra J.

Abstract The aim was to assess whether subject’s participation in early-phase chemoprevention trials was satisfactory and identify features associated with subjects’ satisfaction. Thirteen trials that investigated a range of candidate agents from 2006 to 2021 by the Cancer Prevention Network were included. The five-item “Was It Worth It?” (WIWI) questionnaire was administered to all subjects at the end of each trial’s intervention or at early termination. Satisfied overall was defined as a participant response of “yes” to the first three questions. Six hundred ninety-one participants from the United States, Canada, Puerto Rico, and Honduras enrolled on a trial. Six hundred fifty-two (94.4%) completed the WIWI questionnaire. Of these, 493 (75.6%) were White, non-Hispanic/Latino; 39 (6.0%) Black, non-Hispanic/Latino; 98 (15.0%) Hispanic/Latino; and 8 (1.2%) of another race/ethnicity. One hundred ninety-three were women (29.6%), 121 (17.5%) were ≥65 years, and 517 (79.3%) participated in a placebo-controlled trial. Eighty-five percent indicated being satisfied overall. Compared with White, non-Hispanic/Latino, the odds of not satisfied overall were 2.96 times higher for Black/Asian/>1 race, non-Hispanic/Latino (P < 0.001) and 0.40 times lower for Hispanic/Latino (P = 0.004). The odds of not satisfied overall was 1.9 times higher when the number of preintervention adverse events experienced was ≥1 (P = 0.012), 1.8 times higher when the percentage of the intervention duration with adverse events was >5% (P = 0.024), and 7.4 times higher for subjects who terminated the intervention early (P < 0.001). These findings can inform the design of future chemoprevention trials and help investigators improve accrual, retention, adherence, and diversity in this underexplored research setting. Prevention Relevance: The five-item “WIWI?” questionnaire, which captures the participant-reported experience of trial participation, gives the subject a voice in the development of new chemopreventative agents. This study in 652 subjects looked at satisfaction with participation in early-phase chemoprevention trials for higher-risk, cancer-free men and women. See related Spotlight, p. 7

11507 Background: Advanced uterine leiomyosarcoma (uLMS) is an aggressive malignancy with poor prognosis. Standard-of-care treatments, including trabectedin (Tb) or pazopanib (P), provide median progression-free survival (PFS) of 3-4 months (mo) and objective response rates (ORR) of ~11%. Homologous recombination deficiency (HRD) in a subset of uLMS supports the use of PARP inhibitors combined with DNA-damaging agents. Preclinical studies demonstrated synergistic activity of olaparib and temozolomide (T+O), and a prior single-arm Phase II study of T+O showed promising efficacy independent of an established biomarker, warranting further investigation in a randomized setting. Methods: Alliance A092104 is a Phase II/III trial evaluating olaparib (200 mg BID) plus temozolomide (75 mg/m² daily, days 1-7, every 21 days) versus investigator’s choice of Tb or P in patients (pts) with advanced uLMS who progressed on ≥2 prior systemic therapies. Stratification factors included ECOG (0-1 vs. 2) and prior lines (2 vs. ≥3). The Phase II (Phase III) primary endpoint was PFS (OS), with a planned suspension of accrual at the end of Phase II. A total of 70 evaluable pts (58 PFS events) were needed to detect an improvement in PFS from 4 vs. 8 mo with power of 90% and 1-sided type I error of 10%, with futility assessed after 29 PFS events. Upon meeting the Phase II futility threshold for PFS, the trial was permanently closed. Data were released from the data and safety monitoring board. Pts continue to be followed for outcomes. Results: 74 pts enrolled (Arm 1: T+O, n = 37; Arm 2: investigator’s choice, n = 37 (Tb, 18; P, 13; 6 pts did not start treatment). The arms were balanced for baseline demographics except race, with the T+O arm having a higher proportion of black/African American (29.7% vs. 16.2%). 21 pts remain on treatment. Hematologic adverse events (AEs) were more frequent in the T+O arm, with Grade 4 neutropenia (19.5%) and thrombocytopenia (8.3%) both managed by dose reductions. Non-hematologic Grade 3 AEs were higher in the investigator’s choice arm (45.2% vs. 13.9%). No Grade 5 AEs were reported. In the first 70 pts, with a median follow-up of 5.9 mo, and 39 total PFS events, the median PFS was 3.2 mo (95% CI: 2.0-NE) for T+O versus 5.6 mo (95% CI: 2.8-NE) for investigator’s choice (HR = 1.00; 95% CI: 0.60-2.17; 1-sided stratified log rank p = 0.50). Within Arm 2, the median PFS for Tb and P were respectively 5.6 (95% CI: 3.1-NE) and 3.8 (95% CI: 1.5-NE) mo. 3 pts in the T+0 arm and 1 patient in the investigator’s choice arm (Tb) had a confirmed partial response. Conclusions: The trial did not meet its primary endpoint of PFS in Phase II. This suggests that a biomarker may be needed before there is further exploration of PARP inhibitor-based regimens in uLMS. Overall survival and analysis of tissue-based biomarkers will be presented. Clinical trial information: NCT05432791 .

TPS8113 Background: There are currently three approved approaches for patients with resectable NSCLC including neoadjuvant chemoimmunotherapy, adjuvant chemoimmunotherapy and perioperative treatment with neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy. All regimens were approved after showing event-free survival (EFS) or disease-free survival (DFS) benefit with the addition of immunotherapy to chemotherapy compared to chemotherapy alone. Each approach has its benefits and risks. Starting immunotherapy prior to surgery may improve treatment compliance and efficacy of immunotherapy. Nevertheless, neoadjuvant chemoimmunotherapy may result in missing an opportunity for curative surgery and increase the complexity of tumor resection. PROSPECT-LUNG (NCT06632327) is a randomized study evaluating whether starting chemoimmunotherapy before or after surgery leads to better outcomes. Methods: This is a randomized phase 3 trial in which patients will be randomized 1:1 to surgery followed by chemoimmunotherapy (adjuvant arm) or neoadjuvant chemoimmunotherapy followed by surgery and adjuvant therapy (perioperative arm). Patients with histologic or cytologic confirmation of surgically resectable stage IIA-IIIB NSCLC (per AJCC 9th edition) or stage IIA to IIIB per AJCC 8 th edition up to single ipsilateral mediastinal station (N2a), ECOG PS ≤ 2 (or Karnofsky ≥ 60%), no prior treatment for NSCLC and no previous malignancy within 3 years are eligible. The dual primary endpoints are real-world event free survival (rwEFS) defined as date from randomization to date of the first of the following events: failure to undergo resection for any reason, progression prior to surgery that precludes resection, recurrence or progression at any time after surgery or death from any cause, and overall survival (OS) defined as time from randomization to death from any cause. The target accrual is 1,100 patients assuming one-sided type I error of 0.03 for OS endpoint and 0.02 for rwEFS endpoint. This sample size will enable the detection of a 3-year rwEFS improvement from 55% in the adjuvant therapy arm to 64% in the perioperative arm with an 84% power. This sample size would detect an HR of 0.73 (improvement in median OS from 8.1 to 11 years in favor of the perioperative arm, 5-year OS from 65% in the adjuvant arm to 73% in the perioperative arm, assuming exponential survival) with 83.6% power. The study has a pragmatic design with minimal data collection, reporting of adverse events that lead to discontinuation of therapy, hospitalization or death only. It allows providers to choose therapy per standard of care (FDA approved or on NCCN), includes patients with ECOG performance status 2, permits use of local laboratory testing and imaging studies and determination of recurrence/progression will be done by local treating physicians with no use of RECIST. Clinical trial information: NCT06632327 .

Background: C10603/RATFIY was the first AML trial to show the benefit of adding a targeted agent to intensive chemotherapy for a specific genetically determined subset (Stone R et al, NEJM 2017). The addition of the multi-kinase inhibitor midostaurin (M) to chemotherapy in previously untreated adults with FLT3-mutant AML resulted in superior event-free (EFS) and overall survival (OS) compared to placebo (P) and led to the approval of this agent in combination therapy. Subsequently, additional targeted drugs including gilteritinib for relapsed/refractory FLT3-mutant AML and quizartinib plus chemotherapy in untreated adults with AML with FLT3-ITD disease have gained approval. Long-term follow-up after reporting of the primary endpoint, especially if met, is important in oncology. Objective: We report the EFS and OS data from C10603 using 10 years of follow up to determine the persistence of a midostaurin benefit and to assess the nature of late relapses or toxicity. Methods: C10603 enrolled 717 pts (360 on the M and 357 on the P arm; median age 47.8 years (range 18-61), 398 women (55.5%) of whom 51.7% were randomized to M and 59.4% to P (p=0.04), and 89% white) from 2011-2015 with previously untreated AML who had either a FLT3-TKD or ITD mutation with allelic ratio of >0.05 to receive daunorubicin/cytarabine (3+7) induction (one reinduction permitted) followed by up to 4 consolidation cycles with cytarabine 3 g/m2 every 12h on days 1, 3 and 5. M (50 mg bid) or P was given orally on days 8-22 of each chemotherapy cycle as well as daily during one year of single-agent maintenance. Allogeneic transplantation (alloHCT) was employed at investigator's discretion; study drug was not continued post-HCT. Pts stayed on their randomized arm and were not re-randomized prior to maintenance. Pts were followed for relapse and survival after the end of protocol therapy, regardless of subsequent therapy, for 10 years. Log-rank tests, Kaplan-Meier methods, and Cox proportional hazard models were used to evaluate the treatment effect in EFS and OS, as well as the alloHCT effect. All p values are two-sided. Results: We have completed the 10-year FU on this trial and data collection has concluded. The median EFS was 8.2 months (95% CI, 5.5-11.4) on the M arm compared with 3.0 months for P (95% CI, 1.9-6.0) with a HR of 0.79 (95% CI 0.67-0.94, p=0.0067). Among the 420 CR pts who achieved complete remission (CR) by the protocol specified time of 60 days, 253 have had an event (death in 69 and relapse in 184); these events were relatively equal on each arm. OS, the co-primary endpoint, remained marginally superior for those randomized to M compared to P; the 10-year OS estimate was 43.7% (95% CI, 38.7-49.3%) vs 38.6% (95% CI, 33.6-44.4%) (p= 0.0485). The hazard ratios for OS favored randomization to M in each key biological subgroup (FLT3-ITD low or high allelic ratio or FLT3-TKD), but smaller subsets precluded statistical significance. There was a 10-year OS benefit in favor of M in men (p=0.005), but not women (p=0.9). A total of 414 transplants were performed: only 5 in the latter half of the follow-up period. Transplantation in CR1 was highly beneficial overall (10-year OS, 56% vs 35.8% without transplantation, p=0.001). Among those transplanted in CR1, randomization to M was marginally better than P (61.5% vs 49%, p=.064). After censoring for alloHCT in CR1, there was an OS trend in favor of M (51.8% v 48.0%, p=0.102). In CR1 patients who were randomized to maintenance therapy, M reduced the cumulative incidence of relapse in ELN 2017 favorable and intermediate risk pts, but not in those with adverse risk disease (HR 0.71, 0.47, and 1.01, respectively); maintenance M had no effect on OS. Only 3 pts relapsed after 5 years (all randomized to M). 25 pts randomized to M vs 13 P pts died after 5 years of follow-up. 5 pts on each arm died of a new primary cancer whereas 17 M and 5 P pts were coded as having died from treatment-related causes. None of the 3 pts who relapsed after 4 years had spliceosome mutations at diagnosis; whereas 18% (21/117) patients pts who had relapsed earlier had spliceosome mutations at diagnosis (p=0.419). Conclusions: The EFS benefit of randomization to midostaurin vs placebo when added to chemotherapy was maintained over time, although the benefit for OS was diminished, likely due in part to aging. Patient and disease factors differed between early vs late relapses, which could suggest the use of alternative therapies during distinct therapeutic stages.

Abstract The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late-phase trials that enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the effect of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late-phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress toward implementation, and the development of new streamlined standard practices for data collection for late-phase NCTN trials effective January 1, 2025.

AbstractBackgroundThe use of electronic health record (EHR) data for research is limited by a lack of structure and a standard data model. The objective of the ICAREdata (Integrating Clinical Trials and Real‐World Endpoints Data) project was to structure key research data elements in EHRs using a minimal Common Oncology Data Elements (mCODE) data model to extract and transmit data.MethodsThe ICAREdata project captured two EHR data elements essential to clinical trials: cancer disease status and treatment plan change. The project was implemented in clinical sites participating in Alliance for Clinical Trials in Oncology trials. Data were extracted from EHRs and sent by secure Fast Healthcare Interoperability Resource messaging (a standard for exchanging EHRs) to a database. Selected elements were compared with corresponding data from the trial's electronic data capture (EDC) system, Medidata Rave.ResultsBy December 2023, data were extracted and transmitted from 10 sites for 35 patients, involving 367 clinical encounters across 15 clinical trials. Data through March 2023 demonstrated that concordance for the elements treatment plan change and cancer disease status was 79% and 34%, respectively. When disease evaluation was reported by both EHR and EDC (n = 15), there was 87% agreement on cancer disease status.ConclusionsDocumentation, extraction, and aggregation of structured data elements in EHRs using mCODE and ICAREdata methods is feasible in multi‐institutional cancer clinical trials. EDC as a reference data set allowed assessment of the completeness of EHR data capture. Future initiatives will focus on elements with shared definitions in clinical and research environments and efficient workflows.Plain Language Summary Clinical trials use electronic case report forms to report data, and data must be manually entered on these forms, which is costly and time consuming. ICAREdata methods use structured, organized data from clinical trials that can be more easily shared instead having to enter free text into electronic health records.

TPS5642 Background: The landscape in the management of recurrent or persistent endometrial cancer (EC) continues to evolve. Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Recent studies have also shown a benefit with adding ICI to standard of care chemotherapy in the frontline setting. Pts with MSI-H/dMMR tumors seem to derive the greatest benefit. Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy. The AFT-50/EndoMAP study is a phase IB/II non-randomized, multicenter, 2-arm, multi-cohort platform trial designed to evaluate the efficacy and safety of biomarker-driven combination regimens, both with Atezo (AFT-50A) and without Atezo (AFT-50B) with biomarker-defined targeted agents in pts with recurrent or persistent EC. Methods: Eligible pts have recurrent or persistent EC with no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual. Each cohort will enroll ~20 pts with potential adjustment to account for statistical and clinical considerations. AFT-50A pts will receive Atezo in addition to a targeted agent (per study-approved dosing schedule) until progression, unacceptable toxicity, pt withdrawal, death, or study termination. AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors). The primary endpoint for AFT-50A is confirmed overall response rate (ORR) for each arm, and for AFT-50B is 6-month progression free survival. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability. As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .