Cohort 2a Research Articles

A phase 1, first-in-child, multicenter study to evaluate the safety and efficacy of the oncolytic herpes virus talimogene laherparepvec in pediatric patients with advanced solid tumors.

The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non-central nervous system tumors. T-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST). Fifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to <12 years old (melanoma, n = 2). Overall, patients received treatment for a median (range) of 5.1 (0.1, 39.4) weeks. No DLTs were observed during the evaluation period. All patients experienced at least one treatment-emergent adverse event (TEAE), and 53.3% of patients reported grade ≥3 TEAEs. Overall, 86.7% of patients reported treatment-related TEAEs. No complete or partial responses were observed, and three patients (20%) overall exhibited stable disease as the best response. T-VEC was tolerable as assessed by the observation of no DLTs. The safety data were consistent with the patients' underlying cancer and the known safety profile of T-VEC from studies in the adult population. No objective responses were observed. ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Background & AimsPEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. MethodsPEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22–24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0–4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). ResultsIn cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22–24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22–24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. ConclusionsOdevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials RegistrationThis study is registered at ClinicalTrials.gov (NCT03659916). Impact and ImplicationsDisrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Abstract 5060: Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study

Abstract Background: Oxaliplatin (OX)-containing regimens are frequently utilized to treat gastrointestinal (GI) cancers. OX is eliminated predominately via urinary excretion (GFR and active tubular secretion). The contribution of active transport via OCT2 and MATE1/2-K to OX clearance is not fully understood. Tyrosine kinase inhibitors (TKIs) are frequently found to interact with OCT2/MATE transporters; however, a gap in knowledge remains between their clinical potential to impact OX pharmacokinetics (PK) and in turn, impact renal function. Tucatinib (TUC) is a highly selective human epidermal growth factor receptor 2 (HER2)-directed TKI approved in multiple regions in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer and is currently being investigated in other HER2+ tumors. TUC inhibits OCT2/MATE-mediated transport of metformin and creatinine in vitro and in vivo. In this study, we investigated the impact of TUC on OX plasma PK, OX renal clearance (Clr), and renal function. Methods: In vitro inhibition of OCT2/MATE-mediated transport of OX by TUC was assessed in OCT2, MATE1, or MATE2-K-expressing MDCK-II cells. SGNTUC-024 (NCT04430738) is a Ph1b/2 clinical study in patients with HER2+ GI cancers evaluating the impact of TUC on the safety and PK of OX. Patients received TUC 150 mg (Cohort 1A) or 300 mg (Cohort 1B) BID starting on C1D8 of a 2-week cycle in combination with modified FOLFOX6/7. Intensive PK was collected in plasma and urine for OX alone (C1D1) or with steady-state TUC (C2D1). Total plasma platinum (Pt, analyzed as a surrogate for OX and catabolites), plasma Pt ultrafiltrate (PUF, unbound), and urine Pt were quantitatively analyzed via ICP-MS. Serum Cystatin C (CysC) was measured as a pharmacodynamic (PD) renal function marker in Cohorts 1A and 1B. Results: TUC inhibited in vitro OX transport by MATE1 (IC50 = 0.0639 µM), MATE2-K (IC50 = 0.0382 µM), and OCT2 (IC50 = 0.491 µM). In 11 patients, total Pt and PUF AUC0-8h geometric mean ratio (GMR) and 90% confidence intervals (CI) between patients who received OX alone compared to in combination were 1.1 (0.98, 1.3) and 1.0 (0.78, 1.4) in Cohort 1A (n=4) and 1.1 (0.96, 1.2) and 1.0 (0.98, 1.1) in Cohort 1B (n=7), respectively. OX GM (%CV) renal clearance (Clr,0-8h in mL/min) and fraction excreted 24h post-dose (fe,0-24h) were similar with and without TUC in both Cohort 1A (C1D1 Clr0-8h = 277 (33), fe,0-24h = 22% (17); C2D1 Clr0-8h = 249 (78), fe,0-24h = 21% (15)) and Cohort 1B (C1D1 Clr0-8h = 189 (37), fe,0-24h = 17.7% (16); C2D1 Clr0-8h = 177 (40), fe,0-24h = 16.6% (35)). Reversible slight increases in CysC (normalized to baseline) on day 3 of each cycle, irrespective of tucatinib, were observed. Conclusions: This investigation of in vitro and in vivo determinants of OX PK demonstrates that TUC does not alter the renal clearance of oxaliplatin nor renal function when OX is administered in combination with TUC. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Vineet Kumar, Michelle Ubowski, JoAl G. Mayor, Layth I. Abdulrasool, Clark M. Henderson, Joseph A. Ware, Christopher J. Endres. Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5060.

Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction

BackgroundNo study has compared the cardiovascular outcomes for sodium–glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)—which also have cardiovascular benefits—in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction.MethodsMedicare fee-for-service data (2013–2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting.ResultsAmong HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses.ConclusionsBias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.

Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Côte d'Ivoire and Kenya: an open-label, partly randomised, phase 3 trial

WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children. This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2-6 years were eligible. In cohort 1, participants aged 4-6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2-3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17-21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140. Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1-6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6-93·5] in cohort 1a vs 81·3% [67·4-91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]). Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis. The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

A Phase 1b/2 Study of Atezolizumab with or Without Bacille Calmette-Guérin in Patients with High-risk Non–muscle-invasive Bladder Cancer

BackgroundBacille Calmette-Guérin (BCG) is the standard therapy after transurethral resection of bladder tumour for high-risk non–muscle-invasive bladder cancer (NMIBC). However, post-BCG recurrence/progression occurs frequently, and noncystectomy options are limited. ObjectiveTo evaluate the safety and clinical activity of atezolizumab ± BCG in high-risk BCG-unresponsive NMIBC. Design, setting, and participantsThis phase 1b/2 GU-123 study (NCT02792192) treated patients with BCG-unresponsive NMIBC who had carcinoma in situ with atezolizumab ± BCG. InterventionPatients in cohorts 1A and 1B received atezolizumab 1200 mg IV q3w for ≤96 wk. Those in cohort 1B also received standard BCG induction (six weekly doses) and maintenance courses (three doses weekly starting at month 3) with optional maintenance at 6, 12, 18, 24, and 30 mo. Outcome measurements and statistical analysisCoprimary endpoints were safety and 6-mo complete response (CR) rate. Secondary endpoints included 3-mo CR rate and duration of CR; 95% confidence intervals were calculated using the Clopper-Pearson method. Results and limitationsAt data cut-off (September 29, 2020), 24 patients were enrolled (cohort 1A, n = 12; cohort 1B, n = 12), and the recommended BCG dose was 50 mg in cohort 1B. Four patients (33%) had adverse events (AEs) leading to BCG dose modification/interruption. Three patients (25%) in cohort 1A reported atezolizumab-related grade 3 AEs; cohort 1B had no atezolizumab- or BCG-related grade ≥3 AEs. No grade 4/5 AEs were reported. The 6-mo CR rate was 33% in cohort 1A (median duration of CR, 6.8 mo) and 42% in cohort 1B (median duration of CR, not reached [≥12 mo]). These results are limited by the small sample size of GU-123. ConclusionsIn this first report of the atezolizumab-BCG combination in NMIBC, atezolizumab ± BCG was well tolerated, with no new safety signals or treatment-related deaths. Preliminary results suggested clinically meaningful activity; the combination favoured a longer duration of response. Patient summaryWe studied atezolizumab with and without bacille Calmette-Guérin (BCG) to determine whether this combination was safe and had clinical activity in patients with high-risk noninvasive bladder cancer (high-grade bladder tumours that affect the outermost lining of the bladder wall) that has previously been treated with BCG and is still present or occurred again. Our results suggest that atezolizumab with or without BCG was generally safe and could be used to treat patients unresponsive to BCG.

First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817

BackgroundCheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment...

ONCX-NAV-G201: A phase 2 basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors—Colorectal Cancer Cohort (trial in progress).

TPS263 Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC. Methods: Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of &lt;5% and a 25% PFS rate at 4 months, with targets of 15% and 50% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel biomarker subtypes. Clinical trial information: NCT05453825 .

Dual Immune Checkpoint Agents in Combination with Rituximab for Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is an inherently immunosensitive cancer. While PD-1 blockade was associated with a low objective response rate (ORR) in FL, some durable responses were seen. Manipulation of other checkpoint pathways, like 4-1BB, have shown promising activity (Gopal, CCR 2020) and OX40 stimulation may enhance activity of other immunotherapies. We therefore conducted a multi-cohort phase 1b trial testing different combinations of immune checkpoint therapy targeting 4-1BB (utomilumab), OX-40 (PF-04518600), and PD-L1 (avelumab) all in combination with rituximab (R) among patients (pts) with relapsed/refractory (R/R) FL. Methods: Adult pts with R/R grade 1-3a FL who had received ≥ 1 prior therapies (including a CD20 monoclonal antibody) were enrolled. All pts had measurable disease and required therapy based on modified GELF criteria. Pts in need of urgent cytoreductive therapy were excluded. Pts were enrolled onto 2 of 3 planned cohorts (A1 - R, utomilumab, avelumab; A2 - PF-04518600 +/- R, utomilumab). The trial was closed early when development of utomilumab and PF-04518600 was halted by Pfizer. Enrollment ended before dose expansion was completed for cohorts A1 and A2 and before enrollment began for a 3rd cohort (R, avelumab, PF-04518600). Each cohort began with a dose escalation stage (using a standard 3+3 design) followed by a dose expansion stage at the recommended phase 2 dose (RP2D) (15 pts). Treatment consisted of six 28-day cycles for both cohorts (see table for dose levels and dosing details). The co-primary endpoints were RP2D and complete response rate (CRR), assessed using 2014 Lugano criteria. Peripheral blood, stool samples, and tissue biopsies were collected for correlative studies. Results: 24 pts were enrolled at 4 centers, including 1 pt who was initially treated on cohort A2 (with R + PF-04518600), ended treatment due to progression, and then enrolled on cohort A1. In total, 16 pts were treated on cohort A1 and 9 on cohort A2. The median age was 58 (42-76). Pts had received a median of 2 (1-9) prior therapies. 11 pts (46%) had progression within 24 months of initial therapy (POD24). At trial entry, 6 pts (25%) were R-refractory, defined as no response to last R-containing regimen or progression ≤6 months after last R dose. The highest planned dose level (dose level 2) was selected as the RP2D for cohorts A1 and A2. There were no treatment discontinuations due to adverse events (AEs) and no treatment-related deaths. 1 dose-limiting toxicity (grade 3 gastric obstruction, unrelated to study treatment) was observed for a pt in cohort A1. In total, 19/25 (76%) pts had at least 1 treatment-related (tr)AE of any grade, including 7 (28%) pts with grade 3 trAEs. Typical immune-related AEs were not observed. The most common trAEs of any grade were fatigue (24%) and infusion reaction (20%). Grade 3 trAEs included neutropenia in 2 pts (8%), and hypertension, hypertriglyceridemia, hypophosphatemia, lymphopenia, COVID infection, and thromboembolic event in 1 pt each (4%). In cohort A1, the ORR and CRR were 44% and 19%, respectively. Among 10 pts treated at the RP2D, the ORR and CRR were 50% and 30%, respectively. ORRs were observed in 2/5 POD24 pts and 1/4 R-refractory pts in cohort A1. In cohort A2, no responses were observed. After a median follow-up of 16 months, the median progression-free survivals in cohorts A1 and A2 were 7.0 and 3.2 months (m), respectively. The median duration of response in A1 was 9.7m. The 18m overall survivals in cohorts A1 and A2 were 81% and 100%, respectively. We performed 16S ribosomal RNA sequencing of pre- and on-treatment stool samples from pts in cohort A1 and found a positive association between abundance of Akkermansia and ORR to study therapy (p<0.001). Other correlative studies including multiplex immunofluorescence and single-cell analyses (assessing serial biopsy samples) are ongoing. Conclusions: We observed clinical activity with the combination of utomilumab, avelumab, and R, supporting a possible role for 4-1BB agonist therapy in FL. In contrast, our limited results do not support a role for OX40 targeting in this disease. Correlatives studies are ongoing which may shed further light on predictors of response. Interestingly, we found an association between Akkermansia and response, which has been reported in checkpoint blockade studies in solid tumors and supports the hypothesis that the microbiome impacts response to immunotherapies in lymphomas. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS. Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS). Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 - 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34). In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%). Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934). Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day cycle in the ongoing Phase 2 study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

KarMMa-2 Cohort 2a: Efficacy and Safety of Idecabtagene Vicleucel in Clinical High-Risk Multiple Myeloma Patients with Early Relapse after Frontline Autologous Stem Cell Transplantation

**Co-lead author Introduction Patients with multiple myeloma (MM) who relapse early after frontline therapy with autologous stem cell transplant (ASCT) have a poor prognosis. Novel therapies are needed to improve outcomes (Paiva Blood 2012; Bygrave Br J Haematol 2020). In the pivotal phase 2 KarMMa study (NCT03361748), treatment with the B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel) resulted in frequent, deep, and durable responses in pts with relapsed and refractory MM (RRMM) who were triple-class exposed and refractory to last treatment (Munshi N Engl J Med 2021). KarMMa-2 is a multicohort, phase 2, multicenter trial (NCT03601078) of ide-cel in RRMM and in clinical high-risk MM, defined as early relapse after frontline therapy (cohorts 2a, 2b) or inadequate response after frontline ASCT (2c). The efficacy and safety of ide-cel in cohort 2a are presented. Methods Eligible pts in cohort 2a had early relapse after frontline therapy, defined as progressive disease (PD) <18 mo from starting treatment containing induction, ASCT (single or tandem), and lenalidomide-containing maintenance. After lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 × 3), pts received a single infusion of ide-cel at 150-450 × 106 CAR+ T cells. The primary efficacy endpoint was complete response (CR) rate (CRR; CR and stringent CR) by investigator per IMWG criteria. Secondary endpoints included overall response rate (ORR; ≥ partial response), time to response (TTR), duration of response (DOR), PFS, OS, safety, and pharmacokinetics (PK). Exploratory endpoints included assessment of soluble BCMA (sBCMA) level and minimal residual disease negativity (MRD-) by next-generation sequencing (<10-5 nucleated cells). Efficacy and safety were analyzed in all pts who received ide-cel; PK and sBCMA were analyzed in evaluable pts. MRD- is reported for evaluable pts with ≥CR. Results Ide-cel was successfully manufactured and infused in 37/39 pts. Median age was 57 y; median time since diagnosis was 1.6 y. A total of 62.2% pts had ECOG PS 0, and 70.3% received bridging therapies (corticosteroids, alkylating agents, immunomodulatory agents, proteasome inhibitors [PI], and/or anti-CD38 antibodies) for MM. At study entry, 13.5%/51.4%/5.4% pts had R-ISS stage I/II/III disease, 32.4% had high-risk cytogenetics, 18.9% had bone marrow biopsy-determined high tumor burden (≥50% bone marrow CD138+ plasma cells), and 8.1% had extramedullary disease. Most pts had disease refractory to an immunomodulatory agent (86.5%) or PI (89.2%); 86.5% had double refractory disease. At data cut-off (14 Mar 2022), median follow-up was 21.5 mo (range 2-31). CRR was 45.9% (95% CI 29.5-63.1), and ORR was 83.8% (95% CI 68.0-93.8) (Table 1). At 6 mo post-ide-cel, MRD− was observed in 11/13 (85%; 95% CI 57.8-95.7) pts. At 12 mo, MRD− was observed in 7/10 (70%; 95% CI 39.7-89.2) pts; of the 7 pts, 1 had PD at 20.8 mo, 5 sustained MRD− at ≥18 mo, and >12 mo data was unavailable for 1 pt. Median TTR was 1 mo (range 0.9-2.9). Median DOR was 15.7 mo (95% CI 7.62-19.81). Median PFS was 11.4 mo (95% CI 5.55-19.58); median OS was not reached. Time to event endpoint results for DOR, PFS, and OS are shown in Table 1. Grade (Gr) 3-4 AEs on or after ide-cel infusion occurred in all pts, most commonly neutropenia in 35 (94.6%) pts, anemia in 17 (45.9%), and thrombocytopenia in 14 (37.8%). Two pts died due to pneumonia and pseudomonal sepsis. Gr 1/2 cytokine release syndrome (CRS) occurred in 30 (81.1%) pts; 1 (2.7%) pt had a Gr 3 event (Table 1). Gr 1/2 investigator-identified neurotoxicity (NT) occurred in 8 (21.6%) pts; no pts had ≥Gr 3 NT. Robust cell expansion was seen in 36 evaluable pts (Table 2). Ide-cel cellular expansion levels were higher in pts who had ≥CR vs those who had <CR with ide-cel (Table 2). sBCMA (range 15.0-737.0 ng/mL at infusion, n = 36) was cleared within 2 mo post-ide-cel infusion in 25/37 (67.6%) pts, including all pts who had ≥CR. Conclusions Ide-cel treatment demonstrated frequent, deep responses in pts who experienced an early relapse after frontline therapy with ASCT. MRD− was sustained in a subset of pts >18 mo. The incidence of CRS and NT were similar in these pts vs those treated with ide-cel in later lines. These results support a favorable clinical benefit-risk profile of ide-cel and its potential use in earlier lines of treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CTNI-19. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) FOR RECURRENT OR PROGRESSIVE CHILDHOOD EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG)

Abstract Childhood ependymoma and HGG are difficult tumors to treat. Recurrent ependymoma is treated with re-resection and multiple rounds of external beam radiation therapy (EBRT). HGG is treated with chemoradiation followed by clinical trials, if available. While EBRT remains a central component of management, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation with excellent tumor retention. In an adult Phase 1 trial for recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor was 392 Gy (CI 306 – 478), markedly higher than absorbed doses typically delivered by EBRT. Despite this, no dose-limiting toxicity was observed and no treatment-related serious adverse events have occurred. Here, we describe the first pediatric trial using a two-part, Phase 1 dose-finding study followed by expansion cohorts to explore efficacy. Enrolling subjects will be 6 to 21 years of age with a diagnosis of recurrent ependymoma or HGG. Subjects will be allowed to enroll either if they have exhausted standard of care options or if they are clinically stable and surgical resection can be deferred by 4 weeks. Part 1 will enroll up to 24 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by CED. Tumor size and concentration of infusate will be escalated in each cohort (A-D) to a maximum tumor diameter of 6 cm (114.1 mL) and a concentration of 2mCi/ml. Up to 4 CED catheters will be used. Part 2 will independently evaluate 186RNL in 2 different expansion cohorts: Cohort 2A: recurrent ependymoma; Cohort B: recurrent HGG. The primary endpoint for Cohort 2A is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria and the primary endpoint for Cohort 2B is progression free survival. Planned enrollment will begin in early 2023.

Evaluating the Role of Adjuvant Radiation Therapy in Node-Positive Male Breast Cancer Patients Using the NCDB

<h3>Purpose/Objective(s)</h3> The survival benefit associated with adjuvant external beam radiation therapy (EBRT), following mastectomy and breast conserving surgery, in the treatment of female patients with lymph node-positive (LN+) breast cancer is well established. Treatment of LN+ male breast cancer is largely extrapolated from randomized clinical trials and meta-analyses including females only. This study retrospectively examines the impact of adjuvant EBRT, after either mastectomy or breast conserving surgery, in LN+ male breast cancer patients using data from the National Cancer Database (NCDB). We hypothesize that a survival benefit will also be seen in LN+ male breast cancer patients receiving adjuvant EBRT. <h3>Materials/Methods</h3> The NCDB was queried for male patients with a diagnosis of invasive breast cancer who were pathologically node positive from 2004 to 2017. Patients were excluded if they had metastatic disease at time of diagnosis or pathologically node negative disease. We included males irrespective of type of surgery performed, including mastectomy, lumpectomy, sentinel lymph node biopsy, and/or axillary lymph node dissection. Cohorts were separated based upon treatment with or without EBRT. Cox regression was used for multivariate survival analyses taking into account patient's insurance, Charlson-Deyo-Comorbidity score, hormone receptor status, age at diagnosis, number of LNs involved, and if adjuvant chemotherapy and/or hormone therapy were delivered. <h3>Results</h3> A total of 7,558 men were identified, with 3,852 (51%) having received EBRT (cohort 1a) and 3,706 who did not receive EBRT (cohort 1b). See the table below for some of the patient characteristics. Numbers listed in the table represent the total number of patients with percentages of each cohort in parenthesis. Five-year overall survival was 72.3% for those who received EBRT in comparison to 64.6% for those who did not receive EBRT. When using multi-variate survival analysis, the hazard ratio for cohort 1b as compared to cohort 1a was 1.30 (p <0.01), signifying that those who did not receive EBRT were 30% more likely to die in comparison to those who did receive EBRT. <h3>Conclusion</h3> There appears to be an overall survival benefit associated with adjuvant EBRT in LN+ male breast cancer patients, despite those patients presenting with higher stage. Consideration for adjuvant radiation therapy in LN+ male breast cancer patients should be discussed.

10 Oral - CBX-12-101: A first-in-human study of CBX-12, an alphalex peptide drug conjugate (PDC) in patients with advanced or metastatic solid tumors

10 Oral - CBX-12-101: A first-in-human study of CBX-12, an alphalex peptide drug conjugate (PDC) in patients with advanced or metastatic solid tumors

Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study

AbstractAALL1931, a phase 2/3 study conducted in collaboration with the Children’s Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli–derived asparaginases. Each dose of a pegylated E coli–derived asparaginase remaining in patients’ treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.

An Indirect Comparison of the Efficacy and Safety of Dostarlimab and Doxorubicin for the Treatment of Advanced and Recurrent Endometrial Cancer.

There is no clear standard of care for advanced/recurrent endometrial cancer (EC) following platinum-based therapy. Dostarlimab is approved for patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) advanced/recurrent EC. This indirect treatment comparison (ITC) assessed dostarlimab efficacy and safety from the single-arm GARNET (NCT02715284) trial compared with doxorubicin from ZoptEC (NCT01767155). Patient-level data and study variables from GARNET Cohort A1 (dMMR/MSI-H EC) and the ZoptEC doxorubicin control arm were merged. Patients were matched based on eligibility criteria (main analysis population). Safety population included all patients who received treatment. The primary efficacy comparison outcome, overall survival (OS), was calculated using a Cox proportional hazards model, with adjusted stabilized inverse probability of treatment weighting. Modified assessment-scheduled matching Kaplan--Meier analysis was used for progression-free survival (PFS) and time to deterioration (TTD) in quality of life (QoL). In the main analysis population, median (95% CI) OS was not reached (NR; 18.0 months--NR) for dostarlimab (n = 92) and was 11.2 (10.0-13.1) months for doxorubicin (n = 233; HR: 0.41 [95% CI: 0.28-0.61]); median PFS was 12.2 (3.3-NR) and 4.9 (4.1-6.6) months, respectively. Median TTD in QoL was NR (2.5-NR; n = 61) and 4.5 (4.1-5.4; n = 188) months, respectively. Similar rates of adverse events (AEs, 11.6% vs 15.3%) and serious AEs (34.1% vs 30.1%) were observed with dostarlimab (n = 129) and doxorubicin (n = 249). Grade ≥3 AEs occurred in 48.1% vs 78.3%, respectively. This ITC suggests a favorable benefit:risk profile for dostarlimab in patients with dMMR/MSI-H advanced/recurrent EC.

547P Efficacy of dostarlimab in endometrial cancer (EC) by molecular subtype: A post hoc analysis of the GARNET study

Biomarkers are used to classify EC into molecular subtypes such as TCGA and/or a surrogate classification (POLε mutated [mut], mismatch repair/microsatellite instability [MMR/MSI], TP53mut, and no specific mutation profile [NSMP]) or by estrogen receptor (ER) status. Here, we report on a post hoc analysis of objective response rate (ORR) by a surrogate classification for EC in patients (pts) receiving dostarlimab monotherapy. GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (MMR deficient/MSI–high [dMMR/MSI-H EC]) or A2 (MMR proficient/microsatellite stable [MMRp/MSS] EC) based on local assessment. Pts received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints were ORR and duration of response by blinded independent central review. Molecular subtype was determined by POLε and TP53 mutation status by Foundation Medicine, and MMR/MSI status was determined by local immunohistochemistry (IHC) or next-generation sequencing; all others were assigned as NSMP. The hierarchy for classification was POLεmut → MMR/MSI → TP53 status → NSMP. ER status was determined by local IHC testing. Only pts with samples available for additional biomarker testing were included in the biomarker assessment. 143 dMMR/MSI-H and 156 MMRp/MSS pts were included in the efficacy evaluable population. ORR was determined for molecular subtypes and ER expression (table). Safety has been previously reported.Table: 547PA1A2Overall65/143, 45.5% (37.1–54.0)24/156, 15.4% (10.1–22.0)Molecular subtypeN=101N=153Polεmut2/3, 66.7% (9.4–99.2)0/2, 0% (0.0–84.2)dMMR/MSI-H43/98, 43.9% (33.9–54.3)TP53mut10/26,38.5% (20.2–59.4)TP53wt33/72,45.8% (34.0–58.0)ERpos19/44,43.2% (28.3–59.0)ERneg1/2,50.0% (1.3–98.7)ERunk23/52, 44.2% (28.3–59.0)TP53mut17/94, 18.1% (10.9–27.4)ERpos4/28, 14.3% (4.0–32.7)ERneg7/19,36.8% (16.3–61.6)ERunk6/47,12.8% (4.8–25.7)NSMP7/57 12.3% (5.1–23.7)ERpos2/19,10.5% (1.3–33.1)ERneg2/11,18.2% (2.3–51.8)ERunk3/27,11.1% (2.4–29.2)Data are n/N, % (95% CI). Datacut: 1 Nov 2021. ERneg, ER negative; ERpos, ER positive; ERunk, ER unknown; wt, wild-type. Open table in a new tab Data are n/N, % (95% CI). Datacut: 1 Nov 2021. ERneg, ER negative; ERpos, ER positive; ERunk, ER unknown; wt, wild-type. The observed ORRs in each molecular subgroup were consistent with the overall ORR in each cohort. Differences by ER expression status were not observed. These findings support the importance of testing pts with EC for MMR/MSI biomarker status as a predictor of response. Additionally, data suggest that TP53 mutation or ER expression should not modify treatment approach. The data are of interest for hypothesis generation.

548P Progression-free survival (PFS) and overall survival (OS) in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC) treated with dostarlimab in the GARNET study

Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the EU as a monotherapy in patients (pts) with dMMR/MSI-H AR EC that has progressed on or after platinum-based chemotherapy; and in the US as a monotherapy in pts with dMMR AR EC that has progressed on or after platinum-based chemotherapy or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. We report on PFS and OS in 2 expansion cohorts of the GARNET trial that enrolled pts with EC. GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or A2 (MMRp/MSS EC) based on local immunohistochemistry assessment. Pts received 500 mg of dostarlimab IV every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. PFS and OS are secondary efficacy endpoints. 153 pts with dMMR/MSI-H and 161 pts with MMRp/MSS EC were enrolled and treated. The efficacy-evaluable population included 143 pts with dMMR/MSI-H EC and 156 pts with MMRp/MSS EC with measurable disease at baseline and ≥6 mo of follow-up. Median follow-up was 27.6 mo for dMMR/MSI-H and 33.0 mo for MMRp/MSS EC (Table). For pts with dMMR/MSI-H EC, median PFS (mPFS) was 6.0 mo, with 3-year estimated PFS rate of 40.1%. With 37.3% of pts experiencing an event, mOS was not reached; estimated 3-year OS was >50%. For pts with MMRp/MSS EC, mPFS was 2.7 mo. mOS was 16.9 mo with 68.9% of pts experiencing an event. Safety has been previously reported.Table: 548PdMMR/MSI-H ECN=143MMRp/MSS ECN=156Median follow-up, mo27.633.0mPFS (95% CI), mo6.0 (4.1–18.0)2.7 (2.6–2.8)Estimated probability of PFS, %12 mo24 mo36 mo46.440.140.113.39.46.8N=153N=161mOS (95% CI), moNR (25.7–NR)16.9 (13.0–21.8)Estimated probability of survival, %12 mo24 mo36 mo73.360.558.460.638.422.2Datacut: 1 Nov 2021. NR, not reached Open table in a new tab Datacut: 1 Nov 2021. NR, not reached Dostarlimab demonstrated durable antitumor activity in dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with longer PFS and OS than MMRp/MSS as expected.

549P Progression-free survival (PFS) and overall survival (OS) in patients (pts) with mismatch repair deficient (dMMR) solid tumors treated with dostarlimab in the GARNET study

Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the EU as a monotherapy in pts with dMMR/microsatellite instability–high advanced/recurrent endometrial cancer (EC) that has progressed on or after platinum-based treatment; and in the US as a monotherapy in pts with dMMR advanced/recurrent EC that has progressed on or after platinum-based treatment or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. We report on PFS and OS in pts with dMMR solid tumors from 2 expansion cohorts of the GARNET trial. GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR EC) or cohort F (dMMR non-EC solid tumors) based on local immunohistochemistry assessment. Pts received 500 mg of dostarlimab intravenously every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. PFS and OS are secondary efficacy endpoints. For the third interim analysis, 356 pts with dMMR solid tumors were enrolled and treated. The efficacy-evaluable population included 327 pts with dMMR solid tumors with measurable disease at baseline who enrolled on or before June 1, 2021, to allow sufficient follow-up time to assess response. Median follow-up was 27.7 mo for dMMR solid tumors (Table). Overall median PFS was 6.9 mo with 3-year estimated PFS rate of 39.7%. With 38.8% maturity, overall dMMR solid tumor median OS was not reached, and 3-year estimated OS was 55.9%. Safety for both cohorts has been previously reported.Table: 549PdMMR ECN=141dMMR non-EC solid tumorsN=186Overall dMMR solid tumN=327Median follow-up, mo27.629.827.7Median PFS (95% CI), mo5.6 (4.1–16.6)7.0 (3.6–16.5)6.9 (4.2–13.6)Estimated probability of PFS, %12 mo24 mo36 mo46.039.639.645.641.439.645.840.639.7OS maturity, %39.038.738.8Median OS (95% CI), moNR (25.7–NR)NR (21.7–NR)NR (31.6–NR)Estimated probability of survival, %12 mo24 mo36 mo71.259.457.069.657.955.070.358.655.9Datacut: 1 Nov 2021. dMMR, mismatch repair deficient; EC, endometrial cancer; NR, not reached; OS, overall survival; PFS, progression-free survival Open table in a new tab Datacut: 1 Nov 2021. dMMR, mismatch repair deficient; EC, endometrial cancer; NR, not reached; OS, overall survival; PFS, progression-free survival Dostarlimab demonstrated durable antitumor activity and favorable PFS and OS in dMMR solid tumors, including EC, gastrointestinal, and other tumor types. The secondary endpoints demonstrate the benefit of dostarlimab in pts with dMMR solid tumors, in line with the primary endpoints previously reported.

484P CHARIOT trial (cohort A2): A phase I dose-escalation study combining the ATR inhibitor berzosertib with cisplatin and capecitabine

Berzosertib is a potent inhibitor of ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR). Preclinical studies have shown that ATR inhibition enhances the cytotoxic effects of DNA damaging drugs. Cohort A2 of the CHARIOT trial (NCT03641547) explored the combination of berzosertib with cisplatin and capecitabine in advanced solid tumours to assess the optimal treatment schedule, safety and preliminary efficacy.