e16614 Background: Concurrent chemoradiotherapy (CRT) is a bladder-preserving option for patients (pts) with MIBC but is limited by systemic radiosensitizer toxicity from conventional chemotherapy agents. Novel agents with improved tolerability and efficacy are needed to be able to combine with RT. Sacituzumab govitecan (SG) is a Trop-2–directed antibody drug conjugate (ADC) with activity in metastatic urothelial carcinoma. RAD-SG is a single-arm phase I trial evaluating concurrent SG with adaptive radiation therapy (RT) in localized MIBC. Methods: Key eligibility include pts with MIBC (T2-T4aN0M0), including variant histology, ECOG PS Score 0-2, normal organ/marrow function, cr cl ≥ 30 mL/min, TURBT within ≤ 60 days prior to treatment. Pts with bilateral hydronephrosis and prior pelvic RT were excluded. Pts receive SG 7.5 mg/kg IV every 21d starting prior to RT then 2 cycles with concurrent adaptive RT over 6 wks (64 Gy) and undergo a mid-treatment cystoscopy evaluation. The primary endpoint is safety, tolerability, and feasibility of TMT with concurrent SG and adaptive RT. Secondary endpoints are bladder intact event-free survival (BI-EFS) defined as time from treatment to first occurrence of residual/recurrent MIBC, nodal or distant metastases, RC, or death from any cause. Correlative objectives include genetic and microenvironmental correlatives, characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following TMT. Planned enrollment is 20 pts. Results: The study has accrued 14/20 patients at Cleveland Clinic. Treatment was generally well tolerated with common grade 1–2 treatment-related adverse events (TRAEs) being alopecia (77%), anemia (69%), fatigue (62%), and lymphopenia (54%). Grade 3-4 TRAEs included lymphopenia (31%), anemia (8%), proteinuria (8%), and neutropenia (8%). DLT was seen in 2 pts, each with grade 3 neutropenia which recovered without G-CSF. No treatment-related deaths occurred. Four pts experienced recurrence; 2 required salvage RC and 1 developed metastatic disease. Enrollment is ongoing. Conclusions: SG with adaptive RT is feasible and safe in localized MIBC; efficacy and correlative analyses are ongoing. This is the first study to combine an ADC with RT in bladder cancer. Clinical trial information: NCT05833867 .

PURPOSE:Stereotactic body radiation therapy is standard of care for inoperable early-stage non-small cell lung cancer. Here, we report the long-term outcomes of 30 Gy in 1 fraction (arm 1) versus 60 Gy in 3 fractions (arm 2). METHODS AND MATERIALS:This was a multi-institutional randomized, phase 2, 2-arm clinical trial. Medically inoperable patients with peripheral clinical T1-T2/N0M0 disease were enrolled. All patients had biopsy-confirmed disease. Patients were stratified by performance status and randomized to arm 1 or arm 2. The primary endpoint was thoracic grade 3 or higher adverse events per the Common Terminology Criteria for Adverse Events. Secondary endpoints included freedom from local failure, freedom from distal failure, progression-free (PFS) and overall survival (OS). RESULTS:Between September 2008 and April 2015, 98 patients were randomized. Median survival was 40.3 months. There were no new attributable adverse events within the additional follow-up period. There were no differences in time to local failure, time to distant failure, PFS, or OS (P = .14, .17, .98, and .78, respectively). CONCLUSIONS:This randomized phase 2 study demonstrated that 30 Gy in 1 fraction was equivalent to 60 Gy in 3 fractions in terms of toxicity, local failure, distant failure, PFS, and OS.

TPS896 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for pts with MIBC interested in bladder-preservation and/or not candidates for radical cystectomy (RC). Systemic radio-sensitizing chemotherapy may have off target side effects and exploring novel agents with radiation is an unmet need. SG is an antibody drug conjugate (ADC) and has shown efficacy in metastatic urothelial cancer (UC). RAD-SG is a single-arm phase 1 trial investigating the concurrent administration of SG with adaptive radiotherapy (RT) in pts with MIBC. Methods: Eligibility criteria include pts with localized MIBC (T2-T4aN0M0), ECOG PS Score of 0-2, normal organ and marrow function including creatinine clearance ≥ 30 mL/min, must undergo a TURBT within ≤ 60 days prior to treatment. Variant subtypes are allowed. Pts must not have had UC or any histological variant at any site outside of bladder within 24 months except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal, pelvis, and ureter if underwent complete nephroureterectomy. Other exclusion criteria include bilateral hydronephrosis and prior pelvic / local RT for MIBC or any other cancer type. SG targets TROP-2, a surface protein expressed in UC, it will be given IV at 7.5 mg/kg every 21days starting prior to RT and 2 subsequent cycles with concurrent adaptive RT over a period of 6 weeks (64 Gy). The primary endpoint is safety, tolerability, and feasibility of trimodality therapy with concurrent SG and adaptive image-guided radiation therapy for patients with localized MIBC. The secondary endpoints are bladder intact event-free survival (BI-EFS) with concurrent SG and RT for MIBC and compare historical controls with other concurrent CRT regimens. BI-EFS is defined as the time from treatment to the first documented occurrence of residual/recurrent MIBC, nodal or distant metastases on imaging, RC, or death from any cause. Correlative objectives include 1) elucidation of the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined ADC plus RT and 2) characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with SG plus RT. The study will accrue 20 pts at Cleveland Clinic Foundation and enrollment is ongoing. (NCT05833867). Clinical trial information: NCT05833867 .

PURPOSE:To characterize outcomes for solid organ transplant patients with medically inoperable early-stage lung cancer (ES-LC) treated with lung stereotactic body radiotherapy (SBRT). METHODS:We surveyed our institutional review board-approved prospective lung SBRT data registry from 2003 to 2023 for any transplant patients. Patterns of failure were assessed, as well as overall survival (OS) and disease-free survival (DFS). Univariate prognostic factors for OS and DFS were identified with Cox proportional hazards regression. RESULTS:Twenty-eight of 1976 definitively treated patients (1.4%) met study criteria. Median follow up was 12.4 months. Patient characteristics included: male (67.9%), median pack-years smoking of 34; median age 70.0 years; median Karnofsky Performance Status (KPS) 80. Organs transplanted were lung (57.2%), liver (21.4%), heart (21.4%). Tumor characteristics included: median size 2.4 cm; 85.7% with biopsy-proven cancer. Toxicity (any grade/type) was reported in 9 (32.1%) patients. Failure patterns were local 21.4%, lobar 7.1%, nodal 10.7% and distant 32.1%. First site of failure was distant in 50.0% patients. Median DFS and OS were 17.1 and 14.5 months, respectively. Increasing pack-years smoking was the only factor associated with increased disease failure on univariate analysis (UVA) (P = .0016). KPS and tumor size were significantly associated with OS on UVA and on multivariable analysis (P = .0075) and (P = .0181), respectively. CONCLUSIONS:Organ transplant patients with inoperable ES-LC had higher than expected rates of local failure, decreased cancer control and poorer overall survival after SBRT. We hypothesize that transplant-associated immunosuppression promotes metastatic progression and a tumor biology resistant to SBRT.

To compare proton plans (IMPT) to VMAT plans and intercompare proton plans using 3 different spot sizes with robustness: cyclotron-generated proton beams (CPB) (σ: 2.7-7.0 mm), linear accelerator proton beams (LPB) (σ: 2.9-5.5 mm), and linear accelerator proton mini beams (LPMB) (σ: 0.9-3.9 mm) for the treatment of early-stage lung cancer. Twenty-two lesions from a total of twenty patients with early-stage lung cancer, originally treated with SBRT, were replanned using CPBs, LPBs, LPMBs, and VMAT using the same treatment planning system and dose calculation algorithm. The average intensity projected CTs (AIP-CT) were used for planning and 3D robust optimization was used for all proton plans. Conformity index (CI), homogeneity index (HI), R50, lung V20 Gy, and mean lung dose were compared among all proton plan types and with VMAT plans. Set-up uncertainties of ±5 mm and ±3.5% range uncertainty were included in the IMPT robust optimization and evaluation, using V100%Rx > 98% of the ITV. The Wilcoxon signed-rank test was used to evaluate statistical differences between VMAT plans and all proton plan types. When compared to VMAT plans, all proton plans generally show improvement in CI, HI, Lung V20 Gy, Mean lung dose, and R50. The LPMB plans showed the most improvement from VMAT plans. Comparison between CPB and linear accelerator proton plans showed statistical significance (p < 0.05). R50 and mean lung dose for the CPB, LPB and LPMB plans were 3.6 ± 0.9, 3.1 ± 0.8 and 2.6 ± 0.6; 2.2 ± 1.1 Gy, 1.9 ± 1 Gy and 1.6 ± 0.9 Gy, respectively (p < 0.05). The mean R50 and mean lung dose from the VMAT plans were 4.1 ± 0.4 and 3.8 ± 2 Gy, respectively. The V20 Gy (%) of lung and mean lung dose were improved across all proton plans when compared with those of VMAT plans. When evaluated for robustness in the worst-case scenario at V100%Rx of the ITV > 98%, average ITV coverage of 98.6 ± 0.3%, 98.6 ± 0.6%, and 98.9 ± 0.6% were achieved for CPB plans, LPB plans, and LPMB plans, respectively. With decreased spot size, the LPB and LPMB plans are excellent alternatives to VMAT and cyclotron-generated proton plans with reduced dose to normal tissue and improved plan quality for early-stage lung cancer treatments.

In modern radiotherapy, multiple courses of radiation are becoming increasingly common as a treatment regimen to extend progression-free and overall survival in patients with oligometastatic disease. However, normal tissue recovery over time has not been well characterized, and there are few models for clinicians to use when evaluating potential toxicities in subsequent radiation treatments. The lack of standardization when documenting a patient's radiotherapy history presents a major barrier to conducting large scale studies. To advance our understanding of normal tissue recovery post-radiation, we propose the addition of a new object accompanied by a suite of mathematical models linked to toxicity information in a patient's medical record. This object leverages the Digital Imaging and Communications in Medicine (DICOM) standard to serve as a centralized data store for radiotherapy planning and treatment, thereby facilitating a better analysis of therapeutic outcomes and tissue response over the course of radiotherapy. ### Competing Interest Statement Jonathan W. Piper - Works for and is compensated by MIM Software ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Waiver of ethical approval was received from the Cleveland Clinic IRB I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be provided upon request.

8506 Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC. Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1 st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83. Results: NRG-LU002 accrual was initiated in 4/2017 and suspended in 11/2021 when the RPhII portion sample size was met. Following the planned interim analysis, the study was closed in 12/2023. Overall, 215 patients (81 -LCT arm, 134 +LCT arm) were enrolled from 68 sites with a median age of 65 years (40-86), 77% white, 95% PS 0/1, 78% non-squamous histology, and 90% having received IO-based systemic therapy. Median follow-up among all/surviving patients were 21.9/29.4 months, respectively. With 138 PFS events from both arms, estimated 1-yr and 2-yr PFS rates were 48% (95% CI: 35.9, 59.0) and 36% (95% CI: 24.8, 47.2) in the maintenance systemic therapy arm and 52% (95% CI: 42.5, 59.8) and 40% (95% CI: 31.5, 48.6) in the LCT + maintenance systemic therapy arm, respectively (2-sided log-rank test p-value = 0.66). Corresponding HR was 0.93 (95% CI: 0.66, 1.31). Of 185 patients treated with IO-containing regimens, the PFS HR was 0.90 (95% CI: 0.61, 1.32). OS HR between two arms was 1.05 (0.70, 1.56) among all patients and 1.05 (0.68, 1.63) among IO-treated patients. For adverse events reported as definitely, probably or possibly related to treatment, there were more LCT + maintenance systemic therapy patients with overall grade 2 or higher toxicities (73% vs 84%) and grade 3 or higher pneumonitis (1% vs 10%). Conclusions: LCT added to IO-based 1 st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771 .

BACKGROUND:Pencil beam scanning (PBS) proton therapy for moving targets is known to be impacted by interplay effects between the scanning beam and organ motion. While respiratory motion in the thoracic region is the major cause for organ motion, interplay effects depend on the delivery characteristics of proton accelerators. PURPOSE:To evaluate the impact of different types of PBS proton accelerators and spot sizes on interplay effects, mitigations, and plan quality for Stereotactic Body Radiation Therapy (SBRT) treatment of non-small cell lung cancer (NSCLC). METHODS:Twenty NSCLC patients treated with photon SBRT were selected to represent varying tumor volumes and respiratory motion amplitudes (median: 0.6 cm with abdominal compression) for this retrospective study. For each patient, plans were created using: (1) cyclotron-generated proton beams (CPB) with spot sizes of σ = 2.7-7.0 mm; (2) linear accelerator proton beams (LPB) (σ = 2.9-5.5 mm); and (3) linear accelerator proton minibeams (LPMB) (σ = 0.9-3.9 mm). The energy switching time is one second for CPB, and 0.005 s for LPMB and LPB. Plans were robustly optimized on the gross tumor volume (GTV) using each individual phase of four-dimensional computed tomography (4DCT) scans. Initially, single-field optimization (SFO) plans were evaluated; if the plan quality did not meet the dosimetric requirement, multi-field optimization (MFO) was used. MFO plans were created for all patients for comparisons. For each patient, all plans were normalized to have the same dose received by 99% of the GTV. Interplay effects were evaluated by computing the dose on 10 breathing phases, based on the spot distribution. Volumetric repainting (VR) was performed 2-6 times for each plan. We compared volume receiving 100% of the prescribed dose (V100%RX) of the GTV, and normal lung V20Gy. RESULTS:Twelve of 20 plans can be optimized sufficiently with SFO. SFO plans were less sensitive to the interplay effect compared to MFO plans in terms of target coverage for both LPB and LPMB. The following comparisons showed results utilizing the MFO technique. In the interplay evaluation without repainting, the mean V100%RX of the GTV were 99.42 ± 0.6%, 97.52 ± 3.9%, and 94.49 ± 7.3% for CPB, LPB, and LPMB plans, respectively. Following VR (2 × for CPB; 3 × for LPB; 5 × for LPMB), V100%RX of the GTV were improved (on average) by 0.13%, 1.84%, and 4.63%, respectively, achieving the acceptance criteria of V100%RX > 95%. Because of fast energy switch in linear accelerator proton machines, the delivery time for VR plans was the lowest for LPB plans, while delivery time for LPMB was on average 1 min longer than CPB plans. The advantage of small spot machines was better sparing in normal lung V20Gy, even when VR was applied. CONCLUSION:In the absence of repainting, proton machines with large spot sizes generated more robust plans against interplay effects. The number of VR increased with decreasing spot sizes to achieve the acceptance criteria. VR improved the plan robustness against interplay effects for modalities with small spot sizes and fast energy changes, preserving the low dose sparing aspect of the LPMB, even when motion is included.

Unresectable stage III NSCLC is now treated with chemoradiation (CRT) followed by immune checkpoint inhibitors (ICI). Pneumonitis, a common CRT complication, has heightened risk with ICI, potentially causing severe outcomes. Currently, there are no biomarkers to predict pneumonitis risk or differentiate between radiation-induced pneumonitis (RTP) and ICI-induced pneumonitis (IIP). This study analyzed 293 patients from two institutions, with 140 experiencing pneumonitis (RTP: 84, IIP: 56). Two models were developed: M1 predicted pneumonitis risk using seven radiomic features, achieving high accuracy across internal and external datasets (AUCs: 0.76 and 0.85). M2 differentiated RTP from IIP, with strong performance (AUCs: 0.86 and 0.81). Gene set enrichment analysis linked high pneumonitis risk to pathways such as ECM-receptor interaction and T-cell signaling, while high IIP risk correlated with MAPK and JAK-STAT pathways. Radiomic models show promise in early pneumonitis risk stratification and distinguishing pneumonitis types, potentially guiding personalized NSCLC treatment.