TPS5632 Background: Concurrent chemoradiation therapy (CCRT) is the standard of care for locally advanced cervical cancer (LACC); however, outcomes remain suboptimal in patients with high-risk disease. Recent studies suggest that integration of immunotherapy (IO) with definitive chemoradiation, or induction chemotherapy prior to CCRT improves outcomes. Whether treatment intensification with induction systemic therapy and IO prior to CCRT and IO further improves disease control remains unknown. Induction chemotherapy may reduce tumor burden, eradicate micrometastatic disease, and improve tumor immunogenicity prior to definitive CCRT. Preclinical and clinical data support synergy between systemic therapy or radiotherapy and immune checkpoint blockade, providing the rationale for evaluating an induction strategy incorporating chemotherapy and immunotherapy before standard CCRT with immunotherapy, followed by maintenance immunotherapy. Optional tumor tissue and blood samples will be collected for exploratory correlative analyses, including immune and molecular biomarkers associated with response, resistance, and patterns of failure. Methods: NRG-GY037 is a prospective, multi-institutional phase III randomized trial conducted through NRG Oncology. A total of 336 patients will be enrolled (168 per arm). Patients will be stratified by FIGO stage (III vs. IVA) and presence or absence of para-aortic lymph nodes (N2). The primary endpoint is progression free survival (PFS). The study has 90% power to detect PFS hazard ratio of 0.65 in the experimental arm. Treatment: Patients with previously untreated, high-risk LACC are randomized to receive either induction chemotherapy with pembrolizumab for 6 weeks followed by CCRT with pembrolizumab and pembrolizumab maintenance, or standard CCRT with pembrolizumab followed by pembrolizumab maintenance. Major Eligibility Criteria: Eligible patients have histologically confirmed cervical carcinoma (squamous, adenocarcinoma, or adenosquamous), TNM T3 and T4 disease, N0-2, ECOG performance status 0–1, and no prior definitive therapy for cervical cancer. Current Enrollment Status: The trial is actively accruing patients. No efficacy or safety data are available at the time of submission. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT07061977. Clinical trial information: NCT07061977 .

OBJECTIVES:Advances in radiation (RT) treatment planning enhance the need for uniform quality oversight on clinical trials. NRG GY-017 was a randomized trial of the anti-program ligand death 1 (PD-L1) antibody, atezolizumab, before and concurrent (arm A) or concurrent with chemoradiaton (arm B) for locally advanced cervical cancer. We describe the prospectively collected pretreatment RT quality and workflow. METHODS:Forty patients were consented and randomized. Thirty-seven patients submitted pretreatment RT plans for central review, and 36 patients ultimately received protocol therapy. Intensity modulated radiation therapy (IMRT) contouring guidelines and dose specifics were outlined in the protocol, with volume and dose deviations specified as per protocol, minor and major variation. Each site had to pass a standardized IMRT credentialing process. Sites were required to submit an IMRT plan for physician expert contour target and organ-at-risk review in a rapid pretreatment manner. An expert physician then scored the contours and plan as per protocol or as a deviation. For major deviations, the sites were required to revise and resubmit the plans, which were then re-reviewed prior to protocol start. RESULTS:The median follow-up time was 20 months. Thirty-seven participants had a central expert review of the pretreatment external beam radiation therapy plan. Thirteen plans (35%) were scored as a major deviation requiring revision: 11 secondary to contours (5 bowel and 6 nodal volumes) and 2 secondary to incorrect expansion on the volume or the dose distribution. The major deviation plans were resubmitted; however, 2 of them required revisions for a total of 3 plans. Because of the quality review, all patients had per-protocol scores prior to the treatment administration. CONCLUSIONS:Our data indicate that 35% of the baseline submitted advanced technology IMRT plans required revision and resubmission in order to meet protocol standards. RT plan quality workflow continues to evolve with advanced techniques and has implications in clinical trial review. Pretreatment plan review is an important quality measure for cervical cancer clinical trials.

BACKGROUND:Cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (LACC) is standard. Intrinsic overexpression of ribonucleotide reductase (RNR) may enhance DNA damage repair from CRT. We report on outcomes of adding RNR inhibitor, triapine (T), to CRT. METHODS:NRG-GY006 is an open-label randomized phase III trial. FIGO 2009 LACC (stages IB2, II, IIIB or IVA) without para-aortic nodal involvement or stages II-IV vaginal cancer were eligible. Random assignment to CRT or in combination with thrice-weekly T (CRT + T) occurred. Radiation consisted of either 3D conformal (3DCRT) or image-guided intensity modulated RT (IG-IMRT) followed by intracavitary brachytherapy. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was secondary. Exploratory endpoints included complete metabolic response rate on post treatment PET/CT imaging and comparative toxicity and outcomes for 3DCRT vs. IG-IMRT. FINDINGS:Four-hundred-fifty patients were randomized including 448 eligible (224 in CRT and 224 in CRT + T). Median age was 47 (range 23-85). The majority had cervical cancer (93.3 %) with squamous histology (82 %). 52 % had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8 %), black (15.2 %) and Hispanic/Latina (22.5 %). At randomization, IG-IMRT was planned in 74.3 % and HDR brachytherapy in 98.2 %. No differences in Grade 3-5 toxicities were observed: CRT: 52 % and CRT + T: 49 %, with two G5 toxicities (cardiac arrest and acidosis) in the CRT + T arm. The median patient follow-up was 28 months (IQR 15-45). HR for death was 1.018 (95 % CI 0.634-1.635) while HR for progression was 1.021 (95 % CI 0.694-1.501). INTERPRETATION:Triapine added to CRT did not improve OS.

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC. The primary endpoint was the fraction of expanded tumor-associated T-cell receptor (TCR) clones in blood at day 21 as a surrogate measure of anti-tumor immune response. Secondary objectives were safety and feasibility, 2-year disease-free survival (DFS), and predictive value of PD-L1 expression. Forty patients were randomized, 36 received treatment, and 25 were evaluable for the primary endpoint. After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B (p = 0.0025) that remained higher at day 21, meeting the pre-specified endpoint on two-sample T-test (p = 0.052), but not on sensitivity analysis by Wilcoxon test (p = 0.13). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B (p = 0.28). There were no new safety signals. In conclusion, neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies.

PURPOSE:Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)-p16-Rb pathway, features shared with hormone receptor-positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS:This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION:Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

INTRODUCTION Brachytherapy is a critical component of curative treatment in locally advanced cervical cancer. NRG GY-017 is a randomized Phase I trial of the anti-PD-L1 antibody atezolizumab administered neoadjuvantly and concurrently with chemoradiation (Arm A) or only concurrently with chemoradiation (Arm B) in patients with node positive locally advanced cervical cancer. Image guided brachytherapy (IGBT) was mandated in the protocol with a quality assurance (QA) workflow. Herein, we report the BT quality data on NRG GY-017 trial and practice patterns from the participating centers in this trial as a guide for future protocol brachytherapy QA. METHODS The participating sites were to submit brachytherapy plans online after BT was completed. IROC QA center compiled the BT fractions for each patient using the trial specific dosimetry evaluation template. An expert physician reviewer scored the contours and plans as per protocol, variation acceptable or major deviation as prespecified in the protocol dose metrics. RESULTS The BT dosimetry results were available for 32 patients. Seventeen patients (53%) had intracavitary applicator, and 15 patients (47%) had hybrid or interstitial applicators. Point A directed planning was performed for 4 patients (12.5%) and 28 patients had volume directed plans (87.5%). For imaging use, 2 patients had MRI based plans, and 30 had CT based planning (94%). For the dose constraints compliance per protocol, 7 patients had 9 events scored as major deviations (22%). CONCLUSION BT trial specific QA has the potential to enhance BT quality for clinical trials. This report will help guide future gynecologic BT trial data collection and QA process.

Few advancements in treating limited-stage small-cell lung cancer (LS-SCLC) have been made in decades. We aim to explore the efficacy and safety of immune checkpoint inhibitors (ICIs) in combination with concurrent chemoradiotherapy (cCRT) for treating LS-SCLC. This study recruited patients with LS-SCLC. cCRT consisted of etoposide and a platin with once daily (60 Gy/30 fractions) or twice daily radiotherapy (45 Gy/30 fractions). ICIs was started concurrently with cCRT and continued for up to 2 years. The primary endpoint was progression-free survival (PFS) and safety. A total of 29 patients were enrolled. All patients underwent at least one cycle of ICI during cCRT. With the median follow-up duration of 28.4 months, the median PFS was 13.1 months (95

OBJECTIVE:To prospectively evaluate the impact of adjuvant chemoradiation (RT + CIS) versus radiation (RT) on quality of life (QOL) and patient-reported outcomes (PROs) among patients with intermediate-risk, stage I-IIA cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy. METHODS:Patients enrolled in GOG-0263 completed PRO/QOL assessments at baseline, 3, 7, and 36 weeks using the FACT-Cx Trial Outcome Index (FACT-Cx TOI), FACT/GOG-Neurotoxicity subscale (FACT/GOG-Ntx-4), the worst pain item from the Brief Pain Inventory (BPI), and five gastrointestinal/genitourinary (GI/GU) symptom items. Linear mixed models adjusted for baseline score, treatment, age, performance status, and country. RESULTS:Among 316 randomized eligible patients (RT + CIS: n = 158; RT: n = 158), questionnaire completion rates were 98 %, 90 %, 88 %, and 81 % at baseline, weeks 3, 7, and 36, respectively. Patients receiving RT + CIS reported a mean FACT-Cx TOI score 5.1 points lower than RT at 3 weeks (97.5 % CI: -8.6 to -1.6; p = 0.004) and 6.3 points lower at 7 weeks (97.5 % CI: -10.2 to -2.4; p = 0.002). By 36 weeks, scores had returned to baseline in both groups, with no significant difference (p = 0.386). Patient-reported neuropathy scores (FACT/GOG-Ntx-4) did not differ significantly between groups at any time point (p = 0.82). Patient-reported GI/GU symptoms and pain worsened at 3 weeks in both arms, followed by recovery to baseline by 36 weeks. CONCLUSION:QOL declined in both groups after treatment initiation, with greater short-term deterioration in the RT + CIS group. By 36 weeks, QOL and other PROs returned to baseline in both groups. Neuropathy, GI/GU symptoms, and pain showed no significant differences between treatment arms over time.

PURPOSE To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. METHODS Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. RESULTS Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. CONCLUSION Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

Introduction Advances in RT planning enhance the need for uniform quality oversight on clinical trials. NRG GY-17 was a randomized trial of the anti PD-L1 antibody, atezolizumab, before and concurrent (Arm A) or concurrent with CRT (Arm B). We describe the prospectively collected pre-treatment RT quality and workflow. Methods 40 patients were consented; 36 patients with locally advanced, LN+ cervical cancer were randomized. IMRT contouring guidelines and dose specifics were outlined in the protocol with deviations specified as per protocol and major. Each site had to pass a rigorous IMRT credentialing process. Sites were required to submit a pre-treatment IMRT plan for physician expert contour target and organ at risk review in a rapid pre-treatment manner. The expert physician then scored the contours and plan as per protocol or as a major deviation. For major deviations the sites were required to revise and resubmit the plans which were then re-reviewed prior to protocol start. Results The median follow-up time was 20 months. 37 participants had central review of the pre-treatment EBRT plan. 13 plans (35%) were scored as a major deviation requiring revision: 11 due to contours (5 bowel and 6 LN) and 2 due to incorrect expansion/dose. The major deviation plans were resubmitted and passed; 2 required revisions for a total of 3 plans. Conclusion/Implications Our data indicate that 35% of the submitted advanced technology IMRT plans required revision and resubmission in order to meet per protocol standards. Pre- treatment plan review is an important quality measure for cervical cancer clinical trials.

OBJECTIVE:Detection of lymph node metastases in cervical cancer patients is important for guiding treatment decisions, however accuracies of current detection methods are limited. We evaluated associations of abnormal glycosylation, represented by Tn and STn antigens on mucin (MUC) proteins, in primary tumor specimens with lymph node metastasis or recurrence of cervical cancer patients. METHODS:Surgical specimens were prospectively collected from 139 patients with locally-advanced cervical cancer undergoing lymphadenectomy enrolled in a nation-wide clinical trial (NCT00460356). Of these patients, 133 had primary cervix tumor, 67 had pelvic lymph node (PLN) and 28 had para-aortic lymph node (PALN) specimens. Fixed tissue serial sections were immunohistochemically stained for Tn, STn, MUC1 or MUC4. Neuraminidase was used to validate Tn versus STn antibody specificity. Stain scores were compared with clinical characteristics. RESULTS:Primary tumor STn expression above the median was associated with negative PLN status (p-value: 0.0387; odds ratio 0.439, 95% CI: 0.206 to 0.935). PLN had higher STn compared to primary tumor, while primary tumor had higher MUC1 compared to PALN, and MUC4 compared to PALN or PLN (p = 0.017, p = 0.011, p = 0.016 and p < 0.001, respectively). Tn and STn expression correlated in primary tumor, PALN, and PLN, Tn and MUC1 expression correlated in primary tumors only (Spearman correlation coefficient [r] = 0.301, r = 0.686, r = 0.603 and r = 0.249, respectively). CONCLUSIONS:STn antigen expression in primary cervical tumors is a candidate biomarker for guiding treatment decisions and for mechanistic involvement in PLN metastases.

3-way interaction analyses between outcome, treatment, and markers.

Quartile analysis of IL6. Median survival times are given in months, and HR's represent treatment hazard ratios.

Several clinical trials have evaluated concurrent immune checkpoint blockade (ICB) and chemoradiation (CRT) in locally advanced cervical cancer (LACC). However, optimal ICB-CRT sequencing is unknown, as CRT concurrent with ICB carries the potential to kill the proliferating T cells in tumor-draining lymph nodes (LN) and worsen outcomes. To address this critical knowledge gap, we performed NRG-GY017, a randomized trial of the anti-PD-L1 antibody atezolizumab before and concurrent (Arm A) or concurrent with CRT (Arm B) in patients with high-risk pelvic or para-aortic LN-positive LACC.

5502 Background: Definitive cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (FIGO IB3-IVA) results in sustained survival for 60-70% of patients. Recent studies integrating anti-PD-1 checkpoint immunotherapy (CALLA, NCT03830866) or consolidation chemotherapy (OUTBACK, ACTRN12610000732088) have not demonstrated a survival benefit over CRT. Intrinsic overexpression of ribonucleotide reductase may enhance DNA damage repair due to CRT. We report on the efficacy and tolerability of adding the ribonucleotide reductase inhibitor, triapine, to CRT. Methods: NRG GY006 is a randomized, open-label phase III clinical trial. Eligible patients had FIGO 2009 locally advanced cervical (stages IB2, II, IIIB or IVA without radiographic evidence of para-aortic nodal involvement) or stages II-IV vaginal cancer. Patients were randomly assigned to receive cisplatin (40 mg/m2 weekly) with RT 45 Gy + lymph node boost alone (CRT) or CRT in combination with 15 total infusions of triapine (25 mg/m2 IV) Mon/Wed/Fri (CRT + T). Both image guided IMRT or 3D RT were allowed but needed to be specified and pass a rigorous credentialing process. All RT plans had a pre-treatment review with expert planning feedback to the sites. The primary endpoint was overall survival (OS); secondary endpoint was progression-free survival. Exploratory endpoints included rate of complete metabolic response on post treatment PET/CT imaging at 3 months and knowledge-based planning for image guided IMRT. The target sample was 450 with 127 OS events. The design was to provide 80% power to detect a 10% improvement in OS at 3 years over the control (or HR = 0.6) at 2.5% significance level including one interim futility analysis at 50% information time. Results: Between 1/15/16 and 9/22/22 448 eligible patients were randomized to CRT (n=224) or CRT+T (n=224). The database was locked on 10/18/22 with 69 deaths. Median age was 47 years (range 23-85 years). The majority had cervical cancer (93.3%) and squamous cell carcinoma (82%). 52% had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8%), Hispanic/Latina (22.5%), and black (15.2%). IMRT was used in (74.3%) and HDR brachytherapy (98.2%) of cases. No differences in Grade 3-5 toxicities were observed: CRT =52% and CRT +T= 49% with Two G5 toxicities (cardiac arrest and acidosis) in the CRT+T arm. 343 patients have completed all protocol directed therapy. With a median follow-up of 28 months (IQR 15-45 months), the median PFS and OS for both arms were not reached yet. HR for death was 1.018 (95% CI 0.634-1.635), the conditional power was 15% to detect a HR = 0.6 at 100% information time. Conclusions: The addition of triapine to CRT did not improve OS. Clinical trial information: NCT02466971 .