Aljumaily, Raid

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

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 .

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

3077 Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]

3076 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (Cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]

Abstract Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.