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.

Purpose: Anaplastic lymphoma kinase (ALK) dysregulation is implicated in numerous cancers. Tyrosine kinase inhibitors (TKIs) targeting ALK have improved disease outcomes, but resistance mechanisms are common. This first-in-human trial evaluates ESK-440, a dual inhibitor of ALK and focal adhesion kinase, as a novel strategy for cancers with resistance to ALK-targeting TKIs. Methods: This phase 1, open-label, dose-finding study evaluated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics of ESK-440 in participants with advanced or metastatic solid tumors (ClinicalTrials.gov: NCT01922752). A 3 + 3 dose-escalation design, with daily doses ranging from 25 to 700 mg/day of ESK-440 for each 28-day treatment cycle (6 to 8 cycles) was utilized to identify the MTD. A phase 1b was planned to further evaluate ESK-440 safety and antitumor activity at the MTD but was not performed due to sponsor decision. Results: 32 participants were enrolled and 24 (75 %) completed cycle 1 of treatment. Three dose-limiting toxicities, all grade 3 nausea, were reported (n = 1, 500 mg; n = 2, 700 mg). The MTD was determined to be 500 mg daily. The most frequent adverse events (AEs) were fatigue and nausea (53 % each) and vomiting (38 %). Seven participants (22 %) withdrew from treatment due to AEs and 4 deaths occurred, none related to ESK-440. No participant had a complete or partial response; the best overall response was stable disease in 7 participants. Conclusions: ESK-440 was safe and tolerable with a maximum tolerated dose of 500 mg daily; however, the study was terminated early based on sponsor decision.

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.

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.

2596 Background: Tifcemalimab, a humanized IgG4 antibody against BTLA, showed a tolerable safety profile and preliminary single-agent anti-tumor activity in pretreated pts with advanced malignancies. Here we report the dose escalation and cohort expansion study of tifcemalimab in combination with toripalimab (anti-PD-1) in pts with pretreated advanced malignancies. Methods: Eligible pts with advanced malignancies refractory to standard therapies were enrolled in the dose escalation and the cohort expansion phases of this study (NCT04137900). During dose escalation, tifcemalimab was administered at escalating doses of 20, 70, 200 and 500 mg in combination with 240 mg toripalimab given intravenously once every three weeks (Q3W) until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated. Study objectives included safety and efficacy. During cohort expansion, the combination of tifcemalimab (200mg Q3W) and toripalimab (240 mg Q3W) were further evaluated in five indication-specific cohorts (melanoma, non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC], urothelial carcinoma [UC] and lymphoma) for safety and efficacy. Results: By December 16, 2023, a total of 16 pts received study treatment during dose escalation and 69 pts were treated during cohort expansion from 18 participating sites from the US. Pts were heavily pretreated with a median of 4 prior lines of therapy. The median age was 65 (range 32-85) years, 69% of pts were male. As of December 16, 2023, the median follow-up was 11.4 weeks. No DLT was observed during dose escalation. Treatment-emergent adverse event (TEAEs) occurred in 92% pts, 44% experienced grade 3 or higher TEAEs, including 2 (2%) treatment-related Grade 5 events. The most common TEAEs included: fatigue (27%), diarrhea (17%), nausea (17%), anemia (15%), arthralgia (15%), decreased appetite (15%), and dyspnea (15%). TEAE led to discontinuation of study drug in 6% of pts. Nineteen percent of pts experienced immune-related AEs. No new safety signal was identified outside the known risk profiles of tifcemalimab and toripalimab. Among 14 evaluable pts in the dose escalation phase, 8 had stable disease. Among 57 evaluable pts in the cohort expansion phase, 1 complete response (lymphoma), 6 partial responses (2 melanoma, 2 RCC, 1 NSCLC, 1 UC) and 17 stable disease were observed. The ORRs were 5%, 11%, 17%, 18% and 33% in the NSCLC, melanoma, UC, RCC and lymphoma cohorts respectively. All responders were refractory to prior immunotherapy and all responses were still ongoing by the cutoff date. Conclusions: Tifcemalimab in combination with toripalimab showed preliminary efficacy in immunotherapy-refractory pts with a manageable safety profile. Phase II combination studies in various advanced solid tumors are ongoing. Clinical trial information: NCT04137900 .

Purpose/Objective(s) NRG GY-017 is a randomized Phase I trial of the anti-PD-L1 antibody atezolizumab administered neoadjuvantly and concurrently (Arm A) or concurrently with chemo RT (Arm B) in patients with node positive locally advanced cervical cancer, with 3 total cycles on each arm. All subjects were treated with PALN extended field external beam radiation therapy (EBRT) and brachytherapy (BT) boost. This trial is a pharmacodynamics study, 3D image-based BT was strongly recommended, and a quality assurance workflow was specified in the protocol. Herein, we report the BT dosimetry results from the NRG GY-017 trial and practice patterns from the participating centers in this trial. Materials/Methods All patients were to be treated with 3D image based HDR or PDR BT following EBRT either with point or volume directed plans. The 2D LDR BT was also allowed. CT or MR images were used to delineate the target volume. MRI based target delineation was recommended for identifying the GTV. The MRI could be reused by superimposition for CT based planning, if only CT images for subsequent fractions are used with the applicator in place. Each participating center was to submit brachytherapy plans via TRIAD after the BT course was complete. The clinical trial QA center compiled the BT fractions for each trial patient using the trial specific dosimetry evaluation template. The expert physician scored the contours and plans as per protocol, variation acceptable or major deviation. Results Forty patients were enrolled from 9 institutions among designated “safety lead-in” participating centers for this trial in the United States. But 32 patients from 7 institutions had evaluable BT dosimetry results. Twenty-one BT submissions (66%) were completed during the trial period and the rest of the data were submitted after the trial was closed. For the applicator use, 19 patients (59%) had intracavitary only, and 13 (41%) patients had supplemental interstitial (hybrid) or interstitial applications. Point dose directed planning was performed for 4 patients and 28 patients had volume directed plans (n = 28; 87.5%). For imaging use, 2 patients had MRI plans submitted, and the rest of the patients had CT planning. 31 patients had HDR BT with 27.5 Gy-30 Gy in either 4 or 5 fractions, while 1 patient had LDR BT. For the dose constraints compliance per protocol, there were 7 patients with 9 events scored as major deviations (22%), 7 events exceeding critical organ dose limits and 2 events deviating from the target dose. Conclusion Brachytherapy on this trial showed a wide range of practice patterns and suggest that BT trial-specific quality assurance review and standardized data submission processes may have the potential to enhance quality and safety for clinical trials. This report presents the first modern GYN BT trial dosimetry results, guiding future GYN BT trial data collection and quality assurance processes.

TPS5637 Background: The treatment of recurrent epithelial ovarian cancer remains a challenge, particularly for tumors with low to moderate expression levels of FRα. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR=4), which induces cytotoxic and immunologic cell death. Luvelta was designed to treat multiple cancers with a broad range of FRα expression. Luvelta demonstrated preliminary antitumor activity in women with recurrent ovarian cancer, selected for FRα expression level of ≥25% at any intensity (tumor proportion score [TPS]). In PROC, this cutoff represents an estimated 80% of patients (pts). In a phase 1 study of luvelta in relapsed ovarian cancer, the overall response rate (ORR) was 37.5% with a median duration of response (DOR) of 5.5 months and a median progression-free survival (PFS) of 6.1 months. ORR was higher at 5.2 mg/kg compared with 4.3 mg/kg (43.8% vs 31.3%). The safety profile was manageable, with the most common grade ≥3 adverse events consisting of neutropenia, arthralgia, and anemia (Oaknin et al. J Clin Oncol 2023;41[16 suppl]:5508). These results support further investigation in pts with PROC whose tumors have a broad range of FRα expression. Herein, we describe a phase 2/3 pivotal study (REFRaME-01)of luvelta in this pt population. Methods: This randomized, global, open-label, 2-part phase 2/3 pivotal study has been designed to assess the efficacy and safety of luvelta vs investigator’s choice (IC) chemotherapy in pts with recurrent PROC expressing FRα (NCT05870748). Eligible pts are adults (≥18 years) with relapsed PROC, 1–3 prior lines of therapy (which must include bevacizumab), measurable disease, Eastern Cooperative Oncology Group performance status ≤1, and TPS for FRα expression ≥25% using Ventana validated IHC assay. Part 1 (phase 2) consists of a luvelta dose-optimization stage in which pts are randomized 1:1 to receive intravenous (IV) luvelta every 3 weeks (Q3W) at 4.3 mg/kg or IV luvelta Q3W at 5.2 mg/kg with prophylactic G-CSF for 2 cycles followed by 4.3 mg/kg luvelta from cycle 3 onward. Part 1 data will be used to select the optimal dosing regimen. In part 2 (phase 3) ~550 pts will be enrolled and randomized 1:1 to the optimal luvelta dosing regimen or IC chemotherapy (gemcitabine, paclitaxel, pegylated liposomal doxorubicin, or topotecan). Primary endpoints are PFS and ORR, with response evaluated per RECIST v1.1. Secondary endpoints include overall survival, DOR, safety, and quality of life. Clinical trial information: NCT05870748 .

5508 Background: Luveltamab tazevibulin (luvelta) is a novel FolRα-targeting ADC with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR of 4) that induces cytotoxic and immunologic cell death. Using site-specific conjugation technology, luvelta is designed to target a broad range of FolRα expressing OC. STRO-002-GM1 is a global phase 1 study evaluating luvelta in patients with relapsed OC. We provide updated data from the initial ovarian expansion cohort. Methods: The study enrolled advanced OC pts who had progressive platinum resistant (PROC) after 1-3 prior lines or platinum sensitive disease after 2-3 prior lines of platinum chemotherapy. Pts were randomized 1:1 to received luveltamab at 4.3 or 5.2 mg/kg given IV every 3 weeks until disease progression. Prophylactic corticosteroid eyedrops were not required/administered. FolRα expression was not required for study entry but was analyzed retrospectively in archival tissue using the FOLR1 IHC assay (Ventana Medical Systems). The scoring paradigm assessed percentage of cells with any intensity expression (TPS). TPS >25% was selected for further analysis. Results: 44 pts were enrolled (23 pts at 4.3 mg/kg and 21 pts at 5.2 mg/kg). For pts with a TPS >25% (n=35), the median prior lines of therapy was 2.5 (range 1-3), 69% had prior bevacizumab treatment, and 83% prior PARP inhibitor treatment. Investigator assessed efficacy data for pts with a TPS >25% are presented in the table. The most common grade ≥ 3 treatment emergent adverse events (TEAEs) included neutropenia (70.5%), arthralgia (18.2%), and anemia (13.6%). G3/4 neutropenia had a higher incidence at 5.2 mg/kg than 4.3 mg/kg (76% vs 65%); most notable for G4 neutropenia (52% vs 22%). 1 pt at each dose level had febrile neutropenia. TEAEs led to dose delay in 80% of pts with a higher incidence at 5.2 mg/kg (95% vs. 65%). TEAEs led to dose reduction in 61% of pts with a higher incidence at 5.2 mg/kg (76% vs. 48%). 1 pt had a G5 sepsis with G4 neutropenia. Neutropenia, arthralgia and anemia were managed with standard medical treatment and dose reductions. Conclusions: These dose expansion data confirm activity of luvelta at starting doses ranging from 4.3-5.2 mg/kg in recurrent OC with FolRα expression as low as TPS>25% and supports further clinical study in this population. The global phase 2/3 REFRaME registration study will evaluate luvelta in PROC pts with TPS >25%. Clinical trial information: NCT03748186 . [Table: see text]

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.

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.

Figure S5 shows circulating cytokine analysis of each patient from baseline, post-CRT and post-ipilimumab time points.

5601 Background: Endometrial cancer is the most common gynecologic cancer and is primarily treated with chemotherapy. Many endometrial cancers though express hormone receptors and may respond to hormonal therapy, a potentially attractive non-chemotherapy alternative in such a population of women. The aim of OATH is to investigate the potential of dual hormonal blockade through the combination of antiprogesterone and anti-estrogen therapy via the administration of onapristone extended release (ONA) plus anastrozole (ANA), respectively. OATH is an open-label, multicenter, investigator-initiated, non-randomized, phase 2 study to evaluate the safety and efficacy of ONA + ANA in patients (pts) with endometrial cancer (EC). ClinicalTrials.gov Identifier: NCT04719273. Methods: Pts received ONA 50 mg twice daily plus ANA 1 mg once daily and were treated until progressive disease (PD) or unacceptable toxicity. Co-primary endpoints were 4-month progression-free survival (PFS) rate and overall response rate (ORR). A sample size of 25 pts will achieve 80% power to detect an improvement in 4-month PFS estimates from 25% (historical) to 52% and an improvement in response rate from 15% (historical) to 37%, using two-sided exact test at 5% significance level. Secondary endpoints include PFS, disease control rate (DCR), and safety. Results: As of January 20, 2023, 14 pts were enrolled. Median age was 67 years (44-80). ECOG performance status was 0 (36%), and 1 (64%). Number of prior chemotherapy regimens was 0 (1 pt,7%), 1 (9 pts, 64%) and 2 (4 pts, 29%). Seven (50%) pts received radiotherapy and 3 (21%) pts received prior checkpoint inhibitor therapy. Median treatment duration was 4.2 (1.0-19.9) months, and 8 pts remain on treatment. Adverse events were mainly grade 1 and 2. The most common treatment-related adverse events (AEs) and abnormal laboratory values were hot flashes (36%), alanine transferase (ALT) increased (29%), aspartate aminotransferase (AST) increased (29%), nausea (29%), and diarrhea (21%). No treatment-related serious AE, deaths on treatment, or treatment-related drug discontinuations were reported. The 4-month PFS Kaplan-Meier rate was 63.5%. Among 13 pts who had at least one tumor assessment after baseline, the best overall response was: 1 complete response, 1 partial response (response rate: 15.4%), 9 (69%) stable disease, and 2 (15.4%) progressions. Updated results will be presented. Conclusions: Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273 .

IntroductionIn this multicentre randomized, phase II/III trial, we sought to examine if the 1) combination of anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab (ATEZO) with pegylated-liposomal- doxorubicin (PLD) [Arm 1] and/or 2) addition of ATEZO to PLD and bevacizumab (BEV) [Arm 2] result in an improvement in survival for patients with platinum resistant ovarian cancer (PROC) compared to the standard PLD/BEV [Arm 3].MethodsPatients were randomly assigned 1:1:1 to PLD/ATEZO, PLD/BEV/ATEZO or PLD/BEV (IV PLD 40 mg/m2 q4weeks; BEV 10 mg/kg q2weeks; ATEZO 800 mg q2weeks). Key eligibility: 1–2 prior lines of therapy (no PLD), ECOG 0–2, and RECIST measurable/evaluable PROC. No stratification by PD-L1 status. The phase II primary endpoint was PFS. The phase III coprimary endpoints were PFS/OS.ResultsFrom 05/2017–10/2021 444 patients with PROC were enrolled. The median age was 63 yrs (35–86). All had received prior chemotherapy; 434 (97.7%) prior surgery and 9 (2%) prior biological therapy. At the phase III interim analysis Arm 1 (PLD/ATEZO) was discontinued for futility. The phase III OS/PFS analysis included accruals to Arms 2 (PLD/BEV/ATEZO) and 3 (PLD/BEV) from all phases. With median follow-up of 47 months, median PFS was 7.4 months and 5.6 months (HR 0.79 with 99.99% 1-sided CI 0.0–1.21), and median OS was 14.9 months and 12.3 months (HR 0.80; 98.78% 1-sided CI 0.00–1.06; 1-sided p=0.038) for Arms 2 and 3, respectively. Adverse events were as expected.Conclusion/ImplicationsThe addition of ATEZO to PLD/BEV did not result in a statistically significant longer OS than PLD/BEV in PROC. Subset analysis are planned to evaluate survival outcomes with high PD-L1 expression (NRG-GY009/NCT02839707).

Figure S2 shows the association of T cell subsets and T cell activation status to ipilimumab dose level received.

Figure S3 shows the association of changes in circulating T cell memory subsets with clinical response.

Figure S4 shows the association of changes in immune biomarkers with overall survival

Figure S6 shows the association of circulating cytokine levels with objective clinical response.